NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

T-Cell Lymphomas
NCCN Evidence BlocksTM
Version 4.2024 — May 28, 2024
[Link]

NCCN recognizes the importance of clinical trials and encourages participation when applicable and available.
Trials should be designed to maximize inclusiveness and broad representative enrollment.

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T-Cell Lymphomas Table of Contents
Discussion
NCCN Evidence BlocksTM
*Steven M. Horwitz, MD/Chair † Þ Bradley M. Haverkos, MD, MPH, MS † Peter Riedell, MD
Memorial Sloan Kettering Cancer Center University of Colorado Cancer Center The UChicago Medicine
*Stephen Ansell, MD, PhD/Vice-Chair ‡ Francisco Hernandez-Ilizaliturri, MD † Comprehensive Cancer Center
Mayo Clinic Comprehensive Cancer Center Roswell Park Comprehensive Cancer Center Sima Rozati, MD, PhD ϖ
Weiyun Z. Ai, MD, PhD † ‡ Richard T. Hoppe, MD § The Sidney Kimmel Comprehensive
UCSF Helen Diller Family Stanford Cancer Institute Cancer Center at Johns Hopkins
Comprehensive Cancer Center Eric Jacobsen, MD † Jonathan Said, MD ≠
Jeffrey Barnes, MD, PhD † Dana-Farber/Brigham and Women's UCLA Jonsson Comprehensive Cancer Center
Mass General Cancer Center Cancer Center Aaron Shaver, MD, PhD ≠
Vanderbilt-Ingram Cancer Center
*Stefan K. Barta, MD, MRCP, MS † ‡ *Deepa Jagadeesh, MD, MPH † ‡
Abramson Cancer Center Case Comprehensive Cancer Center/ *Lauren Shea, MD ‡
at the University of Pennsylvania University Hospitals Seidman Cancer Center O'Neal Comprehensive Cancer Center at UAB
*Jonathan Brammer, MD ‡ and Cleveland Clinic Taussig Cancer Institute Michi M. Shinohara, MD ϖ ≠
The Ohio State University Comprehensive Allison Jones, MD ϖ Fred Hutchinson Cancer Center
Cancer Center - James Cancer Hospital St. Jude Children's Research Hospital/The Lubomir Sokol, MD, PhD † ‡ Þ
and Solove Research Institute University of Tennessee Health Science Center Moffitt Cancer Center
*Mark W. Clemens, MD ʘ Youn H. Kim, MD ϖ † Matthew Stephany, MD ϖ
The University of Texas Stanford Cancer Institute Fred & Pamela Buffett Cancer Center
MD Anderson Cancer Center Kiran Kumar, MD, MBA § Susan Thornton ¥
UT Southwestern Simmons Patient advocate
Utpal P. Davé, MD ‡ Comprehensive Cancer Center
Indiana University Melvin and Bren Simon Carlos Torres-Cabala, MD ≠
Comprehensive Cancer Center Neha Mehta-Shah, MD, MSCI † ‡ The University of Texas
Siteman Cancer Center at Barnes- MD Anderson Cancer Center
Ahmet Dogan, MD, PhD ≠ Jewish Hospital and Washington
Memorial Sloan Kettering Cancer Center University School of Medicine Ryan Wilcox, MD, PhD † ‡
*Francine Foss, MD † ‡ ξ University of Michigan
Elise A. Olsen, MD ϖ † Rogel Cancer Center
Yale Cancer Center/Smilow Cancer Hospital Duke Cancer Institute
Zachary Frosch, MD, MSHP ‡ Peggy Wu, MD, MPH ϖ
Dorothy Pan, MD † UC Davis Comprehensive Cancer Center
Fox Chase Cancer Center Roswell Park Comprehensive Cancer Center
Aaron M. Goodman, MD ‡ ξ Jasmine Zain, MD † ‡
Saurabh A. Rajguru, MD † ‡ City of Hope National Medical Center
UC San Diego Moores Cancer Center University of Wisconsin NCCN
Joan Guitart, MD ≠ ϖ Carbone Cancer Center Mary Dwyer, MS
Robert H. Lurie Comprehensive Cancer Hema Sundar, PhD
Center of Northwestern University ξ Bone marrow transplantation ≠ Pathology
Ahmad Halwani, MD ‡ Continue ϖ Dermatology ¥ Patient advocacy
Huntsman Cancer Institute ‡ Hematology/Hematology ʘ Plastic surgery
at the University of Utah oncology § Radiotherapy/Radiation oncology
Þ Internal medicine * Discussion Section Writing
NCCN Guidelines Panel Disclosures † Medical oncology Committee Member
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The NCCN Evidence Blocks™ are subject to certain U.S. and foreign patents. Each approved use of the design of the NCCN Evidence Blocks™ requires the written approval of NCCN. Visit [Link]/patents for current list of applicable patents.
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NCCN Guidelines Version 4.2024 NCCN Guidelines Index

T-Cell Lymphomas Table of Contents
Discussion
NCCN Evidence BlocksTM
NCCN T-Cell Lymphomas Panel Members
Clinical Trials: NCCN believes that the
NCCN Evidence Blocks Definitions (EB-1)
best management for any patient with
cancer is in a clinical trial.
• Peripheral T-Cell Lymphomas (PTCL-1) Participation in clinical trials is
• Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIAA-INTRO) especially encouraged.
• T-Cell Large Granular Lymphocytic Leukemia (LGLL-INTRO) Find an NCCN Member Institution:
• T-Cell Prolymphocytic Leukemia (TPLL-1) [Link]
• Adult T-Cell Leukemia/Lymphoma (ATLL-1) institutions.
• Hepatosplenic T-Cell Lymphoma (HSTCL-INTRO) NCCN Categories of Evidence and
• Extranodal NK/T-Cell Lymphomas (ENKL-1) Consensus: All recommendations are
category 2A unless otherwise indicated.
See NCCN Categories of Evidence
• Principles of Molecular Analysis in T-Cell Lymphomas (TCLYM-A) and Consensus.
• Supportive Care (TCLYM-B)
NCCN Categories of Preference:
• Lugano Response Criteria for Non-Hodgkin Lymphoma (TCLYM-C)
All recommendations are considered
• Principles of Radiation Therapy (TCLYM-D) appropriate.
• Use of Immunophenotyping/Genetic Testing in Differential Diagnosis of NK/T-
See NCCN Categories of Preference.
Cell Neoplasms (TCLYM-E)
• NCCN Guidelines for Primary Cutaneous Lymphomas
Primary Cutaneous B-Cell Lymphomas
Mycosis Fungoides/Sézary Syndrome NCCN Guidelines for Patients®
Primary Cutaneous CD30+ T-Cell Lymphoproliferative Disorders available at [Link]/patients
Classification and Staging (ST-1)
Abbreviations (ABBR-1)

The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to
treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual
clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations
or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN
Evidence BlocksTM and NCCN Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Evidence
BlocksTM, NCCN Guidelines, and the illustrations herein may not be reproduced in any form without the express written permission of NCCN. ©2024.
Version 4.2024, 05/28/24 © 2024 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Evidence Blocks™, NCCN Guidelines®, and this illustration may not be reproduced in any form without the express written permission of NCCN.
The NCCN Evidence Blocks™ are subject to certain U.S. and foreign patents. Each approved use of the design of the NCCN Evidence Blocks™ requires the written approval of NCCN. Visit [Link]/patents for current list of applicable patents.
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T-Cell Lymphomas Table of Contents
Discussion
NCCN Evidence BlocksTM
NCCN EVIDENCE BLOCKS CATEGORIES AND DEFINITIONS Example Evidence Block
5 E = Efficacy of Regimen/Agent 5 E=4
4 S = Safety of Regimen/Agent 4 S=4
3 Q = Quality of Evidence 3 Q=3
C = Consistency of Evidence C=4
2 2
A = Affordability of Regimen/Agent A=3
1 1
E S Q C A E S Q C A
Efficacy of Regimen/Agent Quality of Evidence
5 Highly effective: Cure likely and often provides long-term 5 High quality: Multiple well-designed randomized trials and/or
survival advantage meta-analyses
4 Very effective: Cure unlikely but sometimes provides long-term 4 Good quality: One or more well-designed randomized trials
survival advantage 3 Average quality: Low quality randomized trial(s) or well-designed
3 Moderately effective: Modest impact on survival, but often non-randomized trial(s)
provides control of disease 2 Low quality: Case reports or extensive clinical experience
2 Minimally effective: No, or unknown impact on survival, but 1 Poor quality: Little or no evidence
sometimes provides control of disease
1 Palliative: Provides symptomatic benefit only Consistency of Evidence
5 Highly consistent: Multiple trials with similar outcomes
Safety of Regimen/Agent
4 Mainly consistent: Multiple trials with some variability in outcome
5 Usually no meaningful toxicity: Uncommon or minimal
toxicities; no interference with activities of daily living (ADLs) 3 May be consistent: Few trials or only trials with few patients,
whether randomized or not, with some variability in outcome
4 Occasionally toxic: Rare significant toxicities or low-grade 2 Inconsistent: Meaningful differences in direction of outcome
toxicities only; little interference with ADLs between quality trials
3 Mildly toxic: Mild toxicity that interferes with ADLs 1 Anecdotal evidence only: Evidence in humans based upon
2 Moderately toxic: Significant toxicities often occur but life anecdotal experience
threatening/fatal toxicity is uncommon; interference with ADLs
is frequent Affordability of Regimen/Agent (includes drug cost, supportive
care, infusions, toxicity monitoring, management of toxicity)
1 Highly toxic: Significant toxicities or life threatening/fatal
toxicity occurs often; interference with ADLs is usual and severe 5 Very inexpensive
4 Inexpensive
Note: For significant chronic or long-term toxicities, score decreased by 1
3 Moderately expensive
2 Expensive
1 Very expensive

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EB-1
The NCCN Evidence Blocks™ are subject to certain U.S. and foreign patents. Each approved use of the design of the NCCN Evidence Blocks™ requires the written approval of NCCN. Visit [Link]/patents for current list of applicable patents.
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Peripheral T-Cell Lymphomas Table of Contents
Discussion
NCCN Evidence BlocksTM
DIAGNOSISa
ESSENTIAL:
• Review of all slides with at least one paraffin block representative of the tumor should be done by a
hematopathologist with expertise in the diagnosis of peripheral T-cell lymphomas (PTCL). Rebiopsy if
consult material is nondiagnostic.
• Excisional or incisional biopsy is preferred over core needle biopsy. A fine-needle aspiration (FNA)
biopsy alone is not sufficient for the initial diagnosis of lymphoma. A core needle biopsy is not optimal
but can be used under certain circumstances. In certain circumstances, when a lymph node is not easily
accessible for excisional or incisional biopsy, a combination of core needle biopsy and FNA biopsy in
conjunction with appropriate ancillary techniques may be sufficient for diagnosis.
• Adequate immunophenotyping to establish diagnosisb
Immunohistochemistry (IHC) panel may include CD20, CD3, CD10, BCL6, Ki-67, CD5, CD30, CD2, CD4,
CD8, CD7, CD56, CD21, CD23, TCRβ, TCRẟ, PD1/CD279, ALK, TP63
with or without Diagnostic subtypes
Cell surface marker analysis by flow cytometry may include kappa/lambda, CD45, CD3, CD5, CD19, (PTCL-2)
CD10, CD20, CD30, CD4, CD8, CD7, CD2; TCRαβ, TCRɣδ, TRBC1
T-follicular helper [TFH] cell markers (CXCL13, ICOS) if PTCL not otherwise specified (PTCL-NOS) of
TFH phenotype is suspected
• Epstein-Barr encoding region in situ hybridization (EBER-ISH)

USEFUL UNDER CERTAIN CIRCUMSTANCES:

• Molecular analysis to detect clonal TCR gene rearrangements or other assessment of clonalityc
• Consider molecular analysis to detect DUSP22 rearrangement if anaplastic large cell lymphoma (ALCL),
ALK negativea; TP63 rearrangement if IHC is positive for TP63
• Consider next-generation sequencing (NGS) panel to support the diagnosis of TFH subtypesa
• Additional immunohistochemical studies to characterize subsets of PTCL including cytotoxic T-cell
markers (TIA-1, granzyme B, perforin)
• Assessment of human T-cell lymphotropic virus (HTLV)-1/2d by serology or other methods is
encouraged, as results can impact therapy.

a Principles of Molecular Analysis in T-Cell Lymphomas (TCLYM-A).

b Use of Immunophenotyping/Genetic Testing in Differential Diagnosis of Mature B-Cell and NK/T-Cell Neoplasms (TCLYM-E).
c Clonal TCR gene rearrangements alone are not sufficient for diagnosis, as these can also be seen in patients with non-malignant conditions. Results
should be interpreted in the context of overall presentation. See Principles of Molecular Analysis in T-Cell Lymphomas (TCLYM-A).
d See map for prevalence of HTLV-1/2 by geographic region. HTLV-1/2 has been described in patients in non-endemic areas.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
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PTCL-1
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Peripheral T-Cell Lymphomas Table of Contents
Discussion
NCCN Evidence BlocksTM
SUBTYPES
Subtypes included:e
• PTCL-NOS
• Enteropathy-associated T-cell lymphoma (EATL)
• Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL)f
• ALCL, ALK positive
• ALCL, ALK negative Workup
• Angioimmunoblastic T-cell lymphoma (AITL)/(follicular helper T-cell lymphoma (PTCL-3)
[TFH lymphoma], angioimmunoblastic type [ICC]/nodal TFH cell lymphoma,
angioimmunoblastic-type [WHO5])g
• Nodal PTCL with TFH phenotype (nodal PTCL, TFH)/TFH lymphoma, NOS (ICC)/
nodal TFH cell lymphoma (WHO5)
• Follicular T-cell lymphoma (FTCL)/TFH lymphoma, follicular type (ICC)/nodal
TFH cell lymphoma, follicular-type (WHO5)
• All other T-cell lymphomas
Breast implant-associated ALCL (BIA-ALCL) BIAA-1
T-cell large granular lymphocytic leukemia (T-LGLL) LGLL-1
Adult T-cell leukemia/lymphoma (ATLL) ATLL-1
T-cell prolymphocytic leukemia (T-PLL) TPLL-1
Extranodal natural killer (NK)/T-cell lymphoma (ENKL) ENKL-1
Hepatosplenic T-cell lymphoma (HSTCL) HSTCL-1
Subtypes not included:
• Primary cutaneous ALCL (NCCN Guidelines for Primary Cutaneous Lymphomas)

e Primary cutaneous PTCLs with limited skin involvement may have an indolent disease course, are very heterogeneous, and the optimal management may not be
along these guidelines.
f MEITL has only recently been separated as its own entity and optimal treatment has not been defined.
g AITL may occasionally present with concurrent diffuse large B-cell lymphoma (DLBCL) and Epstein-Barr virus (EBV) and appropriate IHC should be performed. Clonal
hematopoiesis in AITL is considered as a risk factor for cardiovascular disease.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
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PTCL-2
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Peripheral T-Cell Lymphomas Table of Contents
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NCCN Evidence BlocksTM
WORKUP SUBTYPES
ESSENTIAL:
• History and physical (H&P) examination; full skin examination; attention to node-
bearing areas, including Waldeyer's ring; evaluation of size of liver and spleen,
nasopharynx
• Performance status
• B symptoms
• Complete blood count (CBC) with differential
• Bone marrow biopsy ± aspirate ALCL, ALK positive PTCL-4
• Lactate dehydrogenase (LDH)
• Comprehensive metabolic panel
• Uric acid
• Fluorodeoxyglucose (FDG)-PET/CT scanh (preferred) and/or chest/abdominal/
pelvic (C/A/P) CT with contrast of diagnostic quality
• Calculation of International Prognostic Index (IPI)i
• Echocardiogram or multigated acquisition (MUGA) scan if anthracycline-based
regimen is indicated
• Pregnancy testing in those of childbearing potential (if chemotherapy or RT is
planned)

USEFUL IN CERTAIN CIRCUMSTANCES: • PTCL-NOS

• Neck CT with contrast • EATL
• Head CT or MRI with contrast • MEITL
• Consider central nervous system (CNS) evaluation, if clinical signs/symptomsj • ALCL, ALK negative PTCL-4
• Skin biopsy • AITL
• HIV testing • Nodal PTCL, TFH
• Hepatitis B and C testing • FTCL
• Consider quantitative Epstein-Barr virus (EBV) polymerase chain reaction (PCR)
• Consider evaluating for celiac disease in patients with newly diagnosed EATL
• Assessment of HTLV-1/2 by serology or other methods is encouraged, if not
previously done, as results can impact therapyd
• Discuss fertility preservationk
d See map for prevalence of HTLV-1/2 by geographic region. HTLV-1/2 has been described in patients in non-endemic areas.
h Patients with T-cell lymphomas often have extranodal disease, which may be inadequately imaged by CT. PET scan is preferred.
i International Prognostic Index (PTCL-A).
j The role of intrathecal prophylaxis in PTCL is largely unknown.
k Fertility preservation options include: sperm banking, semen cryopreservation, in vitro fertilization (IVF), or ovarian tissue or oocyte cryopreservation.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
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PTCL-3
The NCCN Evidence Blocks™ are subject to certain U.S. and foreign patents. Each approved use of the design of the NCCN Evidence Blocks™ requires the written approval of NCCN. Visit [Link]/patents for current list of applicable patents.
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Peripheral T-Cell Lymphomas Table of Contents
Discussion
NCCN Evidence BlocksTM
SUBTYPEl STAGE FIRST-LINE THERAPYn INTERIM RESTAGING

Multiagent chemotherapyo
x 6 cycles ± involved-site RT (ISRT)p
Stage I, II or
Multiagent chemotherapyo
x 3–4 cycles + ISRTp (category 2B) Restage after 3–4 cycles with
FDG-PET/CTh (preferred) or PTCL-5
ALCL, ALK C/A/P CT scan with contrastq
positive

Multiagent chemotherapyo
Stage III, IV
x 6 cycles

Other histologies:
• PTCL-NOS
• EATL
• MEITLf Clinical trial (preferred)
• ALCL, ALK or
Stage I–IV Restage after 3–4 cycles with
negativem Multiagent chemotherapyo
FDG-PET/CTh (preferred) or PTCL-6
• AITL 6 cycles ± ISRTp
C/A/P CT scan with contrastq
• Nodal PTCL, TFH
• FTCL

f MEITL has only recently been separated as its own entity and optimal treatment has not been defined.
h Patients with T-cell lymphomas often have extranodal disease, which may be inadequately imaged by CT. PET scan is preferred.
l For selected patients, palliative therapy for symptom management may be considered. See PTCL-B 2 of 8 for palliative treatment options.
m ALCL, ALK-negative with a DUSP22 rearrangement has been variably associated with a prognosis more similar to ALK-positive disease and treatment according to
the ALCL, ALK-positive algorithm may be considered for ALK-negative ALCL with DUSP22 rearrangement (Parrilla Castellar ER, et al. Blood 2014;124:1473-1480;
Pedersen MB, et al. Blood 2017;130:554-557; Hapgood G, et al. Br J Haematol 2019;186:e28-e31).
n Consider prophylaxis for tumor lysis syndrome (TLS) (TCLYM-B).
o Suggested Treatment Regimens (PTCL-B).
p Principles of Radiation Therapy (TCLYM-D).
q Other baseline imaging studies relevant for response assessment should be repeated as well.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
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PTCL-4
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Peripheral T-Cell Lymphomas Table of Contents
Discussion
NCCN Evidence BlocksTM
ALCL, ALK-POSITIVE: ADDITIONAL THERAPY BASED ON RESPONSE

END-OF- END-OF- CONSOLIDATION/ FOLLOW-UP

TREATMENT TREATMENT ADDITIONAL THERAPYn
RESTAGING RESPONSE
Clinical
Observe • H&P for every 3–6 mo for
or 2 y and then as clinically
Consider autologous indicated
CRr (PET hematopoietic cell Imaging Relapse
negative) transplant (HCT) • Surveillance imagingh (no
At completion patients with high- more often than every 6 mo
of treatment, risk IPIt for 2 y and then annually for
Complete
Complete repeat FDG- 5 y or as clinically indicated)
(CR) or
planned PET/CTh
Partial PRr,s (PET
course of (preferred)
response positive)
treatment or C/A/P CT
(PR)r
scan with
contrastq
Progressive
diseaser,s Relapsed/Refractory
Disease (PTCL-7)

No
response or
Progressive
diseaser

h Patients with T-cell lymphomas often have extranodal disease, which may be inadequately imaged by CT. PET scan is preferred.
n Consider prophylaxis for TLS (TCLYM-B).
q Other baseline imaging studies relevant for response assessment should be repeated as well.
r Lugano Response Criteria for Non-Hodgkin Lymphoma (TCLYM-C).
s Repeat biopsy should be considered (strongly consider for AITL since it may occasionally present with concurrent DLBCL) for persistent or new PET-positive lesions
prior to additional therapy.
t Localized areas can be irradiated before or after autologous HCT. See Principles of Radiation Therapy (TCLYM-D).

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
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PTCL-5
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NCCN Evidence BlocksTM
OTHER HISTOLOGIES: ADDITIONAL THERAPY BASED ON RESPONSE
END-OF- END-OF- CONSOLIDATION/ FOLLOW-UP
TREATMENT TREATMENT ADDITIONAL THERAPYn
RESTAGING RESPONSE
Clinical
• H&P for every 3–6 mo for
Clinical trial
2 y and then as clinically
or
CRr (PET Consider autologous HCTt
indicated
At completion negative) Imaging Relapse
or
of treatment, • Surveillance imagingh (no
Observe
Complete repeat FDG- more often than every 6 mo
CR or planned PET/CTh for 2 y and then annually for
PRr course of (preferred) PRr,s 5 y or as clinically indicated)
treatment or C/A/P CT (PET positive)
scan with
contrastq

Progressive
diseaser,s Relapsed/Refractory
Disease (PTCL-7)
No
response or
Progressive
diseaser

h Patients with T-cell lymphomas often have extranodal disease, which may be inadequately imaged by CT. PET scan is preferred.
n Consider prophylaxis for TLS (TCLYM-B).
q Other baseline imaging studies relevant for response assessment should be repeated as well.
r Lugano Response Criteria for Non-Hodgkin Lymphoma (TCLYM-C).
s Repeat biopsy should be considered (strongly consider for AITL since it may occasionally present with concurrent DLBCL) for persistent or new PET-positive lesions
prior to additional therapy.
t Localized areas can be irradiated before or after autologous HCT. See Principles of Radiation Therapy (TCLYM-D).

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
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PTCL-6
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Peripheral T-Cell Lymphomas Table of Contents
Discussion
NCCN Evidence BlocksTM
RELAPSED/ SECOND-LINE THERAPYn CONSOLIDATION/
REFRACTORY ADDITIONAL THERAPYn
DISEASE

If CRr or PR,r,s
Alternative
No responser
or consider allogeneic
Second-Line Therapy
Progressive diseaser or autologous
Clinical trial (preferred) (PTCL-B 3 of 8)
HCTt,u
Intention to or
proceed to Second-line therapy; See
transplant Suggested Regimens
(PTCL-B 3 of 8) Clinical trial
or
CRr or PRr,s Consider allogeneic See Follow-up
or autologous HCTt,u (PTCL-8)
Relapse/
refractory
disease
Continue treatment
CRr or PRr,s or See Follow-up
Clinical trial (preferred) or
Clinical benefit (PTCL-8)
or Observe
Second-line therapy;
No intention See Suggested Regimens
to proceed to (PTCL-B 3 of 8)
transplant or
Palliative RTp See Treatment
and/or No responser or options for
Best supportive care Progressive diseaser,s Relapse #2 or
n Consider prophylaxis for TLS (TCLYM-B). Greater (PTCL-8)
p Principles of Radiation Therapy (TCLYM-D).
r Lugano Response Criteria for Non-Hodgkin Lymphoma (TCLYM-C).
s Repeat biopsy should be considered (strongly consider for AITL since it may occasionally present with concurrent DLBCL) for persistent or new PET-positive lesions
prior to additional therapy.
t Localized areas can be irradiated before or after HCT. See Principles of Radiation Therapy (TCLYM-D).
u Allogeneic HCT is recommended in this setting.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
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PTCL-7
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NCCN Evidence BlocksTM
FOLLOW-UP TREATMENT OPTIONS FOR
RELAPSE #2 OR GREATER

Clinical Clinical trial

• H&P for every 3–6 mo for 2 y and then or
Follow-up after as clinically indicated Alternative second-line therapy (PTCL-B 3 of 8)
completion of Imaging or
treatment for • Surveillance imagingh (no more Palliative RTp
relapsed/refractory often than every 6 m for 2 y and and/or
disease then annually for 5 y or as clinically Best supportive care
indicated) (NCCN Guidelines for Palliative Care)

h Patients with T-cell lymphomas often have extranodal disease, which may be inadequately imaged by CT. PET scan is preferred.
p Principles of Radiation Therapy (TCLYM-D).

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
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INTERNATIONAL PROGNOSTIC INDEX (ALL PATIENTS)a PROGNOSTIC INDEX FOR PTCL-U (PIT)b
ALL PATIENTS: RISK GROUPS: RISK FACTORS: RISK GROUPS:
• Age >60 years • Low 0 or 1 • Age >60 years • Group 1 0
• Serum LDH > normal • Low-intermediate 2 • Serum LDH > normal • Group 2 1
• ECOG Performance • High-intermediate 3 • ECOG Performance • Group 3 2
Status 2–4 Status 2–4
• Stage III or IV • High 4 or 5 • Bone marrow involvement • Group 4 3 or 4
• Extranodal involvement
>1 site

AGE-ADJUSTED INTERNATIONAL PROGNOSTIC INDEXa PROGNOSTIC INDEX FOR PTCL-U (modified-PIT)c

PATIENTS ≤60 YEARS: RISK GROUPS: RISK FACTORS: RISK GROUPS:
• Stage III or IV • Low 0 • Age >60 years • Group 1 0 or 1
• Serum LDH > normal • Low-intermediate 1 • Serum LDH > normal • Group 2 2
• ECOG Performance • High-intermediate 2 • ECOG Performance • Group 3 3 or 4
Status 2–4 • High 3 Status 2–4
• Ki-67 ≥80%

T-CELL SCORE (INTERNATIONAL T-CELL LYMPHOMA PROJECT)d

RISK FACTORS: RISK GROUPS:
• Stage III–IV • Low risk 0
• ECOG Performance Status 2–4 • Intermediate risk 1–2
• Serum albumin <35 g/L • High risk 3–4
• Absolute neutrophil count (ANC) >6.5 x 10 /L 9

a International Non-Hodgkin’s Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med 1993;329:987-994.
b Gallamini A, Stelitano C, Calvi R, et al. Peripheral T-cell lymphoma unspecified (PTCL-U): A new prognostic model from a retrospective multicentric clinical study. Blood
2004;103:2474-2479.
c Went P, Agostinelli C, Gallamini A, et al. Marker expression in peripheral T-cell lymphoma: a proposed clinical-pathologic prognostic score. J Clin Oncol 2006;24:2472-
2479.
d Federico M, Bellei M, Marcheselli L, et al. Peripheral T cell lymphoma, not otherwise specified (PTCL-NOS). A new prognostic model developed by the International T cell
Project Network. Br J Haematol 2018;181:760-769.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
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PTCL-A
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SUGGESTED TREATMENT REGIMENSa,b

FIRST-LINE THERAPYc
ALCLd Preferred regimen
• Brentuximab vedotin + CHP (cyclophosphamide, doxorubicin, and prednisone)e (category 1)
Other recommended regimens
• CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)
• CHOEPf (cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone)
• Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin)

Other histologies Preferred regimens (alphabetical order)

(PTCL-NOS; • Brentuximab vedotin + CHP for CD30+ histologiese,h
EATL; MEITLg; • CHOEPf
AITL; nodal • CHOP
PTCL, TFH; and • Dose-adjusted EPOCH
FTCL) Other recommended regimens (alphabetical order)
• CHOP followed by IVE (ifosfamide, etoposide, and epirubicin) alternating with intermediate-dose methotrexate
(Newcastle Regimen; studied only in patients with EATL)i
• HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with high-dose methotrexate
and cytarabine (category 3)

FIRST-LINE CONSOLIDATION
• Consider consolidation with autologous HCT
Footnotes on PTCL-B 6 of 8
See Evidence Blocks on PTCL-B (EB-1)

See Initial Palliative-Intent Therapy (PTCL-B 2 of 8)

See Second-line and Subsequent Therapy:
• PTCL-NOS; EATL; MEITL; FTCL (PTCL-B 3 of 8)
• AITL, including nodal PTCL, TFH (PTCL-B 4 of 8)
• ALCL (PTCL-B 5 of 8)

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
PTCL-B
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4
E = Efficacy of Regimen/Agent
S = Safety of Regimen/Agent NCCN Guidelines Index
Peripheral T-Cell Lymphomas 3
2
Q = Quality of Evidence
C = Consistency of Evidence Table of Contents
A = Affordability of Regimen/Agent
Discussion
NCCN Evidence BlocksTM
1
E S Q C A

EVIDENCE BLOCKS: FIRST-LINE THERAPY FOR ALCL

ALCL, ALK-positive ALCL, ALK-negative

Preferred Regimen

Brentuximab vedotin/CHP

Other Recommended Regimens

CHOEP

CHOP

Dose-adjusted EPOCH

EVIDENCE BLOCKS: FIRST-LINE THERAPY FOR OTHER HISTOLOGIES (PTCL, NOS AND AITL)

PTCL-NOS AITL

Preferred Regimens

Brentuximab vedotin/CHP (for CD30-positive histology)

CHOEP

CHOP

Dose-adjusted EPOCH

Other Recommended Regimens

CHOP followed by IVE

Hyper-CVAD alternating with high-dose methotrexate and cytarabine

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1. PTCL-B
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EB-1
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SUGGESTED TREATMENT REGIMENSa,b

INITIAL PALLIATIVE-INTENT THERAPY

PTCL-NOS; EATL; MEITLg AITL, NODAL PTCL, TFH, and FTCL ALCL
Preferred regimens (regimens in Preferred regimens (regimens in alphabetical Preferred regimen (regimens in alphabetical
alphabetical order) order) order)
• Clinical trial • Clinical trial • Clinical trial
• Belinostat • Belinostat • Brentuximab vedotine
• Brentuximab vedotin for CD30+ PTCLe,h • Brentuximab vedotin for CD30+ AITLe,h
• Duvelisibj • Duvelisibj Other recommended regimens
• Pralatrexate • Romidepsin (alphabetical order by category)
• Romidepsin • ALK inhibitors (for ALK-positive ALCL only):q
Other recommended regimens Alectinib
Other recommended regimens (alphabetical order by category) Brigatinib
(alphabetical order by category) • Alemtuzumabk Ceritinib
• Alemtuzumabk • Bendamustinee Crizotinib
• Bendamustinee • Cyclophosphamide and/or etoposide (IV or PO) • Belinostat
• Cyclophosphamide and/or etoposide (IV • Cyclosporinen • Bendamustinee
or PO) • Gemcitabine • Cyclophosphamide and/or etoposide (IV or PO)
• Gemcitabine • Lenalidomidee • Duvelisibj
• Lenalidomidee • Pralatrexate o • Gemcitabine
• RTl • RTl • Pralatrexate
• Bortezomibm (category 2B) • Azacitidine (PO/IV/SC)p (category 2B) • RTl
• Ruxolitinib (category 2B) m
• Bortezomib (category 2B) • Romidepsin
• Ruxolitinib (category 2B) • Bortezomibm (category 2B)
• Ruxolitinib (category 2B)

Footnotes on PTCL-B 6 of 8
See First-line Therapy on PTCL-B 1 of 8.
See Second-line and Subsequent Therapy:
PTCL-NOS; EATL; MEITL (PTCL-B 3 of 8)
AITL, including nodal PTCL, TFH, and FTCL (PTCL-B 4 of 8)
ALCL (PTCL-B 5 of 8)

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
PTCL-B
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SUGGESTED TREATMENT REGIMENSa,b
PTCL-NOS; EATL; MEITLg
SECOND-LINE THERAPY AND SUBSEQUENT THERAPY SECOND-LINE AND SUBSEQUENT THERAPY
(INTENTION TO PROCEED TO TRANSPLANT) (NO INTENTION TO PROCEED TO TRANSPLANT)
Preferred regimens (regimens in alphabetical order) Preferred regimens (regimens in alphabetical order)
• Clinical trial • Clinical trial
• Single agents (alphabetical order) • Belinostat
Belinostat
e,h
• Brentuximab vedotin for CD30+ PTCLe,h
Brentuximab vedotin for CD30+ PTCL • Duvelisibj
Duvelisib j
• Pralatrexate
Pralatrexate • Romidepsin
Romidepsin
• Combination regimens (alphabetical order) Other recommended regimens (alphabetical order by category)
DHA (dexamethasone and cytarabine) + platinum (carboplatin, • Single agents
cisplatin, or oxaliplatin)
Alemtuzumabk
ESHA (etoposide, methylprednisolone, and cytarabine) +
platinum (cisplatin or oxaliplatin) Bendamustinee
GDP (gemcitabine, dexamethasone, and cisplatin) Cyclophosphamide and/or etoposide (IV or PO)
GemOx (gemcitabine and oxaliplatin) Gemcitabine
ICE (ifosfamide, carboplatin, and etoposide) Lenalidomidee
RTl
Other recommended regimens (alphabetical order by category) Bortezomibm (category 2B)
• Single agents Ruxolitinib (category 2B)
Bendamustine e • Combination regimen
Gemcitabine Brentuximab vedotin and bendamustine for CD30+ PTCLe,h
Lenalidomidee (category 2B)
Ruxolitinib (category 2B)
• Combination regimens
Brentuximab vedotin and bendamustine for CD30+ PTCLe,h
(category 2B) Footnotes on PTCL-B 6 of 8
GVD (gemcitabine, vinorelbine, and liposomal doxorubicin)q
See First-line Therapy on PTCL-B 1 of 8.
See Second-line and Subsequent Therapy:
AITL, including nodal PTCL, TFH, and FTCL (PTCL-B 4 of 8)
ALCL (PTCL-B 5 of 8)

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
PTCL-B
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SUGGESTED TREATMENT REGIMENSa,b
AITL, NODAL PTCL, TFH, AND FTCL
SECOND-LINE THERAPY AND SUBSEQUENT THERAPY SECOND-LINE AND SUBSEQUENT THERAPY
(INTENTION TO PROCEED TO TRANSPLANT) (NO INTENTION TO PROCEED TO TRANSPLANT)
Preferred regimens (regimens in alphabetical order) Preferred regimens (regimens in alphabetical order)
• Clinical trial • Clinical trial
• Single agents (alphabetical order) • Belinostat
Belinostat • Brentuximab vedotin for CD30+ AITLe,h
Brentuximab vedotin for CD30+ AITLe,h • Duvelisibj
Duvelisibj • Romidepsin
Romidepsin
• Combination regimens (alphabetical order) Other recommended regimens (alphabetical order by category)
DHA (dexamethasone and cytarabine) + platinum (carboplatin, • Single agents
cisplatin, or oxaliplatin) Alemtuzumabk
ESHA (etoposide, methylprednisolone, and cytarabine) + Azacitidine (PO/IV/SC)p
platinum (cisplatin or oxaliplatin) Bendamustinee
GDP (gemcitabine, dexamethasone, and cisplatin) Cyclophosphamide and/or etoposide (IV or PO)
GemOx (gemcitabine and oxaliplatin) Cyclosporinen
ICE (ifosfamide, carboplatin, and etoposide) Gemcitabine
Lenalidomidee
Other recommended regimens (alphabetical order by category) Pralatrexateo
• Single agents RTl
Azacitidine (PO/IV/SC)p Bortezomibm (category 2B)
Bendamustinee Ruxolitinib (category 2B)
Gemcitabine • Combination regimen
Lenalidomidee Brentuximab vedotin and bendamustine for CD30+ PTCLe,h
Pralatrexateo (category 2B)
Ruxolitinib (category 2B)
• Combination regimens
GVD (gemcitabine, vinorelbine, and liposomal doxorubicin)r
Brentuximab vedotin and bendamustine for CD30+ PTCLe,h Footnotes on PTCL-B 6 of 8
(category 2B) See First-line Therapy on PTCL-B 1 of 8.
See Second-line and Subsequent Therapy:
PTCL-NOS; EATL; MEITL (PTCL-B 3 of 8)
ALCL (PTCL-B 5 of 8)

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
PTCL-B
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SUGGESTED TREATMENT REGIMENSa,b
ALCL
SECOND-LINE THERAPY AND SUBSEQUENT THERAPY SECOND-LINE AND SUBSEQUENT THERAPY
(WITH INTENTION TO PROCEED TO TRANSPLANT) (NO INTENTION TO PROCEED TO TRANSPLANT)
Preferred regimen Preferred regimen
• Clinical trial • Clinical trial
• Brentuximab vedotine • Brentuximab vedotine

Other recommended regimens (alphabetical order by category) Other recommended regimens (alphabetical order by category)
• Single agents • Single agents
ALK inhibitors (for ALK-positive ALCL only):q ALK inhibitors (for ALK-positive ALCL only):q
◊ Alectinib ◊ Alectinib
◊ Brigatinib ◊ Brigatinib
◊ Ceritinib ◊ Ceritinib
◊ Crizotinib ◊ Crizotinib
◊ Lorlatinib ◊ Lorlatinib
Belinostat Belinostat
Bendamustinee Bendamustinee
Duvelisibj Cyclophosphamide and/or etoposide (IV or PO)
Gemcitabine Duvelisibj
Pralatrexate Gemcitabine
Romidepsin Pralatrexate
Ruxolitinib (category 2B) RTl
• Combination regimens Romidepsin
DHA (dexamethasone and cytarabine) + platinum (carboplatin, Bortezomibj (category 2B)
cisplatin, or oxaliplatin) Ruxolitinib (category 2B)
ESHA (etoposide, methylprednisolone, and cytarabine) + • Combination regimen
platinum (cisplatin or oxaliplatin) Brentuximab vedotin and bendamustinee (category 2B)
GDP (gemcitabine, dexamethasone, and cisplatin)
GVD (gemcitabine, vinorelbine, and liposomal doxorubicin)q
GemOx (gemcitabine and oxaliplatin) Footnotes on PTCL-B 6 of 8
ICE (ifosfamide, carboplatin, and etoposide) See First-line Therapy on PTCL-B 1 of 8.
Brentuximab vedotin and bendamustinee (category 2B) See Second-line and Subsequent Therapy:
PTCL-NOS; EATL; MEITL (PTCL-B 3 of 8)
AITL, including nodal PTCL, TFH, and FTCL (PTCL-B 4 of 8)
See Evidence Blocks on PTCL-B (EB-2), PTCL-B (EB-3), and PTCL-B (EB-4)

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
PTCL-B
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NCCN Guidelines Version 4.2024 5

4
E = Efficacy of Regimen/Agent
S = Safety of Regimen/Agent NCCN Guidelines Index
Peripheral T-Cell Lymphomas 3
2
Q = Quality of Evidence
C = Consistency of Evidence Table of Contents
A = Affordability of Regimen/Agent
Discussion
NCCN Evidence BlocksTM
1
E S Q C A

EVIDENCE BLOCKS FOR SECOND-LINE AND SUBSEQUENT THERAPY: ALCL

Single Agents Combination Regimens

ALK inhibitors (for ALK-positive ALCL only) DHAP (dexamethasone, cytarabine, cisplatin)
Alectinib DHAX (dexamethasone, cytarabine, oxaliplatin)
Brigatinib DHA (dexamethasone and cytarabine) + carboplatin
Ceritinib ESHA (etoposide, methylprednisolone, cytarabine)
+ cisplatin
Crizotinib
ESHA (etoposide, methylprednisolone, cytarabine)
Lorlatinib + oxaliplatin
ICE (ifosfamide, carboplatin, etoposide)
Brentuximab vedotin
GDP (gemcitabine, dexamethasone, cisplatin)
Belinostat
GemOx (gemcitabine, oxaliplatin)
Romidepsin
GVD (gemcitabine, vinorelbine, and liposomal
Duvelisib doxorubicin)

Bendamustine Brentuximab vedotin and bendamustine

Bortezomib

Cyclophosphamide

Etoposide

Cyclophosphamide and etoposide

Gemcitabine

Pralatrexate

Ruxolitinib

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1. PTCL-B
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EB-2
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NCCN Guidelines Version 4.2024 5

4
E = Efficacy of Regimen/Agent
S = Safety of Regimen/Agent NCCN Guidelines Index
Peripheral T-Cell Lymphomas 3
2
Q = Quality of Evidence
C = Consistency of Evidence Table of Contents
A = Affordability of Regimen/Agent
Discussion
NCCN Evidence BlocksTM
1
E S Q C A

EVIDENCE BLOCKS FOR SECOND-LINE AND SUBSEQUENT THERAPY: PTCL-NOS

Single Agents Combination Regimens

Alemtuzumab DHA (dexamethasone, cytarabine) + carboplatin

Belinostat DHAP (dexamethasone, cytarabine, cisplatin)

Bendamustine DHAX (dexamethasone, cytarabine, oxaliplatin)

Bortezomib ESHA (etoposide, methylprednisolone, cytarabine) +

cisplatin
Brentuximab vedotin ESHA (etoposide, methylprednisolone, cytarabine) +
oxaliplatin)
Cyclophosphamide
GDP (gemcitabine, dexamethasone, cisplatin)
Cyclophosphamide and etoposide
GemOx (gemcitabine, oxaliplatin)
Etoposide GVD (gemcitabine, vinorelbine, and liposomal
doxorubicin)
Duvelisib
ICE (ifosfamide, carboplatin, etoposide)
Gemcitabine
Brentuximab vedotin and bendamustine
Lenalidomide

Pralatrexate

Romidepsin

Ruxolitinib

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1. PTCL-B
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EB-3
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NCCN Guidelines Version 4.2024 5

4
E = Efficacy of Regimen/Agent
S = Safety of Regimen/Agent NCCN Guidelines Index
Peripheral T-Cell Lymphomas 3
2
Q = Quality of Evidence
C = Consistency of Evidence Table of Contents
A = Affordability of Regimen/Agent
Discussion
NCCN Evidence BlocksTM
1
E S Q C A

EVIDENCE BLOCKS FOR SECOND-LINE AND SUBSEQUENT THERAPY: AITL

Single Agents Combination Regimens

Alemtuzumab DHA (dexamethasone, cytarabine) + carboplatin

Azacitidine DHAP (dexamethasone, cytarabine, cisplatin)

Belinostat DHAX (dexamethasone, cytarabine, oxaliplatin)

Bendamustine ESHA (etoposide, methylprednisolone, cytarabine) +

cisplatin
Bortezomib ESHA (etoposide, methylprednisolone, cytarabine) +
oxaliplatin)
Brentuximab vedotin
GDP (gemcitabine, dexamethasone, cisplatin)
Cyclophosphamide
GemOx (gemcitabine, oxaliplatin)
Cyclophosphamide and etoposide GVD (gemcitabine, vinorelbine, and liposomal
doxorubicin)
Etoposide
ICE (ifosfamide, carboplatin, etoposide)
Cyclosporine
Brentuximab vedotin and bendamustine
Duvelisib

Gemcitabine

Lenalidomide

Pralatrexate

Romidepsin

Ruxolitinib

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NCCN Guidelines Version 4.2024 5

4
E = Efficacy of Regimen/Agent
S = Safety of Regimen/Agent NCCN Guidelines Index
Peripheral T-Cell Lymphomas 3
2
Q = Quality of Evidence
C = Consistency of Evidence Table of Contents
A = Affordability of Regimen/Agent
Discussion
NCCN Evidence BlocksTM
1
E S Q C A

EVIDENCE BLOCKS FOR SECOND-LINE AND SUBSEQUENT THERAPY: AITL

Single Agents Combination Regimens

Alemtuzumab DHA (dexamethasone, cytarabine) + carboplatin

Azacitidine DHAP (dexamethasone, cytarabine, cisplatin)

Belinostat DHAX (dexamethasone, cytarabine, oxaliplatin)

Bendamustine ESHA (etoposide, methylprednisolone, cytarabine) +

cisplatin
Bortezomib ESHA (etoposide, methylprednisolone, cytarabine) +
oxaliplatin)
Brentuximab vedotin
GDP (gemcitabine, dexamethasone, cisplatin)
Cyclophosphamide
GemOx (gemcitabine, oxaliplatin)
Cyclophosphamide and etoposide GVD (gemcitabine, vinorelbine, and liposomal
doxorubicin)
Etoposide
ICE (ifosfamide, carboplatin, etoposide)
Cyclosporine
Brentuximab vedotin and bendamustine
Duvelisib

Gemcitabine

Lenalidomide

Pralatrexate

Romidepsin

Ruxolitinib

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Peripheral T-Cell Lymphomas Table of Contents
Discussion
NCCN Evidence BlocksTM
SUGGESTED TREATMENT REGIMENS
FOOTNOTES
a See references for regimens on PTCL-B 7 of 8 and PTCL-B 8 of 8.
b Consider prophylaxis for TLS (TCLYM-B).
c While anthracycline-based regimens confer a favorable prognosis in ALCL, ALK-positive, these regimens have not provided the same favorable results for other PTCL
histologies; clinical trial is therefore preferred for the management of these other histologies.
d ALCL, ALK-negative with a DUSP22 rearrangement has been variably associated with a prognosis more similar to ALK-positive disease and treatment according to
the ALCL, ALK-positive algorithm may be considered (Parrilla Castellar ER, et al. Blood 2014;124:1473-1480; Hapgood G, et al. Br J Haematol 2019;186:e28-e31;
Pedersen MB, et al. Blood 2017;130:554-557).
e Supportive Care (TCLYM-B).
f Oral etoposide dose of 200 mg/m2 (PO dosing of etoposide is 2x the IV dose) may be substituted on day 2 and 3 for IV etoposide. Consider splitting the daily doses of
oral etoposide over 200 mg.
g MEITL has only recently been separated as its own entity and optimal treatment has not been defined.
h Interpretation of CD30 expression is not universally standardized. Responses have been seen in patients with a low level of CD30 positivity.
i CHOP followed by IVE regimen includes HCT.
j In the phase II study, the preferred dosing regimen of duvelisib was 75 mg BID for 2 cycles followed by 25 mg BID for long-term disease control.
k While alemtuzumab is no longer commercially available, it may be obtained for clinical use. Cytomegalovirus (CMV) monitoring or prophylaxis is recommended
(TCLYM-B).
l Principles of Radiation Therapy (TCLYM-D).
m Activity has been demonstrated in small clinical trials and additional larger trials are needed.
n With close follow-up of renal function.
o In AITL, pralatrexate has limited activity.
p Dosing for oral azacitidine differs from that of IV or SC azacitidine.
q Second-generation (ie, alectinib, brigatinib, ceritinib) and third-generation (lorlatinib) ALK inhibitors have shown activity in patients with CNS involvement.
r Data suggest there may be excessive pulmonary toxicity with GVD (gemcitabine, vinorelbine, and liposomal doxorubicin) regimen when used in combination
with unconjugated anti-CD30 monoclonal antibodies for the treatment of Hodgkin lymphoma (Blum KA, et al. Ann Oncol 2010;21:2246-2254). A similar regimen,
gemcitabine and liposomal doxorubicin, may be used for mature T-cell lymphoma; however, it is recommended to wait 3 to 4 weeks following treatment with
brentuximab vedotin before initiation.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
PTCL-B
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Peripheral T-Cell Lymphomas Table of Contents
Discussion
NCCN Evidence BlocksTM
SUGGESTED TREATMENT REGIMENS
REFERENCES
First-Line Therapy Second-Line Therapy
Brentuximab vedotin + CHP (cyclophosphamide, doxorubicin, and prednisone) ALK inhibitors
Horwitz S, O'Connor OA, Pro B, et al. The ECHELON-2 Trial: 5-year results of a randomized, phase III Alectinib
study of brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma. Ann Fukano R, Mori T, Sekimizu M, et al. Alectinib for relapsed or refractory anaplastic lymphoma kinase-
Oncol 2022;33:288-298.
positive anaplastic large cell lymphoma: an open-label phase II trial. Cancer Sci 2020;111:4540-
CHOEP
4547.
Cederleuf H, Bjerregard Pedersen M, Jerkeman M, et al. The addition of etoposide to CHOP
Brigatinib
is associated with improved outcome in ALK+ adult anaplastic large cell lymphoma: A Nordic
Veleanu L, Tesson B, Lamant L, et al. Brigatinib in patients with ALK-positive anaplastic large cell
Lymphoma Group study. Br J Haematol 2017;178:739-746.
lymphoma who have failed brentuximab vedotin. Hematological Oncology 2023;41:505-506.
Schmitz N, Trümper L, Ziepert M, et al. Treatment and prognosis of mature T-cell and NK-cell
Ceritinib
lymphoma: an analysis of patients with T-cell lymphoma treated in studies of the German High-
Richly H, Kim TM, Schuler M, et al. Ceritinib in patients with advanced anaplastic lymphoma kinase-
Grade Non-Hodgkin Lymphoma Study Group. Blood 2010;116:3418-3425.
rearranged anaplastic large-cell lymphoma. Blood 2015;126:1257-1258.
Dose-adjusted EPOCH
Crizotinib
Dunleavy K, Pittaluga S, Shovlin M, et al. Phase II trial of dose-adjusted EPOCH in untreated systemic
Gambacorti Passerini C, Farina F, Stasia A, et al. Crizotinib in advanced, chemoresistant anaplastic
anaplastic large cell lymphoma. Haematologica 2016;101:e27-e29.
lymphoma kinase-positive lymphoma patients. J Natl Cancer Inst 2014;106:djt378.
Maeda Y, Nishimori H, Yoshida I, et al. Dose-adjusted EPOCH chemotherapy for untreated
Bossi E, Aroldi A, Brioschi F, et al. Phase two study of crizotinib in patients with anaplastic lymphoma
peripheral T-cell lymphomas: a multicenter phase II trial of West-JHOG PTCL0707. Haematologica
kinase (ALK)-positive anaplastic large cell lymphoma relapsed/refractory to chemotherapy Am J
2017;102:2097-2103.
Hematol 2020;95:E319-E321.
CHOP followed by IVE
Lorlatinib
Sieniawski M, Angamuthu N, Boyd K, et al. Evaluation of enteropathy-associated T-cell lymphoma
Ripamonti A, Aroldi A, Cocito F, et al. Preliminary Results of Phase 2 Open Label Study of Lorlatinib
comparing standard therapies with a novel regimen including autologous stem cell transplantation.
Monotherapy in Relapsed/Refractory ALK + Lymphomas Previously Treated with Other Tyrosine Kinase
Blood 2010;115:3664-3670.
HyperCVAD alternating with high-dose methotrexate and cytarabine Inhibitors [abstract]. Blood 2023;142: Abstract 4474
Escalon MP, Liu NS, Yang Y, et al. Prognostic factors and treatment of patients with T-cell non-Hodgkin
lymphoma: the M. D. Anderson Cancer Center experience. Cancer 2005;103:2091-2098. Alemtuzumab
Pozadzides JV, Perini G, Hess M, et al. Prognosis and treatment of patients with peripheral T-cell Enblad G, Hagberg H, Erlanson M, et al. A pilot study of alemtuzumab (anti-CD52 monoclonal antibody)
lymphoma: The M. D. Anderson Cancer Center experience [abstract]. J Clin Oncol 2010;28: Abstract therapy for patients with relapsed or chemotherapy-refractory peripheral T-cell lymphomas. Blood
8051. 2004;103:2920-2924.
Azacitidine
Dupuis J, Tsukasaki K, Bachy E, et al. Oral azacytidine in patients with relapsed/refractory
angioimmunoblastic T-cell lymphoma: Final analysis of the Oracle phase III study [abstract]. Blood
2022;140(suppl 1):2310-2312.
Belinostat
O'Connor OA, Horwitz S, Masszi T, et al. Belinostat in patients with relapsed or refractory peripheral T-cell
lymphoma: Results of the pivotal phase II BELIEF (CLN-19) study. J Clin Oncol 2015;33:2492-2499.
Bendamustine
Damaj G, Gressin R, Bouabdallah K, et al. Results from a prospective, open-label, phase II trial of
bendamustine in refractory or relapsed T-cell lymphomas: the BENTLY trial. J Clin Oncol 2013;31:104-
110.

Continued

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
PTCL-B
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Printed by vo dat on 9/16/2024 10:40:20 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved.

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Peripheral T-Cell Lymphomas Table of Contents
Discussion
NCCN Evidence BlocksTM
SUGGESTED TREATMENT REGIMENS
REFERENCES
Bortezomib
Zinzani P, Musuraca G, Tani M, et al. Phase II trial of proteasome inhibitor bortezomib in patients with Gemcitabine
relapsed or refractory cutaneous T-cell lymphoma. J Clin Oncol 2007;25:4293-4297. Zinzani PL, Venturini F, Stefoni V, et al. Gemcitabine as single agent in pretreated T-cell lymphoma patients:
Brentuximab vedotin evaluation of the long-term outcome. Ann Oncol 2010;21:860-863.
Horwitz SM, Advani RH, Bartlett NL, et al. Objective responses in relapsed T-cell lymphomas with single GDP (gemcitabine, dexamethasone, and cisplatin)
agent brentuximab vedotin. Blood 2014;123 3095-3100. Connors JM, Sehn LH, Villa D, et al. Gemcitabine, dexamethasone, and cisplatin (GDP) as secondary
Pro B, Advani R, Brice P, et al. Five-year results of brentuximab vedotin in patients with relapsed or chemotherapy in relapsed/refractory peripheral T-cell lymphoma [abstract]. Blood 2013;122:Abstract 4345.
refractory systemic anaplastic large cell lymphoma. Blood 2017;130:2709-2717. Park BB, Kim WS, Suh C, et al. Salvage chemotherapy of gemcitabine, dexamethasone, and cisplatin
Brentuximab vedotin + bendamustine (GDP) for patients with relapsed or refractory peripheral T-cell lymphomas: a consortium for improving
Aubrais R, Bouabdallah K, Chartier L, et al. Salvage therapy with brentuximab-vedotin and bendamustine survival of lymphoma (CISL) trial. Ann Hematol 2015;94:1845-1851.
for patients with R/R PTCL: a retrospective study from the LYSA group. Blood Adv 2023;7:5733-5742. GVD (gemcitabine, vinorelbine, and liposomal doxorubicin)
Cyclosporine for AITL Qian Z, Song Z, Zhang H, et al. Gemcitabine, navelbine, and doxorubicin as treatment for patients with
Advani R, Horwitz S, Zelenetz A, Horning SJ. Angioimmunoblastic T cell lymphoma: treatment experience refractory or relapsed T-cell lymphoma. Biomed Res Int 2015;2015:606752.
with cyclosporine. Leuk Lymphoma 2007;48:521-525. GemOX (gemcitabine, oxaliplatin)
Wang X, Zhang D, Wang L, et al. Cyclosporine treatment of angioimmunoblastic T-cell lymphoma relapsed Lopez A, Gutierrez A, Palacios A, et al. GEMOX-R regimen is a highly effective salvage regimen in patients
after an autologous hematopoietic stem cell transplant. Exp Clin Transplant 2015;13:203-205. with refractory/relapsing diffuse large-cell lymphoma: A phase II study. Eur J Haematol 2008;80:127-132.
DHAP (dexamethasone, cytarabine, and cisplatin) + platinum (carboplatin, cisplatin or oxaliplatin) ICE (ifosfamide, carboplatin, and etoposide)
Velasquez WS, Cabanillas F, Salvador P, et al. Effective salvage therapy for lymphoma with cisplatin in Horwitz S, Moskowitz C, Kewalramani T, et al. Second-line therapy with ICE followed by high dose therapy
combination with high-dose Ara-C and dexamethasone (DHAP). Blood 1988;71:117-122. and autologous stem cell transplantation for relapsed/refractory peripheral T-cell lymphomas: minimal
Mey UJ, Orlopp KS, Flieger D, et al. Dexamethasone, high-dose cytarabine, and cisplatin in combination benefit when analyzed by intent to treat [abstract]. Blood 2005;106:Abstract 2679.
with rituximab as salvage treatment for patients with relapsed or refractory aggressive non-Hodgkin's Lenalidomide
lymphoma. Cancer Invest 2006;24:593-600. Morschhauser, Fitoussi O, Haioun C, et al. A phase 2, multicentre, single-arm, open-label study to evaluate
Rigacci L, Fabbri A, Puccini B, et al. Oxaliplatin-based chemotherapy (dexamethasone, high-dose the safety and efficacy of single-agent lenalidomide (Revlimid) in subjects with relapsed or refractory
cytarabine, and oxaliplatin) ± rituximab is an effective salvage regimen in patients with relapsed or peripheral T-cell non-Hodgkin lymphoma: the EXPECT trial. Eur J Cancer 2013;49:2869-2876.
refractory lymphoma. Cancer 2010;116:4573-4579. Toumishey E, Prasad A, Dueck G, et al. Final report of a phase 2 clinical trial of lenalidomide monotherapy
Tixier F, Ranchon F, Iltis A, et al. Comparative toxicities of 3 platinum-containing chemotherapy regimens in for patients with T-cell lymphoma. Cancer 2015;121:716-723.
relapsed/refractory lymphoma patients. Hematol Oncol 2017;35:584-590. Pralatrexate
Tessoulin B, Thomare P, Delande E, et al. Carboplatin instead of cisplatin in combination with O'Connor OA, Pro B, Pinter-Brown L, et al. Pralatrexate in patients with relapsed or refractory peripheral
dexamethasone, high-dose cytarabine with or without rituximab (DHAC+/-R) is an effective treatment with T-cell lymphoma: Results from the pivotal PROPEL study. J Clin Oncol 2011;29:1182-1189.
low toxicity in Hodgkin's and non-Hodgkin's lymphomas. Ann Hematol 2017;96:943-950. Romidepsin
Duvelisib Coiffier B, Pro B, Prince HM, et al. Results from a pivotal, open-label, phase II study of romidepsin in
Brammer J, Zinzani P, Zain J, et al. Duvelisib in patients with relapsed/refractory peripheral T-cell relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. J Clin Oncol 2012;30:631-
lymphoma from the phase 2 Primo trial: Results of an interim analysis [abstract]. Blood 2021:138(Suppl 636.
1): Abstract 2456. Coiffier B, Pro B, Prince HM, et al. Romidepsin for the treatment of relapsed/refractory peripheral T-cell
ESHAP (etoposide, methylprednisolone, and cytarabine) + platinum (cisplatin or oxaliplatin) lymphoma: pivotal study update demonstrates durable responses. J Hematol Oncol 2014;7:11.
Velasquez WS, McLaughlin P, Tucker S, et al. ESHAP - an effective chemotherapy regimen in refractory Ruxolitinib
and relapsing lymphoma: a 4-year follow-up study. J Clin Oncol 1994;12:1169-1176. Moskowitz AJ, Ghione P, Jacobsen E, et al. A phase 2 biomarker-driven study of ruxolitinib demonstrates
Sym SJ, Lee DH, Kang HJ, et al. A multicenter phase II trial of etoposide, methylprednisolone, high- effectiveness of JAK/STAT targeting in T-cell lymphomas. Blood 2021;138:2828-2837.
dose cytarabine, and oxaliplatin for patients with primary refractory/relapsed aggressive non-Hodgkin's
lymphoma. Cancer Chemother Pharmacol 2009;64:27-33.
Won YW, Lee H, Eom HS, et al. A phase II study of etoposide, methylprednisolone, high-dose cytarabine,
and oxaliplatin (ESHAOx) for patients with refractory or relapsed Hodgkin's lymphoma. Ann Hematol
2020;99:255-264.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
PTCL-B
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Breast Implant-Associated ALCL Table of Contents
Discussion
NCCN Evidence BlocksTM
OVERVIEW OF BREAST IMPLANT-ASSOCIATED ANAPLASTIC LARGE CELL LYMPHOMA (BIA-ALCL)

Definition
• BIA-ALCL is an uncommon and emerging PTCL most frequently arising around a textured surface breast implant or in a patient with a history
of a textured surface device.a
• BIA-ALCL commonly presents with delayed periprosthetic effusion and breast asymmetry occurring greater than 1 year (average, 7–9 years)
after implantation. See Clinical Presentation (BIAA-1). Rarely, BIA-ALCL can present with a mass, regional lymphadenopathy, overlying skin
rash, and/or capsular contracture.
• The majority of patients with BIA-ALCL exhibit an indolent clinical course with slow progression of disease and an excellent prognosis.
• Regional lymph node metastasis and more rarely distant organ and bone marrow metastasis may be seen in advanced stages.b
Diagnosis
• Tumor cells are CD30+, ALK-, have large anaplastic morphology on cytology, and demonstrate a single T-cell clone.c
• The histopathologic findings of BIA-ALCL need to be correlated with a clinical presentation and history of a breast implant to achieve a
definitive diagnosis.d
• Diagnosis from effusions requires a sufficient volume of fluid (minimum, 50 mL) to achieve diagnosis. Prior serial aspirations may decrease
or dilute tumor burden and make diagnosis more challenging; therefore, pathology review of the first aspiration is advisable.
• Multiple systematic sampling of scar capsulectomy specimen may be necessary to determine early invasive disease and mass formation,
which have implications for prognosis.e
• Secondary review by a tertiary referral center is recommended for equivocal pathology.

GENERAL PRINCIPLES OF BIA-ALCL

• A multidisciplinary team approach involving lymphoma oncology, surgical oncology, hematopathology, and plastic surgery is often optimal
for the treatment of patients with BIA-ALCL, particularly those with advanced disease.
• Given the rarity of the disease, the FDA recommends reporting cases to national disease registries to track cases ([Link]/PROFILE).
• Goals of therapy should be individualized but often include the following:
Generally, complete surgical resection alone of the implant, capsule, and associated mass is used in earlier stage disease confined to the
periprosthetic scar capsule.f
May consider immediate or delayed breast reconstruction with autologous tissue or smooth surface breast implants.g
Local disease relapse may be amenable to re-excision surgery alone without requiring systemic therapies.

d Quesada AE, Medeiros LJ, Clemens MW, et al. Breast implant-associated

a Mehta-Shah N, Clemens MW, Horwitz SM. How I treat breast implant-associated anaplastic large cell lymphoma: A review. Mod Pathol 2019;32:166-188.
anaplastic large cell lymphoma. Blood 2018;132:1889-1898. e Lyapichev KA, Pina-Oviedo S, Medieros LJ, et al. A proposal for pathologic
b Collins MS, Miranda RN, Medeiros LJ, et al. Characteristics and treatment processing of breast implant capsules in patients with suspected breast implant
of advanced breast implant-associated anaplastic large cell lymphoma. Plast anaplastic large cell lymphoma. Mod Pathol 2020;33:367-379.
Reconstr Surg 2019;143:41S-50S. f Clemens MW, Medeiros LJ, Butler CE, et al. Complete surgical excision is essential
c Alaggio R, Amador C, Anagnostopoulos I, et al. The 5th edition of the World for the management of patients with breast implant-associated anaplastic large cell
Health Organization Classification of Haematolymphoid Tumours: Lymphoid lymphoma. J Clin Oncol 2016;34:160-168.
Neoplasms. Leukemia 2022;36:1720-1748; Campo E, Jaffe ES, Cook JR, et al. g Lamaris GA, Butler CE, Deva AK, et al. Breast reconstruction following breast
The International Consensus Classification of Mature Lymphoid Neoplasms: a implant-associated anaplastic large cell lymphoma. Plast Reconstr Surg
report from the Clinical Advisory Committee. Blood 2022;140:1229-1253. 2019;143:51S-58S.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
BIAA-INTRO
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The NCCN Evidence Blocks™ are subject to certain U.S. and foreign patents. Each approved use of the design of the NCCN Evidence Blocks™ requires the written approval of NCCN. Visit [Link]/patents for current list of applicable patents.
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Breast Implant-Associated ALCL Table of Contents
Discussion
NCCN Evidence BlocksTM
CLINICAL INITIAL WORKUP PATHOLOGIC WORKUPe,f
PRESENTATIONa

ESSENTIAL: Second
• Cytology with cell If pathology
block preparationd indeterminate consultation
• IHC and/or flow of lymphoma by tertiary
cytometryd may cancer center
Ultrasound FNA biopsy of include CD2, CD3,
Any
of breast and fluidd around CD4, CD5, CD7, CD8, Refer to
effusiond Negative
axilla breast implant CD30, CD45, and ALKg plastic
Physical signsb or for
surgeon for
(effusion, Breast MRI USEFUL UNDER IN lymphoma
management
enlargement, mass, with and CIRCUMSTANCES:
ulceration) >1 y without Mass Biopsy of mass • If there is solid
post implantation contrast in mass associated Histologic
(average 7–9 y selected cases with the implant,
Breast MRI, if confirmation
post-implantation) or biopsy (excisional BIAA-2
not previously or suspicion
FDG-PET/ or incisional or core
done, and follow of BIA-ALCLh
CT scanc in Ultrasound needle) may be
selected cases pathway above
inconclusive required for diagnosis
for any effusion
or mass (as
appropriate)

a Rare cases with parenchymal breast or nodal involvement may have an aggressive course more in line with systemic ALK-positive ALCL (PTCL-3). Optimal
treatment of these cases is not well defined and management should be individualized.
b A majority of cases have been seen in textured implants (Miranda RN, et al. J Clin Oncol 2014;32:114-120).
c Patients with T-cell lymphomas often have extranodal disease, which may be inadequately imaged by CT. PET scan may be preferred in these instances.
d Larger volume of fluid yields a more accurate diagnosis. If possible, obtain >50 mL for cytology and cell block; >10 mL for flow cytometry immunophenotype.
e Principles of Molecular Analysis in T-Cell Lymphomas (TCLYM-A).
f Jaffe E, et al. J Clin Oncol 2020;38:1102-1111.
g BIA-ALCL is usually ALK-negative but has a good prognosis.
h The FDA recommends reporting all BIA-ALCL cases to the PROFILE Registry: [Link]/PROFILE.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
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BIAA-1
The NCCN Evidence Blocks™ are subject to certain U.S. and foreign patents. Each approved use of the design of the NCCN Evidence Blocks™ requires the written approval of NCCN. Visit [Link]/patents for current list of applicable patents.
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Breast Implant-Associated ALCL Table of Contents
Discussion
NCCN Evidence BlocksTM
LYMPHOMA WORKUP TREATMENT FOLLOW-UP/ADDITIONAL
AND STAGINGi,j THERAPY
Clinical
• H&P for every 3–6 mo for
Complete 2 y and then as clinically
excision with indicated
• Surveillance imagingc (no
no residual more often than every
• Recommend discussion diseasem 6 mo for 2 y and then
of treatment options with annually for 5 y or as
multidisciplinary teamk • Total capsulectomy Localized clinically indicated)
• H&P examination, including and excision of disease to Incomplete
complete skin examination associated mass capsule/ Discuss adjuvant
excision
• CBC with differential with biopsy of implant/breast treatment options with
or Partial
• Comprehensive metabolic suspicious node(s), multidisciplinary team
capsulectomy
panel explantation • RTn for local residual
Histologic with residual
• LDH • Removal of disease ± systemic
confirmation disease ±
• Assessment of HTLV-1/2l by contralateral therapy (as listed below),
or suspicion regional
serology or other methods implantm if node positive or RT
of BIA-ALCLh lymph node
• FDG-PET/CT scanc • Consultation with not feasible
involvement
• Echocardiogram or MUGA surgical oncologist
scan if anthracycline-based recommended
regimen is indicated for patients with If CRo is
• Pregnancy testing in those preoperative tumor achieved after
Extended Consider systemic therapy
of childbearing potential mass systemic
disease - See Suggested Treatment
(if chemotherapy or RT is therapy, treat
(stage II–IV) Regimens (BIAA-A)
planned) as ALCL, ALK-
(PTCL-6)

c Patientswith T-cell lymphomas often have extranodal disease, which may be k Eg, medical oncologist/hematologist, surgical oncologist, plastic surgeon,
inadequately imaged by CT. PET scan may be preferred in these instances. hematopathologist.
h The FDA recommends reporting all BIA-ALCL cases to the PROFILE Registry: l See map for prevalence of HTLV-1/2 by geographic region. HTLV-1/2 has been
[Link]/PROFILE. described in patients in non-endemic areas.
i Proposed TNM Staging for Breast Implant–Associated Anaplastic Large-Cell m In approximately 4.6% of cases, lymphoma was found in the contralateral
Lymphoma (BIAA-B). breast (Clemens MW, et al. J Clin Oncol 2016;34:160-168).
j Bone marrow biopsy is only needed in selected cases (eg, extensive disease or n Principles of Radiation Therapy (TCLYM-D).
unexplained cytopenia). o Lugano Response Criteria for Non-Hodgkin Lymphoma (TCLYM-C).

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All recommendations are category 2A unless otherwise indicated.
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BIAA-2
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Breast Implant-Associated ALCL Table of Contents
Discussion
NCCN Evidence BlocksTM
SUGGESTED TREATMENT REGIMENS
(alphabetical order)

SYSTEMIC THERAPY
Preferred regimens
• Brentuximab vedotina,b
• Brentuximab vedotin + CHP (cyclophosphamide, doxorubicin, and prednisone)b

Other recommended regimens

• CHOP
• CHOEPc
• Dose-adjusted EPOCH

See Evidence Blocks on BIAA-A (EB-1)

References
Pro B, Advani R, Brice P, et al. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study.
J Clin Oncol 2012;30:2190-2196.
Pro B, Advani R, Brice P, et al. Five-year results of brentuximab vedotin in patients with relapsed or refractory systemic anaplastic large cell lymphoma. Blood
2017;130:2709-2717.
Horwitz S, O'Connor OA, Pro B, et al. The ECHELON-2 Trial: 5-year results of a randomized, phase III study of brentuximab vedotin with chemotherapy for CD30-
positive peripheral T-cell lymphoma. Ann Oncol 2022;33:288-298.

Footnotes
a Brentuximab vedotin may be appropriate for low-burden disease in selected patients.
b Supportive Care (TCLYM-B).
c Oral etoposide dose of 200 mg/m2 (PO dosing of etoposide is 2 x the IV dose) may be substituted on days 2 and 3 for IV etoposide. Consider splitting
the daily doses of oral etoposide over 200 mg.

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NCCN Guidelines Version 4.2024 5

4
E = Efficacy of Regimen/Agent
S = Safety of Regimen/Agent NCCN Guidelines Index
Breast Implant-Associated ALCL 3
2
Q = Quality of Evidence
C = Consistency of Evidence Table of Contents
A = Affordability of Regimen/Agent
Discussion
NCCN Evidence BlocksTM
1
E S Q C A

EVIDENCE BLOCKS FOR SYSTEMIC THERAPY FOR BIA-ALCL (EXTENDED DISEASE; STAGE II–IV)

Brentuximab vedotin

Brentuximab vedotin + CHP

CHOEP

CHOP

Dose-adjusted EPOCH

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® ® ®
EB-1
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Breast Implant-Associated ALCL Table of Contents
Discussion
NCCN Evidence BlocksTM
Proposed TNM Staging for Breast Implant–Associated Anaplastic Large-Cell Lymphoma1,2

TNM Description Stage Designation Description

T: tumor extent IA T1 N0 M0
IB T2 N0 M0
T1 Confined to effusion or a layer on luminal side of capsule
IC T3 N0 M0
T2 Early capsule infiltration
IIA T4 N0 M0
T3 Cell aggregates or sheets infiltrating the capsule
IIB T1–3 N1 M0
T4 Lymphoma infiltrates beyond the capsule
III T4 N1–2 M0
N: lymph node
IV T any N any M1
N0 No lymph node involvement
N1 One regional lymph node (+)
N2 Multiple regional lymph nodes (+)
M: metastasis

M0 No distant spread
M1 Spread to other organs/distant sites

1 Clemens MW, Medeiros LJ, Butler CE, et al. Complete surgical excision is essential for the management of patients with breast implant-associated
anaplastic large-cell lymphoma. J Clin Oncol 2016;34:160-168.
2 Bilateral breast implantation for ALCL is not considered in this staging system. Complete excision of bilateral disease may be recommended if it is
determined that 2 independent primaries are present (one on each side). Pathologic staging should be assessed in both sides. Identification of clonal
abnormalities in bilateral cases is desirable and may help in determining if the disease represents metastasis.

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T-Cell Large Granular Lymphocytic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
OVERVIEW AND DEFINITION OF T-CELL LARGE GRANULAR LYMPHOCYTIC LEUKEMIA (LGLL)

• LGLL is an indolent T-cell lymphoproliferative disorder (LPD) of the mature cytotoxic lymphocytes of effector memory cell phenotype. Most
cases have an indolent and non-progressive clinical course, and moderate to severe autoimmune neutropenia is a frequent laboratory
abnormality. Thrombocytopenia and anemia are less common and may accompany neutropenia leading to bilineage or trilineage
cytopenias.
• There is significant clinical and pathophysiologic overlap with autoimmune syndromes, and in the majority of patients, LGLL is
diagnosed concurrently with rheumatologic disease (ie, rheumatoid arthritis [RA] and systemic lupus erythematosus [SLE]) suggesting
immunogenetic polymorphism is a mutual origin. Persistent large granular lymphocytosis (LGL) can also accompany other chronic
autoimmune conditions such as Crohn’s disease, Sjogren’s syndrome, and psoriatic arthritis. It is therefore unclear, especially in
patients with indolent non-progressive clinical course, whether the disease represents true malignant process or persistent maladaptive
autoimmune response to autoantigens on hematopoietic elements with resultant autoimmune cytopenias.
• The diagnosis is generally established based on the persistence (>6 months) of LGL with typical morphologic features (moderate to
copious cytoplasm with prominent azurophilic granules) in the peripheral blood and the bone marrow of the patients (>2000/uL), and
exclusion of other potential conditions or illnesses where LGL is part of the pathologic process (ie, viral infections, other malignancies,
rheumatologic disease). Mild splenomegaly is common, but significant splenic enlargement should trigger investigation of other etiologies.
The degree of blood and bone marrow involvement do not necessarily correlate with disease severity or the grade of cytopenias.
• The TCR clonality studies may demonstrate oligoclonal or monoclonal pattern that does not correlate with disease aggressiveness. T-cell
LGLLs (T-LGLLs) frequently demonstrate normal antigenic profile and express CD2, CD3, CD8, CD57, and TCRαß; in most cases, cells
express cytotoxic markers TIA1, granzyme B, and granzyme M. In rare cases, LGLLs are CD4+ alpha-beta T cells or gamma-delta T cells
(CD8+ or CD4-/CD8-).
• Characteristic genetic features found in approximately 30% of LGLL cases are activating somatic STAT3 mutations affecting the SH2
domain; the majority of the mutations are heterozygous. STAT5B SH2 mutations have also been reported.
• Main differential diagnosis includes HSTCL, aggressive NK-cell leukemia (ANKL) (ENKL-C), EBV-positive T-cell and NK-cell
lymphoproliferative diseases of childhood, and reactive gamma-delta T-cell proliferations.

Diagnosis and Workup (LGLL-1)

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LGLL-INTRO
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T-Cell Large Granular Lymphocytic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
DIAGNOSISa,b WORKUP
ESSENTIAL:
ESSENTIAL:c,d • H&P examination: Evaluation of enlarged spleen, liver;
• Peripheral blood smear analysis for cytology; presence presence of lymphadenopathy (rare)
of large granular lymphocytes characterized by reniform • Presence of autoimmune diseasec (especially RA and SLE)
or round nucleus and abundant cytoplasm containing • Performance status
azurophilic granules • CBC with differential
• Peripheral blood flow cytometry with adequate • Comprehensive metabolic panel
immunophenotyping to establish diagnosise • Pregnancy testing in those of childbearing potential (if
Cell surface marker analysis by flow cytometry may chemotherapy or RT is planned) Indication
include: CD3, CD4, CD5, CD7, CD8, CD56, CD57, TCRαß, for
TCRγδ USEFUL IN CERTAIN CIRCUMSTANCES Treatment
• Serological markers for autoimmune diseasec (LGLL-2)
USEFUL IN CERTAIN CIRCUMSTANCES: • HIV testing
• Bone marrow aspirate and biopsyf • Hepatitis B and C testing
IHC panel may include: CD3, CD4, CD5, CD7, CD8, CD56, • CMV serology if therapy with alemtuzumab is contemplated
CD57, TCRβ, TCRɣ, TIA1, perforin, granzyme B • Consider quantitative EBV PCR
• Mutational analysis: STAT3 and STAT5B • Assessment of HTLV-1/2h by serology or other methods
• Molecular analysis to detect clonal TCR gene • Ultrasound of liver/spleen
rearrangements or other assessment of clonalityg • C/A/P CT with contrast of diagnostic quality
• EBER-ISH • Echocardiogrami
• Discuss fertility preservationj
e Typical
immunophenotype for T-LGLL: CD3+, CD8+, CD16+, CD57+, CD56+/-, CD28,
CD5 dim, and/or CD7 dim, CD45RA+, CD62L-, TCRαβ+, TIA1+, granzyme B+, or
granzyme M+. Overlap with reactive LGL is frequent.
f Typically needed to confirm diagnosis; essential for cases with low large granular
a Approximately 10% of LGLL cases will be of the NK-cell subtype (chronic lymphocyte counts (<0.5 × 109/L) and cases suspicious for concurrent bone marrow
LPD of NK cells [ICC]; NK-large granular lymphocytic leukemia [WHO5]). failure disorders.
These are treated with a similar approach to T-LGLL. g Clonal TCR gene rearrangements alone are not sufficient for diagnosis, as these can also
b Principles of Molecular Analysis in T-Cell Lymphomas (TCLYM-A). be seen in patients with non-malignant conditions. Results should be interpreted in the
c Autoimmune disorders (especially RA and SLE) can occur in patients with context of overall presentation. See Principles of Molecular Analysis in T-Cell Lymphomas
T-LGLL. Small, clinically non-significant clones of T-LGLLs can be detected (TCLYM-A).
concurrently in patients with bone marrow failure disorders. h See map for prevalence of HTLV-1/2 by geographic region. HTLV-1/2 has been described
d Rule out reactive LGL lymphocytosis. Repeat peripheral blood flow in patients in non-endemic areas.
cytometry and clonal TCR gene rearrangement studies in 6 months i In patients with unexplained shortness of breath and/or right heart failure.
in asymptomatic patients with small clonal arge granular lymphocyte j Fertility preservation options include: sperm banking, semen cryopreservation, IVF, or
populations (<0.5 × 109/L) or polyclonal LGL. ovarian tissue or oocyte cryopreservation.

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All recommendations are category 2A unless otherwise indicated.
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T-Cell Large Granular Lymphocytic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
INDICATION FOR FIRST-LINE RESPONSE ADDITIONAL SECOND-LINE
TREATMENT THERAPYn (at 4 mo) THERAPY/ THERAPY
FOLLOW-UP

• ANC <0.5 x 109/L No

indication Observe
• Hemoglobin <10 g/dL or
need for red blood cell
(RBC) transfusion • Preferred
• Platelets <50 x 109/L Clinical trial • Preferred
• Autoimmune diseases Low-dose Continue Clinical trial
with T-LGLLs requiring methotrexate ± treatment or Ruxolitinibs (if
therapyk corticosteroidso CR/PRp,q not previously
intermittent
• Symptomatic Oral therapy used)
splenomegaly cyclophosphamide Progressive Purine
• Severe B symptomsl Indication ± corticosteroidso or refractory analogues t,u
• Pulmonary artery present Cyclosporineo ± disease to all • Other
hypertension secondary corticosteroids Alternate first- first-line recommended
to LGLLm Management line therapy therapies Alemtuzumabr
• ANC <1500 with of underlying No or if not used
documented T-LGLL and cytopenia(s) alone responseq Alemtuzumabr previously
recurrent infections may be appropriate or
See Evidence Blocks on LGLL-2A
in certain Ruxolitinibs CR/PRp,q See above
circumstances q Limit therapy with cyclophosphamide to 4 mo if no response and consider
k Treat underlying autoimmune disease. limiting to ≤12 mo if PR observed at 4 mo due to increased risk of
l Exclude underlying associated malignancy, viral syndrome, or autoimmune disease. bladder toxicity, mutagenesis, and leukemogenesis (Lamy T, et al. Blood
m Grossi O, et al. Euro Respir J 2012;39:493-494. 2011;117:2764-2774).
n Monitoring for cumulative toxicity is recommended for long-term use with r While alemtuzumab is no longer commercially available, it may be obtained
methotrexate. for clinical use. Low-dose alemtuzumab is typically used for LGLL (Dumitriu
o Methotrexate with or without steroids may be beneficial in patients with B, et al. Lancet Haematol 2016;3:e22-e29). CMV monitoring or prophylaxis is
autoimmune disease; cyclophosphamide or cyclosporine may be used as a first- or recommended (TCLYM-B).
second-line option in patients with anemia (Lamy T, et al. Blood 2011;117:2764- s In the phase II studies, ruxolitinib was dosed at 20 mg BID. Due to the
2774; Braunstein Z, et al. Blood Adv 2022;6:2685-2687). prevalence of cytopenias in patients with LGLL, dose reductions to 10 or
p CR is defined as: recovery of blood counts to Hgb >12 g/dL, ANC >1.5 x 109/L, 5 mg BID can be considered. Frequent CBC monitoring is recommended.
platelet >150 x 109/L, resolution of lymphocytosis (<4 x 109/L), and circulating (Moskowitz A, et al. Blood 2021;138:2828-2837; Moskowitz A, et al. Blood
LGLL counts within normal range (<0.5 x 109/L). PR is defined as: recovery of 2023;142:Abstract 183)
hematologic parameters to Hgb >8 g/dL, ANC >0.5 x 109/L, platelet >50 x 109/L, t Supportive Care (TCLYM-B).
and absence of transfusions (Bareau B, et al. Hematologica 2010;95:1534-1541). u Pentostatin, cladribine, and fludarabine have been used in LGLL.

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NCCN Guidelines Version 4.2024 5 E = Efficacy of Regimen/Agent

4 S = Safety of Regimen/Agent
NCCN Guidelines Index
T-Cell Large Granular Lymphocytic Leukemia 3
2
Q = Quality of Evidence
C = Consistency of Evidence
A = Affordability of Regimen/Agent Table of Contents
NCCN Evidence BlocksTM
1
E S Q C A Discussion

EVIDENCE BLOCKS FOR THE TREATMENT OF T-CELL LARGE GRANULAR LYMPHOCYTIC LEUKEMIA

Second-line Therapy
First-line
Regimen No response after Progressive or
Therapy
first-line therapy refractory disease

Low-dose methotrexate —

Low-dose methotrexate + corticosteroid —

Cyclophosphamide —

Cyclophosphamide + corticosteroid —

Cyclosporine —

Cyclosporine + corticosteroid —

Ruxolitinib — * *

Pentostatin — —

Cladribine — —

Fludarabine — —

Alemtuzumab —

*Evidence Block development in progress

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T-Cell Prolymphocytic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
DIAGNOSISa,b WORKUP

ESSENTIAL:
• H&P examination, including complete skin
examination, and evaluation of lymph nodes,
ESSENTIAL: spleen, and liver
• Tissue histology not essential for diagnosis • Performance status
• Peripheral blood smear analysis for • LDH
morphology • CBC with differential Observe until
• Peripheral blood flow cytometry with adequate • Comprehensive metabolic panel Asymptomatic progression
immunophenotyping to establish diagnosisc • Assessment of HTLV-1/2e by serology or other diseaseh or
Cell surface marker analysis may include: methods symptomatic
TdT, CD1a, CD2, CD3, CD4, CD5, CD7, CD8, • FDG-PET/CT scanf and/or C/A/P CT with contrast
CD52, TCRαβ, TCL1 • Pregnancy testing in those of childbearing
• Cytogenetics (fluoresence in situ hybridization potential (if chemotherapy or RT is planned)
[FISH] and karyotype): inv(14)(q11;q32);
t(14;14)(q11;q32); t(X;14)(q28;q11); trisomy 8 USEFUL IN CERTAIN CIRCUMSTANCES
• Echocardiogram or MUGA scan if treatment
USEFUL IN CERTAIN CIRCUMSTANCES: includes regimens containing anthracyclines or
• Molecular analysis to detect clonal TCR gene anthracenediones Symptomatic
disease TPLL-2
rearrangements or other assessment of • Bone marrow evaluation
clonalityd • HIV testing
• Bone marrow aspirate and biopsy • Hepatitis B and C testing
IHC panel may include: CD1a, TdT, CD2, CD3, • Consider screening for active infections and
CD5, TCL1 cytomegalovirus (CMV) serology if therapy with
alemtuzumab is contemplated
• Human leukocyte antigen (HLA) typing
• Discuss fertility preservationg
a Diagnostic Criteria for TPLL (TPLL-A).
b Principles of Molecular Analysis in T-Cell Lymphomas (TCLYM-A).
c Typical immunophenotype: CD1a-, TdT-, CD2+, sCD3+/-, cCD3+/-, CD5+, CD7++, CD52++, TCRαß+, CD4+/CD8- (65%), CD4+/CD8+ (21%), CD4-/CD8+ (13%).
d Clonal TCR gene rearrangements alone are not sufficient for diagnosis, as these can also be seen in patients with non-malignant conditions. Results should be
interpreted in the context of overall presentation. See Principles of Molecular Analysis in T-Cell Lymphomas (TCLYM-A).
e See map for prevalence of HTLV-1/2 by geographic region. HTLV-1/2 has been described in patients in non-endemic areas.
f Patients with T-cell lymphomas often have extranodal disease, which may be inadequately imaged by CT. PET scan may be preferred in these instances.
g Fertility preservation options include: sperm banking, semen cryopreservation, IVF, or ovarian tissue or oocyte cryopreservation.
h In a minority of patients, the disease may be asymptomatic and can follow an indolent course of variable duration. In these selected cases expectant observation is a
reasonable option.

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All recommendations are category 2A unless otherwise indicated.
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TPLL-1
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T-Cell Prolymphocytic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
SYMPTOMATIC FIRST-LINE INITIAL CONSOLIDATION SECOND-LINE
DISEASE THERAPY RESPONSEi THERAPY

Relapse
Consider
or
CR or PR allogeneic
Progressive
HCTj
disease
Symptomatic First-line therapy;
disease See Suggested Regimens (TPLL-B)

No response Second-line therapy;

or progressive See Suggested Regimens
disease (TPLL-B)

i Response Criteria for TPLL (TPLL-C).

j Consider autologous HCT, if a suitable donor is not available.

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All recommendations are category 2A unless otherwise indicated.
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TPLL-2
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T-Cell Prolymphocytic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
DIAGNOSTIC CRITERIA FOR T-CELL PROLYMPHOCYTIC LEUKEMIA (T-PLL)a
• The diagnosis of T-PLL is established if all 3 major criteria are met or if the first 2 major criteria and 1 minor criterion are met.

Major Criteria Minor Criteria (at least 1 required)

• >5 x109/L cells of T-PLL phenotype in peripheral blood or

• Abnormalities involving chromosome 11 (11q22.3; ATM)
bone marrow

• T-cell clonality (by PCR for TRB/TRG, or by flow

• Abnormalities in chromosome 8: idic(8)(p11), t(8;8), trisomy 8q
cytometry)

• Abnormalities of 14q32 or Xq28 OR expression of • Abnormalities in chromosomes 5, 12, 13, 22, or complex karyotype
TCL1A/B, or MTCP1* • Involvement of T-PLL–specific site (eg, splenomegaly, effusions)

*Cases without TCL1A, TCL1B, or MTCP1 rearrangement or their respective overexpression are collected as TCL1-family negative T-PLL.

a StaberP, Herling M, Bellido M, et al. Consensus criteria for diagnosis, staging, and treatment response assessment of T-cell prolymphocytic leukemia. Blood
2019;134:1132-1143.

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TPLL-A
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T-Cell Prolymphocytic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
SUGGESTED TREATMENT REGIMENSa,b

FIRST-LINE THERAPY SECOND-LINE THERAPY OR SUBSEQUENT THERAPY

Preferred regimens Preferred regimens
• Clinical trial • Clinical trial
• Alemtuzumab (IV) alonec,d • Pentostatin

Other recommended regimensc,d Other recommended regimens

• FMC (fludarabine, mitoxantrone, cyclophosphamide) followed by • Alternate regimens not used in first-line therapy
alemtuzumab (IV) in selected patients • Ruxolitinib
• Alemtuzumab (IV) and pentostatin in selected patients
Useful in certain circumstances
• Retreatment with alemtuzumabd (IV) ± pentostatin (if CD52
expression is still positive and relapse after a period of
remission following first-line therapy)

See Evidence Blocks on TPLL-B (EB-1)

a See references for regimens on TPLL-B 2 of 2.

b Consider prophylaxis for TLS (TCLYM-B).
c IV infusion is preferred over SC delivery based on
data showing inferior activity with SC delivery in patients with T-PLL (Dearden CE, et al. Blood 2011;118:5799-
5802).
d While alemtuzumab is no longer commercially available, it may be obtained for clinical use. CMV monitoring or prophylaxis is recommended (TCLYM-B).

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TPLL-B
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4
E = Efficacy of Regimen/Agent
S = Safety of Regimen/Agent NCCN Guidelines Index
T-Cell Prolymphocytic Leukemia 3
2
Q = Quality of Evidence
C = Consistency of Evidence Table of Contents
A = Affordability of Regimen/Agent
Discussion
NCCN Evidence BlocksTM
1
E S Q C A

EVIDENCE BLOCKS FOR THE TREATMENT OF T-CELL PROLYMPHOCYTIC LEUKEMIA

Second-line
Regimen Primary Treatment
Therapy

Alemtuzumab (IV)

FMC (fludarabine, mitoxantrone,

cyclophosphamide) followed by IV
alemtuzumab

Alemtuzumab (IV) and pentostatin

Pentostatin —

Ruxolitinib —

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T-Cell Prolymphocytic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
REFERENCES

Alemtuzumab
Dearden CE, Matutes E, Cazin B, et al. High remission rate in T-cell prolymphocytic leukemia with CAMPATH-1H. Blood 2001;98:1721-1726.
Keating MJ, Cazin B, Coutre S, et al. Campath-1H treatment of T-cell prolymphocytic leukemia in patients for whom at least one prior chemotherapy regimen has failed.
J Clin Oncol 2002;20:205-213.
Dearden CE, Khot A, Else M, et al. Alemtuzumab therapy in T-cell prolymphocytic leukaemia: Comparing efficacy in a series treated intravenously and a study piloting
the subcutaneous route. Blood 2011;118:5799-5802.

Alemtuzumab + pentostatin
Ravandi F, Aribi A, O'Brien S, et al. Phase II study of alemtuzumab in combination with pentostatin in patients with T-cell neoplasms. J Clin Oncol 2009;27:5425-5430.

FMC (fludarabine, mitoxantrone, cyclophosphamide) followed by alemtuzumab

Hopfinger G, Busch R, Pflug N, et al. Sequential chemoimmunotherapy of fludarabine, mitoxantrone, and cyclophosphamide induction followed by alemtuzumab
consolidation is effective in T-cell prolymphocytic leukemia. Cancer 2013;119:2258-2267.

Pentostatin
Döhner H, Ho AD, Thaler J, et al. Pentostatin in prolymphocytic leukemia: phase II trial of the European Organization for Research and Treatment of Cancer Leukemia
Cooperative Study Group. J Natl Cancer Inst 1993;85:658-662.

Ruxolitinib
Moskowitz AJ, Ghione P, Jacobsen E, et al. A phase 2 biomarker-driven study of ruxolitinib demonstrates effectiveness of JAK/STAT targeting in T-cell lymphomas.
Blood 2021;138:2828-2837.

Allogeneic HCT
Castagna L, Nozza A, Bertuzzi A, et al. Allogeneic peripheral blood stem cell transplantation with reduced intensity conditioning in primary refractory prolymphocytic
leukemia: graft-versus-leukemia effect without graft-versus-host disease. Bone Marrow Transplant 2001;28:1155-1156.
Kalaycio ME, Kukreja M, Woolfrey AE, et al. Allogeneic hematopoietic cell transplant for prolymphocytic leukemia. Biol Blood Marrow Transplant 2010;16:543-547.
Murase K, Matsunaga T, Sato T, et al. Allogeneic bone marrow transplantation in a patient with T-prolymphocytic leukemia with small-intestinal involvement. Int J Clin
Oncol 2003;8:391-394.
Wiktor-Jedrzejczak W, Dearden C, de Wreede L, et al. Hematopoietic stem cell transplantation in T-prolymphocytic leukemia: A retrospective study from the European
Group for Blood and Marrow Transplantation and the Royal Marsden Consortium. Leukemia 2012;26:972-976.
Krishnan B, Else M, Tjonnfjord G, et al. Stem cell transplantation after alemtuzumab in T-cell prolymphocytic leukaemia results in longer survival than after alemtuzumab
alone: a multicentre retrospective study. Br J Haematol 2010;149:907-910.

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T-Cell Prolymphocytic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
RESPONSE CRITERIA FOR T-PLLa
Group and Parameter CR (all met) PR (≥2 in A and ≥1 in B) SD (all met) PD (≥1 in A or B met)
Group A
Long-axis diameters to
Lymph nodes Decrease ≥30% in SLD Change of – <30% to + ≤20% Increase >20% in SLD
<1.0 cm
Decrease ≥50% in vertical Change of –49% to +49% Increase ≥50% in vertical
Spleen size Spleen size <13 cm length beyond normal from beyond normal from length beyond normal from
baseline baseline baseline
Constitutional symptoms None Any Any Any
Circulating lymphocyte ≤30 x 10 /L and decrease
9
>30 x 10 /L or change of
9
Increase ≥50% from baseline
<4 x 109/L
count ≥50% from baseline –49% to +49%
T-PLL cells <5% of
Marrow Any Any Any
mononuclear cells
Any other specific site
None Any Any Any
involvement*
Group B
≥100 x 109/L or increase ≥50%
Platelet count ≥100 x 109/L Change of –49% to +49% Decrease ≥50% over baseline
from baseline
≥11 g/dL or increase ≥50% 11.0 g/dL or <50% from Decrease of ≥2 g/dL from
Hemoglobin ≥11.0 g/dL (untransfused)
from baseline baseline, or change <2 g/dL baseline
≥1.5 x 109/L or increase ≥50% Decrease of ≥50% from
Neutrophils ≥1.5 x 109/L Change of –49% to +49%
from baseline baseline

CR, all of the criteria have to be met; CRi, all CR criteria of group A are met but at least 1 in B is not achieved;
PR, at least 2 parameters of group A and 1 of group B need to improve if previously abnormal;
PD, at least 1 of the criteria of group A or group B has to be met; SD, all the criteria have to be met, constitutional symptoms alone do not define PD;
SLD, sum of long-axis diameters of up to 3 target lesions.
*Pleural or peritoneal effusion, skin infiltration, or CNS involvement.

a StaberP, Herling M, Bellido M, et al. Consensus criteria for diagnosis, staging, and treatment response assessment of T-cell prolymphocytic leukemia. Blood
2019;134:1132-1143.

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Adult T-Cell Leukemia/Lymphoma Table of Contents
Discussion
NCCN Evidence BlocksTM
DIAGNOSISa WORKUP ATLL
ESSENTIALb: SUBTYPEd
• CBC with differential and peripheral blood smear ESSENTIAL:
for atypical cellsc: lymphocytosis (ALC >4000/µL in • H&P examination, including complete skin
adults) in acute and chronic subtypesd examination
• Peripheral blood flow cytometry with adequate • Comprehensive metabolic panel
• LDH Smoldering
immunophenotyping to establish diagnosise subtype (ATLL-2)
• Serology for strongyloides
• Cell surface marker analysis by flow cytometry may • FDG-PET/CT scanj ± C/A/P/neck CT with contrast
include: CD2, CD3, CD4, CD5, CD7, CD8, CD25, CD30, • Pregnancy testing in those of childbearing Chronic subtype
TCRαß potential (if chemotherapy or RT is planned) (ATLL-3)
• Assessment of HTLV-1/2 by serology or other USEFUL IN CERTAIN CIRCUMSTANCES:
methodsf • HIV testing
• Hepatitis B and C testing
USEFUL IN CERTAIN CIRCUMSTANCES: • CRP, soluble interleukin-2 receptor (sIL-2R),
• Biopsy of lymph nodes (excisional), skin biopsy, GI serum albumin, and blood urea nitrogen (BUN) Acute subtype
tract, or bone marrow biopsyg is required if: • Upper gastrointestinal endoscopy (ATLL-4)
Diagnosis is not established on peripheral blood, or • Echocardiogram or MUGA scan if anthracycline-
Ruling out an underlying infection (eg, tuberculosis, based regimen is indicated
• CNS evaluation: Head CT or MRI with contrast Lymphoma subtype
histoplasmosis, toxoplasmosis) (ATLL-4)
and/or lumbar puncture in all patients with
• If biopsy performed, the recommended panel for acute or lymphoma subtypes or in patients with
paraffin section IHC is as followse,h,i: CD3, CD4, CD5, neurologic manifestations
CD7, CD8, CD25, CD30 • Uric acid
• Cell surface marker analysis by flow cytometry for • HLA typing
CCR4 • Discuss fertility preservationk
• Consider NGS panel
a Principles of Molecular Analysis in T-Cell Lymphomas (TCLYM-A). f See map for prevalence of HTLV-1/2 by geographic region. HTLV-1/2 has been
b The diagnosis of ATLL requires peripheral blood cytology or tissue histopathology described in patients in non-endemic areas.
and immunophenotyping of tumor lesion, or morphology and immunophenotyping g Bone marrow involvement is an independent poor prognostic factor.
of peripheral blood and HTLV-1 serology. h Use of Immunophenotyping/Genetic Testing in Differential Diagnosis of Mature
c Typical ATLL cells (“flower cells”) have distinctly polylobated nuclei with B-Cell and NK/T-Cell Neoplasms (TCLYM-E).
homogeneous and condensed chromatin, small or absent nucleoli, and i Usually CD4+ T cells with expression of CD2, CD5, CD25, CD45RO, CD29,
agranular and basophilic cytoplasm, but multiple morphologic variations can be T-cell receptor αβ, and HLA-DR. Most cases are CD7- and CD26- with low
encountered. Presence of ≥5% atypical cells by morphology in peripheral blood is CD3 expression. Rare cases are CD8+ or CD4/CD8 double positive or double
required for diagnosis of blood involvement in the absence of other criteria. negative.
d Diagnostic Criteria for ATLL (ATLL-A). j Patients with T-cell lymphomas often have extranodal disease, which may be
e Typical immunophenotype: CD2+, CD3+, CD4+, CD5+, CD7-, CD8-, CD25+, inadequately imaged by CT. PET scan may be preferred in these instances.
CD30-/+, TCRαβ+. Presence of ≥5% T lymphocytes with an abnormal k Fertility preservation options include: sperm banking, semen cryopreservation,
immunophenotype in peripheral blood is required for diagnosis. IVF, or ovarian tissue or oocyte cryopreservation.

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ATLL-1
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Discussion
NCCN Evidence BlocksTM
ATLL SUBTYPEd FIRST-LINE THERAPY INITIAL RESPONSEo ADDITIONAL THERAPYl
(at 2 mo)

Asymptomatic Clinical trial

Symptomatic
(no skin lesions, no or
(see below)
opportunistic infections) Observation

Smoldering

Clinical trial
or Responsep Continue first-line treatment
Symptomatic Skin-directed therapies as clinically
(skin lesions, tumors, indicated (NCCN Guidelines for
opportunistic Primary Cutaneous Lymphomas - Clinical trial
infections) Mycosis Fungoides/Sézary Syndrome or
[MFSS-A]) Systemic therapy
or No responsep (Suggested Initial Therapy
Zidovudine and interferon l,m,n Regimens [ATLL-D])
or
Best supportive care (NCCN
Guidelines for Palliative Care)

d Diagnostic Criteria for ATLL (ATLL-A).

l Outside of a clinical trial, if the disease
is not responding or is progressing, treatment with zidovudine and interferon should be stopped. If there is evidence of clinical
benefit, treatment should continue until best response is achieved. If life-threatening manifestations, treatment can be discontinued before the 2-month period.
m See references for zidovudine and interferon (ATLL-D 2 of 2).
n Peginterferon alfa-2a is the only alpha interferon available for clinical use in the United States and it may be substituted for other alpha interferon preparations (Schiller
M, et al. J Eur Acad Dermatol Venerol 2017;31:1841-1847; Patsatsi A, et al. J Eur Acad Dermatol Venereol 2022;36:e291-e293; Osman S, et al. Dermatologic Therapy
2023;2023:7171937).
o If nodal disease is present, repeat C/A/P CT with contrast or FDG-PET/CT.
p See Response Criteria for ATLL (ATLL-B). Responders include CR, uncertified CR, and PR.

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ATLL-2
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Discussion
NCCN Evidence BlocksTM
ATLL SUBTYPEd FIRST-LINE THERAPY INITIAL RESPONSEo ADDITIONAL THERAPYl
(at 2 mo)
Low risk (sIL-
2R <1000 U/mL)/ Clinical trial
Intermediate risk (sIL- or
2R 1000-6000 U/mL) Zidovudine and interferon l.m.n
Responsep Continue first-line treatment

Clinical trial
Chronic or
Alternate systemic therapy
(Suggested Initial Therapy
No responsep Regimens [ATLL-D])
or
Clinical trial Best supportive care (NCCN
High risk Guidelines for Palliative Care)
or
(elevated LDH,
Zidovudine and interferon l,m,n Consider allogeneic HCT
low albumin, Responsep
or
high BUN, sIL-2R
Systemic therapy (Suggested
>6000 U/mL)
Initial Therapy Regimens Clinical trial
[ATLL-D]) or
No responsep Second-line therapy (ATLL-D)
or
Best supportive care (NCCN
Guidelines for Palliative Care)

d Diagnostic Criteria for ATLL (ATLL-A).

l Outside of a clinical trial, if the disease
is not responding or is progressing, treatment with zidovudine and interferon should be stopped. If there is evidence of clinical
benefit, treatment should continue until best response is achieved. If life-threatening manifestations, treatment can be discontinued before the 2-month period.
m See references for zidovudine and interferon (ATLL-D 2 of 2).
n Peginterferon alfa-2a is the only alpha interferon available for clinical use in the United States and it may be substituted for other alpha interferon preparations (Schiller
M, et al. J Eur Acad Dermatol Venerol 2017;31:1841-1847; Patsatsi A, et al. J Eur Acad Dermatol Venereol 2022;36:e291-e293; Osman S, et al. Dermatologic Therapy
2023;2023:7171937).
o If nodal disease is present, repeat C/A/P CT with contrast or FDG-PET/CT.
p See Response Criteria for ATLL (ATLL-B). Responses include CR, uncertified CR, and PR.

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ATLL-3
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Discussion
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ATLL SUBTYPEd,q FIRST-LINE THERAPY INITIAL RESPONSEo ADDITIONAL THERAPY RESPONSE
(after 2 cycles) ASSESSMENT
Continue first-line treatmentl
Clinical trial Responsep or
or Consider allogeneic HCT
Systemic therapy
(Suggested Initial Therapy Clinical trial
Acutes,t
Regimens [ATLL-D) or
or Alternate regimens not used in Consider
Zidovudine and first-line therapyl
or Responseo,p allogeneic
interferonl.m.n HCT
No responsep Second-line therapy (ATLL-D)
or
Best supportive care (NCCN
Guidelines for Palliative Care)

Clinical trial Continue first-line treatmentl

or Responsep or
Lymphomar,s,t Systemic therapy Consider allogeneic HCT
(Suggested Initial Therapy
Regimens [ATLL-D) Clinical trial
or Consider
No responsep Second-line therapy (ATLL-D) Responseo,p allogeneic
or HCT
Best supportive care (NCCN
Guidelines for Palliative Care)

n Peginterferon alfa-2a is the only alpha interferon available for clinical use in the United
States and it may be substituted for other alpha interferon preparations (Schiller M, et al.
J Eur Acad Dermatol Venerol 2017;31:1841-1847; Patsatsi A, et al. J Eur Acad Dermatol
d Diagnostic Criteria for ATLL (ATLL-A). Venereol 2022;36:e291-e293; Osman S, et al. Dermatologic Therapy 2023;2023:7171937).
l Outside of a clinical trial, if the disease
is not responding or is o If nodal disease is present, repeat C/A/P CT with contrast or FDG-PET/CT.
progressing within a 2-month period, treatment with zidovudine and p See Response Criteria for ATLL (ATLL-B). Responses include CR, uncertified CR, and PR.
interferon should be stopped. If there is evidence of clinical benefit, q Modified Prognostic Index for Aggressive ATLL (ATLL-C).
treatment should continue until best response is achieved. If life- r The long-term efficacy of initial therapies alone is limited. Allogeneic HCT may be a curative
threatening manifestations, treatment can be discontinued before option for some patients.
the 2-month period. s CNS disease is common and prophylaxis is recommended.
m See references for zidovudine and interferon (ATLL-D 2 of 2). t Antiviral therapy is not effective.

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ATLL-4
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DIAGNOSTIC CRITERIA FOR ATLL
Smoldering Chronic Lymphoma Acute

Anti-HTLV-1 antibody + + + +

Lymphocyte (x 109 /1/L) <4 ≥4a <4 *

Abnormal T lymphocytes ≥5% +b ≤1% +b

Flower cells of T-cell marker Occasionally Occasionally No +

LDH ≤1.5N ≤2N * *

Corrected Ca (mmol/1/L) <2.74 <2.74 * * * No essential qualification

except terms required for other
Histology-proven lymphadenopathy No * + * subtype(s).
** No essential qualification if other
Tumor lesion terms are fulfilled, but histology-
proven malignant lesion(s) is
Skin ** * * *
required in case abnormal T
Lung ** * * * lymphocytes are less than 5% in
peripheral blood.
Lymph node No * Yes *

Liver No * * *

Spleen No * * *

CNS No No * *

Bone No No * *

Ascites No No * *

Pleural effusion No No * *

GI tract No No * *
Shimoyama M and members of The Lymphoma Study Group. Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from
the Lymphoma Study Group (1984-87). Br J Haematol 1991;79:428-437.
a Accompanied by T lymphocytosis (3.5 x 109/1 or more).
b In case abnormal T lymphocytes are less than 5% in peripheral blood, histology-proven tumor lesion is required.

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ATLL-A
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Discussion
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RESPONSE CRITERIA FOR ATLLa

Lymph Extranodal Peripheral

Response Definition Spleen, Liver Skin Bone Marrow
Nodes Masses Blood

Complete Disappearance
Normal Normal Normal Normal Normal† Normal
remission* of all disease

Uncertified Stable residual

≥75% ≥75%
complete mass in bulky Normal Normal Normal† Normal
decrease‡ decrease‡
remission* lesion

Partial Regression of ≥50% ≥50% ≥50% ≥50%

No increase Irrelevant
remission* disease decrease‡ decrease‡ decrease decrease

Failure to attain
complete/partial
Stable No change in No change in No change in No change
remission and No change No change
disease* size size size in size
no progressive
disease

Relapsed
New or
disease or New or ≥50% New or ≥50% New or ≥50% ≥50% New or ≥50%
increased Reappearance
progressive increase§ increase§ increase increase increase#
lesions
disease

*Required that each criterion be present for a period of at least 4 weeks. §Defined by ≥50% increase from nadir in the sum of the products of
†Provided that <5% of flower cells remain, complete remission is judged to measurable disease.
have been attained if the absolute lymphocyte count, including flower cells, #Defined by ≥50% increase from nadir in the count of flower cells and an
is <4 x 109/L. absolute lymphocyte count, including flower cells, of >4 x 109/L.
‡Calculated by the sum of the products of the greatest diameters of measurable
disease.

a Tsukasaki K, Hermine O, Bazarbachi A, et al. Definition, prognostic factors, treatment, and response criteria of adult T-cell leukemia-lymphoma:
A proposal from an international consensus meeting. J Clin Oncol 2009;27:453-459.

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ATLL-B
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MODIFIED PROGNOSTIC INDEX FOR AGGRESSIVE ATLLa

RISK FACTORS RISK GROUPS

• Clinical subtype of acute ATLL Low 0–1

• CRP level ≥2.5 mg/dL Intermediate 2–3
• ECOG PS 2–4 High 4–5
• sIL-2R >5,000 U/mL
• Adjusted Ca level ≥12 mg/dL

a Used with permission of Fondazione Adolfo Ferrata ed Edoardo Storti from Fuji S, Yamaguchi T, Inoue Y, et al. Development of a modified prognostic index for
patients with aggressive adult T-cell leukemia-lymphoma aged 70 years or younger: possible risk-adapted management strategies including allogeneic transplantation.
Haematologica 2017;102:1258-1265.

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All recommendations are category 2A unless otherwise indicated.
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ATLL-C
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Adult T-Cell Leukemia/Lymphoma Table of Contents
Discussion
NCCN Evidence BlocksTM
SUGGESTED TREATMENT REGIMENSa,b

INITIAL THERAPY SECOND-LINE THERAPY OR SUBSEQUENT THERAPY

Preferred regimens (regimens in alphabetical order) Preferred regimens (regimens in alphabetical order)
• Clinical trial • Clinical trial
• Brentuximab vedotin + CHP (cyclophosphamide, doxorubicin, • Single agents
and prednisone) for CD30+ cases Brentuximab vedotin for CD30+ cases
• Dose-adjusted EPOCH (etoposide, prednisone, vincristine, Lenalidomided
cyclophosphamide, and doxorubicin) Mogamulizumabd,e
• Zidovudine and interferonc (acute, chronic, and symptomatic • Combination regimens
smoldering subtypes) DHA (dexamethasone and cytarabine) + platinum (carboplatin,
cisplatin, or oxaliplatin)
Other recommended regimens (alphabetical order) ESHA (etoposide, methylprednisolone, and cytarabine) +
• CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, platinum (cisplatin or oxaliplatin)
and prednisone) GDP (gemcitabine, dexamethasone, and cisplatin)
• HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and GemOx (gemcitabine and oxaliplatin)
dexamethasone) alternating with high-dose methotrexate and GVD (gemcitabine, vinorelbine, and liposomal doxorubicin)
cytarabine ICE (ifosfamide, carboplatin, and etoposide)
Zidovudine and interferonc (acute, chronic, and symptomatic
Useful in certain circumstances smoldering subtypes)
• CHOP (cyclophosphamide, doxorubicin, vincristine, and
prednisone) (unable to tolerate intensive regimen or non-CD30 Alternative regimens (alphabetical order)
expressing ATLL) • Single agents
Alemtuzumabf
Arsenic trioxide
See Evidence Blocks on ATLL-D (EB-1), ATLL-D (EB-2), Belinostat
and ATLL-D (EB-3) Bendamustine
Bortezomib
a See ATLL-D 2 of 2) for references for regimens. Gemcitabine
b See Supportive Care (TCLYM-B) for TLS prophylaxis and anti-infective Pralatrexate
prophylaxis. RT in selected cases with localized, symptomatic diseaseg
c Peginterferon alfa-2a is the only alpha interferon available for clinical use in the
United States and it may be substituted for other alpha interferon preparations e Higher responses have been observed in patients with leukemic disease. CCR4
(Schiller M, et al. J Eur Acad Dermatol Venerol 2017;31:1841-1847; Patsatsi gain-of-function mutations have been reported to be predictive of sensitivity to
A, et al. J Eur Acad Dermatol Venereol 2022;36:e291-e293; Osman S, et al. mogamulizumab treatment (Sakamoto Y, et al. Blood 2018;132;758-761).
Dermatologic Therapy 2023;2023:7171937). f While alemtuzumab is no longer commercially available, it may be obtained for clinical
d Lenalidomide and mogamulizumab may be associated with higher incidences of use. CMV monitoring or prophylaxis is recommended (TCLYM-B).
graft-versus-host disease (GVHD) after allogeneic HCT. g Principles of Radiation Therapy (TCLYM-D).

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
ATLL-D
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E = Efficacy of Regimen/Agent
S = Safety of Regimen/Agent NCCN Guidelines Index
Adult T-Cell Leukemia/Lymphoma 3
2
Q = Quality of Evidence
C = Consistency of Evidence Table of Contents
A = Affordability of Regimen/Agent
Discussion
NCCN Evidence BlocksTM
1
E S Q C A

EVIDENCE BLOCKS FOR INITIAL THERAPY

Symptomatic
Regimen Acute Chronic Lymphoma
smoldering

Brentuximab vedotin + CHP —

CHOEP —

CHOP —

Dose-adjusted EPOCH —

HyperCVAD alternating with high-dose methotrexate and cytarabine —

Zidovudine and interferon —

continued

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EB-1
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E = Efficacy of Regimen/Agent
S = Safety of Regimen/Agent NCCN Guidelines Index
Adult T-Cell Leukemia/Lymphoma 3
2
Q = Quality of Evidence
C = Consistency of Evidence Table of Contents
A = Affordability of Regimen/Agent
Discussion
NCCN Evidence BlocksTM
1
E S Q C A

EVIDENCE BLOCKS FOR SECOND-LINE AND SUBSEQUENT THERAPY

Regimen Acute Chronic Lymphoma

Alemtuzumab

Arsenic trioxide

Belinostat

Bendamustine

Bortezomib

Brentuximab vedotin

DHA (dexamethasone and cytarabine) + carboplatin

DHA (dexamethasone and cytarabine) + cisplatin

DHA (dexamethasone and cytarabine) + oxaliplatin

ESHA (etoposide, methylprednisolone, and cytarabine) + cisplatin

ESHA (etoposide, methylprednisolone, and cytarabine) + oxaliplatin

continued

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EB-2
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E = Efficacy of Regimen/Agent
S = Safety of Regimen/Agent NCCN Guidelines Index
Adult T-Cell Leukemia/Lymphoma 3
2
Q = Quality of Evidence
C = Consistency of Evidence Table of Contents
A = Affordability of Regimen/Agent
Discussion
NCCN Evidence BlocksTM
1
E S Q C A

EVIDENCE BLOCKS FOR SECOND-LINE AND SUBSEQUENT THERAPY

Symptomatic
Regimen Acute Chronic Lymphoma
smoldering

GDP (gemcitabine, dexamethasone, and cisplatin) —

Gemcitabine —

GemOx (gemcitabine and oxaliplatin) —

GVD (gemcitabine, vinorelbine, and liposomal doxorubicin) —

ICE (ifosfamide, carboplatin, and etoposide) —

Lenalidomide —

Mogamulizumab —

Pralatrexate —

Zidovudine and interferon —

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EB-3
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Discussion
NCCN Evidence BlocksTM
REFERENCES

Zidovudine and interferon Second-line Therapy or Subsequent Therapy

Bazarbachi A, Hermine O. Treatment with a combination of zidovudine and alpha- Alemtuzumab
interferon in naive and pretreated adult T-cell leukemia/lymphoma patients. J Acquir Sharma K, Janik JE, O'Mahony D, et al. Phase II study of alemtuzumab
Immune Defic Syndr Hum Retrovirol 1996;13 Suppl 1:S186-190. (CAMPATH-1) in patients with HTLV-1-associated adult T-cell leukemia/
Bazarbachi A, Plumelle Y, Carlos Ramos J, et al. Meta-analysis on the use of lymphoma. Clin Cancer Res 2017;23:35-42.
zidovudine and interferon-alfa in adult T-cell leukemia/lymphoma showing improved Arsenic trioxide
survival in the leukemic subtypes. J Clin Oncol 2010;28:4177-4183. Ishitsuka K, Suzumiya J, Aoki M, et al. Therapeutic potential of arsenic
Hermine O, Allard I, Levy V, et al. A prospective phase II clinical trial with the use of trioxide with or without interferon-alpha for relapsed/refractory adult T-cell
zidovudine and interferon-alpha in the acute and lymphoma forms of adult T-cell leukemia/lymphoma. Haematologica 2007;92:719-720.
leukemia/lymphoma. Hematol J 2002;3:276-282. Bortezomib
Hodson A, Crichton S, Montoto S, et al. Use of zidovudine and interferon alfa with Ishitsuka K, Utsunomiya A, Katsuya H, et al. A phase II study of bortezomib
chemotherapy improves survival in both acute and lymphoma subtypes of adult in patients with relapsed or refractory aggressive adult T-cell leukemia/
T-cell leukemia/lymphoma. J Clin Oncol 2011;29:4696-4701. lymphoma. Cancer Sci 2015;106:1219-1223.
White JD, Wharfe G, Stewart DM, et al. The combination of zidovudine and interferon Brentuximab vedotin
alpha-2B in the treatment of adult T-cell leukemia/lymphoma. Leuk Lymphoma Horwitz SM, Advani RH, Bartlett NL, et al. Objective responses in
2001;40:287-294. relapsed T-cell lymphomas with single-agent brentuximab vedotin. Blood
Initial Therapy 2014;123:3095-3100.
Brentuximab vedotin + CHP (cyclophosphamide, doxorubicin, and prednisone) Lenalidomide
Horwitz S, O'Connor OA, Pro B, et al. Brentuximab vedotin with chemotherapy for Ishida T, Fujiwara H, Nosaka K, et al. Multicenter phase II study of
CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, lenalidomide in relapsed or recurrent adult T-cell leukemia/lymphoma:
randomised, phase 3 trial. Lancet 2019;393:229-240. ATLL-002. J Clin Oncol 2016;34:4086-4093.
CHOP Mogamulizumab
Taguchi H, Kinoshita KI, Takatsuki K, et al. An intensive chemotherapy of adult T-cell Ishida T, Utsunomiya A, Jo T, et al. Mogamulizumab for relapsed adult T-cell
leukemia/lymphoma: CHOP followed by etoposide, vindesine, ranimustine, and leukemia-lymphoma: Updated follow-up analysis of phase I and II studies.
mitoxantrone with granulocyte colony-stimulating factor support. J Acquir Immune Cancer Sci 2017;108:2022-2029.
Defic Syndr Hum Retrovirol 1996;12:182-186. Phillips AA, Fields PA, Hermine O, et al. Mogamulizumab versus
Tsukasaki K, Utsunomiya A, Fukuda H, et al. VCAP-AMP-VECP compared with investigator's choice of chemotherapy regimen in relapsed/refractory adult
biweekly CHOP for adult T-cell leukemia-lymphoma: Japan Clinical Oncology Group T-cell leukemia/lymphoma. Haematologica 2019;104:993-1003.
Study JCOG9801. J Clin Oncol 2007;25:5458-5464. Pralatrexate
Dose-adjusted EPOCH Lunning MA, Gonsky J, Ruan J, et al. Pralatrexate in relapsed/refractory
Ratner L, Harrington W, Feng X, et al. Human T-cell leukemia virus reactivation with HTLV-1 associated adult T-cell lymphoma/leukemia: A New York City multi-
progression of adult T-cell leukemia-lymphoma. PLoS ONE 2009;4:e4420. institutional experience [abstract]. Blood 2012;120:Abstract 2735.
Ratner L, Rauch D, Abel H, et al. Dose-adjusted EPOCH chemotherapy with
bortezomib and raltegravir for human T-cell leukemia virus-associated adult T-cell
leukemia lymphoma. Blood Cancer J 2016;6:e408. See PTCL-B (8 of 8) for references for combination regimens.
HyperCVAD
Alduaij A, Butera JN, Treaba D, Castillo J. Complete remission in two cases of
adult T-cell leukemia/lymphoma treated with hyper-CVAD: a case report and
review of the literature. Clin Lymphoma Myeloma Leuk 2010;10:480-483.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
ATLL-D
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Hepatosplenic T-Cell Lymphoma Table of Contents
Discussion
NCCN Evidence BlocksTM
OVERVIEW AND DEFINITION OF HEPATOSPLENIC T-CELL LYMPHOMA (HSTCL)a,b
• HSTCL is a rare, systemic, mature T-cell malignancy most often characterized by spleen, liver, and bone marrow involvement and an
aggressive clinical course. Bulky lymphadenopathy is uncommon.
• The disease predominantly affects patients assigned male at birth with a median age of 35 years. Up to 20% of cases arise in chronic
immune suppression. Patients frequently present with systemic symptoms, hepatosplenomegaly, cytopenias, and sometimes
hemophagocytic lymphohistiocytosis (HLH).
• The diagnosis is most frequently reached by histologic examination of a bone marrow biopsy, and/or a liver biopsy or splenectomy. On
bone marrow histology the neoplastic T cells may be difficult to identify, and IHC is required for the diagnosis.
• The neoplastic cells are cytotoxic T cells, frequently with surface expression of TCRɣẟ, and typically show the following phenotype:
CD2+, CD3+, CD4-, CD5-, CD8-/+, CD56+/-, TIA1+, granzyme B-. A small subset express TCRαβ, which is described as a variant of HSTCL.
• A TCRɣ gene rearrangement on molecular analysis reflects clonality of the T cell, but may be seen in alpha/beta or gamma/delta-
expressing T cells and is NOT necessarily synonymous with a gamma/delta T-cell lymphoma.
• Characteristic genetic features include isochromosome 7q, trisomy 8, activating mutations of JAK/STAT pathway (ie, STAT5B, STAT3),
and chromatin-modifying genes (ie, SETD2, INO80, ARID1B).c
• Main differential diagnosis includes gamma/delta-expressing T-LGLL, reactive gamma/delta T-cell proliferations, ANKL, EBV-positive
T-cell and NK-cell lymphoproliferative diseases of childhood, and, rarely, other T-cell lymphomas that may have gamma/delta expression.
• Long-term remission is primarily or exclusively seen in those who have undergone consolidative HCT.

Diagnosis (HSTCL-1)

a Krishnan M, Lunning M. Hepatosplenic γ-δ T-cell lymphoma: Who is on your speed dial? J Oncol Pract 2019;15:307-312.
b Pro B, Allen PB, Behdad A. Hepatosplenic T-cell lymphoma: A rare but challenging entity. Blood 2020;136:2018-2026.
c McKinney M, Moffitt AB, Gaulard P, et al. The genetic basis of hepatosplenic T-cell lymphoma. Cancer Discov 2017;7:369-379.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
HSTCL-INTRO
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Hepatosplenic T-Cell Lymphoma Table of Contents
Discussion
NCCN Evidence BlocksTM
DIAGNOSISa,b
ESSENTIAL:
• Review of all slides with at least one paraffin block representative of the tumor should be done
by a hematopathologist with expertise in the diagnosis of T-cell lymphomas. Rebiopsy if consult
material is nondiagnostic.
• A core biopsy of bone marrow or liver is required for diagnosis.c Bone marrow aspirate, FNA biopsy
of liver, or evaluation of peripheral blood smear or peripheral blood evaluation may be helpful but
are not alone sufficient for diagnosis.
• Adequate immunophenotyping to establish diagnosisd,e
IHC panel may include: CD20, CD3, CD10, Ki-67, CD5, CD30, CD2, CD4, CD8, CD7, CD56, TCRβ, Workup
TCRẟ, TIA-1, or granzyme B (HSTCL-2)
Cell surface marker analysis by flow cytometry may include: kappa/lambda, CD45, CD3, CD5,
CD19, CD10, CD20, CD30, CD4, CD8, CD7, CD2, TCRαβ, or TCRɣẟ
• EBER-ISH

USEFUL IN CERTAIN CIRCUMSTANCES:

• Molecular analysis to detectd clonal TCR gene rearrangements or other assessment of clonality.f
• Karyotype to establish clonality and investigate the presence of isochromosome 7q and trisomy 8.
• FISH for isochromosome 7q and trisomy 8.
• NGS panel may include STAT3, STAT5B, PIK3CD, SETD2, INO80, TET3, and SMARCA2.

a It is preferred that treatment occur at centers with expertise in the management of this disease.
b Principles of Molecular Analysis in T-Cell Lymphomas (TCLYM-A).
c If the results are equivocal, core biopsy of spleen or splenectomy could be considered in centers with expertise.
d Use of Immunophenotyping/Genetic Testing in Differential Diagnosis of Mature B-Cell and NK/T-Cell Neoplasms (TCLYM-E).
e Typical immunophenotype: CD3+, generally TCRδ+ and TCRβ- (GM3 positive, βF-1 negative), CD4 -, CD8-/+, CD56 +/-, CD5-.
f Clonal TCR gene rearrangements alone are not sufficient for diagnosis, as these can also be seen in patients with non-malignant conditions. Results should be
interpreted in the context of overall presentation. See Principles of Molecular Analysis in T-Cell Lymphomas (TCLYM-A).

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
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HSTCL-1
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Hepatosplenic T-Cell Lymphoma Table of Contents
Discussion
NCCN Evidence BlocksTM
WORKUP
ESSENTIAL:
• H&P examination; full skin examination; attention to node-bearing areas, including
Waldeyer's ring; evaluation of size of liver and spleen, nasopharynx
• Performance status
• B symptoms
• CBC with differential
• Bone marrow biopsy ± aspirate
• LDH
• Comprehensive metabolic panel
• HLH workup (TCLYM-B 2 of 3)
• Uric acid First-Line Therapy
• FDG-PET/CT scang and/or C/A/P CT with contrast of diagnostic quality (HSTCL-3)
• Echocardiogram or MUGA scan if anthracycline-based regimen is indicated
• Pregnancy testing in those of childbearing potential (if chemotherapy or RT is
planned)
• HLA typing

USEFUL IN CERTAIN CIRCUMSTANCES

• Neck CT with contrast
• Head CT or MRI with contrast
• HIV testing
• Hepatitis B and C testing
• Consider quantitative EBV PCR
• Discuss fertility preservationh
• Assessment of HTLV-1/2i by serology or other methods as clinically indicated

g Patients with T-cell lymphomas often have extranodal disease, which may be inadequately imaged by CT. PET scan may be preferred in these instances.
h Fertility preservation options include: sperm banking, semen cryopreservation, IVF, or ovarian tissue or oocyte cryopreservation.
i See map for prevalence of HTLV-1/2 by geographic region. HTLV-1/2 has been described in patients in non-endemic areas.

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All recommendations are category 2A unless otherwise indicated.
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Discussion
NCCN Evidence BlocksTM
FIRST-LINE INITIAL CONSOLIDATION/ADDITIONAL THERAPY
THERAPY RESPONSEk

CR or PRl Allogeneic HCTm (preferred)

• Clinical trial (preferred)

• Suggested regimensj
(HSTCL-A)
Clinical trial (preferred)
CR or PRl
or
Refractory Second-line therapy
• Clinical trial (preferred)
disease regimens recommended
No response • Consider alternate
after 2 for PTCL-NOS (PTCL-B 3
or Progressive regimens not used
disease in first-line therapy
first-line of 8)n
therapy or
(HSTCL-A)
regimens Pentostatin No response
or or Progressive
Cladribine disease

Alternative
second-line
therapy regimens
recommended for
PTCL-NOS (PTCL-B
3 of 8)n
and/or
j CHOP is not adequate therapy (Voss MH et al. Clin Lymphoma Myeloma Leuk 2013;13:8-14; Klebaner D et al. Clin Lymphoma Myeloma Best supportive care
Leuk 2020;20:431-437 e432). (NCCN Guidelines
k Patients should have very low tumor burden at the time of HCT. The goal of therapy is to induce CR or near CR before proceeding to HCT. for Palliative Care)
Full-course chemotherapy may not be needed to achieve adequate response to allow HCT.
l PET scan alone is inadequate for response assessment. PET-negative response should be confirmed by bone marrow biopsy and in selected
cases by liver biopsy. HSTCL is non-nodal and Lugano response criteria do not apply.
m Consider autologous HCT if unfit or lacking a suitable donor.
n Responses have been observed with alemtuzumab, pralatrexate, and ESHAP.

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All recommendations are category 2A unless otherwise indicated.
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HSTCL-3
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Discussion
NCCN Evidence BlocksTM
SUGGESTED TREATMENT REGIMENS

FIRST-LINE THERAPY/ADDITIONAL THERAPYa,b

• Clinical trial (preferred)
Preferred regimen
• ICE

Other recommended regimens (alphabetical order)

• DHA (dexamethasone and cytarabine) + platinum (carboplatin,
cisplatin, or oxaliplatin)
• Dose-adjusted EPOCH
• HyperCVAD alternating with high-dose methotrexate and cytarabine
• IVAC (ifosfamide, etoposide, and cytarabine)

Useful in certain circumstances (alphabetical by category)

• Alemtuzumabc + pentostatin
• CHOEP
• Brentuximab vedotin + CHP (cyclophosphamide, doxorubicin, and
prednisone) for CD30+ casesd (category 2B)

See Evidence Blocks on HSTCL-A (EB-1)

a CHOP is not adequate therapy (Voss MH et al. Clin Lymphoma Myeloma Leuk 2013;13:8-14; Klebaner D et al. Clin Lymphoma Myeloma Leuk 2020;20:431-437 e432).
b See Supportive Care (TCLYM-B).
c While alemtuzumab is no longer commercially available, it may be obtained for clinical use. CMV monitoring or prophylaxis is recommended (Supportive Care
TCLYM-B).
d Patients with HSTCL were eligible for the ECHELON-2 study [Horwitz S, O'Conner OA, Pro B, et al. Brentuximab vedotin with chemotherapy for CD30-positive
peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial. Lancet 2019;393:229-240], but no patients with HSTCL were enrolled.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
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HSTCL-A
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E = Efficacy of Regimen/Agent
S = Safety of Regimen/Agent NCCN Guidelines Index
Hepatosplenic T-Cell Lymphoma 3
2
Q = Quality of Evidence
C = Consistency of Evidence Table of Contents
A = Affordability of Regimen/Agent
Discussion
NCCN Evidence BlocksTM
1
E S Q C A

EVIDENCE BLOCKS FOR THE TREATMENT OF HEPATOSPLENIC T-CELL LYMPHOMA

Additional Therapy (No

First-line Therapy Response or Progressive
Disease after First-line Therapy)
Preferred Regimen
ICE
Other Recommended Regimens
DHAP (dexamethasone, cytarabine, cisplatin)

DHAX (dexamethasone, cytarabine, oxaliplatin)

DHA (dexamethasone and cytarabine) + carboplatin

Hyper-CVAD alternating with high-dose methotrexate and cytarabine

IVAC
Useful in Certain Circumstances
Alemtuzumab/pentostatin

CHOEP

Dose-adjusted EPOCH

Brentuximab vedotin/CHP

Refractory Disease after Two First-line Therapy Regimens

Pentostatin

Cladribine

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1. HSTCL-A
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Extranodal NK/T-Cell Lymphomas Table of Contents
Discussion
NCCN Evidence BlocksTM
DIAGNOSISa,b SUBTYPES
ESSENTIAL:
• Hematopathology review of all slides with at least one paraffin block
representative of the tumor. Rebiopsy if consult material is nondiagnostic.
• Excisional or incisional biopsy is preferred over core needle biopsy. An FNA
biopsy alone is not sufficient for the initial diagnosis of lymphoma.c A core
needle biopsy is not optimal but can be used under certain circumstances. • Subtypes included:
In certain circumstances, when a lymph node is not easily accessible for ENKL, nasal type Workup (ENKL-2)
excisional or incisional biopsy, a combination of core needle biopsy and FNA Extranasal ENKL
biopsy in conjunction with appropriate ancillary techniques may be sufficient
for diagnosis.
• Adequate immunophenotyping to establish diagnosisd,e
IHC panel: For high clinical suspicion of NK/T-cell lymphoma, initial panel
should include: CD2, cCD3ɛ, CD5, CD56, TIA1 • ANKL (ENKL-C)
Cell surface marker analysis by flow cytometry may include: CD2, CD3,
CD4, CD5, CD7, CD8, CD56, TCRαβ, TCRɣẟ
• EBER-ISHf

USEFUL IN CERTAIN CIRCUMSTANCES:

• Molecular analysis to detect clonal TCR gene rearrangements or other
assessment of clonalityg
• IHC panel:
B-cell lineage: CD20
T-cell lineage: CD7, CD8, CD4, granzyme B, TCRβ, TCRẟ
Other: CD30, Ki-67
a It is preferred that treatment occur at centers with expertise in the management of this disease.
b Principles of Molecular Analysis in T-Cell Lymphomas (TCLYM-A).
c Necrosis is very common in diagnostic biopsies and may delay diagnosis significantly. Biopsy should include the edges of lesions to increase the odds of having viable
tissue. It is useful to perform multiple nasopharyngeal biopsies even in areas not clearly involved.
d Use of Immunophenotyping/Genetic Testing in Differential Diagnosis of Mature B-Cell and NK/T-Cell Neoplasms (TCLYM-E).
e Typical NK-cell immunophenotype: CD20-, CD2+, cCD3ɛ+ (surface CD3-), CD4-, CD5-, CD7-/+, CD8-/+, CD43+, CD45RO+, CD56+, TCRαß-, TCRγδ-, EBER+. TCR and Ig
genes are germline (NK lineage). Cytotoxic granule proteins (TIA1, perforin, granzyme B) are usually expressed. Typical T-cell immunophenotype: CD2+, sCD3+, cCD3e+, CD4,
CD5, CD7, CD8 variable, CD56+/-, EBER+, TCRαß+ or TCRγδ+, cytotoxic granule proteins +. TCR genes are clonally rearranged.
f Negative result should prompt pathology review for alternative diagnosis.
g Clonal TCR gene rearrangements alone are not sufficient for diagnosis, as these can also be seen in patients with non-malignant conditions. Results should be interpreted
in the context of overall presentation. See Principles of Molecular Analysis in T-Cell Lymphomas (TCLYM-A).

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
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WORKUPa
ESSENTIAL:
• H&P examination with attention to node-bearing areas (including Waldeyer's ring), testicles, and skin
• Ear, nose, and throat (ENT) evaluation of nasopharynx
• Performance status
• B symptoms
• CBC with differential
• LDH
• Comprehensive metabolic panel
• Uric acid
• Bone marrow biopsy + aspirateh
• FDG-PET/CT scani and/or C/A/P CT with contrast of diagnostic quality
• MRI ± CT pretreatment for RT planning of the nasal cavity, hard palate, anterior fossa, and nasopharynx Induction
• Calculation of Prognostic Index of Natural Killer Lymphoma (PINK)j Therapy (ENKL-3)
• Echocardiogram or MUGA scan if anthracycline-based regimen is indicated
• EBV viral loadk by quantitative EBV PCR
• Concurrent referral to RT for pretreatment evaluation
• Pregnancy testing in those of childbearing potential (if chemotherapy or RT is planned)

USEFUL IN CERTAIN CIRCUMSTANCES:

• HIV testing
• Hepatitis B and C testing
• Assessment of HTLV-1/2m by serology or other methods as clinically indicated
• Ophthalmologic exam
• Lumbar puncture with cerebrospinal fluid (CSF) analysis
• Discuss fertility preservationl

a It is preferred that treatment occur at centers with expertise in the management of this disease.
h Bone marrow aspirate - lymphoid aggregates are rare, and are considered involved if Epstein-Barr virus–encoded RNA (EBER)-1 positive; hemophagocytosis may be
present.
i Patients with T-cell lymphomas often have extranodal disease, which may be inadequately imaged by CT. PET scan may be preferred in these instances.
j Prognostic Index of Natural Killer Lymphoma (PINK) (ENKL-A).
k EBV viral load is important in diagnosis and possibly in monitoring of disease. A positive result is consistent with NK/T-cell. Lack of normalization of EBV viremia should
be considered indirect evidence of persistent disease.
l Fertility preservation options include: sperm banking, semen cryopreservation, IVF, or ovarian tissue or oocyte cryopreservation.
m See map for prevalence of HTLV-1/2 by geographic region. HTLV-1/2 has been described in patients in non-endemic areas.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
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Discussion
NCCN Evidence BlocksTM
CLINICAL STAGEa
PRESENTATION INDUCTION THERAPY

RT alone o,p
Unfit for
or
chemotherapy
Clinical trial

Stage Performance
I, II status

Clinical trial
Fit for
or
chemotherapy
Combined modality therapyq End-of-
Nasal Treatment
Evaluation
(ENKL-4)

Clinical trial
Stage IV or
Combined modality therapyq
or
Combination chemotherapy
Extranasaln Stage I–IV (asparaginase-based) q ± RTp,q

a It is preferred that treatment occur at centers with expertise in the management of this disease.
n In rare circumstances of stage I primary cutaneous NKTL, involved-field RT for solitary lesions can be considered.
E
o RT as a part of initial therapy has an essential role in improved overall and disease-free survival in patients with localized ENKL, nasal type, in the upper aerodigestive
tract.
p Principles of Radiation Therapy (TCLYM-D).
q Suggested Treatment Regimens (ENKL-B).

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
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END-OF- CLINICAL RESPONSE TO ADDITIONAL RELAPSED/
TREATMENT PRESENTATION THERAPYr THERAPY REFRACTORY
EVALUATIONa DISEASE
CRs
Observet
Negative
Stage
PR Biopsy
I, II
Positive See No response below
Clinical trial
Clinical trial (preferred)
or or
No response Alternate chemotherapy Relapsed/
regimen (asparaginase- refractory therapy
Nasal based) q if not previously - See Suggested
used Treatment Regimens
or (ENKL-B 2 of 3)
• Repeat initial imaging Best supportive care (NCCN or
of CT, MRI, or FDG- Guidelines for Palliative Care) HCT,u if eligible
PET/CT scani CR
• Endoscopy with visual Stage Consider HCT,u if
inspection and repeat IV Negative eligible
biopsies
• EBV viral load PR Biopsy
See No
response below Positive
Clinical trial
Stage Clinical trial (preferred)
Extranasal I–IV or
No response or
Alternate chemotherapy Relapsed/
regimen (asparaginase- refractory therapy
a It is preferred that treatment occur at centers with expertise in the management of this disease. based) q if not previously - See Suggested
i Patients with T-cell lymphomas often have extranodal disease, which may be inadequately imaged by CT. used Treatment Regimens
PET scan may be preferred in these instances. or (ENKL-B 2 of 3)
q Suggested Treatment Regimens (ENKL-B). Best supportive care or
r Lugano Response Criteria for Non-Hodgkin Lymphoma (TCLYMP-C). (NCCN Guidelines for HCT,u if eligible
s Includes a negative ENT evaluation. Palliative Care)
t May include H&P, ENT evaluation, FDG-PET/CT scan, and EBV viral load by quantitative PCR.
u There are no clear data to suggest whether allogeneic or autologous HCT is preferred and treatment should be
individualized.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
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Discussion
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PROGNOSTIC INDEX OF NATURAL KILLER LYMPHOMA (PINK)a

RISK FACTORS

Age >60 y
Stage III or IV disease
Distant lymph-node involvement
Non-nasal type disease

Number of risk factors

Low 0
Intermediate 1
High ≥2

PROGNOSTIC INDEX OF NATURAL KILLER CELL LYMPHOMA

WITH EPSTEIN-BARR VIRUS DNA (PINK-E)a

RISK FACTORS

Age >60 y
Stage III or IV disease
Distant lymph-node involvement
Non-nasal type disease
Epstein-Barr virus DNA

Number of risk factors

Low 0–1
Intermediate 2
High ≥3

a Kim SJ, Yoon DH, Jaccard A, et al. A prognostic index for natural killer cell lymphoma after non-anthracycline-based
treatment: a multicentre, retrospective analysis. Lancet Oncol 2016;17:389-400.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
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SUGGESTED TREATMENT REGIMENSa,b
INDUCTION THERAPY
Preferred regimens
Combination • Modified SMILE (steroid [dexamethasone], methotrexate, ifosfamide, pegaspargase,e and etoposide) x 4–6 cycles for
chemotherapy advanced stage
regimens • P-GEMOX (gemcitabine, pegaspargase, and oxaliplatin)e
(asparaginase- • DDGP (dexamethasone, cisplatin, gemcitabine, and pegaspargase)d x 3–6 cycles
based)c,d
Useful in certain circumstances
• AspaMetDex (pegaspargase, methotrexate, and dexamethasone)e,f
Preferred regimens
• Concurrent chemoradiation therapy (CCRT)
RTg and DeVIC (dexamethasone, etoposide, ifosfamide, and carboplatin) x 3 cycles
• Sequential chemoradiation
Modified SMILE x 2–4 cycles followed by RTf
◊ Modified SMILE x 2 cycles is recommended for stage I–II disease
• Sandwich chemoradiationd
GELAD (gemcitabine, etoposide, pegaspargase, and dexamethasone)e x 2 cycles followed by RT followed by 2
Combined
cycles of GELAD
modality therapy
P-GEMOX x 2 cycles followed by RTg followed by P-GEMOX x 2–4 cycles

Other recommended regimens

• CCRT followed by chemotherapy: RTg and cisplatin followed by VIPD (etoposide, ifosfamide, cisplatin, and
dexamethasone) x 3 cycles
• Sequential chemoradiation: DDGP x 3–6 cycles followed by RTg
DDGP x 3 cycles is recommended for stage I–II disease
RT alone (if unfit for chemotherapy)g
• RT as a part of initial therapy has an essential role in improved overall and disease-free survival in patients with localized ENKL, nasal
type, in the upper aerodigestive tract.
a See references for regimens on ENKL-B 3 of 3. See Evidence Blocks on ENKL-B (EB-1) and ENKL-B (EB-2)
b See Supportive Care (TCLYM-B) for TLS prophylaxis and anti-infective prophylaxis. e Asparaginase Erwinia chrysanthemi (recombinant)-rywn can be substituted for
c The panel recommends that the dose of pegaspargase should be capped at one pegaspargase in patients with systemic allergic reaction or anaphylaxis due to
vial (3750 IU). See Asparaginase Toxicity Management in the NCCN Guidelines for pegaspargase hypersensitivity.
Acute Lymphoblastic Leukemia. f AspaMetDex is an option for selected patients who cannot tolerate more
d Pegaspargase-based regimens are preferred. Treatment should be individualized intensive chemotherapy.
based on patient's tolerance and comorbidities. g Principles of Radiation Therapy (TCLYM-D).

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
ENKL-B
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E = Efficacy of Regimen/Agent
S = Safety of Regimen/Agent NCCN Guidelines Index
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2
Q = Quality of Evidence
C = Consistency of Evidence Table of Contents
A = Affordability of Regimen/Agent
Discussion
NCCN Evidence BlocksTM
1
E S Q C A

EVIDENCE BLOCKS FOR THE TREATMENT OF EXTRANODAL NK/T-CELL LYMPHOMAS

Induction Therapy (Combination Chemotherapy)
Nasal Type Extranasal
Preferred Regimens
Stage I–II Stage IV Stage I-IV
Modified–SMILE x 4–6 cycles —

P–GEMOX —

DDGP x 3-6 cycles —

Useful in Certain Circumstances
AspaMetDex —

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
ENKL-B
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E = Efficacy of Regimen/Agent
S = Safety of Regimen/Agent NCCN Guidelines Index
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2
Q = Quality of Evidence
C = Consistency of Evidence Table of Contents
A = Affordability of Regimen/Agent
Discussion
NCCN Evidence BlocksTM
1
E S Q C A

EVIDENCE BLOCKS FOR THE TREATMENT OF EXTRANODAL NK/T-CELL LYMPHOMAS

Induction Therapy (Combined Modality Therapy)
Nasal Type Extranasal
Preferred Regimens
Stage I–II Stage IV Stage I-IV
RT and DeVIC x 3 cycles

Modified-SMILE x 2 cycles followed by RT — —

Modified-SMILE x 2–4 cycles followed by RT —

P–GEMOX x 2 cycles followed by RT followed by P-GEMOX x 2–4 cycles

GELAD x 2 cycles followed by RT followed by GELAD x 2 cycles

Other Recommended Regimens
RT and cisplatin followed by VIPD x 3 cycles

DDGP x 3 cycles followed by RT — —

DDGP x 3-6 cycles followed by RT —

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
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NCCN Evidence BlocksTM
SUGGESTED TREATMENT REGIMENSa,b

RELAPSED/REFRACTORY THERAPY
Preferred regimensh,i
• Clinical trial
• Pembrolizumab
• Nivolumab

Other recommended regimens (alphabetical order)

• Single agents
Brentuximab vedotin for CD30+ disease
Pralatrexate
• Combination regimens (alphabetical order)
Asparaginase-based combination chemotherapy regimen (ENKL-B 1 of 3)
not used in first-line therapy
DHA (dexamethasone and cytarabine) + platinum (cisplatin or oxaliplatin)
DHA (dexamethasone and cytarabine) + carboplatin (category 2B)
ESHA (etoposide, methylprednisolone, and cytarabine) + platinum
(cisplatin or oxaliplatin)
GDP (gemcitabine, dexamethasone, and cisplatin)
GemOx (gemcitabine and oxaliplatin)
ICE (ifosfamide, carboplatin, and etoposide)

Useful in certain circumstances

• RTg
• Belinostatj
• Romidepsinj

a See references for regimens on ENKL-B 3 of 3.

See Evidence Blocks on ENKL-B (EB-3)
b See Supportive Care (TCLYM-B) for TLS prophylaxis and anti-infective prophylaxis.
g Principles of Radiation Therapy (TCLYM-D).
h Clinical trial is the preferred relapsed/refractory option. In the absence of a clinical trial, pembrolizumab or nivolumab are appropriate options.
i The use of checkpoint inhibitors prior to allogeneic HCT may result in increased transplantation-related mortality and severe hyperacute GVHD.
j Reports of EBV reactivation have been seen with histone deacetylase (HDAC) inhibitors; consider monitoring.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
ENKL-B
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E = Efficacy of Regimen/Agent
S = Safety of Regimen/Agent NCCN Guidelines Index
Extranodal NK/T-Cell Lymphomas 3
2
Q = Quality of Evidence
C = Consistency of Evidence Table of Contents
A = Affordability of Regimen/Agent
Discussion
NCCN Evidence BlocksTM
1
E S Q C A

EVIDENCE BLOCKS FOR THE TREATMENT OF EXTRANODAL NK/T-CELL LYMPHOMAS

Relapsed/Refractory Disease

Preferred Regimens Nasal Type Extranasal Useful in Certain Circumstances Nasal Type Extranasal

Pembrolizumab Belinostat

Nivolumab Romidepsin

Other Recommended Regimens

Brentuximab vedotin
for CD30+ disease
Pralatrexate

AspaMetDex

Modified–SMILE x 4–6 cycles

P–GEMOX

DDGP x 3-6 cycles

DHAP (dexamethasone,
cytarabine, cisplatin)
DHAX (dexamethasone,
cytarabine, oxaliplatin)
DHA (dexamethasone and
cytarabine) + carboplatin
ESHAP

GDP

GemOx

ICE

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
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SUGGESTED TREATMENT REGIMENS
REFERENCES
Combination Chemotherapy Regimens Sequential Chemoradiation
Yamaguchi M, Kwong YL, Kim WS, et al. Phase II study of SMILE chemotherapy Ghione P, Qi S, Imber BS, et al. Modified SMILE (mSMILE) and intensity-
for newly diagnosed stage IV, relapsed, or refractory extranodal natural killer modulated radiotherapy (IMRT) for extranodal NK-T lymphoma nasal type in a
(NK)/T-cell lymphoma, nasal type: The NK-Cell Tumor Study Group Study. J Clin single-center population. Leuk Lymphoma 2020;61:3331-3341.
Oncol 2011;29:4410-4416. Zhang L, Wang Y, Li X, et al. Radiotherapy vs sequential pegaspargase,
Ghione P, Qi S, Imber BS, et al. Modified SMILE (mSMILE) and intensity- gemcitabine, cisplatin and dexamethasone and radiotherapy in newly diagnosed
modulated radiotherapy (IMRT) for extranodal NK-T lymphoma nasal type in a early natural killer/T cell lymphoma: A randomized, controlled, open label,
single-center population. Leuk Lymphoma 2020;61:3331-3341. multicenter study. Int J Cancer 2021;148:1470 1477.
Jaccard A, Gachard N, Marin B, et al. Efficacy of L-asparaginase with
methotrexate and dexamethasone (AspaMetDex regimen) in patients with Sandwich Chemoradiation
refractory or relapsing extranodal NK/T-cell lymphoma, a phase 2 study. Blood Tse E, Kwong YL. The diagnosis and management of NK/T-cell lymphomas. J
2011;117:1834-1839. Hematol Oncol 2018;10:85.
Wang JH, Wang H, Wang YJ, et al. Analysis of the efficacy and safety of a Wang L, Wang ZH, Chen XQ, et al. First-line combination of GELOX followed by
combined gemcitabine, oxaliplatin and pegaspargase regimen for NK/T-cell radiation therapy for patients with stage IE/IIE ENKTL: An updated analysis with
lymphoma. Oncotarget 2018;7:35412-35422. long-term follow-up. Oncol Lett 2015;10:1036-1040.
Qi S, Yahalom J, Hsu M, et al. Encouraging experience in the treatment of nasal Bi XW, Xia Y, Zhang WW, et al. Radiotherapy and PGEMOX/GELOX regimen
type extra-nodal NK/T-cell lymphoma in a non-Asian population. Leuk Lymphoma improved prognosis in elderly patients with early-stage extranodal NK/T-cell
2018;57:2575-2583. lymphoma. Ann Hematol 2015;94:1525-1533.
Wang X, Zhang L, Liu X, et al. Efficacy and safety of a pegasparaginase-based
chemotherapy regimen vs an L-asparaginase-based chemotherapy regimen Radiation Therapy Alone
for newly diagnosed advanced extranodal natural killer/T-cell lymphoma: A Huang MJ, Jiang Y, Liu WP, et al. Early or up-front radiotherapy improved
randomized clinical trial. JAMA Oncol 2022;8:1035-1041. survival of localized extranodal NK/T-cell lymphoma, nasal-type in the upper
Zhu Y, Tian S, Xu L, M, et al. GELAD chemotherapy with sandwiched radiotherapy aerodigestive tract. Int J Radiat Oncol Biol Phys 2008;70:166-174.
for patients with newly diagnosed stage IE/IIE natural killer/T-cell lymphoma: a Wu T, Yang Y, Zhu SY, et al. Risk-adapted survival benefit of IMRT in early-stage
prospective multicentre study. Br J Haematol 2022;196:939-946. NKTCL: A multicenter study from the China Lymphoma Collaborative Group.
Blood Adv 2018;2:2369-2377.
Concurrent Chemoradiation Relapsed/Refractory Therapy
Yamaguchi M, Tobinai K, Oguchi M, et al. Concurrent chemoradiotherapy for Kwong YL, Chan TSY, Tan D, et al. PD1 blockade with pembrolizumab is highly
localized nasal natural killer/T-cell lymphoma: an updated analysis of the Japan effective in relapsed or refractory NK/T-cell lymphoma failing l-asparaginase.
clinical oncology group study JCOG0211. J Clin Oncol 2012;30:4044-4046. Blood 2018;129:2437-2442.
Kim SJ, Kim K, Kim BS, et al. Phase II trial of concurrent radiation and weekly Chan TSY, Li J, Loong F, et al. PD1 blockade with low-dose nivolumab in NK/T cell
cisplatin followed by VIPD chemotherapy in newly diagnosed, stage IE to IIE, lymphoma failing L-asparaginase: efficacy and safety. Ann Hematol 2018;97:193-
nasal, extranodal NK/T-cell lymphoma: Consortium for Improving Survival of 196.
Lymphoma study. J Clin Oncol 2009;27:6027-6032.
Yamaguchi M, Suzuki R, Oguchi M, et al. Treatments and outcomes of patients See PTCL-B (8 of 8) for references for combination regimens.
with extranodal natural killer/T-cell lymphoma diagnosed between 2000 and
2013: A cooperative study in Japan. J Clin Oncol 2017;35:32-39.

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All recommendations are category 2A unless otherwise indicated.
ENKL-B
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Extranodal NK/T-Cell Lymphomas Table of Contents
Discussion
NCCN Evidence BlocksTM
AGGRESSIVE NK-CELL LEUKEMIA (ANKL)
Overview and Definition:
• ANKL is a rare leukemic form of an NK cell neoplasm with an aggressive clinical course.
• ANKL predominantly occurs in younger patients with a median age of 40 years, frequently presenting with B symptoms and concomitant
HLH. Patients can also have hepatosplenomegaly and lymphadenopathy.
• In comparison to ENKL, ANKL does not usually have nasal or skin involvement.
• EBV-associated T- and NK-cell LPD, including chronic active EBV infection (CAEBV), can progress to ANKL.
• The diagnosis of ANKL is most frequently reached by bone marrow biopsy.
• Main differential diagnosis includes chronic LPD of NK cells (sometimes referred to as NK-LGL), CAEBV, EBV-positive T-cell and NK-cell
lymphoproliferative diseases of childhood, ENKL, and rarely other EBV-associated T-cell lymphomas.
• Morphology of the malignant NK cell can be similar to that seen in LGLL. Typically, in ANKL the malignant cells are infected by EBV and
therefore have detectable Epstein–Barr virus–encoded RNAs (EBERs) (ie, EBER-ISH positive). Similar to ENKL, quantifying EBV-DNA in
peripheral blood can be useful at diagnosis and possibly in monitoring of disease. Expression of CD16 is characteristic of ANKL contrary to
ENKL, suggesting a distinct differentiation stage of NK cells.1,2
• ANKL is thought to have genetic differences as compared to ENKL.2 Mutations in the JAK/STAT pathway have been observed frequently,
including STAT3 (TCLYM-A 3 of 4). Contrary to ENKL, JAK3 mutations have not been identified in ANKL.

General Principles of Management and Treatment:

• Treatment with anthracycline-based regimens is typically ineffective. Consider combination chemotherapy regimens (asparaginase-based)
on ENKL-B (1 of 3).3
• The NCCN Panel favors consolidation with allogeneic HCT over autologous HCT for patients in first remission.4,5

3 Jung KS, Cho SH, Kim SJ, et al. L-asparaginase-based regimens followed by
allogeneic hematopoietic stem cell transplantation improve outcomes in aggressive
natural killer cell leukemia. J Hematol Oncol 2016;9:41.
1 Suzuki R, Suzumiya J, Nakamura S, et al. Aggressive natural killer-cell leukemia 4 Ishida F, Ko YH, Kim WS, et al. Aggressive natural killer cell leukemia: therapeutic
revisited: large granular lymphocyte leukemia of cytotoxic NK cells. Leukemia potential of L-asparaginase and allogeneic hematopoietic stem cell transplantation.
2004;18:763-770. Cancer Sci 2012;103:1079-1083.
2 Nakashima Y, Tagawa H, Suzuki R, et al. Genome-wide array-based comparative 5 Hamadani M, Kanate AS, DiGilio A, et al. Allogeneic Hematopoietic Cell
genomic hybridization of natural killer cell lymphoma/leukemia: different genomic Transplantation for Aggressive NK Cell Leukemia. A Center for International
alteration patterns of aggressive NK-cell leukemia and extranodal NK/T-cell Blood and Marrow Transplant Research Analysis. Biol Blood Marrow Transplant
lymphoma, nasal type. Genes Chromosomes Cancer 2005;44:247-255. 2017;23:853-866.

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T-Cell Lymphomas Table of Contents
Discussion
NCCN Evidence BlocksTM
PRINCIPLES OF MOLECULAR ANALYSIS IN T-CELL LYMPHOMASa
• Genetic testing, including high-throughput sequencing (HTS), array-based comparative genomic hybridization (CGH), NGS, karyotype, or FISH
to detect somatic mutations or genetic abnormalities are often informative and in some cases essential for an accurate and precise diagnostic
and prognostic assessment of T-cell lymphomas.

TCR Gene Rearrangements

• TCR gene rearrangement testing is recommended to support a diagnosis of T-cell lymphomas.
• Diseases:
PTCLs; T-LGLL; T-PLL; ENKL; and HSTCL.
• Description:
TCR gene rearrangement is indicative of T-cell clonal expansion. The test targets the gamma and/or beta TCR genes using PCR methods
with capillary or gel electrophoresis detection methods. Alternatively, HTS methods are increasingly used. HTS methods are more
sensitive, precise, and capable of providing a unique sequence of the T-cell clone, which allows for comparison and confirmation of
disease evolution and monitoring during remission. Clonal T-cell expansions can also be detected using V beta families in blood or tissue
with flow cytometry methods.
• Diagnostic value:
Clonal TCR gene rearrangements without histopathologic and immunophenotypic evidence of abnormal T-cell population does not
constitute a diagnosis of T-cell lymphoma since it can be identified in patients with non-malignant conditions. Conversely, a negative result
does not exclude the diagnosis of T-cell lymphoma, which occasionally may fail TCR amplification. Nonetheless, it often provides essential
information and increased precision for many of these complex diagnoses.
• Prognostic value:
Identification of clonal TCR gene rearrangement has no definitive established prognostic value; however, it could be helpful when used to
determine clinical staging or assess relapsed or residual disease.

ALK Gene Rearrangement

• A subset of CD30-positive ALCLs expresses ALK by IHC. ALK expression is often associated with t(2;5)(p23;q35), leading to the fusion of
NPM1 to ALK and resulting in a chimeric protein.
• Detection:
FISH using probes to ALK (2p23)
Targeted messenger RNA (mRNA) sequencing
• Diagnostic value:
The current WHO5 classification of ALCLs includes two entities distinguishing ALK-positive and ALK-negative variants.
• Prognostic value:
Systemic ALK-positive ALCL with t(2;5) and ALK-negative ALCL with DUSP22 rearrangement (to a lesser extent) have been associated with
a favorable prognosis.
ALK inhibition can be an effective therapeutic strategy in ALK-positive ALCL.
a See References on TCLYM-A 4 of 4. Continued

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All recommendations are category 2A unless otherwise indicated.
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Discussion
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PRINCIPLES OF MOLECULAR ANALYSIS IN T-CELL LYMPHOMASa
DUSP22-IRF4 Gene Rearrangement
• Testing for DUSP22 rearrangement is considered if CD30-positive ALCL, ALK negative is diagnosed.
• Diseases:
PTCLs
• Description:
DUSP22 is a tyrosine/threonine/serine phosphatase that may function as a tumor suppressor gene. DUSP22 inactivation contributes to
the development of PTCLs.
• Detection:
FISH using probes to DUPS22-IRF4 gene region at 6p25.3.
• Diagnostic value:
• DUSP22 rearrangements are associated with a newly recognized variant of ALK-negative ALCL.
• Prognostic value:
ALCL, ALK-negative with a DUSP22 rearrangement has been variably associated with a prognosis more similar to ALK-positive disease
and treatment according to the ALCL, ALK-positive algorithm may be considered for ALK-negative ALCL with DUSP22 rearrangement.

TP63 Rearrangement
• TP63 gene rearrangements encoding p63 fusion proteins define a subset of ALK-negative ALCL cases and are associated with aggressive
course.
• Detection:
FISH using probes to TP63 (3q28) and TBL1XR1::TP63
Targeted mRNA sequencing
• Disease:
 ALK-negative ALCL
• Diagnostic value:
To identify ALK-negative ALCL associated with aggressive course

TCL1 and TRA Translocation

• Most T-PLL have an inversion or translocation of chromosome 14 with breakpoints in the long arm at q11 and q32 [inv(14)(q11q32) and
t(14;14)(q11;q32)]. These translocations and inversions cause gene overexpression due to juxtaposition with TCRα or TCRß regulatory
elements and activate the oncogenes TCL1A and MTCP1-B1.
• Disease:
T-PLL
• Diagnostic value:
Distinguishing T-PLL from Sézary syndrome or ATLL
• Detection:
FISH, chromosomal karyotype

a See References on TCLYM-A 4 of 4. Continued

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All recommendations are category 2A unless otherwise indicated.
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T-Cell Lymphomas Table of Contents
Discussion
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PRINCIPLES OF MOLECULAR ANALYSIS IN T-CELL LYMPHOMASa
TET2/IDH1/IDH2/RHOA/DNMT3A Mutations
• High incidence of somatic mutations in IDH2 and TET2 genes has been identified in AITLs. IDH2 and TET2 encode for proteins involved
in epigenetic regulation, suggesting that disruption of gene expression regulation by methylation and acetylation may be involved
in AITL development and/or progression. Additional genetic findings include the presence of mutations affecting RHOA G17V and
DNMT3A.
• Disease:
Suspected AITL versus other PTCL.
• Detection method:
Bidirectional sequencing of the entire coding or selected exons in the genes IDH1, IDH2, DNMT3A, TET2, and RHOA.
• Diagnostic value:
Diagnosis of AITL versus other PTCLs. This pathway has been preliminarily associated with higher rates of response to histone
deacetylase (HDAC) inhibitors and other epigenetic modifiers. Clinical trials of this approach are currently ongoing.

STAT3/STAT5B Mutations
• STAT3 mutation testing is recommended under certain circumstances for diagnosis of LGLL and NK leukemias. STAT5B mutations
may be associated with aggressive subtypes.
• Diseases:
LGLL and ANKL. Similar mutations are also reported in HSTCL.
• Description:
STAT3 mutations have been identified in approximately 50% of LGLL and NK leukemias, including Y640F, N647I, E638Q, I659L, and
K657R (1/18, 5.6%).
• Detection:
Bidirectional sequencing of STAT3 (exons 13–21) and/or STAT5B.
• Diagnostic value:
Diagnosis of LGLL and ANKL.

a See References on TCLYM-A 4 of 4.

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All recommendations are category 2A unless otherwise indicated.
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Discussion
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PRINCIPLES OF MOLECULAR ANALYSIS IN T-CELL LYMPHOMAS
REFERENCES

Chiarle R, Voena C, Ambrogio C, Piva R, et al. The anaplastic lymphoma kinase in the pathogenesis of cancer. Nat Rev Cancer 2008;8:11-23.

De Schouwer PJ, Dyer MJ, Brito-Babapulle VB, et al. T-cell prolymphocytic leukemia: antigen receptor gene rearrangement and a novel mode of MTCP1-B1 activation.
Br J Haematol 2000;110:831-838.

Hapgood G, Ben-Neriah S, Mottok A, et al. Identification of high-risk DUSP22-rearranged ALK-negative anaplastic large cell lymphoma. Br J Haematol 2019;186:e28-e31.

Hu Z, Medeiros LJ, Fang L, et al. Prognostic significance of cytogenetic abnormalities in T-cell prolymphocytic leukemia. Am J Hematol 2017;92:441-447.

Morris SW, Kirstein MN, Valentine MB, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s Lymphoma. Science 1994;263:1281-1284.

Odejide O, Weigert O, Lane AA, et al. A targeted mutational landscape of angioimmunoblastic T-cell lymphoma. Blood 2014;123:1293-1296.

Parrilla Castellar ER, Jaffe ES, Said JW, et al. ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical
outcomes. Blood 2014;124:1473-1480.

Pedersen MB, Hamilton-Dutoit SJ, Bendix K, et al. DUSP22 and TP63 rearrangements predict outcome of ALK-negative anaplastic large cell lymphoma: a Danish cohort
study. Blood 2017;130:554-557.

Wada DA, Law ME, Hsi ED, et al. Specificity of IRF4 translocations for primary cutaneous anaplastic large cell lymphoma: a multicenter study of 204 skin biopsies. Mod
Pathol 2011;24:596-605.

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All recommendations are category 2A unless otherwise indicated.
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SUPPORTIVE CARE
Tumor Lysis Syndrome (TLS)
• Treatment of TLS:
• Laboratory hallmarks of TLS:
TLS is best managed if anticipated and treatment is started prior to
High potassium
chemotherapy.
High uric acid
Centerpiece of treatment includes:
High phosphorous
◊ Rigorous hydration
Low calcium
◊ Management of hyperuricemia
Elevated creatinine
◊ Frequent monitoring of electrolytes and aggressive correction
(essential)
• Symptoms of TLS:
First-line and at retreatment for hyperuricemia
Nausea and vomiting, shortness of breath, irregular heartbeat,
◊ Glucose-6-phosphate dehydrogenase (G6PD) testing is required
clouding of urine, lethargy, and/or joint discomfort.
prior to use of rasburicase. Rasburicase is contraindicated in
patients with a history consistent with G6PD. In these patients,
• TLS features:
rasburicase should be substituted with allopurinol.
Consider TLS prophylaxis for patients with the following risk
◊ Low-Risk Disease:
factors:
Allopurinol or febuxostat beginning 2–3 days prior to
◊ Spontaneous TLS
chemoimmunotherapy and continued for 10–14 days
◊ High tumor burden or bulky disease
◊ Intermediate-Risk Disease: Stage I/II and LDH <2X upper limit of
◊ Elevated white blood cell (WBC) count
normal (ULN):
◊ Bone marrow involvement
Allopurinol or febuxostat
◊ Pre-existing elevated uric acid
OR
◊ Renal disease or renal involvement by tumor
Rasburicase if renal dysfunction and uric acid, potassium,
and/or phosphate >ULN
◊ High-Risk Disease: Stage III/IV and/or LDH ≥2X ULN:
Rasburicase
Rasburicase (Doses of 3–6 mg are usually effective.a One dose
of rasburicase is frequently adequate. Re-dosing should be
individualized.) is indicated for patients with any of the following risk
factors:
- Urgent need to initiate therapy in a high-bulk patient
- Situations where adequate hydration may be difficult or
impossible
- Acute renal failure
If TLS is untreated, its progression may cause acute kidney failure,
cardiac arrhythmias, seizures, loss of muscle control, and death.
a There are data to support that fixed-dose rasburicase is very effective in adult patients.
Continued

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
TCLYM-B
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SUPPORTIVE CARE
Hemophagocytic Lymphohistiocytosis (HLH)b
• Syndrome of extreme immune activation resulting in life-threatening • Diagnostic evaluationc
inflammation Labs including CBC with differential, triglycerides,
fibrinogen, ferritin, sCD25, liver function tests (LFTs), LDH,
• Clinical signs and symptoms may include: (these may overlap with and D-dimer
features of underlying lymphoma) Bone marrow biopsy
Fever ◊ Consider repeat bone marrow biopsy if strong suspicion
Hepatosplenomegaly of HLH
Cytopenias (affecting 2 of 3 lineages in the peripheral blood) Consider liver biopsy
◊ Hemoglobin <9 g/dL
◊ Platelets <100 x 103/mL • Managementd
◊ Neutrophils <1 x 103/mL Recommend expert consultation
Hypertriglyceridemia and/or hypofibrinogenemia Treatment of the underlying T-cell lymphoma with
◊ Fasting triglycerides >3.0 mmol/L (ie, >265 mg/dL) preference for etoposide- and steroid-containing regimens.
◊ Fibrinogen <1.5 g/L Start with HLH-directed therapy if cytopenias preclude
Hemophagocytosis in bone marrow or spleen or lymph nodes standard anti-lymphoma therapy, and then initiate standard
Ferritin >500 ng/mL anti-lymphoma therapy when cytopenias improve.
sIL-2R (also known as soluble CD25 [sCD25]) >2400 U/mL Antiviral therapy - See Monoclonal Antibody Therapy and
Elevated transaminases and bilirubin Viral Reactivation (TCLYM-B 3 of 4)
Elevated LDH
Elevated D-dimer
Elevated CSF cells and/or protein

b HLH in adults is often associated with an underlying T-cell lymphoma. Diagnostic workup to confirm the lymphoma subtype and prompt initiation of treatment for
underlying T-cell lymphoma is often required.
c Consider optimized HLH inflammatory (OHI) index [combined elevation of sCD25 (>3900 U/mL) and ferritin (>1000 ng/mL)] to simplify the diagnosis of HLH in
patients with hematologic malignancies (Zoref-Lorenz A, Murakami J, Hofstetter L, et al. An improved index for diagnosis and mortality prediction in malignancy-
associated hemophagocytic lymphohistiocytosis. Blood 2022;139:1098-1110).
d La Rosée P, Horne A, Hines M, et al. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood 2019;133:2465-2477;
Setiadi A, Zoref-Lorenz A, Lee CY, et al. Malignancy-associated haemophagocytic lymphohistiocytosis. Lancet Haematol 2022;9:e217-e227.
Continued

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SUPPORTIVE CARE
For other immunosuppressive situations, see NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections.
Monoclonal Antibody Therapy and Viral Reactivation
• Alemtuzumab (anti-CD52 antibody):
CMV reactivation:
◊ The current appropriate management is controversial; some NCCN Member Institutions use ganciclovir (PO or IV) preemptively if viremia
is present, others only if viral load is rising.
◊ CMV viremia should be measured by quantitative PCR at least every 2–3 weeks.
Anti-infective prophylaxis
◊ Herpes simplex virus (HSV) prophylaxis with acyclovir or equivalent.
◊ Pneumocystis jiroveci pneumonia (PJP) prophylaxis with sulfamethoxazole/trimethoprim or equivalent.
◊ Consider screening and treatment (if needed) for strongyloidiasis in patients with ATLL.
◊ Consider antifungal prophylaxis.
◊ Consultation with an infectious disease expert may be necessary. See NCCN Guidelines for Prevention and Treatment of Cancer-Related
Infections.
Consider evaluating for CD52 expression before initiating treatment with alemtuzumab-based regimens.
• Brentuximab vedotin (anti-CD30 antibody-drug conjugate)
Progressive multifocal leukoencephalopathy (PML):
◊ Caused by reactivation of the John Cunningham virus (JCV) and is usually fatal.
◊ Diagnosis made by PCR of CSF and in some cases brain biopsy.
◊ Clinical indications may include changes in behavior such as confusion, dizziness or loss of balance, difficulty talking or walking, and
vision problems.
◊ No known effective treatment.

Continued

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All recommendations are category 2A unless otherwise indicated.
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SUPPORTIVE CARE
For other immunosuppressive situations, see NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections.

Tumor Flare Reactions

• Management of tumor flare is recommended for patients receiving lenalidomide.
• Tumor flare reactions are painful lymph node enlargements or lymph node enlargements with evidence of local inflammation, occurring with
treatment initiation; may also be associated with spleen enlargement, low-grade fever, and/or rash.
• Treatment: Steroids (eg, prednisone 25–50 mg PO for 5–10 days); antihistamines for rash and pruritus (eg, cetirizine 10 mg PO once daily or
loratadine 10 mg PO daily).
• Prophylaxis: Consider in patients with bulky lymph nodes (>5 cm); administer steroids (eg, prednisone 20 mg PO for 5–7 days followed by
rapid taper over 5–7 days).
Prevention of Pralatrexate-Induced Mucositise,f,g
• Vitamin B12 (cyanocobalamin) at a dose of 1000 mcg intramuscular to be started no more than 10 weeks prior to starting therapy with
pralatrexate and then every 8–10 weeks.
• Oral folic acid 1–1.25 mg daily to be started within 10 days of starting therapy and continuing for 30 days after the last dose of pralatrexate.
• Consider use of oral leucovorin 25 mg 3 times daily for 2 consecutive days (total of 6 doses), starting 24 hours after each dose of
pralatrexate.
Adverse Events Associated with Mogamulizumab:
• Graft-versus-host disease (GVHD): A retrospective study showed a particularly high risk of developing GVHD in patients proceeding to
allogeneic HCT within 50 days of mogamulizumab.h
• Mogamulizumab-associated rash (MAR): Mogamulizumab has been associated with a drug eruption (termed as MAR) that can clinically
mimic cutaneous T-cell lymphoma. Skin biopsy is recommended to distinguish progression of disease versus drug eruption.i

e Mould DR, Sweeney K, Duffull SB, et al. A population pharmacokinetic and pharmacodynamic evaluation of pralatrexate in patients with relapsed or refractory non-
Hodgkin's or Hodgkin's lymphoma. Clin Pharmacol Ther 2009;86:190-196.
f Shustov AR, Shinohara MM, Dakhil SR, et al. Management of mucositis with the use of leucovorin as adjunct to pralatrexate in treatment of peripheral t-cell
lymphomas (PTCL) – Results from a prospective multicenter phase 2 clinical trial. Blood 2018;132:2910.
g Koch E, Story SK, Geskin L. Preemptive leucovorin administration minimizes pralatrexate toxicity without sacrificing efficacy. Leuk Lymphoma 2013;54:2448-2451.
h Fuji S, Inoue Y, Utsunomiya A, et al. Pretransplantation Anti-CCR4 antibody mogamulizumab against adult t-cell leukemia/lymphoma is associated with significantly
increased risks of severe and corticosteroid-refractory graft-versus-host disease, nonrelapse mortality, and overall mortality. J Clin Oncol 2016;34:3426-3433.
i Chen L, Carson K, Staser K, et al. Mogamulizumab-associated cutaneous granulomatous drug eruption mimicking mycosis fungoides but possibly indicating durable
clinical response. JAMA Dermatology 2019;155:968-971; Hirotsu K, Neal T, Khodadoust M, et al. Clinical characterization of mogamulizumab-associated rash during
treatment of mycosis fungoides or Sézary syndrome. JAMA Dermatol 2021;157:700-707.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
TCLYM-B
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LUGANO RESPONSE CRITERIA FOR NON-HODGKIN LYMPHOMA
PET should be done with contrast-enhanced diagnostic CT and can be done simultaneously or at separate procedures.
d
Response Site PET-CT (Metabolic response) CT (Radiologic response)
All of the following:
Lymph nodes and a
Score 1, 2, or 3 with or without a residual mass on 5 Target nodes/nodal masses must regress to ≤1.5 cm in
extralymphatic b,c
point scale (5-PS) longest transverse diameter of a lesion (LDi)
sites
No extralymphatic sites of disease
Complete Non-measured
Not applicable Absent
response lesion
Organ enlargement Not applicable Regress to normal
New Lesions None None
Normal by morphology; if indeterminate, and flow
Bone Marrow No evidence of FDG-avid disease in marrow
cytometry IHC negative
All of the following:
b ≥50% decrease in SPD of up to 6 target measurable
Score 4 or 5 with reduced uptake compared with
nodes and extranodal sites
Lymph nodes and baseline. No new or progressive lesions.
When a lesion is too small to measure on CT, assign
extralymphatic At interim these findings suggest responding disease.
5mm x 5mm as the default value.
sites At end of treatment these findings may indicate residual
When no longer visible, 0x0 mm
disease. For a node >5mm x 5mm, but smaller than normal, use
actual measurement for calculation
Non-measured
Partial Not applicable Absent/normal, regressed, but no increase
lesion
response Spleen must have regressed by >50% in length beyond
Organ enlargement Not applicable
normal
New Lesions None None
Residual uptake higher than uptake in normal marrow but
reduced compared with baseline (diffuse uptake
compatible with reactive changes from chemotherapy
Bone Marrow Not applicable
allowed). If there are persistent focal changes in the
marrow in the context of a nodal response, consider
further evaluation with biopsy, or an interval scan.

Reprinted with permission. © 2014 American Society of Clinical Oncology. All rights reserved. Cheson B, Fisher R, Barrington S, et al. Recommendations for initial
evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 2014;32:3059-3068.
Footnotes on TCLYM-C 3 of 3
Continued

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
TCLYM-C
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Discussion
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LUGANO RESPONSE CRITERIA FOR NON-HODGKIN LYMPHOMA
PET should be done with contrast-enhanced diagnostic CT and can be done simultaneously or at separate procedures.
d
Response Site PET-CT (Metabolic response) CT (Radiologic response)
Target b
Score 4 or 5 with no significant change in FDG uptake <50% decrease from baseline in SPD of up to 6
nodes/nodal
from baseline at interim or end of treatment. No new or dominant, measurable nodes and extranodal sites; no
masses,
No progressive lesions criteria for progressive disease are met
extranodal lesions
response or Non-measured
stable Not applicable No increase consistent with progression
lesion
disease Organ enlargement Not applicable No increase consistent with progression
New Lesions None None
Bone Marrow No change from baseline Not applicable
Requires at least one of the following
PPD progression:
An individual node/lesion must be abnormal with:
b LDi >1.5 cm and
Score 4 or 5 with an increase in intensity of uptake from
Increase by >50% from PPD nadir and
Individual target baseline
An increase in LDi or SDi from nadir
nodes/nodal and/or
0.5 cm for lesions <2 cm
masses New FDG-avid foci consistent with lymphoma at interim
e 1.0 cm for lesions >2 cm
Extranodal lesions or end-of-treatment assessment In the setting of splenomegaly, the splenic length must
increase by >50% of the extent of its prior increase
beyond baseline. If no prior splenomegaly, must
Progressive increase by at least 2 cm from baseline
disease New or recurrent splenomegaly
Non-measured New or clear progression of preexisting nonmeasured
None
lesion lesions
Regrowth of previously resolved lesions
New FDG-avid foci consistent with lymphoma rather than A new node >1.5 cm in any axis
another etiology (eg, infection, inflammation). If A new extranodal site >1.0 cm in any axis; if <1.0 cm in
New Lesions uncertain regarding etiology of new lesions, biopsy or any axis, its presence must be unequivocal and must be
e attributable to lymphoma
interval scan may be considered Assessable disease of any size unequivocally
attributable to lymphoma
Bone Marrow New or recurrent FDG-avid foci New or recurrent involvement

Reprinted with permission. © 2014 American Society of Clinical Oncology. All rights reserved. Cheson B, Fisher R, Barrington S, et al. Recommendations for initial
evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 2014;32:3059-3068.
Footnotes on TCLYM-C 3 of 3
Continued

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
TCLYM-C
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LUGANO RESPONSE CRITERIA FOR NON-HODGKIN LYMPHOMA
Footnotes
a Score 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim scan. However, in trials involving PET where de-
escalation is investigated, it may be preferable to consider score 3 as an inadequate response (to avoid under-treatment).
b See PET Five Point Scale (5-PS).
c It is recognized that in Waldeyer’s ring or extranodal sites with high physiological uptake or with activation within spleen or marrow, e.g. with chemotherapy or
myeloid colony stimulating factors, uptake may be greater than normal mediastinum and/or liver. In this circumstance, CMR may be inferred if uptake at sites of initial
involvement is no greater than surrounding normal tissue even if the tissue has high physiological uptake.
d FDG-avid lymphomas should have response assessed by PET-CT. Diseases that can typically be followed with CT alone include CLL/SLL and marginal zone
lymphomas.
e False-positive PET scans may be observed related to infectious or inflammatory conditions. Biopsy of affected sites remains the gold standard for confirming new or
persistent disease at end of therapy.

PET Five Point Scale (5-PS)

1 No uptake above background
2 Uptake ≤ mediastinum
3 Uptake > mediastinum but ≤ liver
4 Uptake moderately > liver
5 Uptake markedly higher than liver and/or new lesions
X New areas of uptake unlikely to be related to lymphoma
SPD – sum of the product of the perpendicular diameters for multiple lesions
LDi – Longest transverse diameter of a lesion
SDi – Shortest axis perpendicular to the LDi
PPD – Cross product of the LDi and perpendicular diameter

Measured dominant lesions – Up to 6 of the largest dominant nodes, nodal masses and extranodal lesions selected to be clearly measurable in 2 diameters.
Nodes should preferably be from disparate regions of the body, and should include, where applicable, mediastinal and retroperitoneal areas. Non-nodal
lesions include those in solid organs, eg, liver, spleen, kidneys, lungs, etc, gastrointestinal involvement, cutaneous lesions of those noted on palpation.
Non-measured lesions – Any disease not selected as measured, dominant disease and truly assessable disease should be considered not measured. These
sites include any nodes, nodal masses, and extranodal sites not selected as dominant, measurable or which do not meet the requirements for measurability,
but are still considered abnormal. As well as truly assessable disease which is any site of suspected disease that would be difficult to follow quantitatively
with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses and other lesions that cannot be
confirmed and followed by imaging.

Reprinted with permission. © 2014 American Society of Clinical Oncology. All rights reserved. Cheson B, Fisher R, Barrington S, et al. Recommendations for initial
evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 2014;32:3059-3068.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
TCLYM-C
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PRINCIPLES OF RADIATION THERAPYa
General Principles
• Treatment with photons, electrons, or protons may all be appropriate, depending on clinical circumstances.
• Modern general principles of RT using ISRT should be followed.
• Advanced RT technologies such as intensity-modulated RT (IMRT), breath hold or respiratory gating, image-guided RT (IGRT), or proton
therapy may offer significant and clinically relevant advantages in specific instances to spare important organs at risk (OARs) such as the
heart (including coronary arteries and valves), lungs, kidneys, spinal cord, esophagus, bone marrow, breasts, stomach, muscle/soft tissue,
and salivary glands and decrease the risk for late, normal tissue damage while still achieving the primary goal of local tumor control. Achieving
highly conformal dose distributions is especially important for patients who are being treated with curative intent or who have long life
expectancies following therapy.
• The demonstration of significant dose-sparing for these OARs reflects best clinical practice.
• In mediastinal lymphoma, the use of 4D-CT for simulation and the adoption of strategies to deal with respiratory motion such as inspiration
breath-hold techniques and IGRT during treatment delivery is also important.
• Since the advantages of these techniques include tightly conformal doses and steep gradients next to normal tissues, target definition
and delineation and treatment delivery verification require careful monitoring to avoid the risk of tumor geographic miss and subsequent
decrease in tumor control. Image guidance may be required to provide this assurance.
• Randomized studies to test these concepts are unlikely to be done since these techniques are designed to decrease late effects, which
take greater than 10 years to evolve. In light of that, the modalities and techniques that are found to best reduce the doses to the OARs in a
clinically meaningful way without compromising target coverage should be considered.
• Radiation dose constraints: Recommendations for normal tissue dose constraints can be found in the Principles of Radiation Therapy in the
NCCN Guidelines for Hodgkin Lymphoma.

a See references on TCLYM-D 4 of 4.

Continued

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
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PRINCIPLES OF RADIATION THERAPYa
Target Volumes:
• ISRT for nodal disease
ISRT is recommended as the appropriate field for non-Hodgkin lymphoma. Planning for ISRT requires modern CT-based simulation and
planning capabilities. Incorporating other modern imaging such as PET and MRI often enhances treatment volume determination.
ISRT targets the site of the originally involved lymph node(s). The volume encompasses the original suspicious volume prior to
chemotherapy or surgery. Yet, it spares adjacent uninvolved organs (eg, lungs, bone, muscle, kidney) when lymphadenopathy regresses
following chemotherapy.
The pre-chemotherapy or pre-biopsy gross tumor volume (GTV) provides the basis for determining the clinical target volume (CTV).
Concerns for questionable subclinical disease and uncertainties in original imaging accuracy or localization may lead to expansion of the
CTV and are determined individually using clinical judgment.
Possible movement of the target by respiration as determined by 4D-CT or fluoroscopy (internal target volume [ITV]) should also influence
the final CTV.
The planning target volume (PTV) is an additional expansion of the CTV that accounts only for setup variations (see International
Commission on Radiation Units and Measurements [ICRU] definitions).
The OARs should be outlined for optimizing treatment plan decisions.
The treatment plan is designed using conventional, 3-D conformal, or IMRT techniques using clinical treatment planning considerations of
coverage and dose reductions for OARs.

• ISRT for extranodal disease (excluding ENKL)

Similar principles as for ISRT nodal sites (see above).
For most organs, the whole organ comprises the CTV (eg, stomach, salivary gland, thyroid). For other organs, including orbit, breast, lung,
bone, and localized skin, partial organ RT may be appropriate.
Prophylactic irradiation is not required for uninvolved lymph nodes.

a See references on TCLYM-D 4 of 4.

Continued

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
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PRINCIPLES OF RADIATION THERAPYa
• ISRT for ENKL
For optimal treatment planning, both contrast-enhanced CT and contrast-enhanced MRI are essential. An FDG-PET/CT scan is necessary for
defining the presence of nodal disease.
The GTV is defined based on combined abnormalities identified on endoscopy, CT, and MRI.
The ISRT CTV should include the entire involved cavity and adjacent structures due to the high risk for submucosal spread.
◊ For unilateral anterior or mid-nasal cavity, the CTV should include the bilateral nasal cavities, ipsilateral maxillary sinus, and bilateral
anterior ethmoids.
◊ For bilateral nasal cavity involvement, the CTV should include both maxillary sinuses.
◊ If there is posterior nasal cavity involvement, the nasopharynx should be included in the CTV.
◊ If there is anterior ethmoid involvement, the posterior ethmoids should be included in the CTV.
◊ All involved paranasal sinuses should be included in the CTV.
◊ Any areas of soft tissue extension should be included in the CTV.
◊ Prophylactic irradiation is not required for uninvolved lymph nodes.
◊ Experience combining newer chemotherapy regimens with smaller ISRT fields (ie, GTV with minimal expansion to define the CTV) is
limited and the likelihood of local failure with these smaller fields is not known.
The PTV is an additional expansion of the CTV that accounts only for setup variations (see ICRU definitions).
The OARs should be outlined for optimizing treatment plan decisions.
The treatment plan is designed using conventional, 3-D conformal, or IMRT techniques using clinical treatment planning considerations of
coverage and dose reductions for OARs.

a See references on TCLYM-D 4 of 4.

Continued

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
TCLYM-D
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PRINCIPLES OF RADIATION THERAPY
General Dose Guidelines: (RT in conventional fraction sizes)
• PTCL • ENKL
Consolidation after chemotherapy CR: 30–36 Gy; PR: 40–50 Gy RT alone as primary treatment (if unfit for chemotherapy): 50–55 Gy
RT as primary treatment for refractory or non-candidates for RT in combination with chemotherapy: 45–56 Gy
chemotherapy: 40–55 Gy Combined modality therapy (non–asparaginase-based):
In combination with HCT: 20–36 Gy, depending on sites of disease ◊ CCRT:
and prior RT exposure – 50 Gy in combination with DeVIC (dexamethasone, etoposide,
• BIA-ALCL: 24–36 Gy for local residual disease ifosfamide, and carboplatin)
– 50–54 Gy in combination with cisplatin followed by VIPD
(etoposide, ifosfamide, cisplatin, and dexamethasone)
◊ Sequential chemoradiation: Modified SMILE regimen followed by
RT 45–50.4 Gy for stage I–II disease
◊ Sandwich chemoradiation:
– P-GEMOX (2 cycles) followed by RT 56 Gy followed by P-GEMOX
(2–4 cycles)
– GELAD (2 cycles) followed by RT 50-56 Gy followed by GELAD (2
cycles)
• Palliative RT: 20–36 Gy in 5–18 fractions

References
Girinsky T, Pichenot C, Beaudre A, et al. Is intensity-modulated radiotherapy better than conventional radiation treatment and three-dimensional conformal radiotherapy
for mediastinal masses in patients with Hodgkin's disease, and is there a role for beam orientation optimization and dose constraints assigned to virtual volumes? Int J
Radiat Oncol Biol Phys 2006;64:218-226.
Hoskin PJ, Díez P, Williams M, et al. Recommendations for the use of radiotherapy in nodal lymphoma. Clin Oncol (R Coll Radiol) 2013;25:49-58.
Illidge T, Specht L, Yahalom J, et al. Modern radiation therapy for nodal non-Hodgkin lymphoma-target definition and dose guidelines from the International Lymphoma
Radiation Oncology Group. Int J Radiat Oncol Biol Phys 2014;89:49-58.
Li YX, Wang H, Jin J, et al. Radiotherapy alone with curative intent in patients with stage I extranodal nasal-type NK/T-cell lymphoma. Int J Radiat Oncol Biol Phys
2012;82:1809-1815.
Nieder C, Schill S, Kneschaurek P, Molls M. Influence of different treatment techniques on radiation dose to the LAD coronary artery. Radiat Oncol 2007;2:20.
Wang H, Li YX, Wang WH, et al. Mild toxicity and favorable prognosis of high-dose and extended involved-field intensity-modulated radiotherapy for patients with early-
stage nasal NK/T-cell lymphoma. Int J Radiat Oncol Biol Phys 2012;82:1115-1121.
Yahalom J, Illidge T, Specht L, et al. Modern radiation therapy for extranodal lymphomas: field and dose guidelines from the International Lymphoma Radiation Oncology
Group. Int J Radiat Oncol Biol Phys 2015;92:11-31.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
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USE OF IMMUNOPHENOTYPING/GENETIC TESTING IN DIFFERENTIAL DIAGNOSIS OF NK/T-CELL NEOPLASMSa
(TO BE USED IN CONJUNCTION WITH CLINICAL AND MORPHOLOGIC CORRELATION)
General Principles
• Morphology ± clinical features drive both the choice and the interpretation of special studies.
• Differential diagnosis is based on morphology ± clinical setting.
• Begin with a broad panel appropriate to morphologic diagnosis, limiting panel of antibodies based on the differential diagnosis.
Avoid “shotgun” panels of unnecessary antibodies unless a clinically urgent situation warrants.
• Add antigens in additional panels, based on initial results.
• Follow with genetic studies as needed.
• Return to clinical picture if immunophenotype + morphology are not specific.
T- or NK/T-cell antigens positiveb,c
(CD2, CD3, CD5, CD7) (and B-cell antigens negative)
• Morphology
Anaplastic vs. non-anaplastic
Epidermotropic
• Clinical
Age (child, adult) See Initial Morphologic, Clinical, and
Location Immunophenotypic Analysis (TCLYM-E 2 of 5)
◊ Cutaneous
◊ Extranodal noncutaneous (specific site)
◊ Nodal
• Immunophenotype
CD30, ALK*, CD56, ßF1, cytotoxic granule proteins
CD4, CD8, CD5, CD7, TCRαß, TCRγδ, CD1a, TdT
Follicular T cells: CD10, BCL6, CD57, PD1/CD279, CXCL13, ICOS
Viruses: EBV, HTLV1 (clonal)
• Genetic testing
ALK, TCR, HTLV1

*Always do ALK if CD30+

a These are meant to be general guidelines. Interpretation of results should be based on individual circumstances and may vary. Not all tests
will be required in every case.
b Some lymphoid neoplasms may lack pan leukocyte (CD45), pan-B, and pan-T antigens. Selection of additional antibodies should be based on the differential diagnosis
generated by morphologic and clinical features (eg, plasma cell myeloma, ALK+ DLBCL, plasmablastic lymphoma, anaplastic large cell lymphoma [ALCL], NK-cell
lymphomas).
c Usually 1 pan-B (CD20) and 1 pan-T (CD3) markers are done unless a terminally differentiated B-cell or a specific PTCL is suspected.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
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USE OF IMMUNOPHENOTYPING/GENETIC TESTING IN DIFFERENTIAL DIAGNOSIS OF NK/T-CELL NEOPLASMSa
(TO BE USED IN CONJUNCTION WITH CLINICAL AND MORPHOLOGIC CORRELATION)

INITIAL MORPHOLOGIC, CLINICAL, AND IMMUNOPHENOTYPIC ANALYSIS

Small cells

Medium-sized cells See NCCN Guidelines for B-Cell

Lymphomas
B-cell neoplasms
Large cells ± anaplastic
morphology

Cutaneous localization
Lineage based on
immunophenotyped
(Pan-B and Pan-T antigens)
or Anaplastic
TCLYM-E 3 of 5
Suspected by morphology/ morphology
clinical features
Cutaneous localization
TCLYM-E 4 of 5
(non-anaplastic morphology)

T-cell neoplasms
Extranodal, noncutaneous localization
TCLYM-E 5 of 5
(non-anaplastic morphology)

Nodal localization
TCLYM-E 5 of 5
(non-anaplastic morphology)

a These are meant to be general guidelines. Interpretation of results should be based on individual circumstances and may vary. Not all tests will be required in every
case.
d Initial panel will often include additional markers based on morphologic differential diagnosis and clinical features.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
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Discussion
NCCN Evidence BlocksTM
USE OF IMMUNOPHENOTYPING/GENETIC TESTING IN DIFFERENTIAL DIAGNOSIS OF NK/T-CELL NEOPLASMSa
(TO BE USED IN CONJUNCTION WITH CLINICAL AND MORPHOLOGIC CORRELATION)

T-CELL NEOPLASMS
ALK+ ALCL, ALK+
If only one T-cell antigen expressed, could be DLBCL
CD30+ PAX5+
strong,
all cells PAX5 Dim+
Consider CHL (T-cell antigen expression
Panel: CD30, CD15+
may rarely occur in CHL)
CD15, PAX5,s EBER+/-
ALK, EBV- ALK-
Anaplastic EBER, cytotoxic • Cutaneous = Primary cutaneous CD30+ T-cell LPD
morphology granule proteins Polymorphous, regressing = LyP
(granzyme B, Monomorphous, progressing = PC-ALCL
perforin, TIA1), Mycosis fungoides (MF) in transformation (if
CD25, IRF4/MUM1 PAX5- history of MF)
• Non-cutaneous = ALCL, ALK- (caveat: rule out nodal
CD30- involvement by CTCL, CD15 may be + in CTCL)
PTCL-NOS
or focal • Intestinal = EATL (eosinophils: clinical history of
celiac disease or antibodies)
• HTLV1+ = ATLL, anaplastic large cell type (CD25+)

Anaplastic morphology
• Anaplastic large cell lymphoma (ALCL), ALK positive
• ALCL, ALK negative
• Adult T-cell leukemia/lymphoma (ATLL), anaplastic large cell type
• Enteropathy-associated T-cell lymphoma (EATL)
• Primary cutaneous CD30-positive T-cell LPD
Lymphomatoid papulosis (LyP)
Primary cutaneous ALCL (PC-ALCL)

a These are meant to be general guidelines. Interpretation of results should be based on individual circumstances and may vary. Not all tests will be required in every
case.
s Rare T-cell lymphomas may be CD20+ or PAX5+. Assessment of other Pan-T and -B markers is essential. The expression of multiple markers of 1 lineage and only 1
of the other lineages supports lineage assignment. PCR analysis may be required to determine lineage in such cases.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
TCLYM-E
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NCCN Evidence BlocksTM
USE OF IMMUNOPHENOTYPING/GENETIC TESTING IN DIFFERENTIAL DIAGNOSIS OF NK/T-CELL NEOPLASMSa
(TO BE USED IN CONJUNCTION WITH CLINICAL AND MORPHOLOGIC CORRELATION)
T-CELL NEOPLASMS CD30+
strong, CD30+ Cutaneous LPDt
all cells MF,t SS (CD2+ CD5+ CD7- CD8- ßF1+ CGP-)
CD4+
HTLV1 + = ATLL
Panel: CD2, CD5, CD7, CD8 + AECTCLt,u (CD2- CD5- CD7+/-
CD4, CD8, CD30, CD56, CD56 - ßF1+ CGP+)
Cutaneous Epidermotropic
ßF1, TCRγ, cytotoxic Primary cutaneous acral TCL (CD2+ CD5+ CD56-
localization
(non-anaplastic granule proteins CD8+ TIA1+ other cytotoxic granules- Ki-67 <10%)
morphology) (perforin, granzyme B, (Confirm by localization to ear, nose, foot)
CD4-
TIA1), EBV-EBER; Cutaneous γδTCL (CD2+ CD5- CD7+/-
Optional: CD25, CD279 CD8- CD56+/- ßF1- CGP+) (dermis and
CD30- subcutis often involved)
or focal Consider myeloid sarcoma (may be CD2+
CD56+ CD7+ CD56+) or
BPDC (CD3- CD5- CD123+ CD68+ TCL1+)
CD4+
Small/med cells = CD4+ small/medium CTCL/
CD56- T-cell pseudolymphoma (CD279+)
Cutaneous localization (non-anaplastic morphology) Med/large cells = PTCL, NOS
Dermis and
• Primary cutaneous CD30-positive T-cell subcutis SCPTCL (CD2+ CD5- CD7+
ßF1+
lymphoproliferative disorders (LPD) CD56- CGP+)
• Mycosis fungoides, Sézary syndrome (MF, SS) CD8+
Cutaneous γδTCL (CD2+
• Subcutaneous panniculitis-like T-cell lymphoma (SCPTCL) ßF1-
CD4- CD5- CD7+/- CD56+/- CGP+)
• Primary cutaneous gamma-delta T-cell lymphoma (γδTCL)
• Primary cutaneous CD8-positive aggressive ßF1+ PTCL-NOS
epidermotropic cytotoxic T-cell lymphoma (AECTCL) ENK/TL nasal type (CD2+
CD8- EBV+
• Primary cutaneous CD4-positive small/medium T-cell LPD CD7- CD56+ CGP+, TCRγ-)
• Primary cutaneous acral CD8-positive T-cell lymphoma
• Extranodal NK/T-cell lymphoma, nasal type ßF1-
Cutaneous γδTCL
• Peripheral T-cell lymphoma, NOS (PTCL, NOS) EBV- (CD2+ CD5- CD7+/-
• Blastic plasmacytoid dendritic cell (BPDC) neoplasm CD56+/- CGP+, TCRγ+)
a These are meant to be general guidelines. Interpretation of results should be based on individual circumstances and may vary. Not all tests will be required in every case.
t A minority of MF cases can be CD30+, CD4-, CD8+/-, and TIA1+. ATLL may also be CD30+.
u AECTCL has distinctive morphology and clinical presentation.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
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T-Cell Lymphomas Table of Contents
Discussion
NCCN Evidence BlocksTM
USE OF IMMUNOPHENOTYPING/GENETIC TESTING IN DIFFERENTIAL DIAGNOSIS OF NK/T-CELL NEOPLASMSa
(TO BE USED IN CONJUNCTION WITH CLINICAL AND MORPHOLOGIC CORRELATION)
ENKTCL (CD5- CD4- CD8- CD30- CD56+ CGP+, midline face, upper
EBER+
aerodigestive tract, testis, GI tract) (may have T-cell phenotype)
Panel: CD2, CD3, CD4, CD5,
Extranodal, ALK+ ALCL, ALK+ small cell or histiocyte-rich variants
CD7, CD8, CD30, CD56,
noncutaneous
ALK, ßF1, TCRγ, IRF4/MUM1,
localization CD30+ • Intestinal, other abdominal/visceral sites, celiac
cytotoxic granule proteins
(non-anaplastic disease or markers positive = EATL (CD5- CD7-
(perforin, granzyme B, TIA1),
morphology) ALK- CD4- CD8+/- CD56+/- TIA1+ GRB+ Perf+)
EBV-EBER
• Other sites, celiac disease markers negative =
EBER- PTCL, NOS (usually less strongly CD30+)
Extranodal, noncutaneous localization
• Extranodal NK/T-cell lymphoma, nasal type (ENKTCL) • Intestine, epidermorphic = MEITL
• Enteropathy-associated T-cell lymphoma (EATL) • Liver, spleen, bone marrow sinuses, immune
• Monomorphic epitheliotropic intestinal T-cell CD30- suppression = HSTCL (CD5- CD7- CD4- CD8- CD56+
lymphoma (MEITL) TIA1+ GRB- Perf-)
• Hepatosplenic T-cell lymphoma (HSTCL) • Other sites = PTCL, NOS
• Peripheral T-cell lymphoma, NOS (PTCL, NOS)
• ALCL, ALK+ small cell and histiocyte-rich variants
CD30+
ALK+ ALCL, ALK+ small cell or histiocyte-rich variants
Panel: CD2, CD3,
CD4, CD5, CD7, CD8, CD10+
Nodal localization BCL6+
CD30, ALK, CD10, • Vascular proliferation, expanded CD21+ CD23+ FDC = AITL
(non-anaplastic PD1+
BCL6, PD1/CD279, • Nodular CD21+ CD23+ FDC = Follicular PTCL
morphology) CD4+/-
CXCL 13, CD21,
CD23, EBV-EBER CXCL 13+
CD30+/-
ALK- HTLV1+ = ATLL (CD2+ CD5+ CD7- CD25+ CD56-)

CD10-
Nodal localization BCL6-
• Adult T-cell leukemia/lymphoma (ATLL) HTLV1- = PTCL, NOS
• Angioimmunoblastic T-cell lymphoma (AITL)
• Peripheral T-cell lymphoma, NOS (PTCL, NOS) a These are meant to be general guidelines. Interpretation of results should be based on
• ALCL, ALK+ small cell and histiocyte-rich variants individual circumstances and may vary. Not all tests will be required in every case.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
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T-Cell Lymphomas Table of Contents
Discussion
NCCN Evidence BlocksTM
Table 1: Classification of T-Cell Lymphomas
WHO Classification of Hematolymphoid
WHO Classification of the Mature T-Cell, The International Consensus Classification
Tumors: Lymphoid Neoplasms (5th edition,
and NK-Cell Neoplasms (2017) (ICC) of Mature Lymphoid Neoplasms (2022)
2022)
Mature T-cell and NK-cell neoplasms Mature T-cell and NK-cell neoplasms Mature T-cell and NK-cell neoplasms
T-cell prolymphocytic leukemia T-cell prolymphocytic leukemia T-prolymphocytic leukaemia
T-cell large granular lymphocytic leukemia T-cell large granular lymphocytic leukemia T-large granular lymphocytic leukaemia
Chronic lymphoproliferative disorder of NK-cells* Chronic lymphoproliferative disorder of NK cells NK-large granular lymphocytic leukaemia
Aggressive NK-cell leukemia Aggressive NK cell leukemia Aggressive NK-cell leukaemia
Adult T-cell leukemia/lymphoma Adult T-cell leukemia/lymphoma Adult T-cell leukaemia/lymphoma
EBV-positive NK-cell and T-cell lymphomas
Not previously included Primary nodal EBV-positive T-cell/NK-cell lymphoma*
• EBV-positive nodal T- and NK-cell lymphoma
Extranodal NK/T-cell lymphoma, nasal type Extranodal NK/T-cell lymphoma, nasal type • Extranodal NK/T-cell lymphoma
Intestinal T-cell and NK-cell lymphoid proliferations and
Enteropathy-associated T-cell lymphoma
Enteropathy-associated T-cell lymphoma lymphomas
• Type II refractory celiac disease
• Enteropathy-associated T-cell lymphoma
Monomorphic epitheliotropic intestinal T-cell • Monomorphic epitheliotropic intestinal T-cell
Monomorphic epitheliotropic intestinal T-cell lymphoma
lymphoma* lymphoma
Intestinal T-cell lymphoma, NOS Intestinal T-cell lymphoma, NOS • Intestinal T-cell lymphoma, NOS
Indolent T-cell lymphoproliferative disorder of the Indolent clonal T-cell lymphoproliferative disorder of the
• Indolent T-cell lymphoma of the gastrointestinal tract
GI tract* GI tract
Indolent NK-cell lymphoproliferative disorder of the • Indolent NK-cell lymphoproliferative disorder of the
Not previously included
gastrointestinal tract gastrointestinal tract

*Provisional entities are listed in italics.

With permission, Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, ed. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Revised 4th ed. Lyon:
IARC; 2017.
Alaggio R, Amador C, Anagnostopoulos I, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms. Leukemia
2022;36:1720-174.
The International Consensus Classification of Mature Lymphoid Neoplasms: A Report from the Clinical Advisory Committee. Blood 2022;140:1229-1253.
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Discussion
NCCN Evidence BlocksTM
Classification
Table 1: Classification of T-Cell Lymphomas
WHO Classification of the Mature T-Cell, and The International Consensus Classification WHO Classification of Hematolymphoid Tumors:
NK-Cell Neoplasms (2017) (ICC) of Mature Lymphoid Neoplasms (2022) Lymphoid Neoplasms (5th edition, 2022)
Mature T-cell and NK-cell neoplasms Mature T-cell and NK-cell neoplasms Mature T-cell and NK-cell neoplasms
Hepatosplenic T-cell lymphoma Hepatosplenic T-cell lymphoma Hepatosplenic T-cell lymphoma
Peripheral T-cell lymphoma, NOS Peripheral T-cell lymphoma, NOS Peripheral T-cell lymphoma, NOS

Follicular helper T-cell lymphoma (TFH Lymphoma) Nodal T-follicular helper (TFH) cell lymphoma

Follicular helper T-cell lymphoma (TFH Lymphoma)

Nodal T-follicular helper (TFH) cell lymphoma
Angioimmunoblastic T-cell lymphoma • Follicular helper T-cell lymphoma,
• Nodal TFH cell lymphoma, angioimmunoblastic-type
angioimmunoblastic type
Follicular T-cell lymphoma* • Follicular helper T-cell lymphoma, follicular type • Nodal TFH cell lymphoma, follicular-type
Nodal peripheral T-cell lymphoma with TFH
• Follicular helper T-cell lymphoma, NOS • Nodal TFH cell lymphoma, NOS
phenotype*
Anaplastic large cell lymphoma
Anaplastic large-cell lymphoma, ALK positive Anaplastic large cell lymphoma, ALK-positive
• ALK-positive anaplastic large cell lymphoma
Anaplastic large-cell lymphoma, ALK negative Anaplastic large cell lymphoma, ALK-negative • ALK-negative anaplastic large cell lymphoma
Breast implant–associated anaplastic large-cell Breast implant-associated anaplastic large cell • Breast implant-associated anaplastic large cell
lymphoma* lymphoma lymphoma

*Provisional entities are listed in italics.

With permission, Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, ed. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Revised 4th ed. Lyon:
IARC; 2017.
Alaggio R, Amador C, Anagnostopoulos I, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms. Leukemia
2022;36:1720-174.
The International Consensus Classification of Mature Lymphoid Neoplasms: A Report from the Clinical Advisory Committee. Blood 2022;140:1229-1253.
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Discussion
NCCN Evidence BlocksTM
Staging
Lugano Modification of Ann Arbor Staging System*
(for primary nodal lymphomas)
Stage Involvement Extranodal (E) status
Limited One node or a group of Single extranodal lesions
Stage I adjacent nodes without nodal involvement
Stage II Two or more nodal groups Stage I or II by nodal extent
on the same side of the with limited contiguous
diaphragm extranodal involvement
Stage II bulky** II as above with “bulky” Not applicable
disease
Advanced
Stage III Nodes on both sides of Not applicable
the diaphragm
Nodes above the
diaphragm with spleen
involvement
Stage IV Additional non-contiguous Not applicable
extralymphatic involvement

*Extent of disease is determined by PET-CT for avid lymphomas, and CT for non-avid histologies.
Note: Tonsils, Waldeyer’s ring, and spleen are considered nodal tissue.
**Whether II bulky is treated as limited or advanced disease may be determined by histology and a number of prognostic factors.
Categorization of A versus B has been removed from the Lugano Modification of Ann Arbor Staging.

Reprinted with permission. © 2014 American Society of Clinical Oncology. All rights reserved. Cheson B, Fisher R, Barrington S, et al. Recommendations for initial
evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 2014;32:3059-3068.

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Discussion
NCCN Evidence BlocksTM
ABBREVIATIONS

AITL angioimmunoblastic T-cell EATL enteropathy-associated T-cell HCT hematopoietic cell transplant
lymphoma lymphoma HTS high-throughput sequencing
ALC absolute lymphocyte count EBER Epstein-Barr virus–encoded RNA HDAC histone deacetylase
ALCL anaplastic large cell EBER- Epstein-Barr encoding region in H&P history and physical
lymphoma ISH situ hybridization
HIV human immunodeficiency virus
ANC absolute neutrophil count EBV Epstein-Barr virus
HLA human leukocyte antigen
ANKL aggressive natural killer cell ECOG Eastern Cooperative Oncology
leukemia Group HLH hemophagocytic
lymphohistiocytosis
ATLL adult T-cell leukemia/ ENKL extranodal natural killer (NK)/T-
lymphoma cell lymphoma HSTCL hepatosplenic T-cell lymphoma
ENT ear, nose, and throat HTLV human T-cell lymphotropic virus
BIA- breast implant-associated
ALCL anaplastic large cell FDG fluorodeoxyglucose ICRU International Commission
lymphoma on Radiation Units and
FISH fluorescence in situ hybridization Measurements
C/A/P chest/abdominal/pelvic FNA fine-needle aspiration IGRT image-guided radiation therapy
CBC complete blood count FTCL follicular T-cell lymphoma IHC immunohistochemistry
CCRT concurrent chemoradiation IMRT intensity-modulated radiation
therapy GI gastrointestinal therapy
CMV cytomegalovirus G6PD glucose-6-phosphate IPI International Prognostic Index
CNS central nervous system dehydrogenase ISRT involved-site radiation therapy
CR complete response GTV gross tumor volume ITV internal target volume
CSF cerebrospinal fluid GVHD graft-versus-host disease IVF in vitro fertilization
CTV clinical target volume
JCV John Cunningham virus
DLBCL diffuse large B-cell lymphoma

Continued

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Discussion
NCCN Evidence BlocksTM
ABBREVIATIONS

LDH lactate dehydrogenase RA rheumatoid arthritis

LGL large granular lymphocytosis RBC red blood cell
LGLL large granular lymphocytic
lymphoma SLE systemic lupus erythematosus
LFT liver function test
LPD lymphoproliferative disorder TCR T-cell antigen receptor
TFH T-follicular helper
MEITL monomorphic epitheliotropic T-LGLL T-cell large granular
intestinal T-cell lymphoma lymphocytic leukemia
MUGA multigated acquisition TLS tumor lysis syndrome
T-PLL T-cell prolymphocytic leukemia
NGS next-generation sequencing
NK natural killer ULN upper limit of normal
NOS not otherwise specified
WBC white blood cell
OARs organs at risk

PCR polymerase chain reaction

PD progressive disease
PINK Prognostic Index of Natural
Killer Lymphoma
PJP pneumocystis jiroveci
pneumonia
PML progressive multifocal
leukoencephalopathy
PTCL peripheral T-cell lymphoma
PTV planning target volume

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Discussion
NCCN Evidence BlocksTM
NCCN Categories of Evidence and Consensus
Category 1 Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3 Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise indicated.

NCCN Categories of Preference

Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate,
Preferred intervention affordability.
Other recommended Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data;
intervention or significantly less affordable for similar outcomes.
Useful in certain
Other interventions that may be used for selected patient populations (defined with recommendation).
circumstances
All recommendations are considered appropriate.

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This discussion corresponds to the NCCN Guidelines for T-Cell Lymphomas. Last updated: May 28, 2024.

Discussion
Table of Contents

Overview .............................................................................................................................................................................................................. MS-2

Guidelines Update Methodology ........................................................................................................................................................................... MS-2
Sensitive/Inclusive Language Usage .................................................................................................................................................................... MS-2
Classification ........................................................................................................................................................................................................ MS-2
Staging................................................................................................................................................................................................................. MS-3
Response Assessment ......................................................................................................................................................................................... MS-3
Principles of Radiation Therapy ............................................................................................................................................................................ MS-4
Supportive Care ................................................................................................................................................................................................... MS-5
Peripheral T-Cell Lymphomas ............................................................................................................................................................................ MS-11
Breast Implant-Associated ALCL ........................................................................................................................................................................ MS-38
T-Cell Large Granular Lymphocytic Leukemia ..................................................................................................................................................... MS-47
T-Cell Prolymphocytic Leukemia ......................................................................................................................................................................... MS-57
Adult T-Cell Leukemia/Lymphoma ...................................................................................................................................................................... MS-67
Hepatosplenic T-Cell Lymphoma ........................................................................................................................................................................ MS-84
Extranodal Natural Killer/T-Cell Lymphomas, Nasal Type.................................................................................................................................... MS-93
Aggressive NK-Cell Leukemia .......................................................................................................................................................................... MS-102

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Overview Sensitive/Inclusive Language Usage

Non-Hodgkin lymphomas (NHLs) are a heterogeneous group of NCCN Guidelines strive to use language that advances the goals of
lymphoproliferative disorders originating in B lymphocytes, T lymphocytes, equity, inclusion, and representation. NCCN Guidelines endeavor to use
or natural killer (NK) cells. NK/T-cell lymphomas are very rare. In 2024, an language that is person-first; not stigmatizing; anti-racist, anti-classist,
estimated 80,620 people will be diagnosed with NHL and there will be anti-misogynist, anti-ageist, anti-ableist, and anti-weight-biased; and
approximately 20,140 deaths due to the disease.1 In prospectively inclusive of individuals of all sexual orientations and gender identities.
collected data from the National Cancer Data Base, diffuse large B-cell NCCN Guidelines incorporate non-gendered language, instead focusing
lymphoma (DLBCL; 32%), chronic lymphocytic leukemia/small lymphocytic on organ-specific recommendations. This language is both more accurate
lymphoma (CLL/SLL; 19%), follicular lymphoma (FL; 17%), marginal zone and more inclusive and can help fully address the needs of individuals of
lymphoma (MZL; 8%), mantle cell lymphoma (MCL; 4%), and peripheral all sexual orientations and gender identities. NCCN Guidelines will
T-cell lymphoma not-otherwise-specified (PTCL-NOS; 2%) were the major continue to use the terms men, women, female, and male when citing
subtypes of NHL diagnosed in the United States between 1998 and 2011.2 statistics, recommendations, or data from organizations or sources that do
not use inclusive terms. Most studies do not report how sex and gender
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) data are collected and use these terms interchangeably or inconsistently.
provide recommendations for diagnostic workup, treatment, supportive If sources do not differentiate gender from sex assigned at birth or organs
care, and surveillance strategies for the most common subtypes of NHL. present, the information is presumed to predominantly represent cisgender
The most common T-cell lymphoma subtypes that are covered in these individuals. NCCN encourages researchers to collect more specific data in
NCCN Guidelines® for T-Cell Lymphomas are listed below: future studies and organizations to use more inclusive and accurate
language in their future analyses.
• Peripheral T-cell lymphomas (PTCL)
• Breast implant-associated anaplastic large cell lymphoma Classification
(BIA-ALCL)
In 2022, in addition to the newly revised WHO Classification of
• T-cell large granular lymphocytic leukemia (TGLL)
Hematolymphoid Tumors (WHO5),3 another new classification system
• T-cell prolymphocytic leukemia (TPLL)
known as International Consensus Classification (ICC) was also
• Adult T-cell leukemia/lymphoma (ATLL) published.4 While both the ICC and WHO5 continue to classify the
• Hepatosplenic T-cell lymphoma (HSTCL) lymphoid malignancies based on morphology, clinical features, cell lineage
• Extranodal NK/T-cell lymphomas (ENKL) (immunophenotype), and cytogenetic and molecular features, there are
differences between the two classifications in terms of nomenclature and
Guidelines Update Methodology
diagnostic criteria. These are discussed under the respective subtypes of
The complete details of the Development and Update of the NCCN T-cell lymphomas.
Guidelines are available at [Link].

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Staging remains the gold standard for confirming new or persistent disease at
PET/CT scans are now used for initial staging, restaging, and end of therapy.
end-of-treatment response assessment in the majority of patients with
Response Assessment
NHL. PET is positive at diagnosis in 90% of patients with T-cell
lymphoma.5 However, a number of benign conditions including sarcoid, The guidelines for response criteria for lymphoma were first published in
infection, and inflammation can result in false-positive PET scans, 1999 by the International Working Group (IWG).9 These response criteria
complicating the interpretation. Lesions smaller than 1 cm are not reliably are based on the reduction in size of the enlarged lymph node as
visualized with PET scans. Although PET scans may detect additional measured by CT scan and the extent of bone marrow involvement that is
disease sites at diagnosis, the clinical stage is modified in only 15% to determined by bone marrow aspirate and biopsy.9 These guidelines were
20% of patients and a change in treatment in only 8% of patients. PET revised in 2007 by the International Harmonization Project to incorporate
scans are now virtually always performed as combined PET/CT scans. immunohistochemistry (IHC), flow cytometry, and PET scans in the
definition of response for lymphoma.10 In the revised guidelines, the
PET/CT has distinct advantages in both staging and restaging compared response is categorized as complete response (CR), partial response
to full-dose diagnostic CT or PET alone.6,7 In a retrospective study, (PR), stable disease (SD), and relapsed disease or progressive disease
PET/CT performed with low-dose non-enhanced CT was found to be (PD) based on the result of a PET scan. The response category of
more sensitive and specific than the routine contrast-enhanced CT in the complete response uncertain (CRu) was essentially eliminated.
evaluation of lymph node and organ involvement in patients with Hodgkin
disease or high-grade NHL.6 Preliminary results of another recent In 2014, revised response criteria, known as the Lugano criteria, were
prospective study (47 patients; patients who had undergone prior introduced for response assessment using PET/CT scans according to
diagnostic CT were excluded) showed a good correlation between the 5-PS.8,11 The 5-PS is based on the visual assessment of FDG uptake
low-dose unenhanced PET/CT and full-dose enhanced PET/CT in the in the involved sites relative to that of the mediastinum and the liver.12-14
evaluation of lymph nodes and extranodal disease in lymphomas.7 A score of 1 denotes no abnormal FDG avidity, while a score of 2
PET/CT is particularly important for staging before consideration of represents uptake less than the mediastinum. A score of 3 denotes
radiation therapy (RT) and baseline PET/CT will aid in the interpretation uptake greater than the mediastinum but less than the liver, while scores
of post-treatment response evaluation based on the 5-point scale (5-PS) of 4 and 5 denote uptake greater than the liver, and greater than the liver
as described above.8 with new sites of disease, respectively. Different clinical trials have
considered scores of either 1 to 2 or 1 to 3 to be PET-negative, but a
PET/CT is recommended for initial staging of 18F-fluorodeoxyglucose score of 1 to 3 is now widely considered to be PET negative. Scores of 4
(FDG)-avid lymphomas. PET should be done with contrast-enhanced to 5 are universally considered PET positive. A score of 4 on an interim
diagnostic CT. FDG-avid lymphomas should have response assessed by or end-of-treatment restaging scan may be consistent with a PR if the
PET/CT using the 5-PS. False-positive PET scans may be observed FDG avidity has declined from initial staging, while a score of 5 denotes
related to infectious or inflammatory conditions. Biopsy of affected sites PD.

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However, the application of PET/CT to response assessment is limited to clinically meaningful manner without compromising target coverage should
FDG-avid lymphomas and the revised response criteria have thus far be considered.
only been validated for DLBCL and Hodgkin lymphoma. The application
of the revised response criteria to other histologies requires validation Involved-site RT (ISRT) is intended to limit radiation exposure to adjacent
and the original IWG guidelines should be used. False-positive PET uninvolved organs (eg, lungs, bone, muscle, kidney) when
scans may be observed related to infectious or inflammatory conditions. lymphadenopathy regresses following chemotherapy, thus minimizing the
Biopsy of affected sites remains the gold standard for confirming new or potential long-term complications. Extended-field RT (EFRT) and
persistent disease at end of therapy. involved-field RT (IFRT) techniques have now been replaced by ISRT in
an effort to restrict the size of the RT fields to smaller volumes.15,16 ISRT
Principles of Radiation Therapy targets the initially involved nodal and extranodal sites detectable at
RT can be delivered with photons, electrons, or protons depending on presentation.15,16 Larger RT fields should be considered for limited-stage
clinical circumstances. Advanced RT techniques emphasize tightly indolent NHL, often treated with RT alone.15
conformal doses and steep gradients next to normal tissues. Therefore,
Treatment planning for ISRT requires the use of CT-based simulation. The
target definition and delineation and treatment delivery verification require
incorporation of additional imaging techniques such as PET and MRI often
careful monitoring to avoid the risk of missing geographic location of the
enhances the treatment planning. The OAR should be outlined for
tumor and subsequent decrease in tumor control. Image guidance may be
optimizing treatment plan decisions. The treatment plan is designed using
required to facilitate target definition. Significant dose reduction to organs
conventional, 3D conformal, or IMRT techniques using clinical treatment
at risk (OAR; eg, lungs, heart, breasts, kidneys, spinal cord, esophagus,
planning considerations of coverage and dose reductions for OAR.15
carotid artery, bone marrow, stomach, muscle, soft tissue, salivary glands)
can be achieved with advanced RT planning and delivery techniques such The principles of ISRT are similar for both nodal and extranodal disease.
as 4D-CT simulation, intensity-modulated RT (IMRT), image-guided RT The gross tumor volume (GTV) defined by radiologic imaging prior to
(IGRT), respiratory gating, or deep inspiration breath hold.15,16 These biopsy, chemotherapy, or surgery provides the basis for determining the
techniques offer significant and clinically relevant advantages in specific clinical target volume (CTV).19 Possible movement of the target by
instances to spare OAR and decrease the risk for normal tissue damage respiration as determined by 4D-CT or fluoroscopy should also influence
and late effects without compromising the primary goal of local tumor the final CTV. The presence of suspected subclinical disease and
control.15-18 uncertainties in original imaging accuracy or localization may lead to the
expansion of the CTV. The planning treatment volume (PTV) is an
Randomized prospective studies to test these concepts are unlikely to be
additional expansion of the CTV that accounts only for setup variations.
done since these techniques are designed to decrease late effects, which
usually develop greater than or equal to 10 years after completion of In the case of extranodal disease, the whole organ (eg, stomach, salivary
treatment. Therefore, the guidelines recommend that RT delivery gland, thyroid) comprises the CTV in most cases. For other organs,
techniques that are found to best reduce the doses to the OAR in a including orbit, breast, lung, bone, and localized skin, and in some cases

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T-Cell Lymphomas

when RT is consolidation after chemotherapy, partial organ RT may be Allopurinol is a xanthine analog and a competitive inhibitor of xanthine
appropriate. No radiation is required for uninvolved lymph nodes for most oxidase, thereby blocking the conversion of purine metabolites to uric
NHL subtypes. acid and decreasing the formation of uric acid production.22 Since the
drug inhibits new uric acid formation rather than reduce existing uric
The treatment planning recommendations and general dose guidelines for acid, it can take several days for elevated levels of uric acid to normalize
individual subtypes of T-cell lymphomas are outlined in the Principles of after the initiation of allopurinol, which may delay the start of
RT section of the Guidelines. Recommendations for normal tissue dose chemoimmunotherapy. Furthermore, allopurinol may lead to the
constraints can be found in the Principles of Radiation Therapy section of accumulation of xanthine crystals in renal tubules leading to acute
the NCCN Guidelines for Hodgkin Lymphoma. obstructive uropathy. Allopurinol will also reduce clearance of
6-mercaptopurine and high-dose methotrexate.
Supportive Care
Tumor Lysis Syndrome Rasburicase, a recombinant urate oxidase, has been shown to be safe
and highly effective in the prevention and treatment of
Tumor lysis syndrome (TLS) is a potentially serious complication of
anticancer therapy characterized by metabolic and electrolyte chemotherapy-induced hyperuricemia in both children and adults with
hematologic malignancies.23-25 In a prospective, multicenter, randomized
abnormalities caused by the disintegration of malignant cells by
anticancer therapy and rapid release of intracellular contents into phase III trial of adult patients with hematologic malignancies at high or
potential risk for TLS (275 patients; rasburicase alone, n = 92;
peripheral blood. It is usually observed within 12 to 72 hours after start of
rasburicase combined with allopurinol, n = 92; allopurinol alone, [n = 91),
chemotherapy.20
the response rate with rasburicase was superior to allopurinol in the
Laboratory TLS is defined as a 25% increase in the levels of serum uric overall study population (87% vs. 66%, as above; P = .001) as well as in
acid, potassium, or phosphorus or a 25% decrease in calcium levels.21 patients with high-risk TLS (89% vs. 68%; P = .001) and in patients with
Clinical TLS refers to laboratory TLS with clinical toxicity that requires baseline hyperuricemia (90% vs. 53%; P = .015).25 The incidence of
intervention. Hyperkalemia, hyperuricemia, hyperphosphatemia, and clinical TLS was similar across treatment arms, occurring in 3%, 3%, and
hypocalcemia are the primary electrolyte abnormalities associated with 4% of patients, respectively. The incidence of laboratory TLS was 21%,
TLS. Clinical symptoms may include nausea and vomiting, diarrhea, 27%, and 41%, respectively, with significantly lower incidence observed
seizures, shortness of breath, renal insufficiency, or cardiac arrhythmias. in the rasburicase arm compared with allopurinol (P = .003). Potential
Untreated TLS can induce profound metabolic changes resulting in hypersensitivity to study regimen was reported in 4% of patients in the
cardiac arrhythmias, seizures, loss of muscle control, acute renal failure, rasburicase arm and 1% in the combination arm; no anaphylaxis or
and even death. The cornerstone of TLS management is hydration and grade 4 hypersensitivity reactions were reported in this trial.25 However,
the management of hyperuricemia. Allopurinol, febuxostat, and rasburicase can induce anaphylactic reactions. Other adverse reactions
rasburicase are highly effective for the management of hyperuricemia. include methemoglobinemia and severe hemolysis in patients with
glucose-6-phosphate dehydrogenase (G6PD) deficiency.

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There are data to suggest that single fixed dose (6 mg or 3 mg) or single patients with any of these risk factors. Frequent monitoring of electrolytes
weight-based dose of rasburicase (0.05–0.15 mg/kg) are effective in and aggressive correction are essential.
adult patients with hyperuricemia or high-risk factors for TLS.26-31 In the
phase II randomized trial that compared the efficacy of rasburicase Allopurinol or febuxostat is recommended for patients with low-risk or
administered as a single dose (0.15 mg/kg, followed by additional days intermediate-risk disease. Rasburicase is recommended for
of dosing as needed) versus rasburicase (0.15 mg/kg/day) given for 5 intermediate-risk disease (if renal dysfunction and uric acid, potassium,
days in 80 adult patients at high risk or potential risk for TLS, nearly all and/or phosphate greater than upper limit of normal [ULN]) or high-risk
treated patients (99%) showed normalization of uric acid levels within 4 disease. Allopurinol and febuxostat should be started 2 to 3 days prior to
hours after the first dose of rasburicase; levels of uric acid were the initiation of chemotherapy and continued for 10 to 14 days. A single
undetectable (<0.7 mg/dL) in 84% of patients.31 The median dose of rasburicase (3 mg or 6 mg) is adequate in most circumstances
pretreatment uric acid level was 8.5 mg/dL for patients at high risk for and repeat dosing should be individualized based on the presence of any
TLS (n = 40) and 5.6 mg/dL for patients at potential risk for TLS (n = 40). of the following risk factors: bulky disease requiring immediate therapy;
In the single-dose rasburicase arm, 85% of patients had sustained uric adequate hydration is not possible; or acute renal failure. Rasburicase is
acid response compared with 98% of patients in the 5-day rasburicase contraindicated in patients with G6PD deficiency due to an increased risk
arm. Among patients with high-risk disease within the single-dose arm, 6 of methemoglobinemia or hemolysis.34 G6PD testing should be
patients received a second dose of rasburicase to achieve uric acid considered prior to the initiation of rasburicase. Rasburicase should be
response. substituted with allopurinol G6PD deficiency.

In a randomized trial that compared the efficacy and safety of febuxostat Viral Reactivation and Infections
and allopurinol in 346 adult patients with hematologic malignancies at Cytomegalovirus Reactivation
intermediate or high risk for TLS, one fixed dose of febuxostat achieved Cytomegalovirus (CMV) reactivation is a well-documented infectious
a significantly superior serum uric acid control in comparison to complication in patients receiving treatment with alemtuzumab, occurring
allopurinol with comparable renal function preservation and safety in up to 25% of treated patients. CMV reactivation may occur among
profile.32 patients with hematologic malignancies treated with alemtuzumab
containing regimens, most frequently between 3 to 6 weeks after initiation
TLS is best managed if anticipated and when treatment is started prior to of therapy when T-cell counts reach a nadir. The panel recommends
chemoimmunotherapy. Histologies of Burkitt lymphoma (BL), measurement of CMV viremia using quantitative polymerase chain
lymphoblastic lymphoma and occasionally DLBCL, bone marrow reaction (PCR) at least every 2 to 3 weeks during the treatment course
involvement, bulky tumors that are chemosensitive, rapidly proliferative with alemtuzumab and for 2 months following completion of alemtuzumab
or aggressive hematologic malignancies, an elevated leukocyte count or treatment. Current management practices for the prevention of CMV
pretreatment lactate dehydrogenase (LDH), pre-existing elevated uric reactivation include the use of prophylactic ganciclovir prior to
acid, renal disease, or renal involvement of tumor are considered as risk alemtuzumab therapy if CMV viremia is present, or preemptive use of
factors for developing TLS.33 TLS prophylaxis should be considered for
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these drugs when the viral load is found to be increasing during therapy.
Evaluation of CD52 expression should be considered before initiating
treatment with alemtuzumab-based regimens.

Herpes virus prophylaxis with acyclovir or equivalent and pneumocystis

jirovecii pneumonia (PJP) prophylaxis with sulfamethoxazole/trimethoprim
or equivalent is recommended for patients receiving alemtuzumab-based
regimens. Antifungal prophylaxis should be considered.

Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is a rare but serious
and usually fatal central nervous system (CNS) infection caused by
reactivation of the latent John Cunningham (JC) polyomavirus. Patients
with NHL receiving treatment with the anti-CD30 antibody-drug conjugate
brentuximab vedotin may be at potential risk for PML.35 Cases of PML
generally occur in severely immunocompromised individuals, as in the
case of patients with AIDS. Patients with hematologic malignancies who
have profound immunosuppression (due to the underlying disease and/or
immunosuppressive therapies) are also at risk of developing PML.
Development of PML is clinically suspected based on neurologic signs
and symptoms that may include confusion, motor weakness or poor
motor coordination, visual changes, and/or speech changes.35 PML is
usually diagnosed with PCR of cerebrospinal fluid (CSF) or, in some
cases, by analysis of brain biopsy material. There is no effective
treatment for PML. Patients should be carefully monitored for the
development of any neurologic symptoms. There is currently no
consensus on pretreatment evaluations that can be undertaken to predict
for the subsequent development of PML.

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References non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol

2014;32:3059-3068. Available at:
1. Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J [Link]
Clin 2024;74:12-49. Available at:
[Link] 9. Cheson BD, Horning SJ, Coiffier B, et al. Report of an International
Workshop to standardize response criteria for Non-Hodgkin's Lymphomas.
2. Al-Hamadani M, Habermann TM, Cerhan JR, et al. Non-Hodgkin J Clin Oncol 1999;17:1244-1253. Available at:
lymphoma subtype distribution, geodemographic patterns, and survival in [Link]
the US: A longitudinal analysis of the National Cancer Data Base from
1998 to 2011. Am J Hematol 2015;90:790-795. Available at: 10. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for
[Link] malignant lymphoma. J Clin Oncol 2007;25:579-586. Available at:
[Link]
3. Alaggio R, Amador C, Anagnostopoulos I, et al. The 5th edition of the
World Health Organization Classification of Haematolymphoid Tumours: 11. Barrington SF, Mikhaeel NG, Kostakoglu L, et al. Role of imaging in
Lymphoid Neoplasms. Leukemia 2022;36:1720-1748. Available at: the staging and response assessment of lymphoma: Consensus of the
[Link] International Conference on Malignant Lymphomas Imaging Working
Group. J Clin Oncol 2014;32:3048-3058. Available at:
4. Campo E, Jaffe ES, Cook JR, et al. The International Consensus [Link]
Classification of Mature Lymphoid Neoplasms: a report from the Clinical
Advisory Committee. Blood 2022;140:1229-1253. Available at: 12. Barrington SF, Qian W, Somer EJ, et al. Concordance between four
[Link] European centres of PET reporting criteria designed for use in multicentre
trials in Hodgkin lymphoma. Eur J Nucl Medi Imaging 2010;37:1824-1833.
5. Feeney J, Horwitz S, Gonen M, Schoder H. Characterization of T-cell Available at: [Link]
lymphomas by FDG PET/CT. AJR Am J Roentgenol 2010;195:333-340.
Available at: [Link] 13. Meignan M, Gallamini A, Haioun C, Polliack A. Report on the second
international workshop on interim positron emission tomography in
6. Schaefer NG, Hany TF, Taverna C, et al. Non-Hodgkin lymphoma and lymphoma held in Menton, France, 8-9 April 2010. Leuk Lymphoma
Hodgkin disease: Coregistered FDG PET and CT at staging and 2010;51:2171-2180. Available at:
restaging--do we need contrast-enhanced CT? Radiology [Link]
2004;232:823-829. Available at:
[Link] 14. Meignan M, Gallamini A, Itti E, et al. Report on the third international
workshop on interim positron emission tomography in lymphoma held in
7. Rodriguez-Vigil B, Gomez-Leon N, Pinilla I, et al. PET/CT in lymphoma: Menton, France, 26-27 September 2011 and Menton 2011 consensus.
Prospective study of enhanced full-dose PET/CT versus unenhanced Leuk Lymphoma 2012;53:1876-1881. Available at:
low-dose PET/CT. J Nucl Med 2006;47:1643-1648. Available at: [Link]
[Link]
15. Illidge T, Specht L, Yahalom J, et al. Modern radiation therapy for
8. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial nodal non-Hodgkin lymphoma-target definition and dose guidelines from
evaluation, staging, and response assessment of Hodgkin and the International Lymphoma Radiation Oncology Group. Int J Radiat Oncol

Version 4.2024 © 2024 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

Biol Phys 2014;89:49-58. Available at: 23. Bosly A, Sonet A, Pinkerton CR, et al. Rasburicase (recombinant urate
[Link] oxidase) for the management of hyperuricemia in patients with cancer:
report of an international compassionate use study. Cancer
16. Yahalom J, Illidge T, Specht L, et al. Modern radiation therapy for 2003;98:1048-1054. Available at:
extranodal lymphomas: Field and dose guidelines from the International [Link]
Lymphoma Radiation Oncology Group. Int J Radiat Oncol Biol Phys
2015;92:11-31. Available at: 24. Coiffier B, Mounier N, Bologna S, et al. Efficacy and safety of
[Link] rasburicase (recombinant urate oxidase) for the prevention and treatment
of hyperuricemia during induction chemotherapy of aggressive
17. Nieder C, Schill S, Kneschaurek P, Molls M. Influence of different non-Hodgkin's lymphoma: results of the GRAAL1 (Groupe d'Etude des
treatment techniques on radiation dose to the LAD coronary artery. Radiat Lymphomes de l'Adulte Trial on Rasburicase Activity in Adult Lymphoma)
Oncol 2007;2:20. Available at: study. J Clin Oncol 2003;21:4402-4406. Available at:
[Link] [Link]
18. Charpentier AM, Conrad T, Sykes J, et al. Active breathing control for 25. Cortes J, Moore JO, Maziarz RT, et al. Control of plasma uric acid in
patients receiving mediastinal radiation therapy for lymphoma: Impact on adults at risk for tumor lysis syndrome: efficacy and safety of rasburicase
normal tissue dose. Pract Radiat Oncol 2014;4:174-180. Available at: alone and rasburicase followed by allopurinol compared with allopurinol
[Link] alone-results of a multicenter phase III study. J Clin Oncol
2010;28:4207-4213. Available at:
19. Hoskin PJ, Diez P, Williams M, et al. Recommendations for the use of [Link]
radiotherapy in nodal lymphoma. Clin Oncol (R Coll Radiol)
2013;25:49-58. Available at: 26. McDonnell AM, Lenz KL, Frei-Lahr DA, et al. Single-dose rasburicase
[Link] 6 mg in the management of tumor lysis syndrome in adults.
Pharmacotherapy 2006;26:806-812. Available at:
20. Coiffier B, Altman A, Pui C, et al. Guidelines for the management of [Link]
pediatric and adult tumor lysis syndrome: An evidence-based review. J
Clin Oncol 2008;26:2767-2778. Available at: 27. Campara M, Shord SS, Haaf CM. Single-dose rasburicase for tumour
[Link] lysis syndrome in adults: weight-based approach. J Clin Pharm Ther
2009;34:207-213. Available at:
21. Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic [Link]
strategies and classification. Br J Haematol 2004;127:3-11. Available at:
[Link] 28. Trifilio SM, Pi J, Zook J, et al. Effectiveness of a single 3-mg
rasburicase dose for the management of hyperuricemia in patients with
22. Krakoff IH, Meyer RL. Prevention of hyperuricemia in leukemia and hematological malignancies. Bone Marrow Transplant 2011;46:800-805.
lymphoma: use of alopurinol, a xanthine oxidase inhibitor JAMA Available at: [Link]
1965;193:1-6. Available at:
[Link] 29. Vines AN, Shanholtz CB, Thompson JL. Fixed-dose rasburicase 6 mg
for hyperuricemia and tumor lysis syndrome in high-risk cancer patients.

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T-Cell Lymphomas

Ann Pharmacother 2010;44:1529-1537. Available at:

[Link]

30. Knoebel RW, Lo M, Crank CW. Evaluation of a low, weight-based

dose of rasburicase in adult patients for the treatment or prophylaxis of
tumor lysis syndrome. J Oncol Pharm Pract 2011;17:147-154. Available
at: [Link]

31. Vadhan-Raj S, Fayad LE, Fanale MA, et al. A randomized trial of a

single-dose rasburicase versus five-daily doses in patients at risk for tumor
lysis syndrome. Ann Oncol 2012;23:1640-1645. Available at:
[Link]

32. Spina M, Nagy Z, Ribera JM, et al. FLORENCE: A randomized,

double-blind, phase III pivotal study of febuxostat versus allopurinol for the
prevention of tumor lysis syndrome (TLS) in patients with hematologic
malignancies at intermediate to high TLS risk. Ann Oncol
2015;26:2155-2161. Available at:
[Link]

33. Cairo MS, Coiffier B, Reiter A, et al. Recommendations for the

evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults
and children with malignant diseases: an expert TLS panel consensus. Br
J Haematol 2010;149:578-586. Available at:
[Link]

34. Gammal RS, Pirmohamed M, Somogyi AA, et al. Expanded clinical

pharmacogenetics implementation consortium guideline for medication
use in the context of G6PD genotype. Clin Pharmacol Ther 2022.
Available at: [Link]

35. Carson KR, Newsome SD, Kim EJ, et al. Progressive multifocal
leukoencephalopathy associated with brentuximab vedotin therapy: A
report of 5 cases from the Southern Network on Adverse Reactions
(SONAR) project. Cancer 2014;120:2464-2471. Available at:
[Link]

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T-Cell Lymphomas

Peripheral T-Cell Lymphomas Nodal T-cell lymphomas of T-follicular helper (TFH) cell origin have a more
Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of favorable prognosis and also respond better to certain therapies,
lymphoproliferative disorders arising from mature T cells, accounting for particularly therapies targeting epigenetics, such as histone deacetylase
about 10% of non-Hodgkin lymphomas (NHLs). PTCL-not otherwise (HDAC) inhibitors when compared with other PTCL subtypes.14-16 Nodal
specified (PTCL-NOS; 26%) is the most common subtype, followed by T-cell lymphomas of TFH phenotype express TFH cell markers (eg, CD10,
angioimmunoblastic T-cell lymphoma (AITL; 19%), anaplastic large cell BCL6, CXCL13, PD1, ICOS) and recurrent mutations in TET2, DNMT3A,
lymphoma (ALCL), anaplastic lymphoma kinase (ALK)-positive (7%), IDH2, and RHOAG17V genes have been identified in the majority of
ALCL, ALK-negative (6%), and enteropathy-associated T-cell lymphoma cases.17-20 In the 2017 WHO classification, the category of nodal
(EATL; <5%).1 lymphomas of TFH cell origin was created to include the three subtypes:
AITL, PTCL with TFH phenotype, and follicular helper T-cell lymphoma.21
PTCL-NOS most often involves nodal sites; however, many patients In WHO5, all three subtypes of nodal lymphomas of TFH cell origin are
present with extranodal involvement, including the liver, bone marrow, listed under a new category, nodal TFH cell lymphomas and are renamed
gastrointestinal (GI) tract, and skin. PTCL-NOS is associated with poorer as nodal TFH cell lymphoma, angioimmunoblastic-type, nodal TFH cell
overall survival (OS) and event-free survival (EFS) rates compared to lymphoma, NOS and nodal TFH cell lymphoma, follicular-type,
aggressive B-cell lymphomas.2,3 Gene expression profiling (GEP) studies respectively.8 In the ICC, follicular helper T-cell lymphoma is considered
and immunohistochemistry (IHC) algorithms have identified two major as a single entity encompassing the three subtypes (follicular helper T-cell
molecular subgroups of PTCL-NOS (characterized by high expression of lymphoma, angioimmunoblastic type, follicular helper T-cell lymphoma,
either GATA3 or TBX21).4-7 In a multivariate analysis, a high international follicular type and follicular helper T-cell lymphoma, NOS).9
prognostic index (IPI) score and PTCL-GATA3 subtype identified by IHC
were independently associated with poor OS.7 The 2022 WHO ALCL is a CD30-expressing subtype that accounts for less than 5% of all
classification (WHO5) and International Consensus Classification (ICC) cases of NHL. There are now four distinctly recognized subtypes of ALCL:
also recognize the clinical significance of GATA3 and TBX21 expression in systemic ALCL, ALK-positive; systemic ALCL, ALK-negative; breast
PTCL-NOS subtypes.8,9 implant-associated ALCL (BIA-ALCL), and primary cutaneous ALCL.
BIA-ALCL represents a distinct entity from systemic ALCL and other forms
AITL occurs mainly in older patients with a prognosis similar to PTCL-NOS of primary breast lymphoma (which are usually of B-cell origin).8,9
and usually presents with generalized lymphadenopathy, and is often with
associated hypergammaglobulinemia, hepatomegaly or splenomegaly, ALCL, ALK-positive is most common in children and young adults and is
eosinophilia, skin rash, and fever.3,10,11 AITL is also characterized by the characterized by the overexpression of ALK-1 protein, resulting from a
frequent presence of Epstein-Barr virus (EBV)-positive B-cells and cases chromosomal translocation [t(2;5)] in 40% to 60% of patients.22 The
of AITL coexistent EBV+ diffuse large B-cell lymphoma (DLBCL) are majority of patients with systemic ALCL present with advanced stage III or
reported.11-13 IV disease (65% for ALK-positive and 58% for ALK-negative) frequently
associated with systemic symptoms and extranodal involvement.23

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IHC, FISH, and GEP studies have identified molecular subtypes of ALCL, the analysis from the International T-Cell Lymphoma Project, EATL
ALK-negative characterized by the presence of dual-specificity comprised 5% of all PTCL and natural killer (NK)-cell lymphomas included
phosphatase 22 (DUSP22) and TP63 rearrangements.24-29 In earlier in the study.33 EATL was more common (66%) than MEITL (34%). With a
reports, the presence of DUSP22 rearrangement (identified in 30% of all median follow-up of 11 months, the median OS and failure-free survival
ALCL, ALK-negative cases) was associated with a favorable prognosis (FFS) were 10 months and 6 months for EATL and MEITL, respectively.
(5-year OS rate, 80%–90%), whereas the presence of TP63 The 5-year OS and FFS rates were 20% and 4%, respectively. The
rearrangement (occurring in about 8% of cases) was associated with a optimal treatment for MEITL has not yet been defined.
worse prognosis (5-year OS rate of 17%).24,25 Other studies have reported
that ALCL, ALK-negative with a DUSP22 rearrangement is not associated Literature Search Criteria
with better clinical outcome and cases with DUSP22 rearrangement were Prior to the update of this version of the NCCN Clinical Practice Guidelines
also associated with some high-risk features (probably contributing to (NCCN Guidelines®) for T-Cell Lymphomas an electronic search of the
lower survival outcome).27,28 Nevertheless, outcomes in the presence of PubMed database was performed to obtain key literature in peripheral
DUSP22 rearrangement were significantly better than both ALCL, T-cell lymphomas published since the last Guidelines update. The
ALK-negative with TP63 rearrangements and triple negative ALCL PubMed database was chosen as it remains the most widely used
lacking all 3 rearrangements of ALK, DUSP22, and TP63.27,29 In a resource for medical literature and indexes only peer-reviewed biomedical
retrospective study of the Lymphoma Study Association (LYSA), which literature.34
analyzed the outcomes of 104 patients with ALCL, ALK-negative based
on the DUSP22 status, after a median follow-up of 5 years, the 5-year The search results were narrowed by selecting studies in humans
progression-free survival (PFS) rate was 57% for patients with DUSP22 published in English. Results were confined to the following article types:
rearrangement compared to 26% for those with triple negative ALCL.29 Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, Phase IV;
The corresponding 5-year OS rates were 65% and 41%, respectively. Guideline; Randomized Controlled Trial; Meta-Analysis; Systematic
Reviews; and Validation Studies.
EATL is a rare T-cell lymphoma of the small intestine, accounting for less
than 1% of all NHLs, and is associated with a very poor prognosis.30-33 The The data from key PubMed articles as well as articles from additional
median age of diagnosis is 60 years. In the previous WHO classifications, sources deemed as relevant to these Guidelines have been included in
EATLs were classified as EATL type I and EATL type II, but only EATL this version of the Discussion section. Recommendations for which
type I was truly associated with enteropathy (celiac disease). In the 2017 high-level evidence is lacking are based on the Panel’s review of
WHO classification, the two diseases were redefined as separate entities. lower-level evidence and expert opinion.
EATL type 1 (associated with celiac disease) was defined as EATL and
Prognosis
EATL type II was renamed as monomorphic epitheliotropic intestinal T-cell
lymphoma (MEITL).21 In WHO5, both EATL and MEITL are listed under PTCLs carry a poorer prognosis than aggressive B-cell lymphomas since
intestinal T-cell and NK-cell lymphoid proliferations and lymphomas.8 In they are less responsive to and have less frequent durable remissions with

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standard anthracycline-based chemotherapy regimens. Progress has (AITL score) based on age (age ≥60 years; ECOG PS >2; elevated
been further hampered by the relative rarity and the biological C-reactive protein and elevated β2 microglobulin) stratified patients into
heterogeneity. In general, ALCL, ALK-positive is associated with better three risk groups (low-, intermediate-, and high-risk) with estimated
clinical outcomes than ALCL, ALK-negative, PTCL-NOS, or AITL. The 5-year OS rates of 63%, 54%, and 21%, respectively.41
favorable prognosis of ALK-1 positivity, however, is diminished with older
age and higher prognostic risk scores.35-39 In an analysis of 341 patients Historically, the IPI and NCCN-IPI developed for DLBCL have been used
with newly diagnosed PTCL treated with anthracycline-based for the risk stratification of patients with PTCL.2,23,42 Prognostic Index for
chemotherapy, the 3-year PFS and OS rates (32% and 52%, respectively) PTCL-U (PIT) and T-cell score are the new prognostic models that have
were significantly inferior to the matched cohort of patients with DLBCL been developed for the risk stratification of patients with PTCL-NOS.43,44
and there was no clear benefit for patients undergoing consolidative PIT is based on the following risk factors: age >60 years, elevated lactate
hematopoietic cell transplant (HCT).38 Stage I–II disease was the only dehydrogenase (LDH) levels, performance status of 2 or more, and bone
significant pretreatment prognostic factor in the multivariate analysis. ALK marrow involvement.43 The 5-year OS rate was 33% for patients with two
positivity was a prognostic factor on univariate analysis, but lost its risk factors and 18% for those with three or four risk factors. This
significance on multivariate analysis. prognostic index also identified a subset of patients with relatively
favorable prognosis who had no adverse risk factors.43 This group
In the survival analysis from the International T-Cell Lymphoma Project, represented 20% of patients and had a 5-year OS rate of 62%. T-cell
ALCL, ALK-positive was associated with significantly better prognosis with score (developed by the International T-cell Project Network) is based on
anthracycline-containing regimens compared with ALCL, ALK-negative, four clinical variables: serum albumin, performance status, stage, and
both in terms of the 5-year FFS rate (60% vs. 36%; P = .015) and OS rate absolute neutrophil count. T-cell score stratified patients into three risk
(70% vs. 49%; P = .016). ALCL, ALK-negative was associated with groups (low-, intermediate-, and high-risk) with estimated 3-year OS rates
superior survival rates when compared with PTCL-NOS (5-year FFS and of 76%, 43%, and 11%, respectively.44
OS rates were 20% and 32%, respectively).36
In a pooled analysis of three international cohorts of nodal PTCL, all
In a report from the GELA study, which included the largest series of three indices (IPI, NCCN-IPI, and PIT) demonstrated better risk
patients with AITL (n = 157), 5- and 7-year OS rates were 33% and 29%, stratification for ALK-ALCL and PTCL-NOS.45 However, none of the
respectively, reaching an apparent plateau around 6 years.10 The indices was useful for prognostication or stratification in AITL. IPI,
corresponding EFS rates were 29% and 23%, respectively. In the recently NCCN-IPI, and PIT can be used to stratify for prognosis and under certain
published survival analyses from the International T-Cell Lymphoma circumstances may aid in guiding treatment decisions for patients with
Project, 5-year PFS and OS rates were 43% and 49%, respectively, for PTCL.
patients with ALCL, ALK-negative treated with multiagent chemotherapy
regimens and the estimated 5-year PFS and OS rates were 32% and Progression of disease within 24 months (POD24) after primary treatment
44%, respectively, for patients with AITL.40,41 A novel prognostic score has been identified as a predictor of survival in patients with newly
diagnosed PTCL. In a large multinational cohort study of 775 patients with

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newly diagnosed PTCL, the median OS was 5 months versus not reached markers: CD20, CD3, CD10, BCL6, Ki-67, CD5, CD30, CD2, CD4, CD8,
for those without POD24.46 The corresponding 5-year OS rates were 11% CD7, CD56, CD21, CD23, TCRβ, TCRδ, PD1/CD279, ALK, and TP63.
and 78%, respectively. The prognostic significance of POD24 in patients Alternatively, the following markers can be analyzed by flow cytometry:
with newly diagnosed PTCL was also demonstrated in subsequent CD45, CD3, CD5, CD19, CD10, CD20, CD30, CD4, CD8, CD7, and CD2;
studies.41,47-49 These results suggest that patients with primary refractory and TCRα, TCRβ, and TCRγ. As noted earlier, AITL may occasionally
disease or early relapse have extremely poor survival and that POD24 present with concurrent EBV+ DLBCL and EBV evaluation by
could be used for risk stratification of patients with PTCL. Epstein-Barr encoding region in situ hybridization (EBER-ISH) should be
performed.11-13
Diagnosis
Excisional or incisional biopsy is preferred over core needle biopsy if IHC for ALK1 or molecular analysis to detect t(2;5) or variant
possible for initial diagnosis. If only core needle biopsy is feasible due to translocations, is essential to identify ALCL, ALK-positive that has a better
the sites of disease, a combination of core needle biopsy and fine-needle prognosis. IHC for markers of TFH cell origin (CXCL13, ICOS, PD1) are
aspiration (FNA) biopsy in conjunction with appropriate ancillary recommended if PTCL-NOS or TFH phenotype is suspected. The use of
techniques may be sufficient for diagnosis (multiple cores should be next-generation sequencing (NGS) panel may also be useful to support
obtained to allow for adequate workup). the diagnosis of TFH subtypes. IHC for cytotoxic T-cell markers (TIA-1,
granzyme B, perforin) may be useful to characterize subsets of
PTCL-NOS has variable T-cell–associated antigens and usually lacks PTCL.17,52,53
B-cell–associated antigens (although aberrant CD20 expression in T-cell
lymphomas is infrequently encountered). While CD30 expression can be PTCL is often associated with clonal T-cell antigen receptor (TCR) gene
found at times in many T-cell lymphomas, with the exception of systemic rearrangements that are less frequently seen in non-cancer T-cell
ALCL (which has a uniform strong expression of CD30), CD30 expression diseases. Molecular analysis to detect clonal TCR gene rearrangements is
by IHC (score of ≥2) is variable across other subtypes of PTCL (52% in useful for the assessment of T-cell clonality although false-positive results
PTCL-NOS and 21% in AITL).50 The majority of the nodal cases express or non-malignant clones can at times be identified. TRBC1 expression by
CD4 and lack CD8; however, CD4-/CD8+, CD4-/CD8-, and CD4+/CD8+ flow cytometry has been reported as a highly sensitive method for the
cases are seen.51 AITL cells express T-cell–associated antigens and are assessment of T-cell clonality with good correlation with molecular
usually CD4+. Expression of CXCL13 has been identified as a useful methods.54-57
marker that may help distinguish AITL from PTCL-NOS.52,53
Molecular analysis to detect t(2;5) translocations involving the ALK gene
Adequate immunophenotyping is essential to distinguish PTCL subtypes may be useful for patients with ALCL, ALK-positive and molecular analysis
from B-cell lymphomas. The initial paraffin panel for IHC studies may only to detect DUSP22 rearrangement and TP63 rearrangement (if IHC is
include pan–T-cell markers and can be expanded to include antibodies of positive for TP63) may be useful for patients with ALCL, ALK-negative.
T-cell lymphoma, if suspected. The IHC panel may include the following As discussed earlier, ALCL, ALK-negative with DUSP22 rearrangement
is associated with a favorable prognosis more similar to ALK-positive
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ALCL, although the data supporting a truly favorable prognosis is available mainly from retrospective analyses and small prospective
inconsistent, whereas ALCL, ALK-negative with TP63 rearrangements studies (as discussed below).
and triple negative ALCL (lacking all 3 rearrangements of ALK, DUSP22,
and TP63) are associated with an unfavorable prognosis (inferior survival Anthracycline-based chemotherapy regimens (eg, CHOP
outcomes compared to ALCL, ALK-negative with DUSP22 [cyclophosphamide, doxorubicin, vincristine, and prednisone] or CHOP +
rearrangement).24-29 etoposide [CHOEP] or dose-adjusted EPOCH [etoposide, prednisone,
vincristine, cyclophosphamide, and doxorubicin]) are the most commonly
Workup used first-line therapy regimens since these are associated with a trend
The workup for PTCL is similar to the workup for other lymphoid toward significance in mortality reduction.58 However, with the exception
neoplasms, focusing on the determination of stage, routine laboratory of ALK+ ALCL, outcomes are not optimal in other subtypes.3,59-63
studies (bone marrow biopsy ± aspirate, complete blood count [CBC] with
In a retrospective analysis of 289 patients with PTCL treated within the
differential, comprehensive metabolic panel), physical examination
DSHNHL trials, CHOEP was associated with an event-free survival benefit
including a full skin exam, and imaging studies, as indicated. PET/CT scan
in ALCL, ALK-positive in patients <60 to 65 years of age and also in
and/or chest/abdomen/pelvis (C/A/P) CT with contrast of diagnostic quality
patients with subtypes other than ALCL, ALK-positive with low-risk IPI (IPI
are essential during workup. In some cases, CT scan of the neck and CT
<1).60 The Nordic Lymphoma Group also reported similar findings among
or MRI of the head may be useful. Multigated acquisition (MUGA) scan or
122 patients with ALCL, ALK-positive treated with the CHOEP regimen
echocardiogram is also recommended since chemotherapy is usually
(5-year OS and PFS rates were 78% and 64%, respectively).61 CHOEP
anthracycline based.
regimen was associated with an improved OS in patients aged 41 to
In selected cases, serology testing for the human immunodeficiency virus 65 years, even after adjusting for risk factors (P = .05). Bone marrow
(HIV) and human T-cell lymphotropic virus (HTLV-1) may be useful. involvement was independently associated with poorer PFS in a
HTLV-1 positivity, in particular, can lead to the alternate diagnosis and multivariate analysis.
alternate management of adult T-cell leukemia/lymphoma (ATLL) for
In a prospective study of 24 patients with previously untreated ALCL, with
cases that would otherwise be classified as PTCL-NOS by the pathologist
a median follow-up of 14 years, dose-adjusted EPOCH resulted in the
if positive HTLV-1 serology was not known.
EFS rates of 72% and 63% (P = .54), respectively, for patients with ALCL,
First-line Therapy ALK-positive and ALCL, ALK-negative and the OS rates were 78% and
88% (P = .83), respectively.62 However, definitive conclusions from these
In prospective randomized studies, PTCLs have been included with
findings are limited by the small number of patients and possible selection
aggressive B-cell lymphomas and it has not been possible to assess the
bias (24 patients recruited over 16 years; median patient age was 36
impact of chemotherapy in the subgroup of patients with PTCLs due to
years for ALCL, ALK-positive and 43 years for ALCL, ALK-negative). In
small sample size. Data to support the use of multiagent combination
another prospective study from Japan that evaluated dose-adjusted
chemotherapy for the treatment of previously untreated PTCL are
EPOCH as initial therapy in 41 patients with PTCL (PTCL-NOS was the

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predominant subtype [n = 21, 51%] followed by AITL [n = 17, 42%]), the lymphomas compared with other PTCL subtypes.14,15 The addition of
overall response rate (ORR) and complete response (CR) rate were 78% azacitidine to CHOP has also been shown to induce high CR rate in PTCL
and 61%, respectively.63 At a median follow-up of 24 months, the 2-year with TFH phenotype and this combination will be further evaluated in a
PFS and OS rates were 53% and 73%, respectively. The ORR, CR, PFS, randomized study.70
and OS rates were higher among patients ≤60 years of age (94%, 71%,
63%, and 82%, respectively). The phase III randomized trial (ECHELON-2) showed that brentuximab
vedotin (BV) in combination with CHP (cyclophosphamide, doxorubicin,
The use of more intensive chemotherapy regimens also has not resulted and prednisone) was superior to CHOP for the treatment of patients with
in favorable outcomes in patients with PTCL, with the exception of ALCL. previously untreated CD30-positive PTCL (defined in ECHELON-2 as
In a retrospective analysis that compared CHOP with more intensive CD30 expression on ≥10% of cells), resulting in significantly improved
chemotherapy regimens, including hyper-CVAD (hyper-fractionated PFS and OS.71,72 In this trial, 452 patients were randomly assigned to
cyclophosphamide, vincristine, doxorubicin, and prednisone) in 135 either BV + CHP or CHOP and the majority (70%) of patients had ALCL
patients with T-cell malignancies (PTCL-NOS, n = 50; ALCL, n = 40; AITL, (48% ALCL, ALK-negative and 22% ALCL, ALK-positive). After a median
n = 14), there was a trend towards higher 3-year OS rate for patients with follow-up of 48 months, the median PFS was 62 months and 24 months
ALK-positive ALCL treated with hyper-CVAD regimen compared to those for BV + CHP and CHOP, respectively. The estimated 5-year PFS rates
with ALCL, ALK-negative (100% vs. 70%, respectively).64 When the were 51% and 43% for BV + CHP and CHOP, respectively.72 The
subgroup with ALCL was excluded from the analysis, the 3-year OS rate median OS was not reached in either arm and the estimated 5-year OS
with CHOP and intensive regimen were 43% and 49%, respectively. rates were 70% and 61% for BV + CHP and CHOP, respectively. The
ORR (83% vs. 72%) and CR rate (68% vs. 56%) were also higher for BV
Results from more recent studies also suggest that the addition of + CHP compared to CHOP. The estimated 5-year PFS rates were 61%
anti-CD52 monoclonal antibody (alemtuzumab) or histone deacetylase for BV + CHP vs. 48% for CHOP in the subset of patients with ALCL
(HDAC) inhibitor or lenalidomide to CHOP or CHOEP did not improve (HR, 0.55; HR, 0.40 for ALK-positive and HR, 0.58 for ALK-negative).
survival, at least in part due to increased toxicity.65-69 The phase III trial The estimated 5-year OS rates were 76% for BV + CHP and 69% for
comparing romidepsin + CHOP versus CHOP excluded patients with CHOP in the subset of patients with ALCL (HR, 0.66; HR, 0.48 for
ALK-positive, ALCL did not show a statistically significant PFS benefit for ALK-positive and HR, 0.71 for ALK-negative). The survival benefit
romidepsin + CHOP in the entire study population (hazard ratio [HR], (clearly established for the subset of patients with ALCL) was less clear
0.81; 95% CI, 0.63–1.04; P = .096).67 However, an exploratory analysis across other histological subtypes (the HR for PFS and OS were 0.79
suggests a PFS benefit for romidepsin + CHOP in a subgroup of patients and 0.75, respectively, for PTCL-NOS and the corresponding HRs were
with histologically confirmed PTCL with TFH phenotype (20 months vs. 11 1.4 and 1.0, respectively, for AITL), all with wide confidence intervals.72
months for CHOP).66 Although statistical considerations preclude any firm However, this study was not powered to compare efficacy of BV + CHP
conclusion, these findings are consistent with other reports that have within individual histologic subtypes due to small subgroup sizes.
suggested HDAC inhibitors may have superior activity in nodal TFH cell

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Neutropenia (35%), anemia (13%), diarrhea (6%), peripheral neuropathy in patients with all levels of CD30 expression, including in patients with
(4%), and nausea (2%) were the most common grade ≥3 adverse events very low or absent CD30 expression.72,73
with BV + CHP. Peripheral neuropathy associated with BV continued to
improve or resolve with long-term follow-up. Based on the results of the CHOP followed by IVE (ifosfamide, etoposide, and epirubicin) alternating
ECHELON-2 trial, BV in combination with CHP was approved by the U.S. with intermediate-dose methotrexate (MTX) as initial therapy resulted in a
Food and Drug Administration (FDA) as a first-line therapy for patients median PFS and OS of 3 months and 7 months, respectively, in patients
with untreated systemic ALCL or other CD30-expressing subtypes (≥1% with EATL.74 The 5-year PFS and OS rates (52% and 60%, respectively)
CD30 expression) including PTCL-NOS and AITL. were significantly higher in historical comparison with the corresponding
survival rates (5-year PFS and OS rates were 22%) reported with
NCCN Recommendations conventional anthracycline-based chemotherapy regimens. CHOP
Multiagent chemotherapy (6 cycles with or without involved-site radiation followed by IVE alternating with MTX may be an appropriate first-line
therapy [ISRT] or for 3 to 4 cycles with ISRT) is recommended for patients therapy option for patients with EATL.
with stage I,II ALCL, ALK-positive. Multiagent chemotherapy alone for 6
cycles is recommended for patients with stage III–IV ALCL, ALK-positive. First-line Consolidation Therapy
Several non-randomized prospective studies74-85 and retrospective
Participation in clinical trials is the preferred management approach for analyses86-90 have reported favorable outcomes in patients with PTCL
patients with other subtypes (PTCL-NOS, ALCL, ALK-negative, EATL, undergoing first-line consolidation with autologous HCT. Some studies
MEITL, and nodal TFH cell lymphomas). In the absence of suitable clinical have reported that the achievement of CR to first-line therapy is an
trials, multiagent chemotherapy (6 cycles) with or without ISRT is independent predictor of improved survival in patients receiving first-line
recommended for all patients (stage I–IV disease). ALK-negative with a consolidation with autologous HCT.76,80,89,91
DUSP22 rearrangement has been variably associated with a prognosis
more similar to ALK-positive ALCL and could be treated according to the A report from Comprehensive Oncology Measures for Peripheral T-Cell
algorithm for ALCL, ALK-positive.24-29 Lymphoma Treatment (COMPLETE), a prospective multicenter cohort
study, suggests that consolidation of first complete remission (CR1) with
Based on results of the ECHELON-2 trial and FDA approval, BV + CHP is HDT/ASCR may provide a survival benefit in selected patients with PTCL
included as a preferred first-line therapy option for patients with ALCL (eg, patients with advanced-stage disease or intermediate-to-high IPI
(category 1) or other CD30-positive histologies (category 2A). CHOP, scores).92 Consolidation with autologous HCT significantly improved OS
CHOEP, dose-adjusted EPOCH, or hyper-CVAD are included as other and PFS for patients with AITL but not for patients with other PTCL
options for multiagent chemotherapy. As noted earlier, CD30 expression subtypes.
is variable across the PTCL subtypes other than ALCL.50 Interpretation of
CD30 expression is not universally standardized. In the ECHELON-2 In a randomized phase III study that evaluated the role of autologous
study, CD30 expression level did not correlate with response, in versus allogeneic HCT following an anthracycline-based induction
histologies other than ALCL and responses with BV have been observed therapy in patients with high-risk nodal PTCL, the EFS and OS outcomes

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were similar for patients in both treatment arms.93 With a median Response Assessment and Additional Therapy
follow-up of 42 months, the 3-year EFS rates were 43% and 38%, Recent studies that have evaluated the utility of PET scans for
respectively, for patients randomized to allogenic HCT and autologous assessment of response to therapy suggest that a positive interim PET
HCT. The corresponding 3-year OS rates were 57% and 70%, scan after first- or second-line therapy for relapsed/refractory disease is an
respectively. However, autologous HCT was associated with a much independent predictor of survival outcomes, thus suggesting that the use
higher relapse rate (36% vs. 0%) and allogeneic HCT resulted in much of interim PET scans may be helpful for risk stratification and could be
higher transplant-related mortality (31% vs. 0%). used for risk-adapted treatment approach in patients with PTCL.98-104
However, the optimal use of interim PET scans for the evaluation of
In the ECHELON-2 trial, first-line consolidation with HCT was permitted (at
response to treatment has not yet been established in a prospective study.
investigator’s discretion). After a median follow-up of 48 months, the
median PFS was not reached for those who underwent consolidation with The use of a 5-point scale (5-PS) is recommended for the interpretation
HCT compared to 56 months for those who did not undergo HCT.94 The and reporting of PET/CT scans. The 5-PS is based on the visual
PFS benefit with HCT was seen both in ALCL, ALK-negative group and in assessment of FDG uptake in the involved sites relative to that of the
non-ALCL group. In the aforementioned analysis from the International mediastinum and the liver.105-107 Different clinical trials have considered
T-Cell Lymphoma Project, consolidation with autologous HCT following scores of either 1 to 2 or 1 to 3 to be PET negative, while scores of 4 to 5
CR to first-line therapy was associated with improved outcomes in are universally considered PET-positive. A score of 4 on an interim or
patients with AITL.41 end-of-treatment restaging scan may be consistent with a partial
response (PR) if the FDG avidity has declined from initial staging, while a
There is however no definitive study on the benefits of HCT as
score of 5 denotes progression of disease.
consolidation of first remission with other retrospective studies showing no
survival advantage for patients PTCL-NOS, AITL, or ALCL, The guidelines recommend interim restaging with PET/CT (preferred) or
ALK-negative.95-97 CT after 3 to 4 cycles of chemotherapy. Completion of planned course of
treatment followed by end-of treatment restaging is recommended for all
In the absence of data from randomized controlled trials, available
patients achieving CR or PR to first-line therapy. Patients with no
evidence (as discussed above) suggests that autologous HCT is a
response or progressive disease after initial therapy should be treated as
reasonable treatment option only in patients with disease responding to
outlined for relapsed or refractory disease.
induction therapy (although it is associated with a high relapse rate).92-94
Longer follow-up and preferably data from a prospective randomized trial Patients with a CR at end of treatment can either be observed or treated
are necessary to evaluate the impact of first-line consolidation therapy with with first-line consolidation with autologous HCT. First-line consolidation
autologous HCT on time-to-treatment failure and OS outcomes. should be considered for all patients with subtypes other than ALCL,
ALK-positive. Among patients with ALCL, ALK-positive, first-line
consolidation should be considered only for patients with high-risk IPI.

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T-Cell Lymphomas

Localized areas can be treated with RT before or after autologous HCT. patients with relapsed/refractory disease. In the absence of a suitable
Rebiopsy should be considered (especially for patients with AITL since it clinical trial, the initial treatment for relapsed/refractory disease depends
may occasionally present with concurrent DLBCL) prior to addition therapy largely on the patient’s eligibility for transplant.
for patients with PR (persistent or new PET-positive lesions) at
end-of-treatment restaging. Second-line systemic therapy followed by consolidation with autologous or
allogeneic HCT for those with a CR or PR is recommended for patients
Treatment for Relapsed or Refractory Disease who are candidates for transplant. Localized relapse (limited to one or two
Autologous108-114 and allogeneic HCT112,113,115-120 have only been evaluated sites) may be treated with ISRT before or after autologous HCT.
in retrospective studies in patients with relapsed or refractory PTCL-NOS. Allogeneic HCT, when feasible, should be considered for the majority of
patients with relapsed/refractory disease. Autologous HCT may be an
The general conclusion from these studies is that autologous HCT less appropriate option, particularly those with ALCL and for selected patients
frequently results in durable benefit in patients with relapsed or refractory with other subtypes with chemosensitive relapsed disease. Patients who
disease as compared to allogeneic HCT. However, this conclusion is not are not candidates for transplant should be treated with second-line
universal in the literature and autologous HCT has been associated with systemic therapy or palliative radiation therapy (RT).
a survival benefit more often in patients with ALCL subtype and
chemosensitive disease than in those with non-ALCL subtypes and less Data from clinical trials supporting the use of second-line systemic therapy
chemosensitive disease.108,110,112 The cumulative incidence of options recommended in the guidelines are discussed below.
non-relapse mortality (NRM) was also higher with allogeneic HCT
Bendamustine
compared with autologous HCT.112 Allogeneic HCT using
In a multicenter phase II study (BENTLEY trial) of heavily pretreated
reduced-intensity conditioning (RIC) may provide a more reliably curative
patients with relapsed or refractory PTCL (n = 60; AITL, 53%; PTCL-NOS,
option for the majority of patients with relapsed or refractory PTCL,
38%), bendamustine resulted in an ORR of 50% (28% CR) and the
based on the patient’s eligibility for transplant.115-118 Further data from
median duration of response was only 3.5 months.122 Response rates
prospective studies are needed to determine the role of autologous and
were higher in patients with AITL compared to those with other subtypes.
allogeneic HCT in patients with relapsed/refractory PTCL.
The ORR for AITL and PTCL-NOS was 69% and 41%, respectively (P =
Second-line therapy for relapsed/refractory disease remains suboptimal, .47). However, this study was not powered to show differences in
even with the incorporation of autologous or allogeneic HCT. Among the response rates between the different histologic subtypes. The median PFS
420 evaluable patients with relapsed and refractory PTCL from the and OS for all patients were 4 months and 6 months, respectively. The
COMPLETE registry, outcomes were inferior for patients with refractory most common grade 3 or 4 toxicity included neutropenia (30%),
disease compared to those with relapsed disease.121 The median OS was thrombocytopenia (24%), and infectious events (20%).
29 months and 12 months, respectively, for patients with relapsed and
refractory disease. Participation in a clinical trial is strongly preferred for

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

Brentuximab Vedotin duration of response, and median PFS for all patients with T-cell
The safety and efficacy of BV (an antibody-drug conjugate that targets lymphoma were 41%, 8 months, and 3 months, respectively. The ORR
CD30-expressing malignant cells) in patients with relapsed or refractory (54% vs. 33%) and the median PFS (7 vs. 2 months) were better for
systemic ALCL was initially established in a multicenter phase II study.123 patients with AITL than those with PTCL-NOS.
Long-term follow-up results confirmed the durability of clinical benefit of
BV in patients with relapsed or refractory systemic ALCL.124 After a A retrospective study from the LYSA confirmed the efficacy of BV in
median follow-up of approximately 6 years, the ORR of 86% (66% CR and combination with bendamustine in patients with relapsed/refractory PTCL
21% PR) was similar to the previously reported ORR of 86% (59% CR) (n = 82), particularly as a bridge to allogeneic HCT. The ORR was 68%
evaluated by an independent review committee. The estimated 5-year OS (49% CR).126 After a median follow-up of 22 months, the median PFS and
and PFS rates were 60% and 39%, respectively. The 5-year OS rate was OS were 8 months and 26 months respectively. The outcomes were better
higher for patients who achieved a CR (79% compared to 25% for those for patients who underwent allogeneic HCT after achieving CR. The
who did not achieve a CR). The median duration of objective response for median PFS was 19 months and the median OS was not reached.
all patients was 26 months (the median duration of response was not
Duvelisib
reached for patients with a CR). The ORRs were similar for patients with
Preliminary findings from a dose optimization study confirmed that
ALK-negative ALCL (88%; 52% CR) and those with ALK-positive ALCL
duvelisib (phosphatidylinositol 3-kinase [PI3K]-γ/δ inhibitor) monotherapy
(81%; 69% CR). The estimated 5-year OS and PFS rates were 61% and
at 25 or 75 mg BID has clinical activity in patients with relapsed/refractory
39%, respectively, for patients with ALK-negative ALCL. The
PTCL.127 Early progression was seen more frequently in the 25 mg cohort,
corresponding survival rates were 56% and 37%, respectively, for those
suggesting that higher initial doses may be required to achieve a more
with ALK-positive ALCL. Among patients who achieved a CR, the 5-year
rapid tumor response. In the multicenter phase II trial (PRIMO), duvelisib
PFS rate was 60% for patients with ALK-negative ALCL and 50% for those
was given at 75 mg twice daily for two cycles followed by 25 mg twice
with ALK-positive ALCL. Peripheral neuropathy was the most common
daily to maintain long-term disease control for patients with
adverse event reported in 57% of patients, with resolution or improvement
relapsed/refractory PTCL.128 An interim analysis of dose-expansion cohort
reported in the majority of patients with long-term follow-up.124 In August
(78 patients) reported an ORR of 50% (32% CR). This activity was similar
2011, based on the results from this study, BV was approved by the FDA
to the previously reported ORR of 50% (N = 8/16) in patients with PTCL
for the treatment of patients with systemic ALCL after failure of at least
from the phase I study.129 Response rates were consistent across the
one prior multiagent chemotherapy regimen.
most common subtypes including PTCL-NOS and AITL. Neutropenia
The planned subset analysis of a phase II multicenter study that evaluated (22%), infections (12%), elevated alanine transaminase (ALT) (24%) or
the efficacy and safety of BV in relapsed/refractory CD30-positive NHL aspartate aminotransferase (AST) (22%), diarrhea (3%), rash (8%),
showed that it was also effective in other subtypes of relapsed PTCL, decreased lymphocyte count (8%), and sepsis (6%) were the most
particularly AITL.125 This analysis included 35 patients with PTCL (22 frequent grade ≥3 adverse events. This trial is ongoing with a targeted
patients with PTCL-NOS and 13 patients with AITL); the ORR, median enrollment of 125 patients. The Panel consensus supported the inclusion

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T-Cell Lymphomas

of duvelisib (75 mg BID for 2 cycles followed by 25 mg BID until disease Second-generation ALK inhibitors (alectinib, brigatinib, ceritinib) and
progression) as an option for patients with relapsed/refractory PTCL. third- generation ALK inhibitor (lorlatinib) also have demonstrated activity
in relapsed or refractory ALCL, ALK-positive in single arm non-randomized
Pralatrexate
studies.133-138
In the pivotal, international phase II study (PROPEL) of heavily pretreated
patients with relapsed or refractory PTCL (n = 109; 59 patients with In an open-label phase II trial of 10 patients (aged ≥6 years; median age
PTCL-NOS; 13 patients with AITL, and 17 patients with ALCL), 19.5 years), alectinib (300 mg BID; patients weighing less than 35 kg were
pralatrexate resulted in an ORR of 29% (CR 11%; response assessed by given a reduced dose of 150 mg BID), resulted in an ORR of 80% with
an independent central review). While the study was not statistically estimated 1-year PFS and OS rates of 58% and 70%, respectively.135
designed to analyze the ORR in specific subsets, response analyses by Alectinib was approved in Japan for relapsed/refractory ALCL,
key subsets indicated that the ORR was lower in AITL (8%) than in the ALK-positive based on this study).
other two subtypes (32% and 35%, respectively, for PTCL-NOS and
ALCL).130 The median duration of response was 10 months. For all Brigatinib has shown efficacy in patients with relapsed/refractory ALCL,
patients, the median PFS and OS were 4 months and 15 months, ALK-positive after prior therapy with BV and crizotinib.136 In a study of 15
respectively. The most common grade 3–4 adverse events included patients with previously treated ALCL, ALK-positive brigatinib resulted in
thrombocytopenia (32%), neutropenia (22%), anemia (18%), and an ORR of 93% (73% CR). After a median follow-up of 15 months, the
mucositis (22%). 1-year PFS and OS rates were 72% and 85%, respectively.

The result of a pooled analysis from prospective clinical trials of single Ceritinib also resulted in high ORR and longer duration of remission in a
agent pralatrexate (n = 221; 48% patients with PTCL-NOS; 21% of small number of patients (n = 3) with relapsed/refractory ALCL,
patients with AITL and 12% of patients with ALCL, ALK-negative) also ALK-positive included as part of a larger trial evaluating ceritinib in
support the use of pralatrexate for patients with relapsed/refractory PTCL advanced or metastatic ALK-positive tumors.137 Lorlatinib has
(ORR was 41%; the median PFS and OS were 5 months and 16 months, demonstrated activity resulting in high response rates in patients with
respectively).131 ALCL, ALK-positive previously treated with at least one ALK-inhibitor.138

ALK Inhibitors Crizotinib does not have central nervous system (CNS) penetration.
Crizotinib is FDA-approved for relapsed or refractory ALCL, ALK-positive Alectinib, brigatinib, ceritinib, and lorlatinib have CNS penetration and
in pediatric patients and young adults. Crizotinib also has demonstrated could be considered as alternative options for patients with CNS
activity in adult patients with relapsed/refractory ALCL, ALK-positive after involvement.133,134
at least one line of prior cytotoxic therapy.132 In a phase II study of 12
Histone Deacetylase Inhibitors
patients (median age at enrollment was 31 years; range 18–83 years),
HDAC inhibitors (eg, romidepsin, belinostat) have shown single-agent
crizotinib (250 mg BID) resulted in an ORR of 83% (58% CR). The
activity in patients with relapsed or refractory PTCL.139-141
estimated 2-year PFS and OS rates were 65% and 66%, respectively.

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Romidepsin received accelerated FDA approval in June 2011 for the the earlier phase II study and subsequent studies in which romidepsin
treatment of relapsed/refractory PTCL based on the results of the pivotal resulted in durable responses across all three subtypes of PTCL (ALCL,
multicenter phase II study that evaluated the impact of romidepsin on the ALK-negative, PTCL-NOS, and AITL).14,140
surrogate endpoint of ORR (130 patients with relapsed/refractory PTCL;
PTCL-NOS, n = 69 [53%]; AITL, n = 27 [21%]; ALCL, ALK-negative, n = The BELIEF trial evaluated belinostat in 129 patients with relapsed or
21 [16%]).139 Updated results from this study confirmed that responses refractory PTCL (pretreated with more than one prior systemic therapy).141
were durable across all three subtypes of PTCL.140 At a median follow-up The ORR in 120 evaluable patients was 26% (CR rate of 11% and PR rate
of 22 months, there were no significant differences in ORR or rates of CR of 15%). The median duration of response, median PFS, and median OS
between the three most common subtypes of PTCL. The ORRs were were 14 months, 2 months, and 8 months, respectively. The 1-year PFS
29%, 30%, and 24%, respectively, for patients with PTCL-NOS, AITL, and rate was 19%.141 The ORR was higher for AITL compared to other
ALCL, ALK-negative. The corresponding CR rates were 14%, 19%, and subtypes (45% compared to 23% and 15%, respectively, for patients with
19%, respectively. The median PFS was 20 months for all responders and PTCL-NOS and ALCL, ALK-negative). Anemia (11%), thrombocytopenia
it was significantly longer for patients who achieved CR for ≥12 months (7%), dyspnea (6%), and neutropenia (6%) were the most common grade
compared to those who achieved CR for <12 months or PR (29 months, 3 or 4 adverse events. Belinostat was approved by the FDA in July 2014
13 months, and 7 months, respectively). The median OS was not reached for the treatment of relapsed or refractory PTCL. Belinostat induced
for patients who achieved CR and 18 months for those who achieved responses across all types of PTCL (with the exception of ALCL,
PR.140 The most common grade ≥3 adverse events included ALK-positive) and response rates were significantly higher for AITL than
thrombocytopenia (24%), neutropenia (20%), and infections (19%).139 other subtypes.141

Ruxolitinib
In August 2021, the accelerated approval status for romidepsin for the
treatment of relapsed/refractory PTCL was withdrawn following the results A phase II biomarker driven study demonstrated the efficacy of ruxolitinib
of the confirmatory phase III trial, which failed to meet the primary in patients with relapsed/refractory PTCL. In this study (n = 53; 45
endpoint of improved PFS for romidepsin + CHOP in patients with patients with relapsed/refractory PTCL), patients were enrolled into 1 of 3
previously untreated PTCL (421 patients randomized to receive cohorts: presence of activating JAK and/or STAT mutations (cohort 1);
romidepsin + CHOP or CHOP).66 After a median follow-up of 28 months ≥30% pSTAT3 expression by IHC (cohort 2) and cohort 3 had patients
the addition of romidepsin to CHOP did not result in any statistically with neither of these criteria.142 Clinical benefit rate (CBR; defined as the
significant improvement in ORR, PFS, or OS but increased the frequency combination of CR, PR, and stable disease for at least 6 months) was
of grade ≥3 adverse events and the final analysis after a median follow-up the primary endpoint. In the subset of patients with PTCL, the CBR was
of 6 years also confirmed these findings.66,67 While the Panel 53%, 45%, and 13% for cohorts 1, 2, and 3, respectively (cohorts 1 and
acknowledged the change in the regulatory status of romidepsin, the 2 vs. cohort 3; P = .02). The corresponding ORR were 37% (5% CR)
consensus of the Panel was to continue the listing of romidepsin as an 36% (18% CR) and 7% (all CRs).
important option for relapsed or refractory PTCL based on the results of

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T-Cell Lymphomas

Azacitidine patients (10 patients with mycosis fungoides and 2 patients with
The efficacy of 5-azacitidine in patients with relapsed/refractory AITL or PTCL-NOS with isolated skin involvement), bortezomib resulted in an
nodal TFH cell lymphomas was demonstrated in a phase III randomized ORR of 67% (17% CR).
study (86 patients randomized to receive oral azacitidine or single agent
of investigator’s choice [gemcitabine, bendamustine or romidepsin]), Combination Chemotherapy
although the trial did not meet the primary end point for significant There are very limited data available for the specific use of combination
improvement in PFS.143 After a follow-up of 14 months, the median PFS chemotherapy regimens in patients with relapsed or refractory PTCL (as
was 6 months for the azacitidine arm versus 3 months in the control arm. discussed below).154-157
However, it did not reach the study required statistical level of
Aggressive second-line chemotherapy with ICE (ifosfamide, carboplatin,
significance of P < .025 (P = .0421). The median OS was 18 months and
and etoposide) followed by autologous HCT was evaluated in patients with
10 months for the two arms, respectively.
relapsed/refractory PTCL.154 Among 40 patients treated with ICE, 27
Other Single Agents (68%) underwent autologous HCT. Based on intent-to-treat analysis,
Data to support the use of monotherapy with other single agents median PFS was 6 months from the time of last ICE therapy; 70% of
(alemtuzumab, bortezomib, cyclosporine, gemcitabine, and lenalidomide) patients relapsed within 1 year. Patients with relapsed disease had a
are mainly from small single-institution series as described below. significantly higher 3-year PFS rate compared to those with primary
refractory (20% vs. 6%; P = .0005).
Alemtuzumab and gemcitabine have demonstrated activity resulting in an
ORR of 50% to 55% (CR, 30%–33%) in the subset of patients with Gemcitabine, dexamethasone, and cisplatin (GDP) followed by autologous
PTCL-NOS.144-146 Reduced-dose alemtuzumab was less toxic, equally HCT has also been shown to be effective for the treatment of patients with
effective, and was also associated with lower incidences of relapsed or refractory PTCL, resulting in an ORR of 72% to 80% (CR,
cytomegalovirus (CMV) reactivation compared to standard-dose 47%–48%).155,156 Among patients who were treated subsequently with
alemtuzumab.145 HDT/ASCR, the 2-year post-transplant OS was 53% with no difference in
survival rates between patients with relapsed and refractory disease (P =
Cyclosporine has been effective in patients with relapsed AITL following .23). The median PFS and OS after treatment with GDP were 4 months
treatment with steroid or multiagent chemotherapy or HDT/ASCR.147,148 and 7 months, respectively for patients who did not receive transplant.155
Lenalidomide monotherapy has also been effective in the treatment of
relapsed or refractory PTCL resulting in an ORR of 24% and it has been The results of a retrospective analysis showed that the gemcitabine,
particularly active in patients with relapsed or refractory AITL resulting in vinorelbine, and doxorubicin (GND) regimen was effective and well
an ORR of 31% (15% CR).149,150 tolerated by patients with refractory or relapsed T-cell lymphomas (n = 49;
28 patients with PTCL-NOS), with an ORR of 65% and a median OS of 36
Bortezomib has shown activity in relapsed/refractory PTCL-NOS and months. The 5-year estimated OS rate was 32%.157
AITL (mostly in case reports).151-153 In a single institution study of 12

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

The inclusion of other combination chemotherapy regimens for the important than the ability to give a treatment in an ongoing or maintenance
treatment of relapsed/refractory PTCL are derived from aggressive fashion without cumulative toxicity. For patients who are intended for
lymphoma clinical trials that have also included a limited number of transplant soon, combination chemotherapy prior to transplant is often
patients with PTCL. preferred if autologous HCT is being considered. Combination
chemotherapy may also be preferred for patients who are ready to
Selection of Second-line Systemic Therapy
proceed to allogeneic HCT when a suitable donor has already been
There are not enough data to support the use of a particular regimen for identified. However, if there is no donor available, the use of intensive
second-line therapy based on the subtype, with the exception of ALCL. BV combination chemotherapy is not recommended due to the inability to
should be the preferred choice for second-line therapy for maintain a response for longer periods with the continuous treatment.
relapsed/refractory ALCL.123-125
Results from the COMPLETE registry showed that treatment with single
HDAC inhibitors or azacitidine may have superior activity in nodal TFH cell agents were often as effective, with a trend towards increased CR rate as
lymphomas compared to other subtypes.14,15,141,143 In the BELIEF trial, combination regimens (41% vs. 19%; P = .02).158 The median OS (39 vs.
response rates with belinostat were significantly higher for AITL than other 17 months; P = .02) and PFS (11 vs. 7 months; P = .02) were also higher
subtypes.141 Bendamustine and lenalidomide have also induced higher among patients treated with single agents, and more patients receiving
response rates in patients with AITL compared to those with other single agents received HCT (26% vs 8%, P = .07). Similarly, in a
subtypes.122,149 Cyclosporine may be appropriate for patients with relapsed meta-analysis of 151 studies that evaluated the outcomes of 6209 patients
AITL following treatment with steroids or multiagent chemotherapy or with relapsed or refractory T-cell lymphomas treated with either novel
autologous HCT.147,148 However, the aforementioned studies were not single agents, combination chemotherapy, combination of novel agents
sufficiently powered to evaluate the response rates in specific subtypes. and combination chemotherapy, or the combination of novel agents, the
Pralatrexate has very limited activity in AITL compared to other response rates were not statistically different between the treatment
subtypes.130 approaches for the subset of patients with relapsed/refractory PTCL.159
The ORR was 36% for single agents, 48% for combination chemotherapy
ALK inhibitors could be considered for ALCL, ALK-positive. Alectinib,
54% for single novel agents plus combination chemotherapy, and 45%
brigatinib, ceritinib, and lorlatinib could be appropriate options for
for novel agent combinations. This observation remained unchanged
patients with CNS involvement.134 Ruxolitinib has activity across all PTCL
when the analysis was restricted to either PTCL-NOS or AITL
subtypes and the presence of activating JAK/STAT mutations or pSTAT3
respectively.
expression by IHC (≥30%) resulted in higher CBR.142
Thus, for many patients with an intent to proceed to allogeneic HCT, single
The selection of second-line therapy regimen (single agent vs.
agents or combination regimens may be appropriately used as a bridge to
combination regimen) should be based on the patient’s age, performance
transplant. Single agents or lower toxicity regimens may also be more
status, donor availability, agent’s side effect profile, and goals of therapy.
appropriate for older patients with a limited performance status or for those
For instance, if the intent is to transplant, ORR or CR rate may be more

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

patients who are unable to tolerate more intensive combination

chemotherapy. However, the preferential use of single agents versus
combination regimens in patients with an intention to proceed to transplant
has not been evaluated in a prospective randomized trial.

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T-Cell Lymphomas

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NCCN Guidelines Version 4.2024

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

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[Link] [Link]

119. Epperla N, Ahn KW, Litovich C, et al. Allogeneic hematopoietic cell 126. Aubrais R, Bouabdallah K, Chartier L, et al. Salvage therapy with
transplantation provides effective salvage despite refractory disease or brentuximab-vedotin and bendamustine for patients with R/R PTCL: a
failed prior autologous transplant in angioimmunoblastic T-cell lymphoma: retrospective study from the LYSA group. Blood Adv 2023;7:5733-5742.
a CIBMTR analysis. J Hematol Oncol 2019;12:6. Available at: Available at: [Link]
[Link]
127. Horwitz SM, Mehta-Shah N, Pro B, et al. Dose optimization of
120. Domingo-Domenech E, Boumendil A, Climent F, et al. Allogeneic duvelisib in patients with relapsed or refractory peripheral T-cell lymphoma
hematopoietic stem cell transplantation for patients with from the phase II Primo trial: selection of regimen for the dose-expansion
relapsed/refractory systemic anaplastic large cell lymphoma. A phase [abstract]. Blood 2019;134:Abstract 1567. Available at:
retrospective analysis of the Lymphoma Working Party of the European [Link]
Society for Blood and Marrow Transplantation. Bone Marrow Transplant
2020;55:633-640. Available at: 128. Brammer JE, Zinzani PL, Zain J, et al. Duvelisib in Patients with
[Link] Relapsed/Refractory Peripheral T-Cell Lymphoma from the Phase 2 Primo

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

Trial: Results of an Interim Analysis [abstract]. Blood 2021;138:Abstract 136. Veleanu L, Tesson B, Lamant L, et al. Brigatinib in patients with
2456. Available at: [Link] ALK-positive anaplastic large cell lymphoma who have failed brentuximab
vedotin. Hematological Oncology 2023;41:505-506. Available at:
129. Horwitz SM, Koch R, Porcu P, et al. Activity of the PI3K-delta,gamma [Link]
inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell
lymphoma. Blood 2018;131:888-898. Available at: 137. Richly H, Kim TM, Schuler M, et al. Ceritinib in patients with
[Link] advanced anaplastic lymphoma kinase-rearranged anaplastic large-cell
lymphoma. Blood 2015;126:1257-1258. Available at:
130. O'Connor OA, Pro B, Pinter-Brown L, et al. Pralatrexate in patients [Link]
with relapsed or refractory peripheral T-cell lymphoma: Results from the
pivotal PROPEL study. J Clin Oncol 2011;29:1182-1189. Available at: 138. Ripamonti A, Aroldi A, Cocito F, et al. Preliminary results of phase 2
[Link] open label study of lorlatinib monotherapy in relapsed/refractory ALK+
lymphomas previously treated with other tyrosine kinase inhibitors
131. O'Connor OA, Ko BS, Wang MC, et al. Pooled Analysis of [abstract]. Blood 2023;142:Abstract 4474. Available at:
Pralatrexate Single-Agent Studies in Patients With Relapsed/Refractory [Link]
Peripheral T-Cell Lymphoma. Blood Adv 2024. Available at:
[Link] 139. Coiffier B, Pro B, Prince HM, et al. Results From a Pivotal,
Open-Label, Phase II Study of Romidepsin in Relapsed or Refractory
132. Bossi E, Aroldi A, Brioschi FA, et al. Phase two study of crizotinib in Peripheral T-Cell Lymphoma After Prior Systemic Therapy. J Clin Oncol
patients with anaplastic lymphoma kinase (ALK)-positive anaplastic large 2012;30:631-636. Available at:
cell lymphoma relapsed/refractory to chemotherapy. Am J Hematol [Link]
2020;95:E319-E321. Available at:
[Link] 140. Coiffier B, Pro B, Prince HM, et al. Romidepsin for the treatment of
relapsed/refractory peripheral T-cell lymphoma: pivotal study update
133. Reed DR, Hall RD, Gentzler RD, et al. Treatment of Refractory ALK demonstrates durable responses. J Hematol Oncol 2014;7:11. Available
Rearranged Anaplastic Large Cell Lymphoma With Alectinib. Clin at: [Link]
Lymphoma Myeloma Leuk 2019;19:e247-e250. Available at:
[Link] 141. O'Connor OA, Horwitz S, Masszi T, et al. Belinostat in patients with
relapsed or refractory peripheral T-cell lymphoma: results of the pivotal
134. Tomlinson SB, Sandwell S, Chuang ST, et al. Central nervous phase II BELIEF (CLN-19) study. J Clin Oncol 2015;33:2492-2499.
system relapse of systemic ALK-rearranged anaplastic large cell Available at: [Link]
lymphoma treated with alectinib. Leuk Res 2019;83:106164. Available at:
[Link] 142. Moskowitz AJ, Ghione P, Jacobsen E, et al. A phase 2
biomarker-driven study of ruxolitinib demonstrates effectiveness of
135. Fukano R, Mori T, Sekimizu M, et al. Alectinib for relapsed or JAK/STAT targeting in T-cell lymphomas. Blood 2021;138:2828-2837.
refractory anaplastic lymphoma kinase-positive anaplastic large cell Available at: [Link]
lymphoma: An open-label phase II trial. Cancer Sci 2020;111:4540-4547.
Available at: [Link] 143. Dupuis J, Tsukasaki K, Bachy E, et al. Oral Azacytidine in Patients
with Relapsed/Refractory Angioimmunoblastic T-Cell Lymphoma: Final

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

Analysis of the Oracle Phase III Study. Blood 2022;140:2310-2312. lymphoma. Cancer 2015;121:716-723. Available at:
Available at: [Link] [Link]

144. Enblad G, Hagberg H, Erlanson M, et al. A pilot study of 151. Zinzani PL, Musuraca G, Tani M, et al. Phase II trial of proteasome
alemtuzumab (anti-CD52 monoclonal antibody) therapy for patients with inhibitor bortezomib in patients with relapsed or refractory cutaneous T-cell
relapsed or chemotherapy-refractory peripheral T-cell lymphomas. Blood lymphoma. J Clin Oncol 2007;25:4293-4297. Available at:
2004;103:2920-2924. Available at: [Link]
[Link]
152. Du HP, Yang QQ, Zhang YE. Bortezomib-based chemotherapy to
145. Zinzani PL, Alinari L, Tani M, et al. Preliminary observations of a treat refractory angioimmunoblastic T-cell lymphoma: A case report and
phase II study of reduced-dose alemtuzumab treatment in patients with review of the literature. Oncol Lett 2016;11:2310-2314. Available at:
pretreated T-cell lymphoma. Haematologica 2005;90:702-703. Available [Link]
at: [Link]
153. Shibusawa M. Bortezomib Use for a Critically Ill Patient with
146. Zinzani PL, Venturini F, Stefoni V, et al. Gemcitabine as single agent Angioimmunoblastic T-Cell Lymphoma. Case Rep Hematol
in pretreated T-cell lymphoma patients: evaluation of the long-term 2022;2022:6079633. Available at:
outcome. Ann Oncol 2010;21:860-863. Available at: [Link]
[Link]
154. Horwitz S, Moskowitz C, Kewalramani T, et al. Second-line therapy
147. Advani R, Horwitz S, Zelenetz A, Horning SJ. Angioimmunoblastic T with ICE followed by high dose therapy and autologous stem cell
cell lymphoma: treatment experience with cyclosporine. Leuk Lymphoma transplantation for relapsed/refractory peripheral T-cell lymphomas:
2007;48:521-525. Available at: minimal benefit when analyzed by intent to treat [abstract]. Blood
[Link] 2005;106:Abstract 2679. Available at:
[Link]
148. Wang X, Zhang D, Wang L, et al. Cyclosporine treatment of
angioimmunoblastic T-cell lymphoma relapsed after an autologous 155. Connors JM, Sehn LH, Villa D, et al. Gemcitabine, Dexamethasone,
hematopoietic stem cell transplant. Exp Clin Transplant 2015;13:203-205. and Cisplatin (GDP) As Secondary Chemotherapy In Relapsed/Refractory
Available at: [Link] Peripheral T-Cell Lymphoma [abstract]. Blood 2013;122:Abstract 4345.
Available at: [Link]
149. Morschhauser F, Fitoussi O, Haioun C, et al. A phase 2, multicentre,
single-arm, open-label study to evaluate the safety and efficacy of 156. Park BB, Kim WS, Suh C, et al. Salvage chemotherapy of
single-agent lenalidomide (Revlimid) in subjects with relapsed or refractory gemcitabine, dexamethasone, and cisplatin (GDP) for patients with
peripheral T-cell non-Hodgkin lymphoma: the EXPECT trial. Eur J Cancer relapsed or refractory peripheral T-cell lymphomas: a consortium for
2013;49:2869-2876. Available at: improving survival of lymphoma (CISL) trial. Ann Hematol
[Link] 2015;94:1845-1851. Available at:
[Link]
150. Toumishey E, Prasad A, Dueck G, et al. Final report of a phase 2
clinical trial of lenalidomide monotherapy for patients with T-cell 157. Qian Z, Song Z, Zhang H, et al. Gemcitabine, navelbine, and
doxorubicin as treatment for patients with refractory or relapsed T-cell

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

lymphoma. Biomed Res Int 2015;2015:606752. Available at:

[Link]

158. Stuver RN, Khan N, Schwartz M, et al. Single agents vs combination

chemotherapy in relapsed and refractory peripheral T-cell lymphoma:
Results from the comprehensive oncology measures for peripheral T-cell
lymphoma treatment (COMPLETE) registry. Am J Hematol
2019;94:641-649. Available at:
[Link]

159. Shafagati N, Koh MJ, Boussi L, et al. Comparative efficacy and

tolerability of novel agents vs chemotherapy in relapsed and refractory
T-cell lymphomas: a meta-analysis. Blood Adv 2022;6:4740-4762.
Available at: [Link]

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

Breast Implant-Associated ALCL (ICC).19,20 According to the updated information issued by the FDA on
Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is June 30, 2023, a total of 1264 cases of BIA-ALCL have been diagnosed
an uncommon and emerging peripheral T-cell lymphoma (PTCL), first and 63 deaths have been reported worldwide, which includes 330
reported in 1997.1 BIA-ALCL represents a distinct entity from systemic confirmed cases in the United States reported to the PROFILE
ALCL and other forms of primary breast lymphoma (which are usually of registry.21,22 The prevalence of BIA-ALCL in the United States ranges
B-cell origin).2-11 The majority of cases have been reported in patients with from 1:300 to 1:50,000 with incidence rates of 4.5 per 10,000.23 The
a textured surface implant without any documented cases in patients frequency of BIA-ALCL remains underreported (limited mainly to the
receiving only a smooth surface implant.10-17 The risk of BIA-ALCL cases identified in the United States, Europe, and Australia) and the
following textured implants has ranged from 1 in 1000 to 1 in 50,000 exact number of cases remains difficult to determine since the disease is
based upon varied risk estimates due to differences in manufacturer emerging and federal reporting of BIA-ALCL has several limitations.24
texture on implants.10,15,18 In a prospective cohort study of 3546 patients Prophylactic explantation of textured implants is not routinely
who underwent breast reconstructions with macro-textured implants recommended. However, following risk stratification, it may be deemed
(mainly after breast cancer resection, or contralateral prophylactic reasonable for risk reduction in select patients following an informed
mastectomy), the overall risk of BIA-ALCL was 1 in 355 patients with discussion regarding the benefits and risks of surgery.25-27
“salt-loss type” Biocell texture (or 0.311 cases per 1000 person-years),
Literature Search Criteria
which is higher than previously reported.14
Prior to the update of this version of the NCCN Clinical Practice Guidelines
In 2011, the U.S. Food and Drug Administration (FDA released a safety in Oncology (NCCN Guidelines®) for T-Cell Lymphomas, a literature
communication on an association between breast implants and ALCL, search of the PubMed database was performed to obtain key literature in
indicating that patients with breast implants may develop BIA-ALCL in an BIA-ALCL since the previous Guidelines update. The PubMed database
effusion or scar tissue adjacent to an implant. In 2019, the FDA issued a was chosen as it remains the most widely used resource for medical
Class I device recall of Allergan Biocell textured implants and tissue literature and indexes peer-reviewed biomedical literature.28
expanders, and mandated the placement of a black box warning on all
breast implants regarding the increased risk of lymphoma. In 2012, the The search results were narrowed by selecting studies in humans
FDA, the American Society of Plastic Surgeons (ASPS), and the Plastic published in English. The data from key PubMed articles deemed as
Surgery Foundation (PSF) formed a prospective patient registry, entitled relevant to these Guidelines have been included in this version of the
“Patient Registry and Outcomes for Breast Implants and ALCL Etiology Discussion section. Recommendations for which high-level evidence is
and Epidemiology (PROFILE),” to prospectively track patients with lacking are based on the panel’s review of lower-level evidence and
BIA-ALCL. expert opinion.

BIA-ALCL is included as a distinct entity in the updated 2022 WHO

classification (WHO5) and International Consensus Classification

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

Clinical Presentation and Prognosis BIA-ALCL is associated with a good prognosis with the majority of patients
Patients with BIA-ALCL present with physical signs (periprosthetic presenting with localized disease (periprosthetic effusion with no tumor
effusion, breast enlargement, tumor mass, rash, lymphadenopathy, and mass), whereas systemic involvement has also been less commonly
skin ulceration) more than 1 year after receiving a textured surface breast reported (tumor mass with or without effusion or lymph node
implant (mean time of presentation is 8–10 years post-implantation). involvement).6,18,30-33 Unresectable disease and lymph node metastasis
Delayed seromas without systemic symptoms are the most common have higher rates of relapse.30,31,33,34 The event-free survival (EFS) and
presentation of BIA-ALCL.17 BIA-ALCL may be diagnosed at an earlier OS rates were better for patients with resectable BIA-ALCL confined to the
stage in patients with prior history of breast reconstruction due to breast fibrous capsule surrounding the implant compared to patients with invasive
cancer compared to those with cosmetic breast implants.29 BIA-ALCL that had spread beyond the capsule.31 Parenchymal breast or
lymph node involvement, although less common, may have an aggressive
BIA-ALCL may present along a spectrum of stages associated with clinical course more in line with systemic anaplastic lymphoma kinase
different outcomes: in situ BIA-ALCL characterized by effusion around the (ALK)-positive ALCL. A study that assessed the clinical and
implant and anaplastic cell proliferation confined to the fibrous scar histopathologic features of lymph nodes in 70 patients with BIA-ALCL
capsule; infiltrative BIA-ALCL with pleomorphic cells aggregating into a reported lymph node involvement in 20% of patients (regional axillary
mass progressing with adjacent tissue infiltration and chest wall invasion; lymph node involvement was the most frequently observed location in
regional lymph node involvement; and, rarely, organ and bone 93% of patients followed by clavicular and internal mammary lymph node
metastasis.6,30 The effusion-limited variant (presenting in an effusion or basins).33 BIA-ALCL beyond the capsule was associated with higher risk
confined by the fibrous capsule) generally has an indolent disease course of lymph node involvement (38% compared to 12% in patients with tumor
and can be adequately treated with surgery alone with an excellent confined by the capsule). The 5-year OS rates were 75% and 98%,
long-term survival. Infiltrative BIA-ALCL can have a more aggressive respectively, for patients with and without lymph node involvement at
clinical course, and can still be amendable to surgical treatment if presentation.
complete surgical excision is possible; however, it may require additional
treatment following removal of the implant.30 In a retrospective study that Diagnosis and Pathologic Workup
reported the long-term follow-up of 60 patients with BIA-ALCL, the Initial workup should include ultrasound (US) of breast and axilla or breast
complete remission rate was 93% for patients with disease confined to MRI in selected cases or PET/CT scan in selected cases. In patients with
the fibrous capsule compared to 72% for those presenting with a tumor BIA-ALCL, the sensitivity of US for detecting an effusion (84%) or a mass
mass.6 Clinical presentation with a breast mass was also associated with (46%) was similar to that of MRI (82% and 50%, respectively).7 Patients
worse overall survival (OS; P = .052) and progression-free survival (PFS; with suspected BIA-ALCL should be first evaluated with US, regardless of
P = .03). In another retrospective analysis of 19 patients with BIA-ALCL, age or implant type.35 If US is inconclusive, breast MRI should be
after 18 months of median follow-up, the 2-year OS rates were 100% and performed if not done previously.
53%, respectively, for in situ and infiltrative BIA-ALCL.30

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

Cytologic evaluation and biopsy (fine-needle aspiration [FNA] biopsy of Referral to a plastic surgeon for appropriate management of an implant
periprosthetic effusion and/or biopsy of the tumor mass) with adequate seroma is recommended if the pathologic diagnosis is negative for
immunophenotyping (immunohistochemistry [IHC] and flow cytometry) are BIA-ALCL. A second pathology consultation in a tertiary cancer center is
essential for an accurate diagnosis of BIA-ALCL.36-38 Biopsy (excisional or recommended if the pathologic diagnosis is indeterminate for BIA-ALCL.
incisional or core needle) may be required for diagnosis, if there is solid Histologically confirmed BIA-ALCL requires individualized management by
mass associated with the implant. Multiple systematic scar capsule a multidisciplinary team including a medical oncologist, surgical oncologist,
biopsies may be necessary to determine early invasive disease and mass plastic surgeon, and hematopathologist. In accordance with the FDA
formation, which have implications for prognosis.39 recommendation, all cases of histologically confirmed BIA-ALCL should be
reported to the BIA-ALCL PROFILE Registry ([Link]
Biopsy specimens show large pleomorphic tumor cells of T-cell lineage
with a strong and uniform expression of CD30 with variable CD3-, CD5-, Lymphoma Workup and Staging
CD4+, and CD43+.5,6,40 IHC and flow cytometry should include CD2, CD3, The workup should include history and physical examination, routine
CD4, CD5, CD7, CD8, CD30, CD45, and ALK. CD30 enzyme-linked laboratory studies (ie, complete blood count [CBC] with differential,
immunosorbent assay (ELISA) might be a viable screening tool for comprehensive metabolic panel, serum lactate dehydrogenase [LDH]),
BIA-ALCL.41 Flow cytometry immunophenotyping can be used as an and PET/CT scan. Multigated acquisition (MUGA) scan or echocardiogram
adjunct to IHC.42 However, confirmation of diagnosis requires pathology is also recommended, if anthracycline- or anthracenedione-based
evaluation with CD30 IHC and the use of flow cytometry alone as the sole chemotherapy is indicated. Bone marrow biopsy is only needed in
diagnostic method is not recommended to confirm the diagnosis of selected patients with extensive disease or unexplained cytopenia.
BIA-ALCL.
A unique tumor node metastasis (TNM) staging system is used to better
Cases of BIA-ALCL reported to date have all been negative for ALK, stratify and predict prognosis given that the Lugano modification of the
DUSP22, and TP63, which have been associated with systemic ALCL.43 Ann Arbor staging system does not help to risk stratify patients with
Recurrent mutations associated with the constitutive activation of BIA-ALCL.31 This staging system divided patients with BIA-ALCL into a
JAK-STAT3 pathway, TP53 mutations, as well as mutations of epigenetic spectrum of multiple prognostic groups: stage IA (36%); stage IB (12%);
modifiers (eg, DNMT3A) have been identified in some cases.43-50 TP53 stage IC (14%); stage IIA (25%); stage IIB (5%); stage III (9%); and stage
mutation is associated with high-risk disease in a variety hematologic IV (0%). The EFS was significantly higher for patients with stage I disease
malignancies and BIA-ALCL with TP53 mutation appears to have a more than for those with higher stage disease (P = .003), and the rate of events
invasive disease with mass, faster disease progression, and more lymph was 3-fold higher for stage II or III compared with stage I disease.
node metastasis.25,51 Therefore, next-generation sequencing (NGS) to
identify the presence of high-risk mutations may have prognostic value at Treatment
time of diagnosis.44 Total capsulectomy with removal of the breast implant and excision of any
associated mass with a biopsy of suspicious lymph nodes is

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

recommended for all patients.6,31,52 Immediate (early-stage) or delayed should be discussed with a multidisciplinary team.55 RT for local residual
(advanced-stage) breast reconstruction with autologous tissue or smooth disease ± systemic therapy may be beneficial, following incomplete
surface breast implants may be considered.53 Removal of the contralateral excision or partial capsulectomy.6,31 Systemic therapy (if RT is not
implant can be considered since simultaneous or subsequent bilateral feasible) could be considered for patients with lymph node involvement.
breast involvement has been reported in approximately 5% of patients with Advanced-stage disease is associated with higher rates of limited surgery,
BIA-ALCL.31,54 As BIA-ALCL is not a disease of the breast parenchyma, compared to those with early-stage disease.56 Systemic therapy should be
there is no role for mastectomy or sentinel lymph node biopsy. considered for patients presenting with an unresectable mass or those
with extended disease (stage II–IV). High-dose therapy followed by
Consultation with a surgical oncologist is recommended for patients with a autologous hematopoietic cell transplant (HCT) could be considered for
preoperative mass since complete surgical excision alone is the optimal patients achieving complete response to systemic therapy.
treatment for patients with localized disease (stage IA–IC) who present
with effusion (with or without a distinct breast mass). In a retrospective Due to the rarity of advanced BIA-ALCL, the data for the use of systemic
study of 87 patients with BIA-ALCL (52 patients presented with effusion therapy is extrapolated from clinical studies that have evaluated treatment
only; 15 patients presented with a mass only, and 17 patients had effusion options for systemic ALCL. Chemotherapy regimens recommended for
and mass), the OS rates (P = .022) and EFS rates (P = .014) were systemic ALCL have been used in some patients with BIA-ALCL, although
significantly better for patients who underwent complete surgical excision the use of chemotherapy was not associated with better OS or PFS (P =
(total capsulectomy with breast implant removal and complete removal of .44 and P = .28, respectively).6,31,57 Brentuximab vedotin (BV) has also
any disease or mass with negative margins) compared to those who shown promising clinical activity in anecdotal reports.58,59 In the phase III
received partial capsulectomy, systemic chemotherapy, or radiation randomized trial (ECHELON-2), brentuximab vedotin (BV) in combination
therapy (RT).31 The 3-year OS and EFS rates were 94% and 49%, with CHP (cyclophosphamide, doxorubicin, and prednisone) resulted in
respectively, for the entire study group. The 5-year OS and EFS rates significantly improved PFS and OS compared to CHOP
were 91% and 49%, respectively. (cyclophosphamide, doxorubicin, vincristine and prednisone) in patients
with previously untreated CD30-positive PTCL and the survival benefit
Observation (history and physical examination every 3–6 months for 2 was clearly established for the subset of patients with ALCL.60 BV in
years and then as clinically indicated] with or without contrast-enhanced combination with CHP is FDA-approved as first-line therapy for patients
CT or PET/CT [not more often than every 6 months for 2 years and then with untreated systemic ALCL. BV (monotherapy or in combination with
only as clinically indicated]) is recommended for all patients with localized CHP) is included as a preferred systemic therapy option for BIA-ALCL.
disease following complete surgical excision with no residual disease. CHOP, CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide,
and prednisone), or dose-adjusted EPOCH (etoposide, prednisone,
Adjuvant treatment may be required for patients who undergo incomplete
vincristine, cyclophosphamide, and doxorubicin) are included as
surgical excision or partial capsulectomy with residual disease (with or
alternative options (other recommended regimens).
without regional lymph node involvement). However, there are very limited
data to recommend an optimal approach and adjuvant treatment options

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

References 9. Wang SS, Deapen D, Voutsinas J, et al. Breast implants and anaplastic
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8. Brody GS, Deapen D, Taylor CR, et al. Anaplastic large cell lymphoma [Link]
occurring in women with breast implants: analysis of 173 cases. Plast
Reconstr Surg 2015;135:695-705. Available at: 16. Nelson JA, Dabic S, Mehrara BJ, et al. Breast implant-associated
[Link] anaplastic large cell lymphoma incidence: Determining an accurate risk.

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T-Cell Lymphomas

Ann Surg 2020;272:403-409. Available at: States: A systematic review. Aesthet Surg J 2023;44:NP32-NP40.
[Link] Available at: [Link]

17. Tevis SE, Hunt KK, Miranda RN, et al. Breast implant-associated 24. Srinivasa DR, Miranda RN, Kaura A, et al. Global adverse event
anaplastic large cell lymphoma: a prospective series of 52 patients. Ann reports of breast implant-associated ALCL: An international review of 40
Surg 2022;275:e245-e249. Available at: government authority databases. Plast Reconstr Surg
[Link] 2017;139:1029-1039. Available at:
[Link]
18. McCarthy CM, Loyo-Berrios N, Qureshi AA, et al. Patient registry and
outcomes for breast implants and anaplastic large cell lymphoma etiology 25. Santanelli Di Pompeo F, Panagiotakos D, Firmani G, Sorotos M.
and epidemiology (PROFILE): Initial report of findings, 2012-2018. Plast BIA-ALCL epidemiological findings from a retrospective study of 248
Reconstr Surg 2019;143:65S-73S. Available at: cases extracted from relevant case reports and series: A systematic
[Link] review. Aesthet Surg J 2023;43:545-555. Available at:
[Link]
19. Alaggio R, Amador C, Anagnostopoulos I, et al. The 5th edition of the
World Health Organization Classification of Haematolymphoid Tumours: 26. Vittorietti M, Mazzola S, Costantino C, et al. Implant replacement and
Lymphoid Neoplasms. Leukemia 2022;36:1720-1748. Available at: anaplastic large cell lymphoma associated with breast implants: a
[Link] quantitative analysis. Front Oncol 2023;13:1202733. Available at:
[Link]
20. Campo E, Jaffe ES, Cook JR, et al. The International Consensus
Classification of Mature Lymphoid Neoplasms: a report from the Clinical 27. Clemens MW, Myckatyn T, Di Napoli A, et al. Breast implant
Advisory Committee. Blood 2022;140:1229-1253. Available at: associated anaplastic large cell lymphoma: Evidence-based consensus
[Link] conference statement from the American Association of Plastic Surgeons.
Plast Reconstr Surg 2024:Online ahead of Print. Available at:
21. Medical device reports of breast implant-associated anaplastic large [Link]
cell lymphoma. 2023. Available at:
[Link] 28. PubMed Overview. Available at:
ts-breast-implant-associated-anaplastic-large-cell-lymphoma. Accessed [Link] Accessed March 5, 2024.
March 7, 2024.
29. Quesada AE, Medeiros LJ, Clemens MW, et al. Breast
22. McCarthy CM, Roberts J, Mullen E, et al. Patient registry and implant-associated anaplastic large cell lymphoma: a review. Mod Pathol
outcomes for breast implants and anaplastic large cell lymphoma etiology 2019;32:166-188. Available at:
and epidemiology (PROFILE): Updated report 2012-2020. Plast Reconstr [Link]
Surg 2023;152:16S-24S. Available at:
[Link] 30. Laurent C, Delas A, Gaulard P, et al. Breast implant-associated
anaplastic large cell lymphoma: two distinct clinicopathological variants
23. Santanelli di Pompeo F, Clemens MW, Paolini G, et al. Epidemiology with different outcomes. Ann Oncol 2016;27:306-314. Available at:
of breast implant-associated anaplastic large cell lymphoma in the United [Link]

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T-Cell Lymphomas

31. Clemens MW, Medeiros LJ, Butler CE, et al. Complete surgical 38. Jaffe ES, Ashar BS, Clemens MW, et al. Best practices guideline for
excision is essential for the management of patients with breast the pathologic diagnosis of breast implant-associated anaplastic large-cell
implant-associated anaplastic large-cell lymphoma. J Clin Oncol lymphoma. J Clin Oncol 2020;38:1102-1111. Available at:
2016;34:160-168. Available at: [Link]
[Link]
39. Lyapichev KA, Pina-Oviedo S, Medeiros LJ, et al. A proposal for
32. Loghavi S, Medeiros LJ, Javadi S, et al. Breast implant-associated pathologic processing of breast implant capsules in patients with
anaplastic large cell lymphoma with bone marrow involvement. Aesthet suspected breast implant anaplastic large cell lymphoma. Mod Pathol
Surg J 2018;38. Available at: 2020;33:367-379. Available at:
[Link] [Link]

33. Ferrufino-Schmidt MC, Medeiros LJ, Liu H, et al. Clinicopathologic 40. Taylor CR, Siddiqi IN, Brody GS. Anaplastic large cell lymphoma
features and prognostic impact of lymph node involvement in patients with occurring in association with breast implants: review of pathologic and
breast implant-associated anaplastic large cell lymphoma. Am J Surg immunohistochemical features in 103 cases. Appl Immunohistochem Mol
Pathol 2018;42:293-305. Available at: Morphol 2013;21:13-20. Available at:
[Link] [Link]

34. Thompson PA, Prince HM. Breast implant-associated anaplastic large 41. Hanson SE, Hassid VJ, Branch-Brooks C, et al. Validation of a CD30
cell lymphoma: a systematic review of the literature and mini-meta enzyme-linked immunosorbant assay for the rapid detection of breast
analysis. Curr Hematol Malig Rep 2013;8:196-210. Available at: implant-associated anaplastic large cell lymphoma. Aesthet Surg J
[Link] 2020;40:149-153. Available at:
[Link]
35. Expert Panel on Breast I, Lourenco AP, Moy L, et al. ACR
appropriateness criteria® breast implant evaluation. J Am Coll Radiol 42. Chan A, Auclair R, Gao Q, et al. Role of flow cytometric
2018;15:S13-S25. Available at: immunophenotyping in the diagnosis of breast implant-associated
[Link] anaplastic large cell lymphoma: A 6-year, single-institution experience.
Cytometry B Clin Cytom 2024. Available at:
36. Granados R, Lumbreras EM, Delgado M, et al. Cytological diagnosis [Link]
of bilateral breast implant-associated lymphoma of the ALK-negative
anaplastic large-cell type. Clinical implications of peri-implant breast 43. Oishi N, Miranda RN, Feldman AL. Genetics of breast
seroma cytological reporting. Diagn Cytopathol 2016;44:623-627. implant-associated anaplastic large cell lymphoma (BIA-ALCL). Aesthet
Available at: [Link] Surg J 2019;39:S14-S20. Available at:
[Link]
37. Di Napoli A, Pepe G, Giarnieri E, et al. Cytological diagnostic features
of late breast implant seromas: From reactive to anaplastic large cell 44. Di Napoli A, Jain P, Duranti E, et al. Targeted next generation
lymphoma. PLoS One 2017;12:e0181097. Available at: sequencing of breast implant-associated anaplastic large cell lymphoma
[Link] reveals mutations in JAK/STAT signalling pathway genes, TP53 and
DNMT3A. Br J Haematol 2018;180:741-744. Available at:
[Link]

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T-Cell Lymphomas

45. Blombery P, Thompson ER, Prince HM. Molecular drivers of breast Oncol 2024;31:2032-2040. Available at:
implant-associated anaplastic large cell lymphoma. Plast Reconstr Surg [Link]
2019;143:59S-64S. Available at:
[Link] 53. Lamaris GA, Butler CE, Deva AK, et al. Breast reconstruction following
breast implant-associated anaplastic large cell lymphoma. Plast Reconstr
46. DeCoster RC, Clemens MW, Di Napoli A, et al. Cellular and molecular Surg 2019;143:51S-58S. Available at:
mechanisms of breast implant-associated anaplastic large cell lymphoma. [Link]
Plast Reconstr Surg 2021;147:30e-41e. Available at:
[Link] 54. Bautista-Quach MA, Nademanee A, Weisenburger DD, et al.
Implant-associated primary anaplastic large-cell lymphoma with
47. Laurent C, Nicolae A, Laurent C, et al. Gene alterations in epigenetic simultaneous involvement of bilateral breast capsules. Clin Breast Cancer
modifiers and JAK-STAT signaling are frequent in breast 2013;13:492-495. Available at:
implant-associated ALCL. Blood 2020;135:360-370. Available at: [Link]
[Link]
55. Turton P, El-Sharkawi D, Lyburn I, et al. UK guidelines on the
48. Tabanelli V, Corsini C, Fiori S, et al. Recurrent PDL1 expression and diagnosis and treatment of breast implant-associated anaplastic large cell
PDL1 (CD274) copy number alterations in breast implant-associated lymphoma (BIA-ALCL) on behalf of the medicines and healthcare products
anaplastic large cell lymphomas. Hum Pathol 2019;90:60-69. Available at: regulatory agency (MHRA) plastic, reconstructive and aesthetic surgery
[Link] expert advisory group (PRASEAG). Eur J Surg Oncol 2021;47:199-210.
Available at: [Link]
49. Turner SD, Inghirami G, Miranda RN, Kadin ME. Cell of origin and
immunologic events in the pathogenesis of breast implant-associated 56. Collins MS, Miranda RN, Medeiros LJ, et al. Characteristics and
anaplastic large-cell lymphoma. Am J Pathol 2020;190:2-10. Available at: treatment of advanced breast implant-associated anaplastic large cell
[Link] lymphoma. Plast Reconstr Surg 2019;143:41S-50S. Available at:
[Link]
50. Quesada AE, Zhang Y, Ptashkin R, et al. Next generation sequencing
of breast implant-associated anaplastic large cell lymphomas reveals a 57. Mehta-Shah N, Clemens MW, Horwitz SM. How I treat breast
novel STAT3-JAK2 fusion among other activating genetic alterations implant-associated anaplastic large cell lymphoma. Blood
within the JAK-STAT pathway. Breast J 2021;27:314-321. Available at: 2018;132:1889-1898. Available at:
[Link] [Link]

51. Carbonaro R, Accardo G, Mazzocconi L, et al. BIA-ALCL in patients 58. Alderuccio JP, Desai A, Yepes MM, et al. Frontline brentuximab
with genetic predisposition for breast cancer: our experience and a review vedotin in breast implant-associated anaplastic large-cell lymphoma. Clin
of the literature. Eur J Cancer Prev 2023;32:370-376. Available at: Case Rep 2018;6:634-637. Available at:
[Link] [Link]

52. Vorstenbosch J, Ghione P, Plitas G, et al. Surgical management and 59. Stack A, Ali N, Khan N. Breast implant-associated anaplastic large cell
long-term outcomes of BIA-ALCL: A multidisciplinary approach. Ann Surg lymphoma: A review with emphasis on the role of brentuximab vedotin. J

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T-Cell Lymphomas

Cell Immunol 2020;2:80-89. Available at:

[Link]

60. Horwitz S, O'Connor OA, Pro B, et al. The ECHELON-2 Trial: 5-year
results of a randomized, phase III study of brentuximab vedotin with
chemotherapy for CD30-positive peripheral T-cell lymphoma. Ann Oncol
2022;33:288-298. Available at:
[Link]

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The search results were narrowed by selecting studies in humans

T-Cell Large Granular Lymphocytic Leukemia
published in English. Results were confined to the following article types:
Large granular lymphocytic leukemia (LGLL) is a rare chronic Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, Phase IV;
lymphoproliferative disorder originating in the mature T cells and natural Guideline; Randomized Controlled Trial; Meta-Analysis; Systematic
killer (NK) cells, accounting for 2% to 5% of all the chronic Reviews; and Validation Studies.
lymphoproliferative disorders in North America and Europe. In the 2017
WHO classification, LGLL was classified into three categories: T-cell LGLL The data from key PubMed articles deemed as relevant to these
(T-LGLL), chronic lymphoproliferative disorder of NK cells (included as a Guidelines have been included in this version of the Discussion section.
provisional entity), and aggressive NK-cell leukemia (ANKL).1 In the Recommendations for which high-level evidence is lacking are based on
updated 2022 WHO classification (WHO5), chronic lymphoproliferative the panel’s review of lower-level evidence and expert opinion.
disorder of NK cells is renamed as NK-LGLL and is listed as a definite
entity.2 The 2022 International Consensus Classification (ICC) continues Diagnosis
to list chronic lymphoproliferative disorder of NK cells as a provisional The diagnosis of LGLL requires the presence of an expanded clonal
entity.3 population of T- or NK-cell large granular lymphocytes. Large granular
lymphocyte count of greater than 500 x 109/L is typically needed, but not
T-LGLL is the most common subtype, representing approximately 85% of required for the diagnosis of T-LGLL, although patients with concomitant
LGLL cases, and NK-LGLL represents approximately 10% of LGLL bone marrow failure/pancytopenia may not meet this threshold.
cases.4-6 Most of T-LGLL are of αβ T-cell origin, but some also have γδ Therefore, the diagnosis of T-LGLL should be based on clinicopathologic
T-cell phenotype. NK-LGLL has clinical and biologic features similar to findings, especially in those patients with large granular lymphocyte
T-LGLL and is managed similar to T-LGLL.7-9 ANKL, mainly diagnosed in count less than 500 x 109/L in the peripheral blood.
Asia, represents approximately 5% of LGLL cases. It is associated with
Epstein-Barr virus (EBV) infection and the prognosis is very poor since it is Morphologic examinations of peripheral blood smear, as well as flow
refractory to chemotherapy.10 cytometry with adequate immunophenotyping, are essential to confirm
the diagnosis of T-LGLL. Bone marrow aspirate and biopsy is not
Literature Search Criteria essential for initial evaluation. However, bone marrow biopsy with
Prior to the update of this version of the NCCN Clinical Practice Guidelines immunophenotyping is useful for patients with low large granular
in Oncology (NCCN Guidelines®) for T-Cell Lymphomas, a literature lymphocyte count (<0.5 x 109/L) and is also useful when considering the
search of the PubMed database was performed to obtain key literature in differential diagnosis of concurrent bone marrow failure disorders.12-14
T-LGLL since the previous Guidelines update. The PubMed database was
chosen as it remains the most widely used resource for medical literature Typical immunophenotype for T-LGLL is consistent with that of mature
and indexes peer-reviewed biomedical literature.11 post-thymic phenotype in the vast majority of cases. T-LGLL is CD3+,
CD8+, CD16+, CD57+, CD56-, CD28-, CD5 dim and/or CD7 dim,
CD45RA+, CD62L-, TCRαβ+, TIA1+ and granzyme B+, and granzyme

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T-Cell Lymphomas

M+.12-14 Typical immunophenotype for NK-LGLL is CD3−, CD8+, CD16+, by the presence of STAT3 mutations and neutropenia whereas T-LGLL
CD56+, CD4−, CD94+, and TCRαβ−.5 with CD4+/CD8 +/- immunophenotype are devoid of STAT3 mutations but
characterized by STAT5B mutations), and STAT3 mutations have also
Flow cytometry should include the following markers: CD3, CD4, CD5, been associated with reduced overall survival (OS) and shortened time to
CD7, CD8, CD16, CD56, CD57, CD28, TCRαß, TCRγδ, CD45RA, and treatment.31-33
CD62L. The immunohistochemistry (IHC) panel should include CD3,
CD4, CD5, CD7, CD8, CD56, CD57, TCRß, TCRγ, TIA1, perforin, and Mutational analysis for STAT3 and STAT5B is useful under certain
granzyme B. Granzyme M is expressed in LGLL of both T-cell and selected circumstances. Epstein-Barr encoding region (EBER) in situ
NK-cell lineage, and IHC for granzyme M may be useful in selected hybridization is useful under certain selected circumstances for the
circumstances.15 differential diagnosis of ANKL.10

Assessment of T-cell clonality either by molecular analysis for the Workup

detection of clonal TCR gene rearrangements or other assessment of
The initial workup for T-LGLL should include comprehensive medical
clonality is useful under selected circumstances.16-20 However, TCR gene
history and physical examination, including careful evaluation of lymph
rearrangement results should be interpreted with caution, since TCR
nodes, spleen, and liver, in addition to evaluation of performance status
gene rearrangement without cytologic and immunophenotypic evidence
and the presence of autoimmune disorders. Laboratory assessments
of abnormal T-cell population can also be seen in healthy patients.
should include complete blood count (CBC) with differential,
Small, clinically non-significant clones of large granular lymphocytes can
comprehensive metabolic panel, serology studies for the detection of
be detected concurrently in patients with bone marrow failure disorders.
antibodies against HIV (type 1 and type 2) and human T-cell
Therefore, it is essential to rule out reactive large granular lymphocytic
lymphotropic virus (HTLV; type 1 and type 2), as well as polymerase
lymphocytosis in patients with autoimmune or bone marrow failure
chain reaction (PCR) for viral DNA or RNA.
disorders. Flow cytometry and TCR gene rearrangement studies should
be repeated in 6 months in asymptomatic patients with small clonal large Autoimmune disorders and immune-mediated cytopenias can occur in
granular lymphocytes (<0.5 x 109/L) or polyclonal large granular patients with T-LGLL.34,35 Rheumatoid arthritis, often with concomitant
lymphocytic lymphocytosis. Felty syndrome (splenomegaly, neutropenia, and rheumatoid arthritis) is
the most common autoimmune disorder associated with T-LGLL,
Somatic mutations in the STAT3 and STAT5B genes have been identified
although other less common diseases such as Sjogren syndrome or
in patients with LGLL.21 STAT3 mutations are more common in patients
other autoimmune disorders have also been described.35-37 Pure red cell
with T-LGLL and NK-LGLL.22-28 STAT5B mutations have been identified in
aplasia (PRCA) is one of the most common complications of LGLL in
a smaller proportion of patients and are more common in patients with
Asian patients.38 Evaluation of serologic markers such as rheumatoid
CD4+ T-LGLL.29,30 Recent reports have identified specific molecular
factor (RF), antinuclear antibodies (ANA), and erythrocyte sedimentation
subtypes of T-LGLL based on the STAT3 or STAT5B mutation status
rate (ESR) is useful in patients with autoimmune disease.
(CD8+ T-LGLL with CD16+/CD56- immunophenotype was characterized

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

Imaging studies, including ultrasound of liver/spleen and respectively, for cyclosporine, cyclophosphamide, and methotrexate. Many
chest/abdomen/pelvis CT scan with contrast of diagnostic quality patients received multiple therapies due to lack of initial response and/or
echocardiography (for patients with unexplained shortness of breath toxicity. The combined ORRs were 48%, 53%, and 43%, respectively.
and/or right heart failure) may also be useful under selected Methotrexate resulted in more durable responses (36 months) than
circumstances. cyclosporine (21 months) or cyclophosphamide (14 months). STAT3
mutations were associated with significantly longer median OS. After a
Treatment Options median follow-up of 36 months, the median survival was 118 months in
First-line Therapy patients without a STAT3 mutation and the median survival was not
Because T-LGLL is relatively rare, few clinical trials have been conducted reached in those with a STAT3 mutation. However, in a more recent report
and treatment recommendations are based on evidence mainly from STAT3 mutation was independently associated with reduced OS.32
retrospective studies. Methotrexate, cyclophosphamide, and cyclosporine
are used most commonly for first-line therapy.39-54 Another series of 23 patients with T-LGLL reported ORR and CR rates of
78% and 30%, respectively, with cyclosporine as first-line therapy.41 In a
In the first prospective phase II trial of 59 patients with T-LGLL series of 45 patients with LGLL, cyclophosphamide (with or without
(ECOG5998), 55 eligible patients received first-line therapy with low-dose prednisone) as a first-line therapy resulted in an ORR of 71% (47% CR
methotrexate (10 mg/m2) and prednisone (1 mg/kg orally for 30 days and and 24% PR).47 The ORR was 72% and 68%, respectively, for patients
then tapered off in the subsequent 24 days) resulting in an overall with T-LGLL and NK-LGLL, and 72% and 67%, respectively, for patients
response rate (ORR) of 38% (5% complete response [CR] and 33% partial with neutropenia and anemia.
response [PR]).48 The ORRs were 42%, 34%, and 29%, respectively, for
patients with neutropenia, anemia, and rheumatoid arthritis. In another retrospective analysis of 60 patients with T-LGLL that evaluated
the clinical outcomes using the stringent response criteria from the
In a single-center series of 39 patients with T-LGLL (15 patients never ECOG5998 study, the ORR to first-line methotrexate was 41% (10% CR)
required treatment), among the 24 patients requiring treatment, 9 patients and the median duration of response was 17 months.53 No patients treated
received low-dose methotrexate as first-line therapy, resulting in an ORR with first-line cyclosporine or cyclophosphamide had a response. Among
of 89% and the median duration of response was 133 months.49 Among 5 the 10 patients who received first-line methotrexate, cyclophosphamide
patients treated with methotrexate after disease progression on resulted in an ORR of 70%, suggesting this is an effective second-line
prednisolone, the ORR was 100% and the median duration of response therapy option.
was 14 months.
In a single center cohort study of 319 patients with LGLL (295 patients
In another single-center cohort study of 204 patients with LGLL (90% had with T-LGLL), monotherapy with methotrexate, cyclophosphamide, or
T-LGLL and 10% had NK-LGLL), cyclosporine, methotrexate, and cyclosporine were most commonly used as first-line therapy.54 The CR
cyclophosphamide were given as first-line therapy in 37%, 29%, and 19% rates were higher with cyclophosphamide (32%) compared to
of patients, respectively.51 Initial response rates were 45%, 47%, and 44%, methotrexate (16%) or cyclosporine (23%). The presence of autoimmune

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T-Cell Lymphomas

diseases was associated with increased response rates, whereas with cyclophosphamide should be limited due to increased risk of bladder
thrombocytopenia, splenomegaly, and female gender assigned at birth toxicity, mutagenesis, and leukemogenesis (4 months if there is no
(after controlling for autoimmune diseases) were associated with response and up to ≤12 months if PR is achieved at 4 months).56
decreased response rates. Thrombocytopenia was also an independent
Relapsed or Refractory Disease
risk factor for inferior survival.
Cyclophosphamide and cyclosporine are also effective for disease not
An ongoing prospective clinical trial is comparing methotrexate with responding to initial treatment with methotrexate.48,57,58 In the ECOG5998
cyclophosphamide in patients with previously untreated LGLL in need of trial that evaluated methotrexate with prednisone as first-line therapy,
treatment, although early results suggest no clear difference.55 cyclophosphamide resulted in an ORR of 64% in patients with T-LGLL that
did not respond to methotrexate.48 Alemtuzumab is also active in patients
NCCN Recommendations with relapsed and refractory disease, resulting in an ORR of 56%.59 While
Treatment should be initiated in symptomatic patients in the presence of alemtuzumab is no longer commercially available, it may be obtained for
indications for treatment, which include: absolute neutrophil count (ANC) clinical use. Purine analogues, including pentostatin, cladribine, and
less than 0.5 x 109/L, ANC less than 1500 x 109/L with recurrent infections fludarabine have shown activity in refractory T-LGLL (mostly in small
or hospitalizations for neutropenic fever, hemoglobin less than 10 g/dL, or series or case reports).41,42,44,60-62 Splenectomy can be considered in select
the need for red blood cell (RBC) transfusion, platelet count less than 50 x patients non-responsive to standard agents, with concomitant
109/L, autoimmune diseases associated with T-LGLL requiring treatment, splenomegaly and refractory cytopenia, particularly with autoimmune
symptomatic splenomegaly, and pulmonary artery hypertension secondary hemolytic anemia.63
to LGLL.
Ruxolitinib (JAK inhibitor) has been evaluated in patients with relapsed or
Low-dose methotrexate or cyclophosphamide (with or without refractory T-LGLL.64-66 Given the encouraging initial responses with
corticosteroids) or cyclosporine are included as options for first-line ruxolitinib reported in a phase II biomarker driven study (that initially
therapy. Patients with active autoimmune disease should have therapy included patients with other relapsed/refractory T-cell lymphoma
directed toward their autoimmune disease whenever possible, and subtypes), the study included an expansion cohort of patients with
low-dose methotrexate may be beneficial for patients with concomitant relapsed/refractory LGLL (n = 23; 54% of patients had STAT3
autoimmune disease. Cyclophosphamide or cyclosporine may be used in mutations).66 Among 20 patients evaluable for response, the ORR was
patients with anemia. 55% (30% PR and 25% CR). The median EFS was not reached and
21-month EFS rate was 68%. Anemia (70%; grade 3, 44%) and
Response assessment should be done after 4 months of first-line therapy
neutropenia (65%; grade 3, 33%) were the most common adverse events.
and the use of the parameters established in the ECOG5998 study are
STAT3 mutation status was a predictor of improved EFS (P = .007).66 The
recommended for the assessment of response, including the use of
median EFS was not reached and the 21-month EFS rate was 100% for
peripheral blood flow cytometry. Continuation of initial treatment is
recommended for patients achieving CR or PR after 4 months. Treatment

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T-Cell Lymphomas

patients with STAT3 mutation. The median EFS was 20 months and the
21-month EFS rate was 40% for those with no STAT3 mutation.

NCCN Recommendations
Alternate first-line therapy or alemtuzumab or ruxolitinib is recommended
for patients with disease not responding to initial treatment. Clinical trial,
ruxolitinib (if not previously given), and purine analogues are included as
preferred options for second-line therapy for progressive disease or
refractory disease to all regimens. Alemtuzumab (if not previously given) is
an option under other recommended regimens.

Ruxolitinib was dosed at 20 mg BID in the aforementioned phase II

study.66 Due to the prevalence of cytopenias in patients with LGLL,
ruxolitinib dose reductions to 10 or 5 mg BID can be considered. Frequent
CBC monitoring is recommended. Routine monitoring for cytomegalovirus
(CMV) reactivation and the use of anti-infective prophylaxis for herpes
virus and Pneumocystis jirovecii pneumonia (PJP) is recommended for all
patients receiving alemtuzumab-based regimens. See Supportive Care:
Monoclonal Antibody Therapy and Viral Reactivation in the algorithm.

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T-Cell Lymphomas

References 70 patients. Ann Oncol 2014;25:2030-2035. Available at:

[Link]
1. Swerdlow SH, Harris NL, Jaffe ES, et al. WHO Classification of
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France: IARC; 2017. disorder of NK-cells: A single-institution review with emphasis on relative
utility of multimodality diagnostic tools. Eur J Haematol 2018;100:444-454.
2. Alaggio R, Amador C, Anagnostopoulos I, et al. The 5th edition of the Available at: [Link]
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Lymphoid Neoplasms. Leukemia 2022;36:1720-1748. Available at: 10. Suzuki R, Suzumiya J, Nakamura S, et al. Aggressive natural killer-cell
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3. Campo E, Jaffe ES, Cook JR, et al. The International Consensus [Link]
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4. Melenhorst JJ, Eniafe R, Follmann D, et al. T-cell large granular 12. Evans HL, Burks E, Viswanatha D, Larson RS. Utility of
lymphocyte leukemia is characterized by massive TCRBV-restricted clonal immunohistochemistry in bone marrow evaluation of T-lineage large
CD8 expansion and a generalized overexpression of the effector cell granular lymphocyte leukemia. Hum Pathol 2000;31:1266-1273. Available
marker CD57. Hematol J 2003;4:18-25. Available at: at: [Link]
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13. Morice WG, Kurtin PJ, Tefferi A, Hanson CA. Distinct bone marrow
5. Lamy T, Moignet A, Loughran TP, Jr. LGL leukemia: From findings in T-cell granular lymphocytic leukemia revealed by paraffin
pathogenesis to treatment. Blood 2017;129:1082-1094. Available at: section immunoperoxidase stains for CD8, TIA-1, and granzyme B. Blood
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6. Barila G, Calabretto G, Teramo A, et al. T cell large granular
lymphocyte leukemia and chronic NK lymphocytosis. Best Pract Res Clin 14. Osuji N, Beiske K, Randen U, et al. Characteristic appearances of the
Haematol 2019;32:207-216. Available at: bone marrow in T-cell large granular lymphocyte leukaemia.
[Link] Histopathology 2007;50:547-554. Available at:
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7. Bareau B, Rey J, Hamidou M, et al. Analysis of a French cohort of
patients with large granular lymphocyte leukemia: a report on 229 cases. 15. Morice WG, Jevremovic D, Hanson CA. The expression of the novel
Haematologica 2010;95:1534-1541. Available at: cytotoxic protein granzyme M by large granular lymphocytic leukaemias of
[Link] both T-cell and NK-cell lineage: an unexpected finding with implications
regarding the pathobiology of these disorders. Br J Haematol
8. Poullot E, Zambello R, Leblanc F, et al. Chronic natural killer 2007;137:237-239. Available at:
lymphoproliferative disorders: characteristics of an international cohort of [Link]

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

16. Ryan DK, Alexander HD, Morris TC. Routine diagnosis of large 23. Jerez A, Clemente MJ, Makishima H, et al. STAT3 mutations unify the
granular lymphocytic leukaemia by Southern blot and polymerase chain pathogenesis of chronic lymphoproliferative disorders of NK cells and
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24. Andersson EI, Rajala HL, Eldfors S, et al. Novel somatic mutations in
17. Langerak AW, van Den Beemd R, Wolvers-Tettero IL, et al. Molecular large granular lymphocytic leukemia affecting the STAT-pathway and
and flow cytometric analysis of the Vbeta repertoire for clonality T-cell activation. Blood Cancer J 2013;3:e168. Available at:
assessment in mature TCRalphabeta T-cell proliferations. Blood [Link]
2001;98:165-173. Available at:
[Link] 25. Ohgami RS, Ma L, Merker JD, et al. STAT3 mutations are frequent in
CD30+ T-cell lymphomas and T-cell large granular lymphocytic leukemia.
18. Lima M, Almeida J, Santos AH, et al. Immunophenotypic analysis of Leukemia 2013;27:2244-2247. Available at:
the TCR-Vbeta repertoire in 98 persistent expansions of [Link]
CD3(+)/TCR-alphabeta(+) large granular lymphocytes: utility in assessing
clonality and insights into the pathogenesis of the disease. Am J Pathol 26. Rajala HL, Olson T, Clemente MJ, et al. The analysis of clonal
2001;159:1861-1868. Available at: diversity and therapy responses using STAT3 mutations as a molecular
[Link] marker in large granular lymphocytic leukemia. Haematologica
2015;100:91-99. Available at:
19. Feng B, Jorgensen JL, Hu Y, et al. TCR-Vbeta flow cytometric analysis [Link]
of peripheral blood for assessing clonality and disease burden in patients
with T cell large granular lymphocyte leukaemia. J Clin Pathol 27. Shi M, He R, Feldman AL, et al. STAT3 mutation and its clinical and
2010;63:141-146. Available at: histopathologic correlation in T-cell large granular lymphocytic leukemia.
[Link] Hum Pathol 2018;73:74-81. Available at:
[Link]
20. Clemente MJ, Wlodarski MW, Makishima H, et al. Clonal drift
demonstrates unexpected dynamics of the T-cell repertoire in T-large 28. Rivero A, Mozas P, Jimenez L, et al. Clinicobiological characteristics
granular lymphocyte leukemia. Blood 2011;118:4384-4393. Available at: and outcomes of patients with T-cell large granular lymphocytic leukemia
[Link] and chronic lymphoproliferative disorder of natural killer cells from a single
institution. Cancers (Basel) 2021;13:3900. Available at:
21. Moosic KB, Paila U, Olson KC, et al. Genomics of LGL leukemia and [Link]
select other rare leukemia/lymphomas. Best Pract Res Clin Haematol
2019;32:196-206. Available at: 29. Rajala HL, Eldfors S, Kuusanmaki H, et al. Discovery of somatic
[Link] STAT5B mutations in large granular lymphocytic leukemia. Blood
2013;121:4541-4550. Available at:
22. Koskela HL, Eldfors S, Ellonen P, et al. Somatic STAT3 mutations in [Link]
large granular lymphocytic leukemia. N Engl J Med 2012;366:1905-1913.
Available at: [Link] 30. Andersson EI, Tanahashi T, Sekiguchi N, et al. High incidence of
activating STAT5B mutations in CD4-positive T-cell large granular

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T-Cell Lymphomas

lymphocyte leukemia. Blood 2016;128:2465-2468. Available at: cell aplasia. Onco Targets Ther 2019;12:8229-8240. Available at:
[Link] [Link]

31. Teramo A, Barila G, Calabretto G, et al. STAT3 mutation impacts 39. Loughran TP, Jr., Kidd PG, Starkebaum G. Treatment of large
biological and clinical features of T-LGL leukemia. Oncotarget granular lymphocyte leukemia with oral low-dose methotrexate. Blood
2017;8:61876-61889. Available at: 1994;84:2164-2170. Available at:
[Link] [Link]

32. Barila G, Teramo A, Calabretto G, et al. STAT3 mutations impact on 40. Hamidou MA, Sadr FB, Lamy T, et al. Low-dose methotrexate for the
overall survival in large granular lymphocyte leukemia: a single-center treatment of patients with large granular lymphocyte leukemia associated
experience of 205 patients. Leukemia 2020;34:1116-1124. Available at: with rheumatoid arthritis. Am J Med 2000;108:730-732. Available at:
[Link] [Link]

33. Munoz-Garcia N, Jara-Acevedo M, Caldas C, et al. STAT3 and 41. Osuji N, Matutes E, Tjonnfjord G, et al. T-cell large granular
STAT5B mutations in T/NK-cell chronic lymphoproliferative disorders of lymphocyte leukemia: A report on the treatment of 29 patients and a
large granular lymphocytes (LGL): Association with disease features. review of the literature. Cancer 2006;107:570-578. Available at:
Cancers (Basel) 2020;12:3508. Available at: [Link]
[Link]
42. Aribi A, Huh Y, Keating M, et al. T-cell large granular lymphocytic
34. Zhang R, Shah MV, Loughran TP, Jr. The root of many evils: Indolent (T-LGL) leukemia: experience in a single institution over 8 years. Leuk
large granular lymphocyte leukaemia and associated disorders. Hematol Res 2007;31:939-945. Available at:
Oncol 2010;28:105-117. Available at: [Link]
[Link]
43. Fujishima N, Sawada K, Hirokawa M, et al. Long-term responses and
35. Bockorny B, Dasanu CA. Autoimmune manifestations in large granular outcomes following immunosuppressive therapy in large granular
lymphocyte leukemia. Clin Lymphoma Myeloma Leuk 2012;12:400-405. lymphocyte leukemia-associated pure red cell aplasia: a Nationwide
Available at: [Link] Cohort Study in Japan for the PRCA Collaborative Study Group.
Haematologica 2008;93:1555-1559. Available at:
36. Liu X, Loughran TP, Jr. The spectrum of large granular lymphocyte [Link]
leukemia and Felty's syndrome. Curr Opin Hematol 2011;18:254-259.
Available at: [Link] 44. Fortune AF, Kelly K, Sargent J, et al. Large granular lymphocyte
leukemia: Natural history and response to treatment. Leuk Lymphoma
37. Gazitt T, Loughran TP, Jr. Chronic neutropenia in LGL leukemia and 2010;51:839-845. Available at:
rheumatoid arthritis. Hematology Am Soc Hematol Educ Program [Link]
2017;2017:181-186. Available at:
[Link] 45. Pawarode A, Wallace PK, Ford LA, et al. Long-term safety and
efficacy of cyclosporin A therapy for T-cell large granular lymphocyte
38. Qiu ZY, Qin R, Tian GY, et al. Pathophysiologic mechanisms and leukemia. Leuk Lymphoma 2010;51:338-341. Available at:
management of large granular lymphocytic leukemia associated pure red [Link]

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

46. Zhao X, Zhou K, Jing L, et al. Treatment of T-cell large granular 54. Dong N, Castillo Tokumori F, Isenalumhe L, et al. Large granular
lymphocyte leukemia with cyclosporine A: Experience in a Chinese single lymphocytic leukemia - A retrospective study of 319 cases. Am J Hematol
institution. Leuk Res 2013;37:547-551. Available at: 2021;96:772-780. Available at:
[Link] [Link]

47. Moignet A, Hasanali Z, Zambello R, et al. Cyclophosphamide as a 55. Lamy T, Pastoret C, Houot R, et al. Prospective, multicentric phase II
first-line therapy in LGL leukemia. Leukemia 2014;28:1134-1136. randomized trial comparing the efficacy of methotrexate or
Available at: [Link] cyclophosphamide in large granular lymphocytic leukemia: A French
National Study. Report on the interim analysis [abstract]. Blood
48. Loughran TP, Jr., Zickl L, Olson TL, et al. Immunosuppressive therapy 2019;134:Abstract 1545. Available at:
of LGL leukemia: prospective multicenter phase II study by the Eastern [Link]
Cooperative Oncology Group (E5998). Leukemia 2015;29:886-894.
Available at: [Link] 56. Lamy T, Loughran TP, Jr. How I treat LGL leukemia. Blood
2011;117:2764-2774. Available at:
49. Munir T, Bishton MJ, Carter I, et al. Single-center series of bone [Link]
marrow biopsy-defined large granular lymphocyte leukemia: High rates of
sustained response to oral methotrexate. Clin Lymphoma Myeloma Leuk 57. Bible KC, Tefferi A. Cyclosporine A alleviates severe anaemia
2016;16:705-712. Available at: associated with refractory large granular lymphocytic leukaemia and
[Link] chronic natural killer cell lymphocytosis. Br J Haematol 1996;93:406-408.
Available at: [Link]
50. Qiu ZY, Fan L, Wang R, et al. Methotrexate therapy of T-cell large
granular lymphocytic leukemia impact of STAT3 mutation. Oncotarget 58. Peng G, Yang W, Zhang L, et al. Moderate-dose cyclophosphamide in
2016;7:61419-61425. Available at: the treatment of relapsed/refractory T-cell large granular lymphocytic
[Link] leukemia-associated pure red cell aplasia. Hematology 2016;21:138-143.
Available at: [Link]
51. Sanikommu SR, Clemente MJ, Chomczynski P, et al. Clinical features
and treatment outcomes in large granular lymphocytic leukemia (LGLL). 59. Dumitriu B, Ito S, Feng X, et al. Alemtuzumab in T-cell large granular
Leuk Lymphoma 2018;59:416-422. Available at: lymphocytic leukaemia: interim results from a single-arm, open-label,
[Link] phase 2 study. Lancet Haematol 2016;3:e22-29. Available at:
[Link]
52. Zhu Y, Gao Q, Hu J, et al. Clinical features and treatment outcomes in
patients with T-cell large granular lymphocytic leukemia: A 60. Edelman MJ, O'Donnell RT, Meadows I. Treatment of refractory large
single-institution experience. Leuk Res 2020;90:106299. Available at: granular lymphocytic leukemia with 2-chlorodeoxyadenosine. Am J
[Link] Hematol 1997;54:329-331. Available at:
[Link]
53. Braunstein Z, Mishra A, Staub A, et al. Clinical outcomes in T-cell
large granular lymphocytic leukaemia: prognostic factors and treatment 61. Tse E, Chan JC, Pang A, et al. Fludarabine, mitoxantrone and
response. Br J Haematol 2021;192:484-493. Available at: dexamethasone as first-line treatment for T-cell large granular lymphocyte
[Link]

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T-Cell Lymphomas

leukemia. Leukemia 2007;21:2225-2226. Available at:

[Link]

62. Costa RO, Bellesso M, Chamone DA, et al. T-cell large granular
lymphocytic leukemia: treatment experience with fludarabine. Clinics (Sao
Paulo) 2012;67:745-748. Available at:
[Link]

63. Subbiah V, Viny AD, Rosenblatt S, et al. Outcomes of splenectomy in

T-cell large granular lymphocyte leukemia with splenomegaly and
cytopenia. Exp Hematol 2008;36:1078-1083. Available at:
[Link]

64. Moignet A, Pastoret C, Cartron G, et al. Ruxolitinib for refractory large

granular lymphocyte leukemia. American Journal of Hematology
2021;96:E368-E370. Available at:
[Link]

65. Moskowitz AJ, Ghione P, Jacobsen E, et al. A phase 2

biomarker-driven study of ruxolitinib demonstrates effectiveness of
JAK/STAT targeting in T-cell lymphomas. Blood 2021;138:2828-2837.
Available at: [Link]

66. Moskowitz A, Rahman J, Ganesan N, et al. Ruxolitinib promotes

clinical responses in large granular lymphocytic leukemia via suppression
of JAK/STAT-dependent inflammatory cascades [abstract]. Blood
2023;142:Abstract 183. Available at:
[Link]

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

T-Cell Prolymphocytic Leukemia Diagnosis

Overview The diagnosis of TPLL is established if all three major criteria
T-cell prolymphocytic leukemia (T-PLL) is a rare malignancy, comprising (T-lymphocytosis, >5 x109/L cells of T-PLL phenotype in peripheral blood
approximately 2% of all mature lymphoid malignancies.1,2 Clinically, or bone marrow; T-cell clonality confirmed by polymerase chain reaction or
patients frequently present with B symptoms, lymphadenopathy, by flow cytometry; abnormalities in chromosome 14 or overexpression of
hepatomegaly, splenomegaly, and elevated white blood cell (WBC) TCL-1 or MTCP-1 oncogene) or if the first two major criteria and any one
counts.3 Rarely, patients can present with an asymptomatic leukocytosis. of the minor criteria (abnormalities involving chromosome 8 or 11;
Skin lesions can also be present in approximately 30% of patients, abnormalities in chromosomes 5, 12, 13, 22, or complex karyotype or the
although the cutaneous presentation is not well characterized. Central presence of splenomegaly or effusions) are present.3
nervous system (CNS) involvement is rare and is seen in less than 10% of
Morphologic examinations of peripheral blood smear, as well as
patients.4,5
adequate immunophenotyping by flow cytometry, are essential to
Literature Search Criteria establish the diagnosis of T-PLL.3 In most cases (approximately 75%),
the typical morphology comprises medium-sized prolymphocytes with
Prior to the update of this version of the NCCN Clinical Practice
agranular basophilic cytoplasm and a single visible nucleolus, while in
Guidelines in Oncology (NCCN Guidelines®) for T-Cell Lymphomas, a
approximately 20% to 25% of cases, the cell is small and the nucleolus
literature search of the PubMed database was performed to obtain key
may not be readily visible.1,2 Diffuse infiltration in the bone marrow is
literature in T-PLL published since the previous Guidelines update. The
typically observed with T-PLL, but diagnosis is difficult to establish based
PubMed database was chosen as it remains the most widely used
on bone marrow evaluation alone. In general, bone marrow biopsy is not
resource for medical literature and indexes peer-reviewed biomedical
essential for establishing a diagnosis of T-PLL.3
literature.6
The immunophenotype of T-PLL is consistent with a mature post-thymic
The search results were narrowed by selecting studies in humans
T-cell phenotype, with a typical immunophenotype that is TdT-, CD1a-,
published in English. Results were confined to the following article types:
CD2+, CD5+, and CD7+. CD3 expression may be weak on the cell
Clinical Trial, Phase II; Clinical Trial, Phase III; Guideline; Randomized
surface but is usually expressed in the cytoplasm. In 65% of cases, the
Controlled Trial; Meta-Analysis; Systematic Reviews; and Validation
cells are CD4+/CD8- but cases with CD4+/CD8+ (21%) and CD4-/CD8+
Studies.
(13%) can also be seen.7 CD52 is often highly expressed.8 Recurrent
The data from key PubMed articles deemed as relevant to these inversions or translocations involving chromosome 14, inv(14)(q11;q32)
or t(14;14)(q11;q32), resulting in the overexpression of TCL-1 oncogene
Guidelines have been included in this version of the Discussion section.
Recommendations for which high-level evidence is lacking are based on are the most common cytogenetic abnormalities observed in T-PLL.9-12
Abnormalities in chromosome 8, mainly trisomy 8q, are also frequently
the panel’s review of lower-level evidence and expert opinion.
observed.9,10

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T-Cell Lymphomas

Cytogenetics by conventional karyotyping and/or fluorescence in situ evaluation of performance status. Laboratory assessments should
hybridization (FISH) to detect chromosome 14 abnormalities and trisomy include standard blood work including complete blood count (CBC) with
8 should be performed at the time of diagnostic workup. Molecular differential, a comprehensive metabolic panel, as well as measurements
testing to detect clonal TCR gene rearrangements and of serum lactate dehydrogenase (LDH). In a retrospective study of 119
immunohistochemistry (IHC) analysis on bone marrow biopsy samples patients with T-PLL, the presence of pleural effusion, elevated LDH, and
may be useful under certain circumstances. In such cases, the IHC panel low hemoglobin levels were associated with shorter OS.23 Bone marrow
should include TdT, CD1a, CD2, CD3, CD5, and TCL-1. Peripheral blood evaluation is generally unnecessary, as evaluation of peripheral blood
flow cytometry analysis should include the following markers: TdT, smears and immunophenotyping are sufficient to establish the diagnosis
CD1a, CD2, CD3, CD4, CD5, CD7, CD8, CD52, and TCRαβ. Detection of T-PLL, as discussed above; however, bone marrow assessments may
of TCL-1 overexpression by flow cytometry or IHC is more sensitive than be useful in some cases.3 CT scans of the chest, abdomen, and pelvis
cytogenetics.3 should also be performed at the time of initial workup. PET/CT scans
may also be useful in selected cases. If treatment regimens containing
Although less frequent, the translocation t(x;14)(q28;q11), leading to anthracyclines or anthracenediones are being considered, a multigated
overexpression of the MTCP-1 oncogene, may also occur.13,14 Deletions or acquisition (MUGA) scan or echocardiogram should be obtained for the
mutations to the tumor suppressor gene ATM, which localizes to the evaluation of cardiac function, particularly for older patients or for
chromosome region 11q22-23, have also been detected in patients with patients with a prior history of cardiac disease.
T-PLL.15,16 ATM gene is mutated in patients with ataxia telangiectasia, and
these patients appear to be predisposed to developing T-cell lymphomas, Serology for detection of antibodies against the human T-lymphotropic
including T-PLL. Thus, it is postulated that abnormalities in the ATM gene leukemia virus type 1 (HTLV-1) may be useful, especially to distinguish
may also be one of the key events in the pathogenesis of T-PLL.15,16 adult T-cell leukemia/lymphoma from T-PLL (HTLV-1 should be negative
Next-generation sequencing (NGS) studies have identified a high in the latter). If serology shows positivity for HTLV-1 by enzyme-linked
frequency of mutations in genes in the JAK-STAT pathway that could immunoassay (ELISA), a confirmatory Western blot should be
contribute to the pathogenesis of T-PLL,17-20 and JAK3 mutations have performed. Screening for active infections and cytomegalovirus (CMV)
been associated with a significant negative impact on overall survival serology should be strongly considered prior to initiation of treatment
(OS).21 The presence of complex karyotype (≥5 cytogenetic abnormalities) with alemtuzumab alone or in combination regimens. Human leukocyte
has also been reported as a poor prognostic factor in patients with antigen (HLA) typing is recommended for patients eligible for transplant.
T-PLL.22
Treatment Options
Workup Systemic Therapy
The initial workup for T-PLL should comprise a comprehensive medical Pentostatin (monotherapy or in combination with alemtuzumab) has
history and physical examination, including careful evaluation of lymph shown activity in patients with TPLL.7,23-26 In a study of 78 patients with
nodes, spleen, and liver, in addition to a complete skin examination and T-PLL treated with alkylating agents, pentostatin, or CHOP, the median

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T-Cell Lymphomas

OS was only 8 months; among the subgroup of patients with disease previous therapy and 62% were resistant to prior treatments.28 The
responding to pentostatin (n = 15), the median OS was 16 months.7 In a median OS for all patients was 10 months, and was 16 months for
retrospective analysis of patients with post-thymic T-cell malignancies patients with a CR. Following alemtuzumab, 11 patients underwent
treated with pentostatin, the overall response rate (ORR) was 45% hematopoietic cell transplant (HCT) (autologous HCT, n = 7; allogeneic
(complete response [CR] rate of 9%) for patients with T-PLL (n = 55).25 HCT, n = 4).
The median duration of response was short, however, at 6 months
(range, 3-16 months). The median OS from treatment initiation was 18 In a larger study in patients with T-PLL (N = 76; previously treated, n =
months for responding disease and 9 months for non-responding 72), treatment with IV alemtuzumab induced an ORR of 51% (CR rate of
disease.25 40%); among the 4 patients who received alemtuzumab as first-line
therapy, 3 achieved a CR.29 The time to progression (TTP) for all
The anti-CD52 monoclonal antibody alemtuzumab (monotherapy or in patients was 4.5 months, and the median OS was 7.5 months. Among
combination regimens) has also been evaluated in patients with the patients who achieved a CR, the median response duration and OS
T-PLL.23,26-31 In a retrospective analysis of the characteristics and clinical were 9 months and 15 months, respectively.29 The most common
outcome of 119 patients with T-PLL, 55 patients with previously toxicities reported with alemtuzumab in patients with T-PLL included
untreated T-PLL received treatment with an alemtuzumab-based infusion-related reactions, prolonged lymphocytopenia, and infectious
regimen (42 patients received alemtuzumab monotherapy and 13 events, including opportunistic infections.28,29
patients received alemtuzumab combination with pentostatin).23 The
ORR and CR rates for alemtuzumab monotherapy were 83% and 66%, A prospective multicenter phase II study conducted by the German CLL
respectively. The corresponding response rates were 82% and 73%, Study Group evaluated the safety and efficacy of induction
respectively, for alemtuzumab in combination with pentostatin. In this chemotherapy with FCM (fludarabine, cyclophosphamide, and
study, the presence of pleural effusion, high LDH, and low hemoglobin mitoxantrone) followed by alemtuzumab maintenance in patients who
were associated with shorter OS. In a phase II study that evaluated the were previously treated (n = 9) and treatment-naive (n = 16).30,31 Patients
combination of alemtuzumab and pentostatin in patients with T-cell with stable disease (SD) or progression after 2 courses of FCM were
malignancies, this regimen resulted in an ORR of 69% (CR rate of 62%) also eligible to receive alemtuzumab maintenance (21 patients
in the subgroup of patients with T-PLL (n = 13).26 The median subsequently received IV alemtuzumab maintenance following FCM
progression-free survival (PFS) and OS for this subgroup of patients chemotherapy). The ORR after FCM was 69% (31% CR and 38% partial
were 8 months and 10 months, respectively. The study included both response [PR]) and the ORR increased to 92% with a CR rate of 48%
patients with previously treated and untreated disease. (intent-to-treat population) after alemtuzumab maintenance. The median
PFS and OS were 12 months and 17 months, respectively. PFS was
In a study that primarily included patients with pretreated T-PLL, shorter among patients with higher TCL-1 expression levels. Among the
intravenous (IV) alemtuzumab resulted in an ORR of 76% (60% CR 21 patients who received alemtuzumab maintenance, CMV reactivation
rate). The median disease-free interval was 7 months. Among the
28
occurred in 13 patients (62%). Outcomes with this treatment approach
patients with pretreated T-PLL (n = 37), none had achieved a CR to appear promising; however, the high rate of CMV reactivation warrants
© ©
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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

careful monitoring (and preemptive antiviral therapy upon increasing viral In a review of data from the Center for International Blood and Marrow
load) to prevent the development of infectious complications. Transplant Research (CIBMTR) database (47 patients with T-PLL treated
with allogeneic HCT), the 1-year PFS and OS rates were 33% and 48%,
IV alemtuzumab is preferred over subcutaneous (SC) alemtuzumab respectively.39 The median OS was 11 months. For the subgroup of
based on data showing that the SC alemtuzumab is associated with patients with T-PLL (n = 21), the median PFS with allogeneic HCT was 5
inferior response rates and survival compared to IV alemtuzumab.31-33 IV months. The 1-year cumulative incidence of treatment-related mortality
alemtuzumab results in high CR rates in patients with previously (TRM) and the incidence of relapse or disease progression were 28%
untreated T-PLL (ORR of 91%; 81% CR) as well as relapsed/refractory and 39%, respectively.
T-PLL (ORR of 74%; 60% CR) compared to SC alemtuzumab (33%
CR).32 In a retrospective analysis of 41 patients with T-PLL, there was a In another retrospective study that evaluated the outcome of allogeneic
significant survival difference among patients treated with IV and SC HCT in 41 patients with T-PLL from the European Group for Blood and
alemtuzumab (41 vs.14 months; P = .0014).33 The aforementioned Marrow Transplantation (EBMT) database, the median PFS, median OS,
prospective multicenter phase II study that evaluated induction and 3-year relapse-free survival (RFS) and OS rates were 10 months, 12
chemotherapy with FCM followed by alemtuzumab maintenance also months, 19%, and 21%, respectively.40 The 3-year TRM and relapse
confirmed that IV alemtuzumab is preferred over SC alemtuzumab in rates were 41% for both endpoints; most relapses (71% of cases)
patients with T-PLL.31 occurred within the first year following transplant. Patients who
underwent HCT in first remission (CR or PR) tended to have a lower
A biomarker driven study confirmed the efficacy of ruxolitinib (JAK relapse rate (2-year rate: 30% vs. 46%) and higher event-free survival
inhibitor) in patients with relapsed or refractory peripheral T-cell (EFS) rate (2-year rate: 39% vs. 15%) compared with those transplanted
lymphoma (PTCL) subtypes.34 In this study, a total of 53 patients were with advanced disease. Based upon multivariate analysis, the use of
enrolled into one of the 3 cohorts: cohort 1 (presence of activating JAK total body irradiation (TBI) conditioning and a shorter interval between
and/or STAT mutations); cohort 2 ( ≥30% pSTAT3 expression by IHC); diagnosis and transplant were significant independent predictors of
cohort 3 (if neither of the criteria for cohort 1 or 2 are present). The ORR longer RFS with allogeneic HCT. None of the variables evaluated were
were 33%, 29%, and 12%, respectively for patients in cohorts 1, 2, and independent predictors of OS outcomes.
3. Among patients with TPLL (n=8; 7 patients with JAK and/or STAT
mutations; 1 patient with ≥30% pSTAT3 expression by IHC), the ORR In a retrospective study that reported the outcomes of allogeneic HCT in
was 38% (3/8 patients) and all were transient partial responses. 27 patients with T-PLL identified in the registry for French Society for
stem cell transplantation, 21 patients achieved a CR as the best
Hematopoietic Cell Transplant
response following HCT (CR rate of 78% after HCT).41 The majority of
The potential utility of allogeneic HCT in patients with T-PLL has been
patients (85%) had received alemtuzumab prior to HCT (14 patients had
reported in a number of individual case studies and retrospective
a CR and 10 patients had a PR). After a median follow-up of 33 months,
analyses.35-44
10 patients were still alive with a continuous CR. TRM occurred in 6
patients (30%), with early TRM in 2 of the patients. Four deaths occurred
© ©
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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

due to disease progression. The estimated 3-year OS and PFS rates retrospective analysis of 40 patients with T-PLL treated with autologous
were 36% and 26%, respectively. The relapse incidence after HCT was HCT reported an ORR of 88%. The 4-year OS and PFS rates were 34%,
47% occurring at a median of 12 months, and the overall cumulative and 29%, respectively.48
incidence of TRM at 3 years was 31%.
NCCN Recommendations
In an EBMT prospective observational study that assessed the outcome T-PLL is an aggressive malignancy associated with rapid disease
of allogeneic HCT in 37 evaluable patients with T-PLL (95% of patients progression, and the majority of patients are symptomatic at the time of
had received prior alemtuzumab and 30% of patients received a presentation. In a retrospective analysis of 81 patients with T-PLL,
conditioning regimen that included ≥6 Gy of TBI), the 4-year non-relapse patients with inactive disease had a significantly longer OS than patients
mortality (NRM), PFS, and OS rates were 32%, 30%, and 42%, with active disease and among patients with symptomatic disease, the
respectively.44 At the time of transplant, the CR rate was 62%. The presence of B symptoms, low hemoglobin, low platelet count,
median follow-up was 50 months. In a univariate analysis, the use of TBI lymphocyte doubling time of fewer than 3 months, and abnormal
in the conditioning regimen was the only significant predictor for a low cytogenetics were associated with shorter OS.45
relapse risk, and an interval between diagnosis and allogeneic HCT of
Given the poor prognosis associated with T-PLL, the NCCN Guidelines
greater than 12 months was associated with a lower NRM.
Panel recommends that patients should be enrolled in a clinical trial.
Data from retrospective studies discussed above suggest that allogeneic
Observation is a reasonable approach until symptoms develop in the
HCT may offer the best chance for long-term disease control in a
minority of patients who are asymptomatic with a more indolent course of
subgroup of patients with T-PLL, and a more recent retrospective
disease. Systemic therapy with alemtuzumab-based regimens is
analysis also reported that first-line therapy with alemtuzumab followed
recommended for patients with symptomatic disease (disease-related
by consolidation with allogeneic HCT was associated with better
constitutional symptoms; symptomatic bone marrow failure; rapidly
outcomes.45 However, allogeneic HCT is associated with higher rate of
enlarging lymph nodes, spleen, and liver; increasing lymphocytosis; or
TRM. 39-41 Reduced-intensity conditioning prior to allogeneic HCT has
extranodal involvement).3 Monotherapy with IV alemtuzumab is the
been identified as a predictor of long-term disease-free survival in a
preferred primary treatment option.32,33 Sequential therapy with FCM
multivariable analysis.39-41,46
followed by IV alemtuzumab30,31 or pentostatin in combination with
Retrospective studies have also reported favorable survival outcomes alemtuzumab23,26 are included as alternate treatment options for selected
with autologous HCT after alemtuzumab, and autologous HCT could be patients with bulky disease, splenomegaly, and hepatic involvement
an alternative option for consolidation therapy.47,48 In a retrospective whose disease may not respond well to alemtuzumab monotherapy.
study that reviewed the outcomes of 28 patients with T-PLL treated with
Allogeneic HCT should be considered for patients who achieve a CR or
either allogeneic (n = 13) or autologous HCT (n = 15) after alemtuzumab,
PR following initial therapy.39-41,44,45 Autologous HCT may be considered, if
no statistically significant difference in OS was observed between
a donor is not available and if the patient is not physically fit enough to
autologous versus allogeneic HCT (52 vs. 33 months).47 Another

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

undergo allogeneic HCT.47,48 However, it should be noted that there are no

established response criteria based on the imaging studies for T-PLL and
consensus criteria for response assessment have been proposed by the
T-PLL International Study Group based on the evaluation of constitutional
symptoms and the function of the hematopoietic system.3

At this time, the limited availability of data precludes any definitive

recommendations for the management of relapsed disease. Based on the
available data (discussed above), pentostatin (preferred regimen) 24,25 and
ruxolitinib (other recommended regimen) 34 are included as options for the
treatment of relapsed or progressive disease. Treatment with alternate
regimens not used during first-line therapy is also an acceptable option for
disease relapse following an initial response to therapy, disease not
responding to initial therapy, or disease progression during initial therapy.

Loss of CD52 expression has been described as a mechanism of

resistance to alemtuzumab treatment.49,50 If CD52 expression is still
positive at the time of relapse, retreatment with alemtuzumab with or
without pentostatin can be considered for disease relapse after a period of
remission following first-line therapy.

Given the potential risks for viral reactivation and opportunistic infections
associated with alemtuzumab, routine monitoring for CMV reactivation
and the use of anti-infective prophylaxis for herpes virus and
Pneumocystis jirovecii pneumonia (PJP) is recommended for all patients
receiving alemtuzumab-based regimens. See Supportive Care:
Monoclonal Antibody Therapy and Viral Reactivation in the algorithm.

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

References responses to Campath-1H. Leuk Res 1998;22:185-191. Available at:

[Link]
1. Alaggio R, Amador C, Anagnostopoulos I, et al. The 5th edition of the
World Health Organization Classification of Haematolymphoid Tumours: 9. Brito-Babapulle V, Catovsky D. Inversions and tandem translocations
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2. Campo E, Jaffe ES, Cook JR, et al. The International Consensus [Link]
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Advisory Committee. Blood 2022;140:1229-1253. Available at: 10. Maljaei SH, Brito-Babapulle V, Hiorns LR, Catovsky D. Abnormalities
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3. Staber PB, Herling M, Bellido M, et al. Consensus criteria for diagnosis, 1998;103:110-116. Available at:
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T-cell receptor signaling define a hyperproliferative subset of T-cell
5. Hsi AC, Robirds DH, Luo J, et al. T-cell prolymphocytic leukemia prolymphocytic leukemia. Blood 2008;111:328-337. Available at:
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MYC, loss of ATM, and TCL1A rearrangement. Am J Surg Pathol
2014;38:1468-1483. Available at: 13. Stern MH, Soulier J, Rosenzwajg M, et al. MTCP-1: a novel gene on
[Link] the human chromosome Xq28 translocated to the T cell receptor
alpha/delta locus in mature T cell proliferations. Oncogene
6. PubMed Overview. Available at: [Link] 1993;8:2475-2483. Available at:
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7. Matutes E, Brito-Babapulle V, Swansbury J, et al. Clinical and 14. de Oliveira FM, Tone LG, Simoes BP, et al. Translocations
laboratory features of 78 cases of T-prolymphocytic leukemia. Blood t(X;14)(q28;q11) and t(Y;14)(q12;q11) in T-cell prolymphocytic leukemia.
1991;78:3269-3274. Available at: Int J Lab Hematol 2009;31:453-456. Available at:
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8. Ginaldi L, De Martinis M, Matutes E, et al. Levels of expression of CD52 15. Stilgenbauer S, Schaffner C, Litterst A, et al. Biallelic mutations in the
in normal and leukemic B and T cells: correlation with in vivo therapeutic ATM gene in T-prolymphocytic leukemia. Nat Med 1997;3:1155-1159.
Available at: [Link]

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

16. Stoppa-Lyonnet D, Soulier J, Lauge A, et al. Inactivation of the ATM 24. Dohner H, Ho AD, Thaler J, et al. Pentostatin in prolymphocytic
gene in T-cell prolymphocytic leukemias. Blood 1998;91:3920-3926. leukemia: Phase II trial of the European Organization for Research and
Available at: [Link] Treatment of Cancer Leukemia Cooperative Study Group. J Natl Cancer
Inst 1993;85:658-662. Available at:
17. Bergmann AK, Schneppenheim S, Seifert M, et al. Recurrent mutation [Link]
of JAK3 in T-cell prolymphocytic leukemia. Genes Chromosomes Cancer
2014;53:309-316. Available at: 25. Mercieca J, Matutes E, Dearden C, et al. The role of pentostatin in the
[Link] treatment of T-cell malignancies: analysis of response rate in 145 patients
according to disease subtype. J Clin Oncol 1994;12:2588-2593. Available
18. Kiel MJ, Velusamy T, Rolland D, et al. Integrated genomic sequencing at: [Link]
reveals mutational landscape of T-cell prolymphocytic leukemia. Blood
2014;124:1460-1472. Available at: 26. Ravandi F, Aribi A, O'Brien S, et al. Phase II study of alemtuzumab in
[Link] combination with pentostatin in patients with T-cell neoplasms. J Clin
Oncol 2009;27:5425-5430. Available at:
19. Lopez C, Bergmann AK, Paul U, et al. Genes encoding members of [Link]
the JAK-STAT pathway or epigenetic regulators are recurrently mutated in
T-cell prolymphocytic leukaemia. Br J Haematol 2016;173:265-273. 27. Pawson R, Dyer MJ, Barge R, et al. Treatment of T-cell
Available at: [Link] prolymphocytic leukemia with human CD52 antibody. J Clin Oncol
1997;15:2667-2672. Available at:
20. Wahnschaffe L, Braun T, Timonen S, et al. JAK/STAT-activating [Link]
genomic alterations are a hallmark of T-PLL. Cancers (Basel)
2019;11:1833. Available at: 28. Dearden CE, Matutes E, Cazin B, et al. High remission rate in T-cell
[Link] prolymphocytic leukemia with CAMPATH-1H. Blood 2001;98:1721-1726.
Available at: [Link]
21. Stengel A, Kern W, Zenger M, et al. Genetic characterization of T-PLL
reveals two major biologic subgroups and JAK3 mutations as prognostic 29. Keating MJ, Cazin B, Coutre S, et al. Campath-1H treatment of T-cell
marker. Genes Chromosomes Cancer 2016;55:82-94. Available at: prolymphocytic leukemia in patients for whom at least one prior
[Link] chemotherapy regimen has failed. J Clin Oncol 2002;20:205-213.
Available at: [Link]
22. Hu Z, Medeiros LJ, Fang L, et al. Prognostic significance of
cytogenetic abnormalities in T-cell prolymphocytic leukemia. Am J 30. Hopfinger G, Busch R, Pflug N, et al. Sequential
Hematol 2017;92:441-447. Available at: chemoimmunotherapy of fludarabine, mitoxantrone, and
[Link] cyclophosphamide induction followed by alemtuzumab consolidation is
effective in T-cell prolymphocytic leukemia. Cancer 2013;119:2258-2267.
23. Jain P, Aoki E, Keating M, et al. Characteristics, outcomes, prognostic Available at: [Link]
factors and treatment of patients with T-cell prolymphocytic leukemia
(T-PLL). Ann Oncol 2017;28:1554-1559. Available at: 31. Pflug N, Cramer P, Robrecht S, et al. New lessons learned in T-PLL:
[Link] results from a prospective phase-II trial with
fludarabine-mitoxantrone-cyclophosphamide-alemtuzumab induction

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

followed by alemtuzumab maintenance. Leuk Lymphoma remission. Bone Marrow Transplant 2006;37:709-710. Available at:
2019;60:649-657. Available at: [Link]
[Link]
39. Kalaycio ME, Kukreja M, Woolfrey AE, et al. Allogeneic hematopoietic
32. Dearden CE, Khot A, Else M, et al. Alemtuzumab therapy in T-cell cell transplant for prolymphocytic leukemia. Biol Blood Marrow Transplant
prolymphocytic leukaemia: comparing efficacy in a series treated 2010;16:543-547. Available at:
intravenously and a study piloting the subcutaneous route. Blood [Link]
2011;118:5799-5802. Available at:
[Link] 40. Wiktor-Jedrzejczak W, Dearden C, de Wreede L, et al. Hematopoietic
stem cell transplantation in T-prolymphocytic leukemia: a retrospective
33. Damlaj M, Sulai NH, Oliveira JL, et al. Impact of alemtuzumab therapy study from the European Group for Blood and Marrow Transplantation and
and route of administration in T-prolymphocytic leukemia: A single-center the Royal Marsden Consortium. Leukemia 2012;26:972-976. Available at:
experience. Clin Lymphoma Myeloma Leuk 2015;15:699-704. Available at: [Link]
[Link]
41. Guillaume T, Beguin Y, Tabrizi R, et al. Allogeneic hematopoietic stem
34. Moskowitz AJ, Ghione P, Jacobsen E, et al. A phase 2 cell transplantation for T-prolymphocytic leukemia: A report from the
biomarker-driven study of ruxolitinib demonstrates effectiveness of French society for stem cell transplantation (SFGM-TC). Eur J Haematol
JAK/STAT targeting in T-cell lymphomas. Blood 2021;138:2828-2837. 2015;94:265-269. Available at:
Available at: [Link] [Link]

35. Collins RH, Pineiro LA, Agura ED, Fay JW. Treatment of T 42. Dholaria BR, Ayala E, Sokol L, et al. Allogeneic hematopoietic cell
prolymphocytic leukemia with allogeneic bone marrow transplantation. transplantation in T-cell prolymphocytic leukemia: A single-center
Bone Marrow Transplant 1998;21:627-628. Available at: experience. Leuk Res 2018;67:1-5. Available at:
[Link] [Link]

36. Garderet L, Bittencourt H, Kaliski A, et al. Treatment of 43. Yamasaki S, Nitta H, Kondo E, et al. Effect of allogeneic hematopoietic
T-prolymphocytic leukemia with nonmyeloablative allogeneic stem cell cell transplantation for patients with T-prolymphocytic leukemia: a
transplantation. Eur J Haematol 2001;66:137-139. Available at: retrospective study from the Adult Lymphoma Working Group of the Japan
[Link] Society for hematopoietic cell transplantation. Ann Hematol
2019;98:2213-2220. Available at:
37. Murase K, Matsunaga T, Sato T, et al. Allogeneic bone marrow [Link]
transplantation in a patient with T-prolymphocytic leukemia with
small-intestinal involvement. Int J Clin Oncol 2003;8:391-394. Available at: 44. Wiktor-Jedrzejczak W, Drozd-Sokolowska J, Eikema DJ, et al. EBMT
[Link] prospective observational study on allogeneic hematopoietic stem cell
transplantation in T-prolymphocytic leukemia (T-PLL). Bone Marrow
38. de Lavallade H, Faucher C, Furst S, et al. Allogeneic stem cell Transplant 2019;54:1391-1398. Available at:
transplantation after reduced-intensity conditioning in a patient with T-cell [Link]
prolymphocytic leukemia: graft-versus-tumor effect and long-term

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T-Cell Lymphomas

45. Rose A, Zhang L, Jain AG, et al. Delineation of clinical course,

outcomes, and prognostic factors in patients with T-cell prolymphocytic
leukemia. Am J Hematol 2023;98:913-921. Available at:
[Link]

46. Murthy HS, Ahn KW, Estrada-Merly N, et al. Outcomes of allogeneic

hematopoietic cell transplantation in T-cell prolymphocytic leukemia: a
contemporary analysis from the Center for International Blood and Marrow
Transplant Research. Transplant Cell Ther 2022. Available at:
[Link]

47. Krishnan B, Else M, Tjonnfjord GE, et al. Stem cell transplantation

after alemtuzumab in T-cell prolymphocytic leukaemia results in longer
survival than after alemtuzumab alone: a multicentre retrospective study.
Br J Haematol 2010;149:907-910. Available at:
[Link]

48. Drozd-Sokolowska J, Gras L, Koster L, et al. Autologous

hematopoietic cell transplantation for T-cell prolymphocytic leukemia: A
retrospective study on behalf of the Chronic Malignancies Working Party
of the EBMT. Haematologica 2024. Available at:
[Link]

49. Johansson P, Klein-Hitpass L, Roth A, et al. Mutations in PIGA cause

a CD52-/GPI-anchor-deficient phenotype complicating alemtuzumab
treatment in T-cell prolymphocytic leukemia. Eur J Haematol
2020;105:786-796. Available at:
[Link]

50. Tuset E, Matutes E, Brito-Babapulle V, et al. Immunophenotype

changes and loss of CD52 expression in two patients with relapsed T-cell
prolymphocytic leukaemia. Leuk Lymphoma 2001;42:1379-1383. Available
at: [Link]

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T-Cell Lymphomas

Adult T-Cell Leukemia/Lymphoma ULN, and no involvement of CNS, bone, or GI tract; lymphadenopathy and
Overview involvement of liver and spleen may be present.6

Adult T-cell leukemia/lymphoma (ATLL) is malignancy of peripheral T The lymphoma subtype (20%) is characterized by the absence of
lymphocytes caused by the human T-cell lymphotropic virus type I lymphocytosis, less than or equal to 1% abnormal T-lymphocytes, and
(HTLV-1), and is associated with a long period of latency (often histologically proven lymphadenopathy with or without extranodal lesions.3
manifesting several decades after exposure).1-3 ATLL is endemic to
several regions, including southwest regions in Japan, the Caribbean, and The acute subtype (60%) is characterized by elevated LDH levels,
parts of central Africa, owing to the distribution of HTLV-1.1 In the hypercalcemia (with or without lytic bone lesions), B symptoms,
International Peripheral T-Cell Lymphoma (PTCL) Project, ATLL generalized lymphadenopathy, splenomegaly, hepatomegaly, skin
comprised approximately 10% of the diagnosis for confirmed cases of involvement, and organ infiltration.7 The acute subtype is associated with a
PTCL or natural killer (NK)-cell/T-cell lymphomas (n = 1153).4 While ATLL rapidly progressive disease (PD) course and usually presents with
is rare in North America or Europe (≤2%), it has a higher prevalence in leukemic manifestation and tumor lesions, and represents cases that are
Asia (25%), with all cases from Asia originating in Japan. In the United not classified as any of the other three subtypes above.6
States, 2148 cases were reported from 2001 to 2015, representing an
Literature Search Criteria
overall rate of 0.06 per 100,000 population.5
Prior to the update of this version of the NCCN Clinical Practice Guidelines
The Lymphoma Study Group of the Japan Clinical Oncology Group in Oncology (NCCN Guidelines®) T-Cell Lymphomas, a literature search of
(JCOG) has classified ATLL into four subtypes (smoldering, chronic, the PubMed database was performed to obtain key literature in ATLL
acute, or lymphoma) based on laboratory evaluations (eg, serum lactate published since the last Guidelines update. The PubMed database was
dehydrogenase [LDH], hypercalcemia, lymphocytosis) and clinical chosen as it remains the most widely used resource for medical literature
features (eg, lymphadenopathy, hepatosplenomegaly, skin involvement).6 and indexes only peer-reviewed biomedical literature.8

The smoldering (10%) and chronic (10%) subtypes are considered The search results were narrowed by selecting studies in humans
indolent, usually characterized by greater than or equal to 5% abnormal published in English. Results were confined to the following article types:
T-lymphocytes in the peripheral blood, and may have skin or pulmonary Clinical Trial, Phase II; Clinical Trial, Phase III; Guideline; Randomized
lesions (but no ascites or pleural effusion).3 In addition, the smoldering Controlled Trial; Meta-Analysis; Systematic Reviews; and Validation
subtype is also associated with a normal lymphocyte count, normal serum Studies.
calcium level, LDH levels within 1.5 times upper limit of normal (ULN), and
no involvement of the liver, spleen, central nervous system (CNS), bone, The data from key PubMed articles as well as articles from additional
or gastrointestinal (GI) tract.6 The chronic subtype is characterized by sources deemed as relevant to these Guidelines have been included in
absolute lymphocytosis (≥4 x 109/L) with T lymphocytes greater than or this version of the Discussion section. Recommendations for which
equal to 3.5 x 109/L, normal calcium level, LDH levels within two times the

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T-Cell Lymphomas

high-level evidence is lacking are based on the panel’s review of Poor performance status, elevated LDH level, greater than or equal to four
lower-level evidence and expert opinion. total involved lesions, hypercalcemia, and age greater than or equal to 40
years have been identified as major adverse prognostic factors based on
Prognosis data from a large number of patients.11 Among patients with the chronic
The smoldering and chronic subtypes have a more favorable prognosis subtype, poor performance status, greater than or equal to four total
compared with the acute or the lymphoma subtypes.4,6,9,10 In the analysis involved lesions, bone marrow involvement, elevated LDH, elevated blood
of 818 patients with ATLL (median age 57 years) from the Lymphoma urea nitrogen, and low albumin levels have been identified as potential
Study Group of JCOG, the estimated 4-year overall survival (OS) rates for prognostic factors for decreased survival.9 Further studies with a larger
patients with acute, lymphoma, chronic, and smoldering subtypes were number of patients are needed to elucidate prognostic factors that may
5%, 6%, 27%, and 63%, respectively.6 The median OS was 6, 10, 24 help to further risk stratify patients with indolent ATLL.
months, and not yet reached, respectively. The maximum duration of
follow-up was 7 years in this study.6 The poor prognosis of acute and The International PTCL Project reported that the International Prognostic
lymphoma subtypes was also confirmed in another retrospective analysis Index (IPI) was a useful model for predicting outcomes for patients with
that included 1665 patients with ATLL.10 The median survival was 8 aggressive subtypes of ATLL.4 Based on univariate analysis, presence of
months and 11 months, respectively, for patients with acute and B symptoms, platelet count less than 150 x 109/L, and high IPI score (≥3)
lymphoma subtypes compared to 32 months and 55 months, respectively, were found to be associated with decreased OS. However, in a
for those with chronic and smoldering subtypes. The corresponding 4-year multivariate analysis, IPI score was the only independent predictor for OS
OS rates were 11%, 16%, 36%, and 52%, respectively.10 outcomes.4 New prognostic models have been proposed for patients
since IPI scores are not always predictive of ATLL outcomes.
In a report from a long-term follow-up of 90 patients with newly diagnosed
indolent ATLL, the median OS was 4 years and the estimated 5-, 10-, and A prognostic index for indolent ATLL (iATL-PI) was developed based on
15-year survival rates were 47%, 25%, and 14%, respectively.9 In the the soluble interleukin-2 receptor (sIL-2R) levels.12 In a retrospective
subgroup analysis, the 15-year OS rate and median OS tended to be analysis of 248 patients with chronic or smoldering ATLL, iATL PI stratified
higher for the chronic subtype (15% and 5 years, respectively) than the patients into three risk groups (low risk, sIL-2R ≤1000 U/mL; intermediate
smoldering subtype (13% and 3 years, respectively). The heterogeneity in risk, sIL-2R >1000 U/mL and ≤6000 U/mL; and high risk, sIL-2R >6000
outcomes among patients with even the indolent subtype of the disease U/mL). The median survival was not reached for patients with a low-risk
may be explained, in part, by differences in patient- and disease-related score, whereas the median survival was 6 years and 2 years, respectively,
factors. In this study, 65% of patients died of acute ATL with a median for patients with an intermediate- or high-risk score. This prognostic index
time to transformation of 19 months, suggesting that most patients with has to be validated in prospective trials.
indolent disease will eventually die of aggressive disease during their
In a study based on the data from 89 patients with ATLL in North America
long-term disease course.9
(acute or lymphoma subtypes in 79%), the investigators proposed a new
prognostic model that identified three prognostic categories based on

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

Eastern Cooperative Oncology Group (ECOG) performance status, Ann Diagnosis

Arbor stage, age, and serum calcium level at diagnosis.13 The clinical features of ATLL differ by subtype and disease stage, but
patients with the most common acute or lymphoma subtypes may
In a retrospective analysis of 807 patients with newly diagnosed acute or
frequently present with lymphadenopathy (77%), fatigue (32%), anorexia
lymphoma subtypes, Ann Arbor stage, ECOG performance status, and
(26%), skin eruptions (23%), abdominal pain (23%), pulmonary
three continuous variables (age, serum albumin, and sIL-2R) were
complications (18%; due to leukemic infiltration and/or infections),
independent prognostic factors and a prognostic index (ATL-PI) based on
splenomegaly (13%), and hepatomegaly (10%).4 Bone marrow
these variables stratified patients with acute and lymphoma subtypes into
involvement (28%) and CNS involvement (10%) are also not uncommon.4
three risk groups (low, intermediate, and high) with a median survival of 16
months, 7 months, and 4 months, respectively.14 The majority of patients The presence of greater than or equal to 5% T lymphocytes with an
included in the study were 70 years or older (not candidates for abnormal immunophenotype in the peripheral blood is required for the
allogeneic hematopoietic cell transplant [HCT]) and this study excluded diagnosis of ATLL in patients without histologically proven tumor lesions.6
patients who were candidates for allogeneic HCT. The cytologic features of ATLL may be broad, but typical ATLL cells are
characterized by so-called “flower cells,” which show distinct polylobate
A modified prognostic index was developed for the risk stratification of
nuclei with homogeneous and condensed chromatin, small or absent
patients 70 years or younger with aggressive ATLL who may benefit from
nucleoli, and agranular and basophilic cytoplasm.7,16 These cytologic
upfront allogeneic HCT.15 In a study of 1792 patients (70 years or
characteristics are most evident in the acute subtype of the disease.
younger) newly diagnosed aggressive ATLL treated with first-line
chemotherapy, acute subtype, poor performance status, high sIL-2R levels The diagnosis of ATLL requires histopathology and immunophenotyping of
(> 5,000 U/mL), high adjusted calcium levels (≥ 12 mg/dL), and high tumor lesion, peripheral blood smear analysis for atypical cells, flow
C-reactive protein (CRP) levels (≥ 2.5 mg/dL) were independent adverse cytometry on peripheral blood, and HTLV-1 serology.16,17 The
prognostic factors of survival. The modified prognostic index stratified immunophenotyping panel for flow cytometry should at minimum include
patients into 3 risk groups: low risk (scores of 0 and 1), intermediate risk the following markers: CD3, CD4, CD5, CD7, CD8, CD25, CD30 and
(scores of 2 and 3) and high risk (scores of 4 and 5) with significantly TCRαß. The typical immunophenotype in most patients with ATLL involves
different OS rates. The estimated 3-year OS rates were 36%, 23% and 7% mature CD4-positive T cells with expression of CD2, CD5, CD25,
respectively.15 The estimated 3-year OS rate for patients who underwent CD45RO, CD29, TCRαß and HLA-DR.7,16 Most ATLL cells lack CD7 and
allogeneic HCT was 40% in the intermediate-risk group and 27% in the CD26 and have a dim CD3 expression.16 Rare cases are CD8+ or
high-risk group. The corresponding 3-year OS rates were 14% and 1% CD4/CD8 double positive or double negative.
respectively for non-transplant candidates.
If the diagnosis of ATLL is not established on peripheral blood
examination, bone marrow biopsy or biopsy of the lymph nodes or lesions
in skin or the GI tract should be performed. Excisional biopsy is

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NCCN Guidelines Version 4.2024

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recommended instead of core needle biopsy for the lymph nodes.16 Biopsy distinguish ATLL from cutaneous T-cell lymphomas, including mycosis
of the suspicious lesion may also help to rule out certain underlying fungoides (MF), and PTCL, especially in endemic areas.26 HTLV-1
infections (eg, tuberculosis, histoplasmosis, toxoplasmosis). Bone marrow serology should be assessed by enzyme-linked immunoassay (ELISA)
biopsy or aspiration is generally not required to establish the diagnosis of and, if positive, confirmed by western blot. If the result from western blot is
ATLL. However, bone marrow evaluation may be useful as bone marrow indeterminate, then polymerase chain reaction (PCR) analysis for HTLV-1
involvement has been reported as an independent predictor of poor can be performed. Monoclonal integration of HTLV-1 proviral DNA occurs
prognosis in ATLL.18 in all cases of ATLL.

CCR4 gain-of-function mutations are associated with long-term survival in Workup

patients treated with mogamulizumab without allogeneic HCT and The initial workup for ATLL should include a complete history and physical
assessment of CCR4 expression by immunohistochemistry may be useful examination with complete skin examination, and CT scans of the chest,
for the identification of patients with CCR4 gain-of-function mutations who abdomen, and pelvis. Most patients with acute ATLL have elevated LDH
may benefit from mogamulizumab-containing regimens.19,20 levels, and lymphocytosis is found in patients with the acute or chronic
type at presentation. Laboratory evaluations should include a complete
Integrated molecular analysis using targeted sequencing has identified
blood count (CBC) with differential and complete metabolic panel (serum
recurrent mutations in a variety of genes involved in T-cell receptor and
electrolyte levels, calcium, creatinine, and blood urea nitrogen) and
NF-κB signaling and other T cell-related pathways.21-24 Acute and
measurement of serum LDH, CRP and sIL-2R levels. Measurement of
lymphoma subtypes were associated with higher frequencies of TP53 and
serum uric acid levels should be considered for patients with acute or
IRF4 mutations as well as programmed death ligand 1 (PD-L1)
lymphoma subtype since these are associated with a higher risk of
amplifications and CDKN2A deletions compared with chronic and
developing spontaneous tumor lysis syndrome (TLS). See Supportive
smoldering subtypes.22 STAT3 mutations were more characteristic of
Care: Tumor Lysis Syndrome in the Algorithm.
indolent subtype, with phosphorylated STAT3 expression significantly
associated with better OS and progression-free survival (PFS) in the Upper GI tract endoscopy should be considered in selected cases since
smoldering subtype, whereas STAT3 mutation was not associated with GI tract involvement is frequently observed in patients with aggressive
clinical outcome.23 IRF4 mutations, PD-L1 amplifications and CDKN2A ATLL.27-29 CNS evaluation using CT scan, MRI, and/or lumbar puncture
deletions are associated with a worse prognosis in indolent subtypes.22,24 may also be useful for all patients with acute or lymphoma subtypes or in
These findings suggest that ATLL subtypes could be further classified into patients with neurologic manifestations.30 Human leukocyte antigen (HLA)
molecularly distinct subsets with different prognosis and the use of typing is recommended, if considering allogeneic hematopoietic cell
next-generation sequencing (NGS) may be useful to identify the presence transplant (HCT).
of the recurrent gene mutations associated with inferior prognosis.

HTLV-1 integration patterns have been reported to have clinical and

prognostic implications for ATLL.3,25 HTLV-1 serology is essential to

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

Response Criteria Treatment Options

The current response criteria used for ATLL are based on modifications to The optimal chemotherapy regimen is not yet established and the efficacy
the original 1991 JCOG response criteria as suggested at the international of long-term treatment is limited since patients with ATLL have either been
consensus meeting.16,26 These response criteria are based on the underrepresented or excluded from the prospective clinical trials
normalization or reduction in the size of enlarged lymph nodes and evaluating treatment options for T-cell lymphomas. Enrollment in a clinical
extranodal masses (as calculated by the sum of the products of the trial is the preferred treatment option for all patients with newly diagnosed
greatest diameters of measurable disease), reduction in the size of the and relapsed/refractory disease. The chemotherapy regimens included in
spleen or liver, and decrease in the involvement of peripheral blood, bone the NCCN Guidelines are based on limited available data (mostly from
marrow, and skin.16,26 retrospective analyses as discussed below) and institutional preferences.
Screening and treatment (if needed) for strongyloidiasis and Pneumocystis
The response is categorized as a complete response (CR; defined as jirovecii pneumonia (PJP) prophylaxis with sulfamethoxazole/trimethoprim
complete disappearance of all clinical, microscopic, and radiographic or equivalent are recommended for all patients.16
evidence of disease and absolute lymphocyte count, including flower cells,
<4 x 109/L in the peripheral blood), partial response (PR; defined as ≥50% First-line Therapy
reduction in the sum of the products of the greatest diameters of The ATLL subtype is an important factor for deciding appropriate
measurable disease without the appearance of new lesions, no increase in treatment strategies. Smoldering and chronic subtypes are usually
spleen or liver size, ≥50% reduction in skin involvement, and ≥50% managed with watchful waiting until symptomatic disease. In contrast, the
reduction in absolute lymphocyte counts in peripheral blood), stable acute and lymphoma subtypes typically require immediate therapy.
disease (SD; failure to achieve CR or PR with no PD), and relapsed
disease or PD (new or ≥50% increase in lymph node lesions, extranodal The activity of zidovudine in combination with interferon-alfa (IFN-alfa) has
mass, or splenomegaly/hepatomegaly; ≥50% increase in skin involvement; been reported in a number of small studies and case reports.31-35 Among
50% increase from nadir in the count of flower cells; and an increase in patients with primarily treatment-naïve aggressive ATLL, zidovudine in
absolute lymphocyte count, including flower cells, of >4 x 109/L).16 Each combination with IFN-alfa resulted in an overall response rate (ORR) of
criterion for the response categories should be observed for a minimal 58% to 80% and CR rates of 20% to 50%.31,32,35 Outcomes with this
period of 4 weeks to qualify for the response (eg, CR, PR, SD). The therapy were poorer for patients with previously treated relapsed/refractory
response criteria also include a category for uncertified complete response disease, with ORR 17% to 67% (nearly all PRs).33,34
(CRu), defined as greater than or equal to 75% reduction in tumor size but
In a meta-analysis of 254 patients with ATLL, first-line therapy was
with a residual mass after treatment, with an absolute lymphocyte count,
composed of antiviral therapy (n = 75; comprising a combination of
including flower cells, of less than 4 x 109/L. The usefulness of PET or
zidovudine and IFN-alfa in 97% of cases), chemotherapy alone (n = 77;
PET/CT has not been evaluated in the response assessment of patients
CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone] in
with ATLL.
86% of cases), or chemotherapy followed by maintenance antiviral therapy

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NCCN Guidelines Version 4.2024

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(n = 55).36 Most of the patients (n = 207 evaluable) had acute (47%) or A retrospective analysis evaluated outcomes in patients with aggressive
lymphoma (41%) subtypes, with the remaining patients presenting with ATLL (n = 73; 60% had lymphoma subtype) treated with chemotherapy
indolent disease. Among the patients who received first-line antiviral alone (n = 39; primarily with CHOP-like regimens) or combined therapy
therapy alone, 60% had the acute subtype; in contrast, among the patients with chemotherapy and antiviral agents (zidovudine and IFN-alfa; given
who received chemotherapy alone, 62% had the lymphoma subtype. In concurrent or sequential to chemotherapy or deferred).37 The median OS
patients with available survival data and recorded first-line therapy (n = among patients with the acute and lymphoma subtypes was 8 months and
207), the 5-year OS rates were 46%, 20%, and 12%, respectively, for 10 months, respectively. The use of antiviral treatments (at any point in the
patients who received first-line antiviral therapy alone, chemotherapy study) was associated with significant OS benefit for both the subgroups
alone, and chemotherapy followed by antiviral therapy.36 The ORR was with acute and lymphoma ATLL.37 Among patients with the lymphoma
66% (CR in 35%) among patients who received first-line antiviral therapy subtype (n = 32), treatment with first-line combination therapy (with
(n = 62 evaluable) and 88% (CR in 25%) among those who received chemotherapy and antiviral agents) or chemotherapy with deferred
first-line chemotherapy alone (n = 48 evaluable). Among patients who antivirals resulted in significant OS benefits compared with chemotherapy
received chemotherapy followed by antiviral therapy (n = 14 evaluable), alone.37
the ORR was 93% (CR in 50%).36 For all patients with follow-up survival
data (n = 238), the median OS was 12 months and the 5-year OS rate was Combination chemotherapy with CHOP has resulted in an ORR of 64% to
23%. In the subgroup analysis by ATLL subtype, median OS was 6 88% (CR rates of 18%–25%) with median OS ranging from approximately
months, 13 months, and not reached, respectively, in patients with acute 8 to 12 months.13,36,38 In a meta-analysis of patients with ATLL treated with
lymphoma and indolent (chronic or smoldering) subtypes; the 5-year OS first-line therapies, chemotherapy (primarily CHOP) alone resulted in
rate was 15%, 16%, and 76%, respectively.36 median OS of 10 months and chemotherapy with or without maintenance
antiviral therapy resulted in median OS of 12 months.36 Patients with the
In the subgroup analysis by first-line treatment regimen, antiviral therapy lymphoma subtype appeared to benefit more from first-line therapy with
resulted in significantly longer median OS (17 vs. 12 months) and higher CHOP or CHOP-like chemotherapy (with or without maintenance
5-year OS rate (46% vs. 14%) compared with chemotherapy (with or antivirals) than with antivirals alone. In the subgroup of patients with the
without maintenance antiviral therapy). Interestingly, only the patients with lymphoma subtype, OS was significantly improved with first-line
the acute and indolent subtype benefited significantly from first-line chemotherapy (n = 72; median OS 16 months; 5-year OS 18%) compared
antiviral therapy, whereas patients with the lymphoma subtype had worse with first-line antiviral treatment alone (n = 13; median OS 7 months;
survival with antiviral therapy and better outcomes with first-line 5-year OS 0%; P = .009).36
chemotherapy (with or without maintenance antiviral treatment).
Multivariate analysis showed that only the ATLL subtype and type of In a small phase II trial conducted by the AIDS Malignancy Consortium in
first-line treatment were significant independent predictors for poorer OS.36 19 patients with aggressive ATLL, EPOCH (etoposide, prednisone,
These data suggest that zidovudine in combination with IFN-alfa is vincristine, cyclophosphamide, and doxorubicin) followed by antiretroviral
effective in patients with leukemic ATLL, but not in the lymphoma subtype. therapy (zidovudine, lamivudine, IFN-alfa up to 1 year) resulted in an ORR

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of 58% (CR in 10.5%) and a median duration of response of 13 months.39 thrombocytopenia (74% vs. 17%), and grade 3–4 infections (32%
Although this regimen appeared to be active in this patient population, viral vs.15%). In a report from the ATL-PI Project from Japan that included
reactivation during therapy coincided with disease progression, which 1250 patients with acute or lymphoma subtype, CHOP-21 or CHOP-14
likely contributed to treatment failure. The use of dose-adjusted EPOCH in was the most commonly used regimen (n = 579; 50%) followed by
combination with bortezomib and antiviral therapy (raltegravir) resulted in VCAP-AMP-VECP (n = 365; 31%) and modified EPOCH (n = 42; 4%).10
an ORR of 67% in patients with acute and lymphoma subtypes.40 After a The findings from a supplementary analysis of the phase III trial
follow-up of greater than 2 years, the median PFS and OS were both 6 (JCOG9801) that evaluated the benefit based on the risk-group (as
months. In this study, no patients had dose-limiting toxicity, most likely due identified by the ATL-PI) confirmed that while VCAP-AMP-VECP is a
to the lower dose of cyclophosphamide at treatment initiation. suitable regimen for the intermediate-risk group, it was associated with
only a modest benefit in the low-risk group.44
Hyper-CVAD (hyperfractionated cyclophosphamide, vincristine,
doxorubicin, and dexamethasone) has also been reported to be an active VCAP-AMP-VECP and ATL-G-CSF are not recommended in the NCCN
regimen resulting in durable CRs in two patients with ATLL; however, Guidelines since vindesine and ranimustine are not available in the United
prospective evaluations are needed.41 States.

A phase II multicenter study investigated the activity of CHOP followed by NCCN Recommendations
a regimen with vincristine, doxorubicin, cyclophosphamide, prednisolone, Observation is appropriate for patients with asymptomatic smoldering
etoposide, vindesine, ranimustine, mitoxantrone, and G-CSF (ATL-G-CSF) ATLL (no skin lesions or opportunistic infections). In patients with
in patients with ATLL (n = 81).42 The ORR was 74% (CR in 36%) and the symptomatic smoldering ATLL, skin-directed therapies (as recommended
median duration of response was 8 months. The median OS for all for patients with MF or Sézary syndrome [SS] in the NCCN Guidelines for
patients remained rather short, at 8.5 months; the 3-year OS rate was Primary Cutaneous Lymphomas) are appropriate for patients with skin
14%.42 lesions and zidovudine in combination with IFN-alfa is an option for
patients those with tumor lesions.
In a randomized phase III trial (JCOG9801), VCAP (vincristine,
cyclophosphamide, doxorubicin, and prednisone)-AMP (doxorubicin, Treatment options for patients with chronic ATLL is based on the risk
ranimustine, and prednisone)-VECP (vindesine, etoposide, carboplatin, stratification using the iATL-PI (discussed above).12 Zidovudine in
and prednisone) resulted in significantly higher CR rate compared to combination with IFN-alfa is a treatment option for all patients with chronic
CHOP-14 (40% vs. 25%; P = .02), but the median PFS (7 vs. 5 months, ATLL (irrespective of the risk score) whereas combination chemotherapy
respectively), median OS (13 vs. 11 months, respectively),1-year PFS rate is an option only for patients with high-risk disease (sIL-2R >6000 U/mL).
(28% vs. 16%) and 3-year OS rate (24% vs. 13%) were not significantly
different between the treatment arms.43 The VCAP-AMP-VECP regimen Combination chemotherapy is recommended for patients with the acute or
was associated with higher incidence of toxicities compared with lymphoma subtype. Zidovudine in combination with IFN-alfa is a first-line
CHOP-14, including grade 4 neutropenia (98% vs. 83%), grade 4 therapy for patients with acute subtype whereas this combination is not

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

considered effective for patients with lymphoma subtype.36 CNS Second-line Therapy
prophylaxis (with intrathecal methotrexate and cytarabine and Arsenic trioxide in combination with IFN-alfa has been shown to be an
corticosteroids) is recommended in patients with lymphoma subtype. effective treatment option for relapsed or refractory disease despite
significant toxicity.47,48 Alemtuzumab, bortezomib, and pralatrexate also
The duration of initial therapy is usually 2 months. If life-threatening have demonstrated activity as single agents in a small series of patients
manifestations occur, however, treatment can be discontinued before this with relapsed/refractory ATLL.49-52
period. Outside of a clinical trial, treatment with zidovudine and IFN-alfa
should be continued until best response is achieved, if there is evidence of In a phase II study that evaluated the efficacy and safety of lenalidomide in
clinical benefit. If the disease is not responding to or is progressing on 26 patients with relapsed or refractory ATLL, lenalidomide resulted in an
zidovudine and IFN-alfa, treatment should be stopped. ORR of 42% and a tumor control rate of 73%.50 The median PFS and OS
were 4 months and 20 months, respectively. Neutropenia, leukopenia,
Dose-adjusted EPOCH is included as a preferred chemotherapy lymphopenia, and thrombocytopenia were the most common grade
regimen.37,39 CHOEP or hyper-CVAD are included as alternative options greater than or equal to three adverse events occurring in 65%, 38%,
under other recommended regimens.32,34,40 CHOP may be an appropriate 38%, and 23% of patients, respectively.
treatment option for patients unable to tolerate intensive regimens or for
those with non–CD30-positive ATLL.11 Mogamulizumab (a humanized anti-CCR4 monoclonal antibody) is
approved for the treatment of patients with relapsed or refractory
CD30 expression has been reported at variable frequencies in ATLL CCR4-positive ATLL in Japan.53-55 The safety and efficacy of
subtypes with a trend towards a higher frequency of CD30 expression in mogamulizumab for patients with relapsed/refractory ATLL was
lymphoma subtype compared to acute subtype.45 The results of the demonstrated in a prospective randomized study outside of Japan.56 In
ECHELON-2 trial established the superiority of brentuximab vedotin (BV) this study, 71 patients with relapsed or refractory ATLL (acute, chronic and
in combination with cyclophosphamide, doxorubicin, and prednisone lymphomas subtypes) were randomized to either mogamulizumab (n = 47)
(CHP) compared with CHOP in patients with systemic anaplastic large or an investigator choice (IC) regimen (n = 24; GEMOX [gemcitabine and
cell lymphoma (ALCL) and BV in combination with CHP is FDA approved oxaliplatin], DHAP [dexamethasone, cytarabine and cisplatin], or
for the initial treatment of systemic ALCL, CD30-positive PTCL, not pralatrexate).56 Patients in the IC arm were permitted crossover to
otherwise specified and CD30-positive angioimmunoblastic T-cell mogamulizumab upon disease progression. The confirmed ORR as
lymphoma (AITL).46 The ECHELON-2 trial also included seven patients assessed by the investigator, and independent review were higher for
with ATLL and based on the results of this trial, the panel has included patients treated with mogamulizumab (15% and 11%, respectively) than
BV + CHP as a preferred treatment option for patients with for those treated with IC regimen (0% for both). The best ORR as
CD30-positive ATLL. assessed by independent review was 28% for mogamulizumab compared
to 8% for IC regimen, and the best ORR as assessed by investigator
review was 34% and 0%, respectively, for mogamulizumab and IC

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T-Cell Lymphomas

regimen. Responses to mogamulizumab were seen across all ATLL regimens resulted in similar outcomes with allogeneic HCT.67 The
subtypes (the best response rates were 71%, 32%, and 24%, respectively, median OS (survival measured from time of HCT) was 9.5 months and
for chronic, lymphoma, and acute subtypes). Infusion reactions (47%), 10 months, respectively for patients who received myeloablative
drug eruption (19%), thrombocytopenia (13%), and anemia (11%) were conditioning and RIC. The 3-year OS rates were 39% and 34%
the most common adverse events in the mogamulizumab arm. respectively. The 3-year cumulative incidence of TRM was 38% and
33%, respectively, for myeloablative conditioning regimens and RIC
The development of cutaneous adverse reaction (a drug-induced skin regimens. Patients who received RIC regimens were older than those
eruption or mogamulizumab-associated skin rash) that has variable who received myeloablative conditioning regimens (median age, 57 vs.
clinical and pathologic features (and can mimic CTCL) has been 49 years). In the multivariate analysis, older age (>55 years), male sex,
identified as a predictor of efficacy of mogamulizumab treatment.57,58 Skin lack of CR at time of HCT, poorer performance status (PS ≥1), and
biopsy (with adequate immunohistochemical stains and clonality unrelated donor HCT were significant independent factors for decreased
assessment) is recommended to rule out disease progression in patients OS outcomes. Male sex, poorer performance status (PS ≥1), and
experiencing drug-induced skin eruptions or mogamulizumab-associated unrelated donor HCT were significant independent factors for risk of
skin rash.59,60 TRM.67 Older age (>55 years) was a significant independent factor for
poorer OS among patients who received myeloablative conditioning, but
Allogeneic Hematopoietic Cell Transplant
not for those who received RIC regimens.
Available evidence mostly from retrospective studies suggest that
allogeneic HCT may be associated with long term survival in some In the systematic review and meta-analysis that summarized the results
patients with ATLL,61-69 suggesting a contribution of of all the retrospective studies that have assessed the efficacy of
graft-versus-leukemia/lymphoma (GVL) effect.70-72 allogeneic HCT in 1757 patients with ATLL, the pooled CR, OS, and PFS
rates following allogeneic HCT were 73%, 40%, and 37%, respectively.73
In a retrospective analysis of 386 patients with ATLL who underwent
Pooled relapse and non-relapse mortality rates were 36% and 29%,
allogeneic HCT (related or unrelated) (n = 386), after a median follow-up
respectively. There was high rate of heterogeneity among the studies
of 41 months, the 3-year OS rate was 33% and the incidence of
included in this meta-analysis and with the exception of study from the
transplant-related mortality (TRM) was 43%, which was mainly due to
EBMT registry,68 most of the studies included patients undergoing
infectious complications and organ failure.66 Based on multivariate
allogeneic HCT in Japanese medical centers. A more recent single
analysis, patient age (>50 years), male sex, lack of a CR at the time of
institution study has also reported favorable outcomes of allogeneic HCT
transplant, and the use of unrelated or cord blood were identified as
with moderate rates of TRM and graft-versus-host disease (GVHD) in 17
adverse prognostic factors for OS outcomes.
non-Japanese patients with ATLL.74
In another retrospective study of 586 patients with ATLL (majority of
The results of a retrospective analysis showed that induction of GVL effect
patients had either acute [57%] or lymphoma [28%] subtypes), the use of
via donor lymphocyte infusion (DLI) may provide long-lasting remission in
myeloablative conditioning or reduced intensity conditioning (RIC)

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selected patients with relapsed ATLL.75 However, prospective clinical Lenalidomide, brentuximab vedotin and mogamulizumab are included as
trials are needed to confirm these findings. preferred treatment options for second-line therapy. Brentuximab vedotin
is an option for patients with CD30-positive relapsed/refractory disease
HCT-specific comorbidity index (HCT-CI) and EBMT risk score have been based on the extrapolation of data from clinical trials that has
considered as prognostic factors in patients with ATLL receiving allogeneic demonstrated its efficacy in relapsed/refractory CD30-positive PTCL.78
HCT.76 An optimized prognostic index (ATL-HCT-PI; based on age, Mogamulizumab is not approved by the U.S. Food and Drug
HCT-CI, and donor-recipient sex) has been recently developed for Administration (FDA) for the treatment of relapsed or refractory ATLL.
predicting NRM in patients receiving HCT.77 Prospective studies in larger Mogamulizumab (off-label use) is also included as a preferred
groups of patients are warranted to further evaluate the role of allogeneic single-agent second-line therapy option for relapsed or refractory ATLL,
HCT and validate the use of ATL-HCT-PI in the management of patients based on the results of the prospective randomized study (outside of
with ATLL. Japan).56 Mogamulizumab therapy for ATLL prior to allogeneic HCT has
been significantly associated with an increased risk of GVHD-related
NCCN Recommendations
mortality and should be used with caution in patients with ATLL who are
Continuation of the prior therapy is recommended for all patients who
eligible for or proceeding directly to allogeneic HCT.79,80
achieve an initial response to first-line therapy (CR, uncertified PR, or PR
at 2 months following start of treatment). Allogeneic HCT should be Arsenic oxide, alemtuzumab, bortezomib, or pralatrexate are included as
considered (if a donor is available) for patients with high-risk chronic alternate monotherapy options (other recommended regimens) based on
subtype, acute or lymphoma subtype that is responding to first-line or limited available data as discussed above.49-52 Patients receiving
second-line therapy. Among patients with acute and lymphoma subtypes, alemtuzumab should be closely monitored and managed for potential
the modified prognostic index (discussed above) identified allogeneic HCT development of CMV reactivation. See Supportive Care: Monoclonal
as a statistically significant favorable prognostic factor for OS for patients Antibody Therapy and Viral Reactivation in the Algorithm. The risk of
with intermediate and high-risk scores.15 Stevens-Johnson syndrome associated with pralatrexate may be higher
in patients with ATLL compared to those with PTCL.51 Belinostat (histone
Combination chemotherapy regimens (used for first-line therapy) is
deacetylase inhibitor) has shown single-agent activity in patients with
recommended for patients with symptomatic smoldering subtype that is
relapsed or refractory PTCL and is FDA approved the treatment of
not responding to initial therapy (persistent disease or has disease
relapsed or refractory PTCL.81 Belinostat is included as an option
progression at 2 months from start of treatment).
(off-label use; other recommended regimens) for relapsed/refractory
Second-line therapy is recommended for patients with high-risk chronic ATLL.
subtype, acute or lymphoma subtype that is not responding to first-line
The results of retrospective analysis confirmed that RT was a safe and
therapy. Alternate regimen not previously used for first-line therapy is an
effective palliative treatment of localized lesions.82 RT is also included as
appropriate option for patients with low- or intermediate-risk chronic
an option for selected patients with localized, symptomatic disease. The
subtype or acute subtype that is not responding to initial therapy.

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

combination chemotherapy regimens included in the NCCN Guidelines for

second-line therapy are based on institutional preferences. Regimens that
are used for the treatment of relapsed/refractory PTCL are often applied to
the treatment of relapsed or refractory ATLL, as there are limited data for
this subtype. DHAP and GEMOX regimens were used as control arms in
the aforementioned prospective study of mogamulizumab for patients with
relapsed/refractory ATLL and these regimens are included as options
(other recommended regimens) for relapsed or refractory ATLL.56

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

References 8. PubMed Overview. Available at: [Link]

Accessed March 5, 2024.
1. Goncalves DU, Proietti FA, Ribas JG, et al. Epidemiology, treatment,
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3. O'Donnell JS, Hunt SK, Chappell KJ. Integrated molecular and 11. Major prognostic factors of patients with adult T-cell
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Haematologica 2017;102:1258-1265. Available at:

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

16. Tsukasaki K, Hermine O, Bazarbachi A, et al. Definition, prognostic leukemia/lymphoma. Cancer Sci 2019;110:2982-2991. Available at:
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expression predicts better prognosis in smoldering type of adult T-cell

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

31. Gill PS, Harrington W, Kaplan MH, et al. Treatment of adult T-cell 38. Besson C, Panelatti G, Delaunay C, et al. Treatment of adult T-cell
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supplementary analysis of the JCOG9801. Br J Haematol

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

2019;186:440-447. Available at: 52. Ishitsuka K, Utsunomiya A, Katsuya H, et al. A phase II study of
[Link] bortezomib in patients with relapsed or refractory aggressive adult T-cell
leukemia/lymphoma. Cancer Sci 2015;106:1219-1223. Available at:
45. Malpica Castillo LE, Campuzano-Zuluaga G, Toomey NL, et al. [Link]
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48. Ishitsuka K, Suzumiya J, Aoki M, et al. Therapeutic potential of arsenic
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49. Sharma K, Janik JE, O'Mahony D, et al. Phase II study of
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50. Ishida T, Fujiwara H, Nosaka K, et al. Multicenter phase II study of
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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

60. Wang JY, Hirotsu KE, Neal TM, et al. Histopathologic characterization Blood 2012;120:1734-1741. Available at:
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with HTLV-1-associated adult T-cell leukemia/lymphoma after SCT: A
61. Utsunomiya A, Miyazaki Y, Takatsuka Y, et al. Improved outcome of retrospective study by the EBMT LWP. Bone Marrow Transplant
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69. Ito A, Nakano N, Tanaka T, et al. Improved survival of patients with
62. Kami M, Hamaki T, Miyakoshi S, et al. Allogeneic haematopoietic stem aggressive ATL by increased use of allo-HCT: a prospective observational
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70. Shiratori S, Yasumoto A, Tanaka J, et al. A retrospective analysis of
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65. Choi I, Tanosaki R, Uike N, et al. Long-term outcomes after
hematopoietic SCT for adult T-cell leukemia/lymphoma: results of 72. Ishida T, Hishizawa M, Kato K, et al. Impact of graft-versus-host
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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

74. Epstein-Peterson ZD, Ganesan N, Barker JN, et al. Outcomes of adult 81. O'Connor OA, Horwitz S, Masszi T, et al. Belinostat in patients with
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75. Itonaga H, Tsushima H, Taguchi J, et al. Treatment of relapsed adult 82. Maemoto H, Ariga T, Nakachi S, et al. Appropriate radiation dose for
T-cell leukemia/lymphoma after allogeneic hematopoietic stem cell symptomatic relief and local control in patients with adult T cell
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76. Tokunaga M, Uto H, Takeuchi S, et al. Newly identified poor

prognostic factors for adult T-cell leukemia-lymphoma treated with
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77. Yoshimitsu M, Tanosaki R, Kato K, et al. Risk assessment in adult

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78. Horwitz SM, Advani RH, Bartlett NL, et al. Objective responses in
relapsed T-cell lymphomas with single-agent brentuximab vedotin. Blood
2014;123:3095-3100. Available at:
[Link]

79. Fuji S, Inoue Y, Utsunomiya A, et al. Pretransplantation anti-CCR4

antibody mogamulizumab against adult T-cell leukemia/lymphoma is
associated with significantly increased risks of severe and
corticosteroid-refractory graft-versus-host disease, nonrelapse mortality,
and overall mortality. J Clin Oncol 2016;34:3426-3433. Available at:
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80. Sugio T, Kato K, Aoki T, et al. Mogamulizumab treatment prior to

allogeneic hematopoietic stem cell transplantation induces severe acute
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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

Hepatosplenic T-Cell Lymphoma resource for medical literature and indexes peer-reviewed biomedical
Hepatosplenic T-cell lymphoma (HSTCL) is a rare lymphoproliferative literature.16
disorder associated with an aggressive clinical course and a worse
The search results were narrowed by selecting studies in humans
prognosis.1-3 HSTCL accounts for less than or equal to 2% of all cases of
published in English. Results were confined to the following article types:
T-cell lymphomas diagnosed worldwide and in up to 20% of cases
Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial; Guideline;
develops in the setting of chronic immune suppression or immune
Randomized Controlled Trial; Meta-Analysis; Systematic Reviews; and
dysregulation, particularly inflammatory bowel disease (IBD), hematologic
Validation Studies.
malignancies, and previous solid organ transplant.4-6 The concomitant use
of TNF- inhibitors and thiopurine-based immunomodulators has been The data from key PubMed articles deemed as relevant to these
identified as a risk factor for developing HSTCL among patients with Guidelines have been included in this version of the Discussion section.
IBD.7,8 Recommendations for which high-level evidence is lacking are based on
the panel’s review of lower-level evidence and expert opinion.
HSTCL is most often characterized by spleen, liver, and bone marrow
involvement. Lymphadenopathy is uncommon and patients frequently Diagnosis
present with systemic symptoms, hepatosplenomegaly, cytopenias, and
The diagnosis of HSTCL is most frequently established by a core needle
sometimes hemophagocytic lymphohistiocytosis (HLH).9,10 Clinical
biopsy of a bone marrow and/or liver with adequate immunophenotyping
presentation is highly non-specific and high index of suspicion is required
(either by immunohistochemistry [IHC] or cell surface marker analysis by
to make the diagnosis. In the majority of cases, the neoplastic cells
flow cytometry) as well as molecular studies.5 Examination of peripheral
typically arise from lymphocytes having the surface expression of TCRẟ
blood smear, bone marrow aspirate, and fine-needle aspiration (FNA)
and TCRɣẟ.6,11,12 In rare cases, neoplastic cells may express TCRαβ.13-15
biopsy of liver may be helpful but are not solely sufficient for the diagnosis.
TCRɣẟ variant has a male predominance with a median age of 35 years,
Splenectomy may be required in some cases and core needle biopsy of
whereas TCRαβ variant occurs more commonly in females >50 years.4
spleen could be considered in some cases, in centers of excellence with
Both are considered as immunophenotypic variants of the same disease
expertise in performing this procedure.
and are managed in the same way.
The interpretation of cytotoxic cells seen on the bone marrow biopsy
Literature Search Criteria
specimen may be difficult and multiple biopsies may be needed prior to
Prior to the update of this version of the NCCN Clinical Practice making a definitive diagnosis, since biopsy results may be inconclusive.
Guidelines in Oncology (NCCN Guidelines®) for T-Cell Lymphomas, a Additional liver biopsy may be helpful to confirm the diagnosis. Liver
literature search of the PubMed database was performed to obtain key biopsy with adequate immunophenotyping should be reviewed by a
literature in HSTCL published since the previous Guidelines update. The hematopathologist.17
PubMed database was chosen as it remains the most widely used

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HSTCL is typically characterized by the following immunophenotype: It is essential to consider other T-cell/natural killer (NK)-cell neoplasms
CD2+, CD3+, CD4-, CD5-, CD8+/-, CD56+/-, TCRɣẟ+, TIA1+, TdT, and with significant overlapping features with HSTCL in the differential
granzyme B-.18 An IHC panel to evaluate for HSTCL typically includes diagnosis (ɣẟ-T-cell LGLL, T-cell lymphoblastic leukemia, primary
CD20, CD3, CD10, Ki-67, CD5, CD30, CD2, CD4, CD8, CD7, CD56, cutaneous-γδ-T-cell lymphoma, intestinal monomorphic epitheliotropic
EBER-ISH, TCRβ, TCRẟ, TIA-1, and granzyme B. Cell surface marker intestinal T-cell lymphoma, aggressive NK-cell leukemia, Epstein-Barr
analysis by flow cytometry often includes kappa/lambda, CD45, CD3, virus [EBV]-positive T-cell lymphoma, and NK-cell lymphoproliferative
CD5, CD19, CD10, CD20, CD30, CD4, CD8, CD7, CD2; TCRẟ, TCRαβ, diseases of childhood, and, rarely, other T-cell lymphomas with expression
or TCRɣẟ.17 of TCRɣẟ).17,32 Fluorescence in situ hybridization (FISH) and karyotype for
the identification of isochromosome 7q and trisomy 8 and next-generation
Molecular analysis or other assessment of clonality can be used to detect sequencing (NGS) panel including STAT3, STAT5B, PIK3CD, SETD2,
clonal TCR gene rearrangements. The identification of TCRɣ gene INO80, and TET3 would be useful for the differential diagnosis for
rearrangement on molecular analysis reflects the clonality of the T cells. HSTCL.22,23,27
However, the molecular clonality studies cannot be used to define the
T-cell subtype (αβ vs. ɣẟ) since TCRβ and TCRɣ gene rearrangements Non-neoplastic, transient conditions leading to an increase in ɣẟ T-cells
may be seen in both αβ and ɣẟ HSTCL.14 with a similar phenotype, including infections such as ehrlichiosis and
other tick-borne diseases, should also be considered in the differential
Isochromosome 7q and trisomy 8 are the most common chromosomal diagnosis of HSTCL.33,34
abnormalities in HSTCL.6,19-23 Isochromosome 7q and ring chromosome 7
are associated with loss of 7p and amplification of 7q resulting in altered Workup
expressions of several oncogenes located on chromosome 7 (CHN2, The initial workup should include comprehensive medical history and
ABCB1, and PPP1R9A).24 Gene expression profiling studies have physical examination including full skin examination and routine laboratory
identified distinct molecular signatures that distinguish HSTCL from other studies (bone marrow biopsy ± aspirate, complete blood count [CBC] with
T-cell lymphomas.25-27 In a whole exome sequencing study on 68 primary differential, comprehensive metabolic panel, and assessment of serum
HSTCL tumors, mutations in chromatin-modifying genes including SETD2, uric acid and lactate dehydrogenase [LDH]). Fluorodeoxyglucose
INO80, and ARID1B (occurring almost exclusively in HSTCL compared to (FDG)-PET/CT and/or CT of chest/abdomen/pelvis with contrast of
other T-cell lymphoma subtypes) were present in 62% of cases.27 In diagnostic quality are essential for workup. In the absence of
addition, STAT5B, STAT3, and PIK3CD mutations have also been lymphadenopathy, normal FDG uptake in lymph nodes are pertinent
identified in 31%, 9%, and 9% of cases, respectively.27 STAT3 and STAT5 negative findings on PET/CT scan that could differentiate HSTCL from
mutations, however, are not unique to HSTCL and have also been other lymphomas.35 CT scan of the neck and CT or MRI of the head may
identified in large granular lymphocytic leukemia (LGLL) and other T-cell be useful in some cases.
lymphoma subtypes.28-31

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

Multigated acquisition (MUGA) scan or echocardiogram is recommended CHOP-like regimen.38-41 Purine analogs (pentostatin or cladribine) either
under certain circumstances. Quantitative polymerase chain reaction as monotherapy or in combination with alemtuzumab have also
(PCR) for EBV and cytomegalovirus (CMV) reactivation as well as demonstrated modest activity.42-47
serology testing for the HIV and human T-cell lymphotropic virus (HTLV-1)
may be useful in selected cases. Few studies have reported improved survival outcomes with autologous or
allogeneic HCT as consolidation therapy for patients with disease in first or
Human leukocyte antigen (HLA) typing is recommended for all patients second remission.40,48-50 Autologous HCT has also been shown to provide
eligible for transplant, since HSTCL is associated with a poor outcome in some benefit for patients when an allogeneic HCT is not feasible.40 Some
the absence of a consolidative allogeneic hematopoietic cell transplant studies have also reported that graft-versus-lymphoma effect associated
(HCT). Early referral to transplant is advisable for planning purposes.15 with allogeneic HCT may result in long-term survival in a significant
proportion of patients with HSTCL and active disease at the time of
Hemophagocytic Lymphohistiocytosis
transplant was not necessarily associated with poor outcomes.48,49 In a
HLH is a rare but potentially life-threatening hyper-inflammatory syndrome U.S. multicenter collaborative study that evaluated the outcomes of HCT in
and it is most often associated with an underlying hematologic 53 patients with HSTCL, the median OS and progression-free survival
malignancy, especially T-cell lymphomas in adults.9 HSTCL should be (PFS) were 79 months and 54 months, respectively, for the entire study
considered in the differential diagnosis when evaluating patients cohort with no significant differences in OS (P = .245) or PFS (P = .365)
presenting with symptoms associated with HLH. between autologous and allogeneic HCT.50 The 3-year cumulative
incidence of relapse rates were 35% and 43%, respectively, for
Optimized HLH inflammatory (OHI) index can be considered to simplify the
autologous and allogeneic HCT. The 3-year cumulative incidence of
diagnosis of HLH in patients with hematologic malignancies.36 Diagnostic
non-relapse mortality (NRM) rates were 16% and 14%, respectively. The
workup to confirm the lymphoma subtype and prompt initiation of
efficacy of allogeneic HCT in relapsed or refractory disease has also been
treatment for underlying T-cell lymphoma (preferably with etoposide- and
demonstrated in several case reports.51-53
steroid-containing regimens) is often required.36,37
An individual-level meta-analysis (which represents the largest
Treatment
aggregation of all published studies and case reports so far; 166 patients
HSTCL are underrepresented in prospective clinical studies and treatment with a diagnosis of HSTCL) compared the response rates and overall
recommendations are based on the evidence mainly from small case survival (OS) outcomes of 84 patients with HSTCL treated with CHOP or
reports or case series and single-center retrospective studies.5 Outcomes CHOP-like regimens (n = 50) or non–CHOP-based regimens, specifically
are poor with cyclophosphamide, doxorubicin, vincristine, and prednisone those containing cytarabine, platinum, and etoposide (n = 34).41 Non–
(CHOP)-based chemotherapy regimens. More intensive non– CHOP-based regimens were associated with an overall response rate of
CHOP-based chemotherapy regimens like ICE (ifosfamide, carboplatin, 82% compared with 52% for CHOP or CHOP-like regimens (P = .006).
and etoposide) or IVAC (ifosfamide, etoposide, and cytarabine) have been The median survival was 37 months and 18 months, respectively (P =
associated with potentially improved outcomes compared with CHOP or a

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

.00014). The use of a non–CHOP-based regimen was a significant may also be appropriate and are included as options under other
predictor of higher response rate (P = .049) and improved survival (P = recommended regimens.40,41
.026). This study also demonstrated a benefit for HCT on survival and the
superiority of allogeneic HCT over autologous HCT. The 2-year survival The phase III randomized trial (ECHELON-2) showed that brentuximab
rate was 12% for patients who did not receive HCT compared to 41% and vedotin (BV) in combination with CHP (cyclophosphamide, doxorubicin,
56%, respectively, for those who received autologous HCT and allogeneic and prednisone) was superior to CHOP for the treatment of patients with
HCT. previously untreated CD30-positive peripheral T-cell lymphoma (PTCL)
(defined in ECHELON-2 as CD30 expression on ≥10% of cells), resulting
NCCN Recommendations in significantly improved PFS and OS.54 The survival benefit was clearly
The optimal treatment approach remains undefined given the absence of established for the subset of patients with anaplastic large cell lymphoma
data from prospective randomized clinical studies. Clinical trial, if an (ALCL), but the benefit was less clear across other histologic subtypes.54
appropriate one is available, is the preferred initial treatment option for all Based on the results of the ECHELON-2 trial, BV in combination with
patients with HSTCL. The goal of initial therapy is to induce complete or CHP was approved by the FDA as a first-line therapy for patients with
near complete response to allow successful bridging to HCT, preferably an untreated systemic ALCL or other CD30-expressing subtypes (≥1%
allogeneic HCT. Since HSTCL is non-nodal, Lugano response criteria do CD30 expression) including PTCL, not otherwise specified (NOS) and
not apply for response assessment and PET-negative response should be angioimmunoblastic T-cell lymphoma (AITL).
confirmed by bone marrow biopsy and in selected cases by liver biopsy.
Patients with HSTCL were eligible for the ECHELON-2 study but no
CHOP is not considered adequate therapy. In the absence of data from patients were enrolled. Given that BV + CHP has demonstrated activity
prospective and randomized studies, the results of the aforementioned in CD30+ subtypes of PTCL, BV + CHP is included as an alternate
individual-level meta-analysis support the use of induction therapy with treatment option with a category 2B recommendation for patients with
non–CHOP-based regimens followed by consolidation with allogeneic CD30+ HSTCL. Alemtuzumab + pentostatin and CHOEP
HCT as an effective treatment approach (associated with improved (cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone)
survival) for all eligible patients with HSTCL.41 are also included as alternative options (useful in certain circumstances).

ICE is included as the preferred regimen for induction therapy since this Consolidation therapy with allogeneic HCT is recommended for eligible
is used in the majority of NCCN Member Institutions. Other intensive patients with complete response or partial response after initial induction
induction therapy regimens such as DHA (dexamethasone and therapy or second-line therapy.41,46,49,50 Consolidation therapy with
cytarabine) with cisplatin or oxaliplatin, dose-adjusted EPOCH autologous HCT can be considered if a suitable donor is not available or
(etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin), for patients who are ineligible for allogeneic HCT.40,50
IVAC, and hyperCVAD (cyclophosphamide, vincristine, doxorubicin, and
dexamethasone) alternating with high-dose methotrexate and cytarabine Patients with disease not responding to primary treatment or those with
progressive disease should be treated with alternate induction therapy

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

regimens before receiving treatment for relapsed/refractory disease.5

Purine analogs or regimens recommended for second-line therapy for
PTCL-NOS may be appropriate for the treatment of patients with
relapsed/refractory HSTCL. Responses have been observed with
alemtuzumab, pralatrexate, duvelisib and ESHAP (etoposide,
methylprednisolone, cytarabine, and cisplatin).5

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T-Cell Lymphomas

References of 7 patients who did not receive tumor necrosis factor-alpha inhibitor
therapy and literature review. Ann Diagn Pathol 2017;26:16-22. Available
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[Link]
lymphoma arising in patients with immunodysregulatory disorders: a study
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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

16. PubMed Overview. Available at: 23. Desmares A, Bouzy S, Thonier F, et al. Hepatosplenic T-cell
[Link] Accessed March 5, 2024. lymphoma displays an original oyster-shell cytological pattern and a
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18. Cooke CB, Krenacs L, Stetler-Stevenson M, et al. Hepatosplenic T-cell 2014;9:e102977. Available at:
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19. Wang CC, Tien HF, Lin MT, et al. Consistent presence of targets. Blood 2012;119:5795-5806. Available at:
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20. Yao M, Tien HF, Lin MT, et al. Clinical and hematological [Link]
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21. Alonsozana EL, Stamberg J, Kumar D, et al. Isochromosome 7q: the 28. Jerez A, Clemente MJ, Makishima H, et al. STAT3 mutations unify the
primary cytogenetic abnormality in hepatosplenic gammadelta T cell pathogenesis of chronic lymphoproliferative disorders of NK cells and
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22. Wlodarska I, Martin-Garcia N, Achten R, et al. Fluorescence in situ 29. Koskela HL, Eldfors S, Ellonen P, et al. Somatic STAT3 mutations in
hybridization study of chromosome 7 aberrations in hepatosplenic T-cell large granular lymphocytic leukemia. N Engl J Med 2012;366:1905-1913.
lymphoma: isochromosome 7q as a common abnormality accumulating in Available at: [Link]
forms with features of cytologic progression. Genes Chromosomes Cancer
2002;33:243-251. Available at: 30. Ohgami RS, Ma L, Merker JD, et al. STAT3 mutations are frequent in
[Link] CD30+ T-cell lymphomas and T-cell large granular lymphocytic leukemia.
Leukemia 2013;27:2244-2247. Available at:
[Link]

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

31. Blombery P, Thompson ER, Prince HM. Molecular drivers of breast 39. Falchook GS, Vega F, Dang NH, et al. Hepatosplenic gamma-delta
implant-associated anaplastic large cell lymphoma. Plast Reconstr Surg T-cell lymphoma: clinicopathological features and treatment. Ann Oncol
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32. Yabe M, Medeiros LJ, Wang SA, et al. Distinguishing between 40. Voss MH, Lunning MA, Maragulia JC, et al. Intensive induction
hepatosplenic T-cell lymphoma and gammadelta T-cell large granular chemotherapy followed by early high-dose therapy and hematopoietic
lymphocytic leukemia: A clinicopathologic, immunophenotypic, and stem cell transplantation results in improved outcome for patients with
molecular analysis. Am J Surg Pathol 2017;41:82-93. Available at: hepatosplenic T-cell lymphoma: a single institution experience. Clin
[Link] Lymphoma Myeloma Leuk 2013;13:8-14. Available at:
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33. Malani A, Weigand R, Gupta V, et al. Ehrlichiosis mimicking T-cell
lymphoma/leukemia [abstract]. Blood 2005;106:Abstract 4343. Available 41. Klebaner D, Koura D, Tzachanis D, et al. Intensive induction therapy
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34. Marko D, Perry AM, Ponnampalam A, Nasr MR. Cytopenias and clonal [Link]
expansion of gamma/delta T-cells in a patient with anaplasmosis: a
potential diagnostic pitfall. J Clin Exp Hematop 2017;56:160-164. Available 42. Gopcsa L, Banyai A, Tamaska J, et al. Hepatosplenic gamma delta
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2-chlorodeoxyadenosine. Haematologia (Budap) 2002;32:519-527.
35. Cho MW, Chin BB. (18)F-FDG PET/CT findings in hepatosplenic Available at: [Link]
gamma-delta T-cell lymphoma: Case reports and review of the literature.
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series of 21 patients. Blood 2003;102:4261-4269. Available at: 46. Ravandi F, Aribi A, O'Brien S, et al. Phase II study of alemtuzumab in
[Link] combination with pentostatin in patients with T-cell neoplasms. J Clin

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T-Cell Lymphomas

Oncol 2009;27:5425-5430. Available at: report. Medicine (Baltimore) 2018;97:e12941. Available at:
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47. Bennett M, Matutes E, Gaulard P. Hepatosplenic T cell lymphoma 54. Horwitz S, O'Connor OA, Pro B, et al. The ECHELON-2 Trial: 5-year
responsive to 2'-deoxycoformycin therapy. Am J Hematol results of a randomized, phase III study of brentuximab vedotin with
2010;85:727-729. Available at: chemotherapy for CD30-positive peripheral T-cell lymphoma. Ann Oncol
[Link] 2022;33:288-298. Available at:
[Link]
48. Rashidi A, Cashen AF. Outcomes of allogeneic stem cell
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49. Tanase A, Schmitz N, Stein H, et al. Allogeneic and autologous stem

cell transplantation for hepatosplenic T-cell lymphoma: a retrospective
study of the EBMT Lymphoma Working Party. Leukemia 2015;29:686-688.
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50. Moustafa MA, Ramdial JL, Tsalatsanis A, et al. A US multicenter

collaborative study on outcomes of hematopoietic cell transplantation in
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51. Domm JA, Thompson M, Kuttesch JF, et al. Allogeneic bone marrow
transplantation for chemotherapy-refractory hepatosplenic gammadelta
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[Link]

52. Sumi M, Takeda W, Kaiume H, et al. Successful treatment with

reduced-intensity cord blood transplant in a patient with relapsed
refractory hepatosplenic T-cell lymphoma. Leuk Lymphoma
2015;56:1140-1142. Available at:
[Link]

53. Pan H, Huang J, Li JN, et al. Successful second allogeneic stem-cell

transplantation from the same sibling donor for a patient with recurrent
hepatosplenic gamma-delta (gamma/delta) T-cell lymphoma: A case

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T-Cell Lymphomas

Extranodal Natural Killer/T-Cell Lymphomas, Nasal Type search of the PubMed database was performed to obtain key literature in
Overview ENKL published since the last Guidelines update. The PubMed database
was chosen as it remains the most widely used resource for medical
Natural killer (NK)/T-cell lymphomas are a rare and distinct subtype of
literature and indexes peer-reviewed biomedical literature.7
non-Hodgkin lymphomas (NHL) that are predominantly extranodal. The
majority of extranodal NK/T-cell lymphomas (ENKL) are of nasal type, The search results were narrowed by selecting studies in humans
often localized to the upper aerodigestive tract including the nasal cavity, published in English. Results were confined to the following article types:
nasopharynx, paranasal sinuses, tonsils, hypopharynx, and larynx.1,2 Clinical Trial, Phase II; Clinical Trial, Phase III; Guideline; Randomized
However, ENKL can also have an extranasal presentation (ENKL of Controlled Trial; Meta-Analysis; Systematic Reviews; and Validation
non-upper aerodigestive tract), with skin, testis, and gastrointestinal tract Studies.
being the most common sites of extranasal involvement or metastatic
disease.3-6 The data from key PubMed articles as well as articles from additional
sources deemed as relevant to these Guidelines have been included in
ENKL, non-nasal type is associated with more unfavorable prognostic this version of the Discussion section. Recommendations for which
factors and poorer prognosis than ENKL, nasal type.3,6 A greater high-level evidence is lacking are based on the panel’s review of
proportion of the patients with ENKL, non-nasal type present with lower-level evidence and expert opinion.
advanced-stage disease (68% vs. 27%), mass greater than 5 cm (68% vs.
12%), greater than 2 extranodal sites (55% vs. 16%), elevated lactate Diagnosis
dehydrogenase (LDH) levels (60% vs. 45%), and B symptoms (54% vs. The most common clinical features of ENKL, nasal type include nasal
39%).3 ENKL, non-nasal type is associated with shorter median overall obstruction or nasal bleeding. Histopathologic features in most cases of
survival (OS; 4 months vs. 19 months for ENKL, nasal type) and inferior ENKL are characterized by diffuse lymphomatous infiltrates,
OS rate (5-year OS rate was 34% vs. 54% for patients with ENKL, nasal angiocentricity, and angiodestructive growth patterns resulting in tissue
type).3,6 ischemia and necrosis, and ulceration of mucosal sites.1 Lymphoma cells
can be variable, but are usually medium sized or a mixture of small and
The increasing use of non–anthracycline-based chemotherapy regimens
large cells. Necrosis is very common in diagnostic biopsies and may delay
that are more specific for ENKL has resulted in significant improvement in
diagnosis. Biopsy specimen should include edges of the lesions to
survival rates. It is recommended that patients with ENKL be treated at
increase the odds of having a viable tissue sample. It may also be useful
centers with expertise in the management of this disease and, when
to perform multiple nasopharyngeal biopsies for the evaluation of occult
possible, enrolled in clinical trials.
disease even in areas that are not clearly involved on endoscopic
Literature Search Criteria examination.

Prior to the update of this version of the NCCN Clinical Practice Guidelines The typical immunophenotype for NK-cell ENKL is CD20-, CD2+, cCD3+
in Oncology (NCCN Guidelines®) for T-Cell Lymphomas, a literature (surface CD3-), CD4-, CD5-, CD7-/+, CD8-/+, CD43+, CD45RO+, CD56+,

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TCRαβ-, TCRδγ-, Epstein-Barr virus (EBV)-Epstein-Barr encoding region with differential, comprehensive metabolic panel, measurement of serum
(EBER)+, and cytotoxic granule proteins positive (eg, TIA-1+, granzyme uric acid, and LDH. CT scans of chest, abdomen, and pelvis, with
B+).3 For NK-cell lineage, TCR and immunoglobulin gene represent contrast of diagnostic quality and/or PET/CT should be performed. CT
germline sequences. The typical immunophenotype for T-cell lineage is scan or MRI of the nasal cavity, hard palate, anterior fossa, and
CD2+, cCD3+, surface CD3+, variable CD4/CD5/CD7/CD8, TCRαβ+ or nasopharynx is also essential for initial workup. A multigated acquisition
TCRδγ+, EBV-EBER+, and cytotoxic granule proteins positive. (MUGA) scan or echocardiogram should be performed if treatment with
anthracycline or anthracenedione is being considered.
Adequate immunophenotyping is essential to confirm the diagnosis. The
initial immunohistochemistry (IHC) panel should include cytoplasmic Bone marrow involvement is uncommon at diagnosis and occurs in less
CD3(cCD3), CD2, CD5, CD56 and TIA1. Additional recommended than 20% of patients within the disease course.11,12 PET/CT has
markers for the IHC panel include CD20 for B-cell lineage; CD4, CD7, demonstrated satisfactory predictive performance in terms of staging,
CD8, granzyme B, TCRβ, TCRẟ for T-cell lineage; CD30 and Ki-67. EBV and the use of routine bone marrow biopsy is not essential in patients
infection is always present in ENKL and should be determined by with early-stage disease.13 Bone marrow biopsy is recommended to
EBV-encoded RNA in situ hybridization (EBER-ISH).1 EBV-negative ENKL confirm bone marrow involvement in patients with advanced-stage
is very rare and has not been fully investigated.8 A negative EBER-ISH disease. Morphologically negative biopsies should be evaluated by
result should prompt hematopathology review for an alternative diagnosis. EBER-ISH and, if positive, should be considered involved.11,14-16

Clonal TCR gene rearrangements have been found in up to one third of Ocular and central nervous system (CNS) involvement have been
cases with ENKL, nasal type.3 Molecular analysis to detect clonal TCR described (although both are very rare).17-20 CNS involvement at the time
gene rearrangements may be useful under certain circumstances. Ki-67 of initial diagnosis is associated with a poor prognosis, and autologous
expression has been reported to be prognostic in patients with stage I/II hematopoietic cell transplant (HCT) may be associated with improved
ENKL, nasal type.9,10 High Ki-67 expression (≥65%) was associated with a survival outcome in patients with CNS involvement.18,20 Ophthalmologic
shorter OS and disease-free survival (DFS). In a multivariate analysis, exam and lumbar puncture with cerebrospinal fluid (CSF) analysis may
Ki-67 expression and primary site of involvement were found to be be useful in certain circumstances.
independent prognostic factors for both OS and DFS.9
Prognosis
Workup The use of International Prognostic Index (IPI), most commonly used for
The initial workup should include a history and physical (H&P) patients with aggressive lymphomas, is limited in patients with ENKL
examination with attention to node-bearing areas (including Waldeyer’s because most patients present with localized disease, rare involvement of
ring), testicles and skin, complete ear, nose, and throat (ENT) evaluation bone marrow, and the presence of constitutional symptoms even with
of nasopharynx, as well as evaluation of B symptoms and performance localized disease.
status. Laboratory tests should include a complete blood count (CBC)

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T-Cell Lymphomas

Lee et al have proposed a prognostic model specifically for patients with post-treatment) has been shown to be a good predictor of response,
ENKL, nasal type, that stratifies patients into four risk groups (low risk, survival, and early relapse in patients with ENKL, nasal type treated with
low-intermediate risk, intermediate-high risk, and high risk) with different asparaginase- or pegaspargase-based chemotherapy.29-34 In the phase II
survival outcomes based on the presence or absence of four prognostic study from the NK-Cell Tumor Study Group, the overall response rate
factors (B symptoms, disease stage, LDH levels, and regional lymph node (ORR) was significantly higher in patients with less than 105 copies/mL of
involvement).21 Most patients had received anthracycline-based EBV-DNA in whole blood prior to initiation of asparaginase-based
chemotherapy regimens with or without radiation therapy (RT). chemotherapy (90% vs. 20%; P = .007) and in patients with less than 104
copies/mL of EBV-DNA in plasma (95% vs. 29%; P = .002).30 In addition,
The prognostic index of natural killer lymphoma (PINK) is used for the risk the incidence of grade 4 non-hematologic toxicity was significantly higher
stratification of patients with ENKL treated with non–anthracycline-based among patients with greater than or equal to 105 copies/mL of EBV-DNA in
chemotherapy.22 In a retrospective analysis of 527 patients, age >60 whole blood (100% vs. 29%; P = .007) and in patients with greater than or
years, stage III or IV disease, distant lymph node involvement, and equal to 104 copies/mL of EBV-DNA in plasma (86% vs. 26%; P = .002).
non-nasal type disease were identified as predictors of OS and PFS. Pre-treatment EBV-DNA in plasma was also independently associated
Among the 328 patients with documented data for EBV-DNA, detectable with advanced stage and poor PFS in multivariate analysis, suggesting
EBV-DNA measured by quantitative polymerase chain reaction (PCR) was that EBV-DNA level in the plasma has better prognostic value than that in
a significant predictor of OS. Based on these risk factors, PINK stratified whole blood.34
patients into three risk groups (low-risk, no risk factors; intermediate-risk,
one risk factor; and high-risk, ≥2 risk factors) with 3-year OS rates of 81%, Measurement of EBV-DNA viral load by quantitative PCR is useful in the
62%, and 25%, respectively. diagnosis and often in the monitoring of the disease. The NCCN
Guidelines recommend measurement of EBV-DNA load and calculation
PINK-E (for patients with data for EBV-DNA) also stratified patients into prognostic index (PINK or PINK-E) as part of initial workup.
three risk groups (low-risk, 0 or 1 risk factor; intermediate-risk, 2 risk
factors; and high-risk, ≥3 risk factors) with 3-year OS rates of 81%, 55%, Treatment Options
and 28%, respectively. Vitamin D deficiency is an independent prognostic Radiation Therapy
factor for inferior progression-free survival (PFS) and OS in patients with RT is an important component of initial treatment and RT with or without
ENKL. The addition of vitamin D deficiency to the PINK-E scoring system chemotherapy has been effective in achieving higher ORR and complete
had a superior prognostic significance compared PINK-E alone for response (CR) rates compared to chemotherapy alone in patients with
PFS.23,24 early-stage ENKL.3,35-41

EBV-DNA viral load correlates well with clinical stage, tumor burden, Early or up-front RT at doses of greater than or equal to 54 Gy (alone or in
response to therapy, and survival.25-28 Plasma EBV-DNA greater than or combination with chemotherapy) was associated with better survival
equal to 6.1 x 107 copies/mL at presentation has been associated with an outcomes in patients with localized ENKL, nasal type in the upper
inferior DFS.25 Circulating EBV-DNA in whole blood and plasma (pre- or

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T-Cell Lymphomas

aerodigestive tract.38 Among 74 patients who received RT as a component or pegaspargase-based regimens are associated with superior efficacy
of initial therapy, the 5-year OS and DFS rates were 76% and 60%, compared to the conventional anthracycline-based regimens.40,46,47
respectively, for patients treated with RT doses of greater than or equal to Asparaginase-based chemotherapy regimens resulted in higher response
54 Gy, compared with 46% and 33%, respectively, for patients treated with rates than non–asparaginase-based chemotherapy regimens, although
RT doses of less than 54 Gy. Among patients with stage I disease, there were no significant differences in PFS or OS rates between
up-front RT was associated with higher survival rates than early RT asparaginase-based and non–asparaginase-based chemotherapy
following initial chemotherapy (5-year OS rates were 90% vs. 49%; P = regimens.40
.012; 5-year DFS rates were 79% vs. 40%; P = .021).
The SMILE regimen (dexamethasone, methotrexate, ifosfamide,
Involved-site RT (ISRT) is recommended as the appropriate field as it L-asparaginase, and etoposide) or modified SMILE regimen
limits the volume of RT to the region of involvement only.42 An ISRT dose (dexamethasone, methotrexate, ifosfamide, pegaspargase and
of 50 to 55 Gy is recommended when used alone as primary treatment etoposide; a single dose of pegaspargase is substituted for 7 doses of
and 45 to 56 Gy is recommended when used in combination with asparaginase per cycle) have been shown to be effective for the
chemotherapy. When ISRT is used alone, the clinical target volume (CTV) treatment of ENKL.48-50
should encompass the involved region as defined by contrast-enhanced
MRI and contrast-enhanced CT scan, with expansions to include any of In a phase II study from the NK-Cell Tumor Study Group (38 patients with
the sinuses that were initially partially involved, all adjacent paranasal newly diagnosed stage IV, and relapsed or refractory ENKL, nasal type),
sinuses, as well as a 0.5- to 1-cm expansion into soft tissue. In instances the SMILE regimen resulted in an ORR of 79% (45% CR).48 The response
when chemotherapy was given prior to ISRT and has produced a CR, the rates were not different between patients with newly diagnosed stage IV
CTV should include at least the prechemotherapy gross tumor volume and those with relapsed or refractory disease. The 1-year PFS and OS
(GTV) with appropriate margins (0.5–1 cm). Recommendations for rates were 53% and 55%, respectively. Another phase II study from the
planning and treatment with ISRT are outlined in the Principles of Asia Lymphoma Study Group (n = 87) also reported favorable outcomes
Radiation Therapy section of the Algorithm. with the SMILE regimen in patients with newly diagnosed or
relapsed/refractory ENKL, nasal type.49 The ORR was 81% (66% CR),
The use of intensity-modulated RT (IMRT) has been associated with and similar response rates were observed between patients with newly
favorable locoregional control and improved survival outcomes (OS and diagnosed and relapsed/refractory disease. At a median follow-up of 31
PFS) with mild toxicity in patients with early-stage disease.43,44 months, the 4-year DFS and OS rates were 64% and 50%, respectively.

Combination Chemotherapy In a retrospective analysis of 43 patients with ENKL, nasal type treated at
ENKL cells are associated with a high expression of P-glycoprotein a single institution (26 patients with early-stage disease received 2 cycles
leading to multidrug resistance that is likely responsible for the poor of chemotherapy followed by ISRT; 17 patients with advanced-stage
response to conventional anthracycline-based chemotherapy.45 disease received 3 cycles of chemotherapy alone and ISRT to bulky
Retrospective comparative studies have shown that asparaginase-based disease sites), the modified SMILE regimen resulted in a significantly

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higher CR rate than the accelerated-CHOP regimen (80% vs. 30%; P = (eg, elevated transaminase, mucositis, allergy) and grade 3 or 4
.015), and the 2-year OS (87% vs. 21%) and PFS (56% vs.18%) rates hematologic toxicities were higher with the SMILE regimen than with
were significantly higher for patients with early-stage disease than with DDGP. However, the dosing and supportive care used for the SMILE
advanced-stage disease (P < .001) for the total cohort of patients.50 regimen on this study differed from those used for the conventional SMILE
or modified SMILE regimen, which may have contributed to this difference.
Pegaspargase in combination with gemcitabine and oxaliplatin
(P-GEMOX) with or without RT is also an effective treatment option for The AspaMetDex regimen (L-asparaginase, methotrexate and
newly diagnosed as well as relapsed/refractory disease.51-53 In a dexamethasone) was evaluated in a phase II intergroup study in 19
retrospective analysis of 117 patients with ENKTL (96 patients with newly patients with refractory or relapsed ENKL.56 After three cycles, patients
diagnosed ENKL and 21 patients with relapsed/refractory disease), the with localized disease were treated with consolidative RT, if not received
P-GEMOX regimen resulted in an ORR of 88% and responses were previously; those with disseminated disease received high-dose therapy
similar for patients with newly diagnosed and relapsed/refractory ENKL.51 with peripheral blood stem cell infusion. The ORR and CR rates after three
After a median follow-up of 17 months, the 3-year OS and PFS rates were cycles of AspaMetDex were 78% and 61%, respectively. The median PFS
73% and 58%, respectively. In a subgroup analysis, PFS was significantly and OS were both 1 year; the absence of anti-asparaginase antibodies
better for patients with newly diagnosed ENKL than with and the clearance of serum EBV-DNA were significantly associated with a
relapsed/refractory disease, but there were no differences in OS. better outcome.56

The DDGP (dexamethasone, cisplatin, gemcitabine, and pegaspargase) Combined Modality Therapy
regimen is an effective treatment option with a better toxicity profile in In the analysis of the International T-Cell Lymphoma Project, which
patients with newly diagnosed as well as relapsed/refractory ENKL.54,55 In retrospectively reviewed the clinical outcome of 136 patients with ENKL,
a prospective, multicenter, randomized trial (87 eligible patients with newly more patients with ENKL, nasal type received RT with or without
diagnosed ENKL; 80 patients included in the intent-to-treat population anthracycline-based chemotherapy compared with patients with
were randomized to receive the DDGP or SMILE regimen), the DDGP extranasal ENKL (52% vs. 24%).3 In the subgroup of patients with
regimen was better tolerated and was also associated with significant early-stage ENKL, nasal type (n = 57), combined modality therapy
improvement in PFS and OS compared with the SMILE regimen.54 At resulted in significantly improved 3-year OS rate compared to
median follow-up of 42 months, the median PFS and OS were not reached chemotherapy alone (57% vs. 30%; P = .045).3
in patients treated with the DDGP regimen. The median PFS and OS were
7 months and 75 months, respectively, for patients treated with the SMILE In a retrospective review of 105 patients with localized stage I/II ENKL,
regimen. The DDGP regimen was also associated with higher ORR (90% nasal type, RT alone resulted in higher CR rates than with chemotherapy
vs. 60%; P = .002), 3-year PFS rate (57% vs. 42%; P = .004), and 5-year alone (83% vs. 20%); CR rates improved to 81% among patients who
OS rate (74% vs. 52%; P = .02), although there was no difference in CR received RT following chemotherapy.37 Notably, in this study, the addition
rate between the two groups. The incidences of non-hematologic toxicities of chemotherapy to RT did not appear to improve OS outcomes. The
5-year OS rates were similar among the patient groups that received RT

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alone (66%; n = 31), RT followed by chemotherapy (77%; n = 34), and of 67% and 73%, respectively.65 Late toxicities were manageable with few
chemotherapy followed by RT (74%; n = 37). grade 3 or 4 events, which included only one grade 3 event (irregular
menstruation) and one grade 4 event (perforation of nasal skin).
RT is also an independent prognostic factor for OS and PFS in ENKL in
patients with stage I–II ENKL treated with asparaginase-based The results of a retrospective analysis (358 patients; 257 patients had
chemotherapy, and the survival benefit was seen in patients who achieved localized disease) also reported favorable response and survival rates for
CR after chemotherapy.57-60 In a study of 240 patients with early-stage patients treated with the CCRT with DeVIC regimen.66 After a median
ENKL treated with asparaginase-based chemotherapy with or without RT, follow-up of 6 years, the 5-year OS and PFS rates were 72% and 61%,
the use of RT in combination with chemotherapy was associated with respectively. In this analysis, only 4% of patients with localized disease
significantly improved 5-year OS rates (85% vs. 59%; P = .006), DFS were classified as high risk according to PINK. In a multivariate analysis,
rates (76% vs. 44%; P = .001), and locoregional control (85% vs. 62%; P = elevated soluble interleukin-2 receptor was an independent predictive
.026).58 The omission of RT was associated with poor prognosis and factor for worse OS and PFS among patients treated with CCRT with the
resulted in frequent locoregional recurrence even in patients who achieved DeVIC regimen.
a CR after asparaginase-based chemotherapy. The 5-year cumulative
disease recurrence rate was significantly higher for patients treated with Another phase II study also reported promising results with CCRT with
chemotherapy alone (47% vs.19%; P = .003). cisplatin and 40–52.8 Gy RT followed by 3 cycles of etoposide, ifosfamide,
cisplatin, and dexamethasone (VIPD) in patients with ENKL, nasal type (n
The use of IMRT in combination with chemotherapy results in promising = 30; 21 patients had stage I/II disease and 9 patients had stage III/IV
clinical outcomes in patients with early-stage ENKL, with mild toxicities disease).67 The CR rate was 73% after initial chemoradiation and
related to RT.61-63 increased to 80% after VIPD chemotherapy. The estimated 3-year PFS
and OS rates were 85% and 86%, respectively.67 The safety and efficacy
Concurrent Chemoradiation of CCRT followed by consolidation chemotherapy in patients with localized
Concurrent chemoradiation therapy (CCRT; with or without consolidation ENKL, nasal type has also been confirmed in other studies.68,69
chemotherapy) is a feasible and effective treatment for localized ENKL.
Sequential Chemoradiation
In the phase I/II study conducted by the Japanese Clinical Oncology Chemotherapy followed by RT also resulted in significantly higher
Group (JCOG0211 study), patients with high-risk, stage I/II nasal disease response rates and prolonged survival in patients with advanced-stage
(n = 33; with lymph node involvement, B symptoms, and elevated LDH) disease.40 In a retrospective analysis of 73 patients with stage III–IV
were treated with concurrent chemoradiation (RT 50 Gy and 3 courses of disease, the ORR was significantly higher in patients treated with
chemotherapy with dexamethasone, etoposide, ifosfamide, and chemotherapy followed by RT than those treated with chemotherapy alone
carboplatin [DeVIC]).64 With a median follow-up of 32 months, the 2-year (82% vs. 29%; P < .001).40 The 2-year OS rates were 58% versus 15%
OS was 78% and the CR rate was 77%. Long-term follow-up from this (P < .001), and the 2-year PFS rates were 46% versus 8% (P < .001). RT
study (median follow-up of 68 months) reported 5-year PFS and OS rates significantly improved the prognosis of patients who achieved a CR or PR
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after initial chemotherapy (2-year OS rates were 82% vs. 40%; P = .002; [49% CR]) and the 5-year PFS and OS rates were 83% and 86%,
2-year PFS rates were 66% vs. 23%; P = .008) but did not provide a respectively, for sequential chemoradiation with DDGP.70 The
significant survival advantage among those with stable or progressive corresponding survival rates were 57% and 60%, respectively, for RT. In
disease after initial chemotherapy.40 another trial of 40 patients with stage I–II ENKL, the ORR was higher for
DDGP followed by RT (95%; 85% CR) compared to the VIPD followed by
In the aforementioned retrospective analysis that evaluated the modified RT group (65%; 50% CR).71 The 5-year PFS rates were 83% and 44%,
SMILE regimen in patients with ENKL, among the 11 patients with respectively, for the two treatment groups (P = .005), although the 5-year
early-stage disease treated with sequential chemoradiation (2 cycles of OS rate was not significantly different between the two groups (83% vs.
the modified SMILE regimen followed by ISRT), the estimated 2-year PFS 72%; P = .631).
rate was 83% and all patients were alive with no evidence of disease at
the time of publication.50 Sandwich Chemoradiation
Sandwich chemoradiation (2 cycles of chemotherapy followed by
Sequential chemoradiation with the modified SMILE regimen and low-dose
involved-field RT [IFRT] followed by 2–4 cycles of chemotherapy within 7
IMRT resulted in long-term disease control in patients with early-stage
days of completion of IFRT) with the GELOX regimen (L-asparaginase,
ENKL, nasal type.63 In a single-institution study of 28 patients with ENKL
gemcitabine, and oxaliplatin) and P-GEMOX regimen is also effective for
nasal type, the ORR at completion of the modified SMILE regimen was
the treatment of newly diagnosed stage I–II ENKL, nasal type, resulting
93% (68% CR) and increased to 95% (88% CR) after the completion of
in an ORR of 96% (74% CR) and 92% (87% CR), respectively.72,73 After
sequential IMRT. At a median follow-up of 31 months, the PFS and OS
a median follow-up of 63 months, the 5-year OS and PFS rates were 85%
rates were 92% and 100%, respectively, for patients with early-stage
and 74%, respectively, for sandwich chemoradiation with the GELOX
disease (low PINK-E). The corresponding PFS and OS rates were 33%
regimen.72 After a median follow-up of 16 months, the 1-year PFS and OS
and 43%, respectively, for patients with advanced-stage disease.
rates were both 87% for sandwich chemoradiation with the P-GEMOX
Sequential chemoradiation with P-GEMOX and DDGP regimens has also regimen.73
been associated with favorable efficacy and acceptable toxicity in
Sandwich chemoradiation with GELAD (gemcitabine, etoposide,
patients with stage I–II ENKL. In a cohort of 202 patients with early-stage
pegaspargase, and dexamethasone) chemotherapy and IMRT was also
ENKL, sequential chemoradiation with P-GEMOX resulted in an ORR of
effective for the treatment of early-stage ENKL, resulting in an ORR of
96% (83% CR) and the 3-year PFS and OS rates were 75% and 85%,
94% (92% CR).74 After a median follow-up of 32 months, the estimated
respectively, with a median follow-up of 44 months.53 DDGP followed by
4-year PFS and OS rates were 90% and 94%, respectively.
RT also resulted in higher ORR and longer PFS rates compared to RT
alone or VIPD followed by RT in patients with stage I–II ENKL.70,71 In a The results of another study showed that sandwich chemoradiation with
trial of 65 patients with stage I–II ENKL who were randomized to receive the GELOX regimen and IMRT was associated with higher PFS rates
RT or DDGP followed by RT, the ORRs were higher for sequential (92% vs. 71%; P = .011) and a trend towards improved locoregional
chemoradiation with DDGP compared to RT (83% [73% CR] vs. 60% control (22% vs. 8%; P = .051) compared to sequential chemoradiation in
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patients with early-stage ENKL.61 The EBV-DNA copy number after Combined modality therapy is recommended for stage I or II ENKL,
treatment was a significant prognostic factor for locoregional recurrence, nasal type in patients who are fit to receive chemotherapy and also for
PFS, and OS. those with stage IV ENKL, nasal type and ENKL, extranasal type (stage
I–IV).
Long-term benefit of this approach needs to be confirmed in larger
prospective randomized clinical trials. CCRT with DeVIC (3 cycles) and RT65,66 or sequential chemoradiation
(modified SMILE [2–4 cycles; 2 cycles for stage I–II disease] followed by
NCCN Recommendations RT) 50,63 or sandwich chemoradiation (2 cycles of P-GEMOX followed by
The optimal treatment approach has not yet been established for patients RT followed by 2–4 cycles of P-GEMOX or 2 cycles of GELAD followed by
with ENKL. Because ENKL are rare malignancies, few randomized trials RT followed by 2 cycles of GELAD)73,74 are included as options for
comparing different regimens have not been conducted to date. Most of preferred regimens.
the available data are from retrospective analyses and small prospective
series. Participation in a clinical trial is the preferred option for all patients CCRT with cisplatin followed by VIPD chemotherapy (3 cycles) or
with ENKL. Pegaspargase-based regimens are preferred. However, there sequential chemoradiation with DDGP (3–6 cycles; 3 cycles for stage I-II
are no data to recommend one particular regimen over another. Treatment disease) followed by RT are included as options under other
should be individualized based on patient’s tolerance and comorbidities. recommended regimens.67,70,71

Induction Therapy RT alone is recommended for patients with stage I or II nasal disease who
In the NCCN Guidelines, patients with ENKL are stratified by nasal versus are unfit to receive chemotherapy. IFRT for solitary lesions can be
extranasal disease at presentation and then by the stage of the disease. considered in rare circumstances for stage IE primary cutaneous ENKL.
Patients with stage I or II nasal disease are further stratified based on their
Combination chemotherapy (modified SMILE, P-GEMOX, or DDGP) with
performance status and ability to tolerate chemotherapy.
or without RT is also an option for patients with stage IV ENKL, nasal type
Combined modality therapy yields more favorable outcomes for patients and patients with ENKL, extranasal type (stage I–IV).50,51,54 AspaMetDex
with early-stage stage disease who are candidates for chemotherapy. In a is an option for selected patients who cannot tolerate more intensive
retrospective analysis of 123 patients with ENKL treated at major North chemotherapy.56
American academic centers, among the 83 patients with stage I/II disease,
Response Assessment
53 patients (64%) were treated with combined modality therapy.75 The
Results from retrospective studies suggest that measurement of EBV-DNA
outcomes were similar for patients who received combined modality
and interim or post-treatment PET/CT scan using the Deauville 5-PS may
therapy versus RT alone (2-year PFS rates were 53% vs. 47%; [P = .91]
be useful for the assessment of treatment efficacy and response
and the 2-year OS rates were 67% for each group).
assessment in patients with newly diagnosed and relapsed/refractory
disease.31-33,76-81

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Post-treatment EBV-DNA positivity (in whole blood or plasma) was a presence of detectable EBV-DNA as independent predictors of survival
predictor of early relapse and poor prognosis for patients with early-stage following autologous HCT.85,86
ENKL treated with asparaginase- or pegaspargase-based
chemotherapy.31-33,76 A Deauville score of 4–5 on interim PET/CT scan However, there are no clear data to suggest whether allogeneic or
and EBV DNA after completion of initial treatment have been autologous HCT is preferred.88 In a retrospective analysis from the
independently associated with PFS and OS in the multivariable Lymphoma Working Group of the Japan Society for Hematopoietic Cell
analysis.78,81 Transplantation (JSHCT), that compared the outcomes following
autologous HCT (n = 60) and allogeneic HCT (n = 74) in patients with
End-of-treatment evaluation after induction therapy should include ENKL, although the 2-year OS rate was significantly higher with
appropriate imaging studies (CT, MRI, or PET/CT) based on the type of autologous HCT compared with allogeneic HCT (69% vs. 41%), in
imaging performed at the initial workup, endoscopy with visual inspection, multivariate analysis the type of transplant was not a significant prognostic
repeat biopsies, and measurement of EBV-DNA. Given the primarily factor.88 Patients who underwent autologous HCT in this series appeared
extranodal sites of involvement often outside of the chest, abdomen, and to have better prognostic features (greater proportion of patients had stage
pelvis, PET/CT is also preferred for follow-up to better assess these sites. IV disease in the allogeneic HCT group compared to the autologous HCT
group [64% vs. 33%], and the proportion of patients with low-risk IPI
Additional Therapy
scores was also smaller in the allogeneic HCT group [34% vs. 62%]).
Observation (H&P, ENT evaluation, PET/CT scan, and measurement of
EBV viral load by quantitative PCR) is recommended for all patients with Consolidation with HCT should be considered for patients achieving a CR
stage I or II nasal disease achieving a CR or partial response (PR) (with or PR (with negative biopsy) to induction therapy and treatment should be
negative biopsy) to induction therapy. A CR should also include a negative individualized.
ENT evaluation.
Relapsed/Refractory Disease
Autologous HCT has been evaluated as a consolidation therapy for Clinical trial is the preferred treatment option for relapsed/refractory
patients with ENKL responding to primary therapy.82-87 In one retrospective disease following treatment with pegaspargase-based regimens.
analysis, among patients with CR at the time of transplant stratified by risk
based on NK/T-cell prognostic index, the survival benefit with autologous Anti-programmed cell death protein 1 (PD-1) antibodies, pembrolizumab,
HCT was significantly greater (100% vs. 52%) for patients in the high-risk and nivolumab have been shown to induce responses in patients with
group and there was no significant difference in disease-specific survival relapsed/refractory ENKL following treatment with asparaginase-based
rates between the transplant and non-transplant control groups for regimens.89-91 In the absence of a clinical trial, pembrolizumab and
patients with low risk (87% vs. 69%).84 Other retrospective analyses have nivolumab are included as preferred single-agent options for
identified the NK/T-cell prognostic index for limited disease, pre-transplant relapsed/refractory disease.
response status assessed by the Deauville 5-point scale (5-PS), and the

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T-Cell Lymphomas

In a multicenter retrospective study of 135 patients with reported in patients with ENKL treated with histone deacetylase
relapsed/refractory ENKL, the ORR was higher for those treated with inhibitors.101
asparaginase-based regimens (59%) than gemcitabine-based regimens
(45%). Among patients treated with asparaginase-based regimens, the Allogeneic HCT been evaluated in retrospective studies and case reports
ORR were higher for those receiving the regimen for the first time for predominantly in Asian patients.83,102-109 The presence of a detectable level
relapsed/refractory disease (74%) compared to 44% for those who had of EBV-DNA and disease status at the time of transplant were also
been previously treated with asparaginase-based chemotherapy.92 predictive of outcome following allogeneic HCT (CR or PR before
Therefore, an alternate pegaspargase-based combination chemotherapy allogeneic HCT was associated with better survival outcomes than stable
(not previously used for induction therapy) may offer benefit for patients or progressive disease).107 However, in a retrospective analysis from
with primary refractory disease or for those with PR (and positive biopsy) CIBMTR that evaluated allogeneic HCT in a predominantly white patient
after induction therapy.48,49,51,55 cohort, the survival rates were similar regardless of the remission status
prior to allogeneic HCT, suggesting that allogeneic HCT may be
The efficacy and safety of GDP (gemcitabine, dexamethasone, and associated with a survival benefit even in the subset of patients with
cisplatin) in relapsed/refractory ENKL was described in a retrospective chemorefractory disease at the time of transplant.108 The results from a
study (n = 41; 26 patients had relapsed/refractory disease).93 The efficacy retrospective study based on a large cohort of non Asian patients with
of brentuximab vedotin and pralatrexate in relapsed/refractory ENKL have ENKTL showed that HCT provided survival benefit for patients with
been reported only in case reports.94-96 relapsed disease and high-risk clinical features who achieved second
remission.109
Brentuximab vedotin (BV) is approved for the treatment of mycosis
fungoides/Sézary syndrome (MF/SS) and relapsed/refractory systemic These data suggest that consolidation with HCT should be considered in
anaplastic large cell lymphoma (ALCL) and it is also effective in other selected patients with relapsed ENKL. Allogeneic HCT is preferred, if a
subtypes of CD30-positive PTCL. CD30 expression in ENKL is variable, donor is available.
with 38% to 56% of Asian patients having some positivity.97,98 In clinical
studies that have evaluated BV in patients with MF, responses were Aggressive NK-Cell Leukemia
observed across all CD30 expression levels (including negligible CD30 Aggressive NK-cell leukemia (ANKL) is a rare form of large granular
expression).99,100 lymphocyte leukemia (LGLL), characterized by a systemic proliferation of
NK cells, an aggressive clinical course and poor prognosis, and with a
BV (for CD30-positive disease), pralatrexate, GDP, and other combination median survival of less than 2 months.110 ANKL predominantly occurs in
chemotherapy regimens (based on the extrapolation of their use for younger patients with a median age of 40 years. The most common signs
relapsed/refractory peripheral T-cell lymphoma [PTCL]) are included as and symptoms at presentation include fever, B-symptoms with
alternative options (other recommended regimens). Romidepsin and concomitant hemophagocytosis, hepatosplenomegaly, and
belinostat may be useful under certain circumstances. Monitoring for EBV lymphadenopathy.111 ANKL does not usually have nasal or skin
reactivation should be considered since severe EBV reactivation has been

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involvement and clinical EBV infection has been observed in a subset of the outcome of patients with ANKL and the panel favors consolidation with
patients. EBV-associated T- and NK-cell lymphoproliferative disorders allogeneic HCT (over autologous HCT) for patients in first remission.121
(LPD), including chronic active EBV infection (CAEBV), can progress to
ANKL.

EBV infection (detected by EBER-ISH) is present in the majority of cases

with ANKL.111 Similar to ENKL, measurement of EBV-DNA in peripheral
blood by quantitative PCR is useful in the diagnosis and possibly in the
monitoring of the disease. EBV-negative ANKL has also been reported,
occurring mainly in older patients.112,113

ANKL cells consistently express CD2, cytoplasmic CD3 (epsilon chain),

CD16, CD56, CD94, and cytotoxic molecules, such as granzyme B, TIA1,
and perforin A.111 Next-generation sequencing (NGS) studies have
identified TP53 mutations, mutations in epigenetic modifiers, as well as
genetic mutations involved in the JAK/STAT and RAS-MAPK signaling
pathways.114-116

The diagnosis of ANKL is most frequently confirmed by bone marrow

biopsy. Adequate immunophenotyping is essential to confirm the
diagnosis, especially to confirm the diagnosis of EBV-negative ANKL. The
main differential diagnoses include NK-large granular lymphocytic
leukemia (NK-LGLL; included as a definite entity in the 2022 WHO
classification [WHO5]), CAEBV, EBV-positive T-cell and NK-cell
lymphoproliferative diseases of childhood, ENKL, and rarely other
EBV-associated T-cell lymphomas.

Treatment with anthracycline-based regimens is typically ineffective. An

asparaginase-based or pegaspargase-based chemotherapy regimen
(recommended for ENKL) can be used for the treatment of patients with
ANKL.117-120 However, there is no established chemotherapy regimen for
the optimal treatment of ANKL. Allogeneic HCT may be helpful to improve

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T-Cell Lymphomas

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

85. Yhim HY, Kim JS, Mun YC, et al. Clinical outcomes and prognostic 92. Lim SH, Hong JY, Lim ST, et al. Beyond first-line
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91. Chan TSY, Li J, Loong F, et al. PD1 blockade with low-dose nivolumab 98. Kawamoto K, Miyoshi H, Suzuki T, et al. Frequent expression of CD30
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NCCN Guidelines Version 4.2024

T-Cell Lymphomas

99. Duvic M, Tetzlaff MT, Gangar P, et al. Results of a phase II trial of 106. Tse E, Chan TS, Koh LP, et al. Allogeneic haematopoietic SCT for
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T-Cell Lymphomas

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