Acalabrutinib Versus Ibrutinib in

original reports
Previously Treated Chronic Lymphocytic
Leukemia: Results of the First Randomized Phase
III Trial
John C. Byrd, MD1; Peter Hillmen, MD, MBChB, PhD2; Paolo Ghia, MD, PhD3,4; Arnon P. Kater, MD, PhD5; Asher Chanan-Khan, MD6;
Richard R. Furman, MD7; Susan O’Brien, MD8; Mustafa Nuri Yenerel, MD9; Arpad Illés, MD10; Neil Kay, MD11;
Jose A. Garcia-Marco, MD, PhD12; Anthony Mato, MD13; Javier Pinilla-Ibarz, MD, PhD14; John F. Seymour, PhD15;
Stephane Lepretre, MD16,17; Stephan Stilgenbauer, MD18; Tadeusz Robak, PhD19; Wayne Rothbaum, MS20; Raquel Izumi, PhD20;
Ahmed Hamdy, MD20; Priti Patel, MD21; Kara Higgins, MS21; Sophia Sohoni, MD21; and Wojciech Jurczak, MD, PhD22
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abstract

PURPOSE Among Bruton’s tyrosine kinase inhibitors, acalabrutinib has greater selectivity than ibrutinib, which we
Copyright © 2026 American Society of Clinical Oncology. All rights reserved.

hypothesized would improve continuous therapy tolerability. We conducted an open-label, randomized, non-
inferiority, phase III trial comparing acalabrutinib and ibrutinib in patients with chronic lymphocytic leukemia (CLL).
METHODS Patients with previously treated CLL with centrally confirmed del(17)(p13.1) or del(11)(q22.3) were
randomly assigned to oral acalabrutinib 100 mg twice daily or ibrutinib 420 mg once daily until progression or
unacceptable toxicity. The primary end point was independent review committee–assessed noninferiority of
progression-free survival (PFS).
RESULTS Overall, 533 patients (acalabrutinib, n 5 268; ibrutinib, n 5 265) were randomly assigned. At the data
cutoff, 124 (46.3%) acalabrutinib patients and 109 (41.1%) ibrutinib patients remained on treatment. After a
median follow-up of 40.9 months, acalabrutinib was determined to be noninferior to ibrutinib with a median PFS
of 38.4 months in both arms (95% CI acalabrutinib, 33.0 to 38.6 and ibrutinib, 33.0 to 41.6; hazard ratio: 1.00;
95% CI, 0.79 to 1.27). All-grade atrial fibrillation/atrial flutter incidence was significantly lower with acalabrutinib
versus ibrutinib (9.4% v 16.0%; P 5 .02); among other selected secondary end points, grade 3 or higher
infections (30.8% v 30.0%) and Richter transformations (3.8% v 4.9%) were comparable between groups and
median overall survival was not reached in either arm (hazard ratio, 0.82; 95% CI, 0.59 to 1.15), with 63 (23.5%)
deaths with acalabrutinib and 73 (27.5%) with ibrutinib. Treatment discontinuations because of adverse events
occurred in 14.7% of acalabrutinib-treated patients and 21.3% of ibrutinib-treated patients.
CONCLUSION In this first direct comparison of less versus more selective Bruton’s tyrosine kinase inhibitors in
CLL, acalabrutinib demonstrated noninferior PFS with fewer cardiovascular adverse events.
J Clin Oncol 39:3441-3452. © 2021 by American Society of Clinical Oncology
ASSOCIATED Creative Commons Attribution Non-Commercial No Derivatives 4.0 License
CONTENT
See accompanying INTRODUCTION A systematic review and meta-analysis of randomized
editorial on
page 3419 Bruton’s tyrosine kinase (BTK) plays a significant role ibrutinib trials demonstrated an increased risk of atrial
Data Supplement in survival, proliferation, and adhesion of malignant fibrillation and hypertension.12 In the aforementioned
Protocol B lymphocytes in chronic lymphocytic leukemia analyses of the RESONATE-2 and RESONATE trials,
Author affiliations (CLL).1-3 BTK inhibitors (BTKis) have transformed CLL atrial fibrillation rates were 16% and 11%, respec-
and support management.4-7 Ibrutinib, the first inhibitor that irre- tively, and hypertension rates were 26% and 20%,
information (if respectively.10,11 Although the cause of cardiac events
versibly binds BTK,8 is approved for the treatment of
applicable) appear
at the end of this CLL and small lymphocytic lymphoma.9 Long-term with ibrutinib is not completely understood, rodent
article. pivotal phase III trials of ibrutinib versus chemo- studies have suggested that off-target inhibition of the
Accepted on May 25, immunotherapy in previously untreated (RESONATE-2) PI3K-Akt signaling pathway (via tec protein tyrosine
2021 and published at or relapsed (RESONATE) CLL report survival benefits kinase) or C-terminal Src kinase may contribute.13,14 In
[Link]/journal/
with ibrutinib, but with toxicities leading to ibrutinib addition, ibrutinib inhibits human epidermal growth
jco on July 26, 2021:
DOI [Link] discontinuation in 28% and 12% of patients at the factor receptor 2, which is involved in cardiac myocyte
1200/JCO.21.01210 median follow-up of 60 and 44 months, respectively.10,11 homeostasis.15,16 Ibrutinib binds irreversibly to Src

Volume 39, Issue 31 3441

 Byrd et al

kinase and to several non-BTK kinases with analogous Random Assignment and Treatment
cysteine residues at low nanomolar concentrations, which is An interactive web response system randomly assigned
not seen with the BTKi acalabrutinib,17-19 likely contributing to eligible patients in a 1:1 ratio to receive oral acalabrutinib
alternative target adverse events (AEs) with ibrutinib.8,12,18,20 100 mg twice daily or ibrutinib 420 mg once daily (open-
Acalabrutinib is a next-generation, irreversible BTKi ap- label) until disease progression or unacceptable toxicity.
proved for the treatment of CLL and small lymphocytic Dose modifications were allowed for AE management (Data
lymphoma with a shorter plasma half-life and greater se- Supplement). Random assignment was stratified by
lectivity for BTK compared with ibrutinib.8,9,17,21 Acalab- del(17)(p13.1) status (yes or no), Eastern Cooperative
rutinib demonstrated superior progression-free survival Oncology Group performance status score (2 v 1 or less),
(PFS) versus chemoimmunotherapy in phase III studies in and number of prior therapies (1-3 v 4 or more). Crossover
patients with previously untreated (ELEVATE-TN) or re- between treatment groups was not permitted. An inde-
lapsed or refractory (ASCEND) CLL, with toxicity-related pendent review committee (IRC) centrally assessed pro-
treatment discontinuations in 9% and 11% of patients at gression and response data in a blinded manner. An
the median follow-up of 28.3 and 16.1 months, independent data monitoring committee periodically
respectively.6,7 Treatment discontinuations because of AEs reviewed unblinded safety and efficacy data. The study
in longer-term analyses of a phase II clinical trial of aca- team was blinded to data at the aggregate level from the
labrutinib monotherapy in previously untreated or relapsed start of the study until after the final data transfer from the
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or refractory CLL were reported in 6% and 11% of patients, IRC and finalization of the statistical analysis plan. The
respectively, at the median follow-up of 53 and 41 months, study sponsor performed aggregated analyses by treatment
Copyright © 2026 American Society of Clinical Oncology. All rights reserved.

respectively.22,23 Acalabrutinib has also demonstrated ef- group after final results were received from the IRC.
ficacy and tolerability in ibrutinib-intolerant patients with
Study End Points and Assessments
CLL.24
The primary end point was IRC-assessed PFS, defined as
This phase III trial prospectively compared the efficacy
the time from random assignment until disease progression
and safety of acalabrutinib with ibrutinib in patients with
or death from any cause. Response assessments followed
previously treated CLL to test the hypothesis that acalab-
International Workshop on CLL 2008 criteria,25 with
rutinib was noninferior to ibrutinib in PFS with improved
treatment-related lymphocytosis in the absence of other
tolerability.
signs of disease progression not considered progressive
disease (see the Data Supplement). Secondary end points
were the incidences of atrial fibrillation (any grade), in-
METHODS
fections (grade 3 or higher), and Richter transformation and
Patients overall survival (OS) (time from random assignment to any-
Eligible patients were age 18 years or older, had previously cause death). Additional end points are described in the
treated CLL, required therapy by International Workshop on Data Supplement.
CLL criteria,25 had an Eastern Cooperative Oncology Group Safety was assessed by AE, laboratory, and clinical as-
performance status of 2 or less, and had the presence of sessments across the treatment-emergent period, defined
del(17)(p13.1) and/or del(11)(q22.3) confirmed by central as the time from the first study drug dose until 30 days
laboratory testing. Patients with significant cardiovascular after the last dose or the date a patient started a new
disease, concomitant warfarin or equivalent vitamin K anticancer therapy, whichever was earlier. AE severity was
antagonist treatment, prior BTK or BCL-2 inhibitor treat- graded according to the National Cancer Institute-
ment, or requiring treatment with proton-pump inhibitors Common Terminology Criteria for Adverse Events ver-
were excluded. See the Data Supplement (online only) for sion 4.03.
additional eligibility criteria.
Statistical Analysis
Study Oversight and Conduct Sample size was calculated assuming a hazard ratio (HR)
scale margin of 1.429 (noninferiority margin of 30%) be-
This is a phase III, randomized, multicenter, open-label,
tween the acalabrutinib and ibrutinib groups for IRC-
noninferiority study ([Link] identifier: NCT02477696).
assessed median PFS, using a fixed margin method.26
The Protocol (online only) and informed consent were
Assuming an exponential distribution for PFS events,
approved by an Institutional Review Board and Indepen-
500 patients (randomly assigned 1:1 to each arm) would
dent Ethics Committee before study initiation. All patients
provide 80% power at a one-sided, 0.025 significance level
provided a signed informed consent form before enroll-
to test the primary study hypothesis that acalabrutinib is
ment. The study was conducted in accordance with the
noninferior to ibrutinib in IRC-assessed PFS.
protocol, applicable local regulations, and the Declaration
of Helsinki and International Conference on Harmonisation The primary analysis was conducted after completion of
Guidelines for Good Clinical Practices principles. enrollment and accrual of approximately 250 IRC-assessed

3442 © 2021 by American Society of Clinical Oncology Volume 39, Issue 31

 Acalabrutinib Versus Ibrutinib in Chronic Lymphocytic Leukemia

PFS events. The acalabrutinib/ibrutinib HR estimate and (acalabrutinib: 95% CI, 33.0 to 38.6; ibrutinib: 95% CI,
corresponding 95% CI for IRC-assessed PFS were com- 33.0 to 41.6; HR 1.00; 95% CI, 0.79 to 1.27; Fig 2A). IRC-
puted using a Cox proportional-hazards model stratified by assessed PFS was generally comparable across pre-
del(17)(p13.1) status (yes or no) and number of prior specified subgroups (Fig 3) including patients with
therapies (1-3 v 4 or more). All other stratified analyses del(17)(p13.1) and del(11)(q22.3) (Data Supplement) and
used the same strata as the primary analysis. regardless of the number of prior therapies. Median OS was
The primary end point, IRC-assessed PFS, was assessed not reached in either arm, with 63 (23.5%) deaths with
first for noninferiority. The gate-keeping strategy was acalabrutinib and 73 (27.5%) with ibrutinib (HR, 0.82;
implemented to control the family-wise error rate at the 0.05 95% CI, 0.59 to 1.15; Fig 2B; Data Supplement). The IRC-
level given the multiple testing approach for primary and assessed overall response rate was 81.0% (217 of 268;
secondary end points. If acalabrutinib was noninferior to 95% CI, 75.8 to 85.2) for acalabrutinib and 77.0% (204 of
ibrutinib on the primary end point (upper bound of HR two- 265; 95% CI, 71.5 to 81.6) for ibrutinib (Data Supplement).
sided 95% CI below 1.429), acalabrutinib superiority on the Investigator-assessed PFS, IRC- and investigator-assessed
secondary end points was tested at a two-sided 0.05 sig- event-free survival, and investigator-assessed overall re-
nificance level in the following prespecified order: (1) in- sponse rate were also similar between arms (Fig 2C; Data
cidence of any-grade atrial fibrillation, (2) incidence of Supplement). Subsequent anticancer therapy for CLL was
grade 3 or higher infections, (3) incidence of Richter initiated by 60 (23.3%) acalabrutinib patients and 56
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transformation, and (4) OS. If noninferiority on the primary (22.2%) ibrutinib patients (Data Supplement); median time
end point was not met or when superiority on a secondary to next treatment was similar between groups (Data
Copyright © 2026 American Society of Clinical Oncology. All rights reserved.

end point was not met, the P values for all subsequent end Supplement).
points are presented as descriptive. Additional analyses Safety
were not adjusted for multiplicity. Between-group differ- The median treatment exposure duration was
ences were assessed using two-sided Cochran-Mantel- 38.3 months (range, 0.3-55.9 months) with acalabrutinib
Haenszel tests adjusted for del(17)(p13.1) status (yes or and 35.5 months (range, 0.2-57.7 months) with ibrutinib
no) and number of prior therapies (1-3 v 4 or more) for all (Data Supplement). The most common any-grade AEs in
secondary end points except OS, which was assessed using at least 10% of patients in either arm included diarrhea,
Kaplan-Meier methods and a stratified log-rank test. Ad- headache, cough, arthralgia, contusion, atrial fibrillation,
ditional statistical methodologies are described in the Data hypertension, urinary tract infection, back pain, muscle
Supplement. spasms, and dyspepsia (Table 2; Data Supplement).
Efficacy analyses were performed for the intent to-treat Diarrhea, arthralgia, contusion, atrial fibrillation, hyper-
population (all randomly assigned patients). Safety ana- tension, back pain, muscle spasms, and dyspepsia oc-
lyses, including the safety secondary end points, were curred less frequently with acalabrutinib, whereas
performed for the safety population (all patients who re- headache and cough occurred less frequently with
ceived at least one dose of study drug). ibrutinib. Kaplan-Meier analysis showed that diarrhea and
arthralgia had lower cumulative incidences with acalab-
RESULTS rutinib versus ibrutinib over time (Data Supplement).
Grade 3 or higher AEs were observed in 68.8% (n 5 183)
From October 2015 to November 2017, 808 patients were
of patients treated with acalabrutinib and 74.9%
screened for eligibility and 533 patients were randomly
(n 5 197) treated with ibrutinib; the most common grade 3
assigned at 124 centers in 15 countries to receive aca-
or higher AEs in at least 5% of patients in either arm were
labrutinib (n 5 268) or ibrutinib (n 5 265) (Fig 1). Baseline
cytopenias, pneumonia, and hypertension (Table 2; Data
demographics and disease characteristics were balanced
Supplement). The most common serious AEs in at least
between groups (Table 1; Data Supplement). Overall, the
5% of patients in either arm (acalabrutinib v ibrutinib)
median age was 66 years (range, 28-89 years), 241
were pneumonia (n 5 27 [10.2%] and n 5 26 [9.9%]),
(45.2%) patients had del(17)(p13.1), and 342 (64.2%)
anemia (n 5 14 [5.3%] and n 5 13 [4.9%]), and atrial
had del(11)(q22.3). The median number of prior therapies
fibrillation (n 5 6 [2.3%] and n 5 14 [5.3%]; Data
was two in both arms (overall range, 1-12; Table 1; Data
Supplement). AEs led to treatment discontinuation in
Supplement).
14.7% (n 5 39) of patients treated with acalabrutinib and
Efficacy 21.3% (n 5 56) treated with ibrutinib (Data Supplement);
At the data cutoff for the final analysis (September 15, AEs leading to dose interruption or dose reduction oc-
2020), 124 (46.3%) acalabrutinib patients and 109 curred at similar frequencies in both arms (Data
(41.1%) ibrutinib patients remained on treatment. After a Supplement).
median follow-up of 40.9 months (range, 0.0-59.1), the Atrial fibrillation or atrial flutter of any grade was statistically
prespecified criterion for noninferiority was met; the significantly less frequent for acalabrutinib versus ibrutinib
median IRC-assessed PFS was 38.4 months in both arms (n 5 25 [9.4%] v n 5 42 [16.0%]; P 5 .02; Fig 4A); median

Journal of Clinical Oncology 3443

 Byrd et al

Patients assessed for eligibility

(N = 808)

Did not meet eligibility criteria (n = 275)

Did not have del(17p) or del(11q) (n = 146)
Did not meet other eligibility criteria (n = 129)

Randomly assigned patients (n = 533)

Patients with del(17p) (n = 241)
Patients with ECOG PS 2 (n = 42)
Patients with one to three previous therapies (n = 471)

Assigned to receive acalabrutinib and (n = 268) Assigned to receive ibrutinib and (n = 265)
included in the efficacy analysis included in the efficacy analysis

Assigned to receive ibrutinib and (n = 1) Assigned to receive ibrutinib and (n = 1)

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treated with acalabrutiniba treated with acalabrutinib

a
Copyright © 2026 American Society of Clinical Oncology. All rights reserved.

Did not receive study treatment (n = 3)

Randomly assigned in error (n = 2)
(did not meet eligibility criteria) Did not receive study treatment (n = 1)
Pneumonia, sepsis, and cachexia (n = 1) Withdrew consent (n = 1)
before receipt of treatment

Received treatment and included in (n = 266) Received treatment and included in (n = 263)
the safety analysis the safety analysis

Discontinued treatment (n = 142) Discontinued treatment (n = 154)

Disease progression (n = 82) Disease progression (n = 68)
Adverse events (n = 40) Adverse events (n = 59)
Withdrew consent (n = 7) Withdrew consent (n = 7)
Removed per investigator decision (n = 5) Died (n = 6)
Died (n = 5) Removed per investigator decision (n = 5)
Otherb (n = 3) Otherc (n = 9)

Received acalabrutinib at data cutoff (n = 124) Received ibrutinib at data cutoff (n = 109)

FIG 1. CONSORT diagram. aOne patient who was randomly assigned to the ibrutinib treatment arm received
acalabrutinib and ibrutinib during the study and was included in the acalabrutinib safety population. bIncludes
patients who discontinued treatment because of relocation (n 5 1), medical monitor decision (n 5 1), and starting
therapy with ibrutinib (n 5 1) but agreed to remain on study for follow-up. cIncludes patients who discontinued
treatment because of noncompliance (n 5 2), withdrawal of consent for treatment or follow-up (n 5 1), refusal of
medication (n 5 1), relocation (n 5 2), medical monitor decision (n 5 1), early termination because of second
primary malignancy (n 5 1), and IRC- and medical monitor– or sponsor-confirmed progressive disease (n 5 1) but
agreed to remain on study for follow-up. ECOG PS, Eastern Cooperative Oncology Group performance status; IRC,
Independent Review Committee.

time to any-grade (28.8 v 16.0 months) and grade 3 or (14.9%) patients had atrial fibrillation or flutter events with
higher (22.3 v 4.8 months) atrial fibrillation or atrial flutter acalabrutinib or ibrutinib, respectively (Fig 4A). No atrial
events was longer for acalabrutinib. Among acalabrutinib fibrillation events led to treatment discontinuation with
and ibrutinib patients with atrial fibrillation or flutter, eight acalabrutinib versus seven (2.7%) with ibrutinib. Total
(32.0%) and 11 (26.2%) were 75 years or older, respec- cardiac events (acalabrutinib: n 5 64 [24.1%] v ibrutinib:
tively, 10 (40.0%) and five (11.9%) had a history of atrial n 5 79 [30.0%]; Fig 4A; Data Supplement) and hyper-
fibrillation, and 15 (60.0%) and 23 (54.8%) had a history of tension (n 5 25 [9.4%] v n 5 61 [23.2%], respectively)
hypertension. Among patients without a prior history of occurred more frequently with ibrutinib (Fig 4A); grade 3 or
atrial fibrillation or flutter, 15 of 243 (6.2%) and 37 of 249 higher hypertension incidence was higher with ibrutinib

3444 © 2021 by American Society of Clinical Oncology Volume 39, Issue 31

 Acalabrutinib Versus Ibrutinib in Chronic Lymphocytic Leukemia

TABLE 1. Baseline Characteristics

Characteristic Acalabrutinib (n 5 268) Ibrutinib (n 5 265)
Age, years
Median (range) 66 (41-89) 65 (28-88)
75 or older 44 (16.4) 43 (16.2)
Male 185 (69.0) 194 (73.2)
ECOG PS score
0-1 247 (92.2) 243 (91.7)
2 20 (7.5) 22 (8.3)
Bulky disease of at least 5 cm 128 (47.8) 136 (51.3)
Rai stage 3 or 4 131 (48.9) 134 (50.6)
Cytogenetic subgroup
Chromosome 17p13.1 deletion 121 (45.1) 120 (45.3)
Chromosome 11q22.3 deletion 167 (62.3) 175 (66.0)
Complex karyotypea 124 (46.3) 125 (47.2)
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TP53 mutational status

Copyright © 2026 American Society of Clinical Oncology. All rights reserved.

Mutated 100 (37.3) 112 (42.3)

Unmutated 167 (62.3) 153 (57.7)
IGHV mutational status
Mutated 44 (16.4) 28 (10.6)
Unmutated 220 (82.1) 237 (89.4)
Cytopenia at baseline
Hemoglobin # 11.0 g/dL 100 (37.3) 96 (36.2)
Platelet count # 100 3 109/L 96 (35.8) 92 (34.7)
Absolute neutrophil count # 1.5 3 10 /L
9
25 (9.3) 18 (6.8)
No. of prior therapies
Median (range) 2 (1-9) 2 (1-12)
1-3 234 (87.3) 237 (89.4)
4 or more 33 (12.3) 28 (10.6)
b
Most common previous therapies
Alkylators 242 (90.3) 240 (90.6)
Anti-CD20 monoclonal antibodies 227 (84.7) 229 (86.4)
Purine analog 172 (64.2) 158 (59.6)
Steroids 62 (23.1) 62 (23.4)
Chemotherapyc 39 (14.6) 37 (14.0)
Alemtuzumab 16 (6.0) 11 (4.2)
Lenalidomide (monotherapy and in combination) 5 (1.9) 13 (4.9)

NOTE. Data are No. (%) unless otherwise specified.

Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; IGHV, immunoglobulin heavy chain variable region; TP53, tumor
protein p53.
a
Patients with three or more chromosomal abnormalities and one or more structural abnormalities.
b
A patient was only counted once for each category.
c
Includes doxorubicin, bleomycin, vinca/alkaloids, etoposide, and platinum-based regimens.

versus acalabrutinib (n 5 24 [9.1%] v n 5 11 [4.1%], respectively. Kaplan-Meier analyses of cumulative inci-

respectively). Exposure-adjusted frequencies of any-grade dence revealed HRs of 0.52 (95% CI, 0.32 to 0.86)
atrial fibrillation or atrial flutter and hypertension were and 0.34 (95% CI, 0.21 to 0.54) favoring acalabrutinib for
approximately two-fold and three-fold higher with ibrutinib, atrial fibrillation or atrial flutter (Fig 4B) and hypertension

Journal of Clinical Oncology 3445

 Byrd et al

A B
100 100

80 80
PFS (%)

OS (%)
60 60

40 40

Events, No. (%) Median (95% CI) HR (95% CI) Events, No. (%) Median (95% CI) HR (95% CI)
20 20
Acalabrutinib 143 (53.4) 38.4 (33.0 to 38.6) 1.00 (0.79 to 1.27) Acalabrutinib 63 (23.5) NE (NE to NE) 0.82 (0.59 to 1.15)
Ibrutinib 136 (51.3) 38.4 (33.0 to 41.6) Ibrutinib 73 (27.5) NE (NE to NE)

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60

Time (months) Time (months)

No. at risk: No. at risk:
Acalabrutinib 268 250 235 227 219 207 200 193 173 163 148 110 84 59 31 21 13 3 1 0 Acalabrutinib 268 259 247 242 236 231 223 218 210 207 201 196 183 155 127 95 59 32 18 4 0
Ibrutinib 265 240 221 205 186 178 168 160 148 142 130 108 81 66 41 26 15 8 2 0 Ibrutinib 265 252 241 233 227 220 212 205 203 194 191 186 173 143 121 88 60 28 15 2 0

C
100
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80
Copyright © 2026 American Society of Clinical Oncology. All rights reserved.

EFS (%)

60

40

Events, No. (%) Median (95% CI)

20
Acalabrutinib 163 (60.8) 33.2 (32.8 to 38.4)
Ibrutinib 160 (60.4) 33.0 (27.4 to 38.3)

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57

Time (months)
No. at risk:
Acalabrutinib 268 251 235 228 220 209 199 191 172 162 147 110 85 61 34 23 15 3 1 0
Ibrutinib 265 241 222 205 188 177 167 160 150 142 129 105 79 63 40 25 14 7 2 0

FIG 2. PFS, OS, and EFS. (A) Kaplan-Meier curve of IRC-assessed PFS (primary end point). (B) Kaplan-Meier curve of OS (secondary end point). (C)
Kaplan-Meier curve of IRC EFS. The Kaplan-Meier curves for IRC-assessed PFS cross at 33 months, indicating a violation of the proportional hazards
assumption. A sensitivity analysis on the basis of RMST, which is valid under nonproportional hazards, confirmed that acalabrutinib was noninferior to
ibrutinib, with a difference in RMST (acalabrutinib-ibrutinib) of 1.1 month (95% CI: 22.17 to 4.36) over 55 months. The lower bound of the 95% CI was
compared with an RMST noninferiority margin of 25.83 months, derived from the HR noninferiority margin of 1.429. For the PFS analysis, three ibrutinib-
treated patients were censored because of PD or death immediately after missing two or more consecutive visits, and seven acalabrutinib and eight
ibrutinib patients were censored at random assignment because of no baseline assessment and/or no adequate postbaseline assessment. EFS, event-free
survival; HR, hazard ratio; IRC, Independent Review Committee; NE, not estimable; OS, overall survival; PD, progressive disease; PFS, progression-free
survival; RMST, restricted mean survival time.

(Fig 4C), respectively. The cumulative incidences of total cumulative incidences of any-grade and grade 3 or higher
cardiac events also trended toward acalabrutinib (HR, infections are shown by arm in the Data Supplement.
0.72; 95% CI, 0.52 to 1.0; Data Supplement). Any-grade Fungal opportunistic infection occurred in 10 (3.8%)
cardiac events led to treatment discontinuation in two acalabrutinib patients, including five with pneumocystis
(0.8%) acalabrutinib-treated patients compared with 11 jirovecii pneumonia and five with Aspergillus infections,
(4.2%) ibrutinib-treated patients (Data Supplement). No and five (1.9%) ibrutinib patients, including two with As-
ventricular tachyarrhythmia events occurred with acalab- pergillus infections.
rutinib; one ibrutinib patient experienced grade 4 ven- Richter transformation, most commonly manifested as
tricular fibrillation. One case of sudden cardiac death was diffuse large B-cell lymphoma, occurred in 10 (3.8%)
reported with ibrutinib in a 55-year-old male with no prior acalabrutinib and 13 (4.9%) ibrutinib patients; the median
cardiac history after approximately 8 months on treatment. time to onset was 7.1 months (range, 2.0-44.7 months) and
Rates of grade 3 or higher infections were comparable with 11.5 months (range, 2.2-43.6 months), respectively (Data
acalabrutinib (n 5 82 [30.8%]) and ibrutinib (n 5 79 Supplement). Six patients who developed Richter trans-
formation in each arm had del(17)(p13.1).
[30.0%]) (Data Supplement); the most common grade 3 or
higher infections in at least 2% of patients in either arm Bleeding events were less frequent with acalabrutinib
were pneumonia, sepsis, and urinary tract infection. The (n 5 101 [38.0%]) versus ibrutinib (n 5 135 [51.3%]; Data

3446 © 2021 by American Society of Clinical Oncology Volume 39, Issue 31

 Acalabrutinib Versus Ibrutinib in Chronic Lymphocytic Leukemia

No. of Events/Patients
Subgroup Analysis Acalabrutinib Ibrutinib HR (95% CI)

Age group, years

< 65 77/124 66/122 1.09 (0.79 to 1.52)
≥ 65 to < 75 46/100 49/100 0.98 (0.66 to 1.47)
≥ 75 20/44 21/43 0.69 (0.37 to 1.28)

Sex
Male 105/185 101/194 1.06 (0.81 to 1.40)
Female 38/83 35/71 0.88 (0.56 to 1.40)

ECOG at random assignmenta

0, 1 128/248 119/244 1.03 (0.80 to 1.33)
2 15/20 17/21 0.64 (0.32 to 1.29)

Rai stage at screening

0-II 65/130 58/124 1.12 (0.79 to 1.61)
III-IV 77/131 74/134 0.93 (0.67 to 1.28)

Bulky disease, cm
<5 66/138 66/127 0.79 (0.56 to 1.11)
≥5 77/128 70/136 1.25 (0.90 to 1.74)

No. of prior therapiesa

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1-3 122/239 117/238 0.99 (0.77 to 1.27)

≥4 21/29 19/27 1.07 (0.57 to 2.02)
Copyright © 2026 American Society of Clinical Oncology. All rights reserved.

Presence of del(17)(p13.1)a
Yes 76/124 72/121 1.00 (0.73 to 1.38)
No 67/144 64/144 1.00 (0.71 to 1.41)

Presence of del(11)(q22.3)
Yes 85/167 79/175 1.08 (0.80 to 1.47)
No 58/100 57/90 0.86 (0.59 to 1.24)

TP53 mutation
Yes 64/100 73/112 0.95 (0.68 to 1.33)
No 79/167 63/153 1.11 (0.80 to 1.55)

IGHV
Mutated 13/44 13/28 0.60 (0.28 to 1.31)
Unmutated 130/220 123/237 1.09 (0.85 to 1.40)

Complex karyotype
Yes 74/124 66/125 1.04 (0.74 to 1.44)
No 52/116 56/116 0.92 (0.63 to 1.35)

0.05 0.1 0.5 1 5

Favor Favor
Acalabrutinib Ibrutinib

FIG 3. Prespecified subgroup analysis of IRC-assessed PFS. aPer interactive voice-web response system record. ECOG, Eastern Cooperative Oncology
Group; HR, hazard ratio; IGHV, immunoglobulin heavy chain variable region; IRC, Independent Review Committee; PFS, progression-free survival.

Supplement). Rates of major bleeding events were com- BTKi, demonstrated similar efficacy versus ibrutinib on the
parable (acalabrutinib: n 5 12 [4.5%]; ibrutinib: n 5 14 primary end point of IRC-assessed PFS. Concomitantly,
[5.3%]; Data Supplement). Second primary malignancies lower frequencies of common AEs (such as diarrhea, ar-
excluding nonmelanoma skin cancers occurred in 24 thralgia, contusion, back pain, muscle spasms, and dys-
(9.0%) and 20 (7.6%) acalabrutinib and ibrutinib patients, pepsia) and overall cardiac events, including hypertension
respectively (Data Supplement); incidences of all second and significant decreases in atrial fibrillation, were observed
primary malignancies are shown in the Data Supplement. with acalabrutinib. There was increased treatment expo-
Deaths because of AEs within the treatment-emergent sure to acalabrutinib with fewer serious AEs. Other events
period were reported in 17 (6.4%) acalabrutinib and 25 typically associated with CLL natural history, such as
(9.5%) ibrutinib patients (Data Supplement). Richter transformation and noncutaneous malignancies,
were similar between arms. Collectively, this study met the
DISCUSSION primary end point of noninferiority and demonstrated that
Herein, we describe the first randomized, phase III trial acalabrutinib has similar efficacy to ibrutinib but is gen-
comparing ibrutinib with acalabrutinib in patients with erally better tolerated in patients with higher-risk relapsed
relapsed CLL. In this study, acalabrutinib, a more selective or refractory CLL.

Journal of Clinical Oncology 3447

 Byrd et al

TABLE 2. Most Common AEs Occurring in $ 10% (any grade) or $ 5% (grade 3 or comorbidities.27 The cumulative risk of developing atrial fi-
higher) of Patients in Either Treatment Arm brillation has emerged as an important issue in patients
Acalabrutinib Ibrutinib treated with ibrutinib indefinitely.28,29 A retrospective cohort
(n 5 266) (n 5 263)
study of patients with CLL found atrial fibrillation to be the
Event Any Grade Grade ‡ 3 Any Grade Grade ‡ 3 most common toxicity to cause ibrutinib discontinuation.30
Diarrhea a,b
92 (34.6) 3 (1.1) 121 (46.0) 13 (4.9) Atrial fibrillation is associated with an increased risk of all-
a,b
cause and cardiovascular mortality, including stroke and
Headache 92 (34.6) 4 (1.5) 53 (20.2) 0
other cardiac complications.31 The management of atrial
Cougha 77 (28.9) 2 (0.8) 56 (21.3) 1 (0.4) fibrillation is challenging because of increased bleeding risks
Upper respiratory tract 71 (26.7) 5 (1.9) 65 (24.7) 1 (0.4) with prophylactic anticoagulation medication given con-
infection comitantly with BTKis and drug-drug interaction potential
Pyrexia 62 (23.3) 8 (3.0) 50 (19.0) 2 (0.8) with anticoagulants.9,21,32 In this study, there was a signifi-
Anemia 58 (21.8) 31 (11.7) 49 (18.6) 34 (12.9) cantly lower incidence of atrial fibrillation (9.4% v 16.0% with
Neutropenia 56 (21.1) 52 (19.5) 65 (24.7) 60 (22.8) ibrutinib; P 5 .02) and a 48% lower cumulative atrial fi-
brillation risk with acalabrutinib. Clinical studies have sug-
Fatigueb 54 (20.3) 9 (3.4) 44 (16.7) 0
gested that different covalent BTKis have comparable activity
a
Arthralgia 42 (15.8) 0 60 (22.8) 2 (0.8)
but variable AE profiles,6,7,10,11,33 which may relate to the
Downloaded from [Link] by [Link] on April 23, 2026 from [Link]

a,b
Hypertension 23 (8.6) 11 (4.1) 60 (22.8) 23 (8.7) degree of BTK selectivity. This was most recently demon-
Nausea 47 (17.7) 0 49 (18.6) 1 (0.4) strated by data from a phase III study of zanubrutinib
Copyright © 2026 American Society of Clinical Oncology. All rights reserved.

Pneumonia 47 (17.7) 28 (10.5) 43 (16.3) 23 (8.7) compared with ibrutinib in patients with Waldenstrom’s
macroglobulinemia, where despite a short study follow-up,
Thrombocytopenia 40 (15.0) 26 (9.8) 35 (13.3) 18 (6.8)
the findings also support a reduced incidence of atrial fi-
Dyspnea 37 (13.9) 6 (2.3) 23 (8.7) 1 (0.4)
brillation with more selective BTK inhibition.33 Hypertension
Bronchitis 34 (12.8) 3 (1.1) 23 (8.7) 2 (0.8) events were also less frequent with acalabrutinib versus
Constipation 31 (11.7) 0 37 (14.1) 2 (0.8) ibrutinib (9.4% v 23.2%). Hypertension with ibrutinib has
Contusiona 31 (11.7) 0 48 (18.3) 1 (0.4) been previously associated with morbidity and mortality.34
Nasopharyngitis 29 (10.9) 0 27 (10.3) 0
Additionally, treatment discontinuation because of cardiac
events was more than five-fold higher with ibrutinib com-
Dizziness 28 (10.5) 0 26 (9.9) 0
pared with acalabrutinib. Moreover, de novo atrial fibrillation
Vomiting 28 (10.5) 1 (0.4) 36 (13.7) 3 (1.1) or flutter cases were 2.4 times higher with ibrutinib com-
Peripheral edema 26 (9.8) 0 38 (14.4) 1 (0.4) pared with acalabrutinib, and median time to onset for atrial
Rash 26 (9.8) 2 (0.8) 33 (12.5) 0 fibrillation or flutter was longer with acalabrutinib versus
Myalgia 25 (9.4) 2 (0.8) 27 (10.3) 1 (0.4)
ibrutinib. Overall, discontinuations because of AEs were
numerically lower with acalabrutinib (14.7%) compared with
Atrial fibrillationa 24 (9.0) 12 (4.5) 41 (15.6) 9 (3.4)
ibrutinib (21.3%). Of note, the incidence of grade $ 3 AEs,
a
Urinary tract infection 22 (8.3) 3 (1.1) 36 (13.7) 6 (2.3) leading to discontinuation, was similar in both treatment
Back pain a
20 (7.5) 0 34 (12.9) 2 (0.8) arms. These findings underscore the substantial impact that
Epistaxis 19 (7.1) 1 (0.4) 28 (10.6) 1 (0.4) lower-severity AEs, such as atrial fibrillation, can have on
Muscle spasmsa 16 (6.0) 0 35 (13.3) 2 (0.8) patients receiving chronic therapies. In the present study,
survival outcomes were not analyzed by cause of treatment
Dyspepsiaa 10 (3.8) 0 32 (12.2) 0
discontinuation to determine if differences in treatment
NOTE. Data are reported as No. (%). AEs are reported as individual MedDRA discontinuations because of AEs would affect survival.
preferred terms. Higher incidences are shown in bold text for terms with statistical
Other study limitations include the use of an open-label
differences.
versus blinded study design that enabled patients and
Abbreviations: AEs, adverse events; MedDRA, Medical Dictionary for Regulatory
Activities. treating physicians to know which treatment each patient
a
Descriptive two-sided P , .05 on the basis of Barnard’s exact test without received. However, the impact on treatment discontinua-
multiplicity adjustment for all-grade AEs. tion was minimized as both drugs belong to the same class
b
Descriptive two-sided P , .05 on the basis of Barnard’s exact test without and crossover between groups was not allowed. In addition,
multiplicity adjustment for grade 3 or higher AEs. the IRC was blinded to treatment assignment, which should
facilitate unbiased assessments; assessments of quantifi-
ably observed toxicities such as atrial fibrillation and hy-
There has been a paradigm shift in relapsed or refractory
pertension should be relatively independent of bias.
CLL management with ibrutinib therapy; however, treat-
ment until disease progression makes tolerability and long- This study was performed in patients with relapsed CLL with
term safety crucial components of therapy, especially in del(17)(p13.1) or del(11)(q22.3), which are considered
CLL, which tends to affect an older population with high-risk prognostic factors per National Comprehensive

3448 © 2021 by American Society of Clinical Oncology Volume 39, Issue 31

 Acalabrutinib Versus Ibrutinib in Chronic Lymphocytic Leukemia

A
Acalabrutinib Ibrutinib
(n = 266) (n = 263)

Events Any Grade Grade t3 Any Grade Grade t3

Hypertension eventsa 25 (9.4) 11 (4.1) 61 (23.2) 24 (9.1)
Events/100 person-months 0.444 0.133 1.243 0.435
Patients with a history of hypertension 16 (64.0) 9 (81.8) 30 (49.2) 16 (66.7)
Cardiac events 64 (24.1) 23 (8.6) 79 (30.0) 25 (9.5)
Ventricular arrhythmia or cardiac arrest 1 (0.4) 1 (0.4) 5 (1.9) 3 (1.1)
Cardiorespiratory arrest 1 (0.4) 1 (0.4) 0 0
Cardiac arrest 0 0 2 (0.8) 2 (0.8)
Ventricular arrhythmia 0 0 1 (0.4) 0
Ventricular extrasystoles 0 0 1 (0.4) 0
Ventricular fibrillation 0 0 1 (0.4) 1 (0.4)
Downloaded from [Link] by [Link] on April 23, 2026 from [Link]

Atrial fibrillationb 25 (9.4)c 13 (4.9) 42 (16.0) 10 (3.8)

Events/100 person-months 0.366 0.155 0.721 0.124
Copyright © 2026 American Society of Clinical Oncology. All rights reserved.

Age 75 years or older 8 (32.0) 6 (46.2) 11 (26.2) 4 (40.0)

Patients with a history of atrial fibrillation 10 (40.0) 6 (46.2) 5 (11.9) 2 (20.0)

Patients with risk factorsd 23 (92.0) 12 (92.3) 32 (76.2) 8 (80.0)
Hypertension 15 (60.0) 6 (46.2) 23 (54.8) 6 (60.0)
Diabetes mellituse 10 (40.0) 5 (38.5) 4 (9.5) 2 (20.0)
Myocardial infarction/ischemia 3 (12.0) 3 (23.1) 4 (9.5) 0
Cardiac diseasef 2 (8.0) 2 (15.4) 5 (11.9) 2 (20.0)
Time to atrial fibrillation onset, median
(range), months 28.8 (0.4-52.0) 22.3 (0.4-45.1) 16.0 (0.5-48.3) 4.8 (0.5-28.2)

Treatment discontinuations because of atrial

fibrillation 0 0 7 (16.7) 2 (20.0)

Interventional procedures for atrial fibrillation 4 (16.0) 3 (23.1) 6 (14.3) 1 (10.0)

Cardioversion 4 (16.0) 2 (15.4) 5 (11.9) 1 (10.0)
Cardiac pacemaker insertion 1 (4.0) 1 (7.8) 0 0
Cardiac ablation 0 0 1 (2.4) 0

Implantable defibrillator insertion 0 0 1 (2.4) 0

Atrial fibrillation or flutter incidence in patient

subgroups

Age 75 years or older 8 of 44 (18.2) 6 of 44 (13.6) 11 of 42 (26.2) 4 of 42 (9.5)

Without previous history of atrial
fibrillation or flutter 15 of 243 (6.2) 7 of 243 (2.9) 37 of 249 (14.9) 8 of 249 (3.2)

Without risk factorsd 2 of 99 (2.0) 1 of 99 (1.0) 10 of 99 (10.1) 2 of 99 (2.0)

FIG 4. (A) Summary of hypertension and selected cardiac events and cumulative incidence of (B) atrial fibrillation and (C) hypertension. NOTE. Data are
reported as no. (%) unless otherwise specified; within each event type (hypertension, cardiac events, and atrial fibrillation), percentages are based on the
number of patients with the event. aIncludes events with the preferred terms of hypertension, blood pressure increased, and blood pressure systolic
increased; two-sided P value on the basis of Barnard’s exact test without multiplicity adjustment, P , .001 (any-grade) and P 5 .0214 (grade 3 or higher).
b
Includes events with the preferred terms of atrial fibrillation and atrial flutter (a patient was only counted once if he or she experienced both types of
events); atrial flutter was reported in one patient in the acalabrutinib arm and two patients in the ibrutinib arm (one of the two ibrutinib patients also had an
atrial fibrillation event and was counted only once for the combined atrial fibrillation or flutter term). cPart of the multiple testing procedure; difference in
any-grade incidence rates was 26.6% (95% CI: 212.2 to 20.9), P 5 .02. dRisk factors for atrial fibrillation were based on medical review. eIncludes
patients with a history of diabetes mellitus or type 2 diabetes mellitus. fIncludes patients with a history of coronary artery bypass, coronary artery disease,
cardiomyopathy, cardiac failure chronic, or cardiac failure congestive. HR, hazard ratio.

Journal of Clinical Oncology 3449

 Byrd et al

B C
100 Acalabrutinib:Ibrutinib Acalabrutinib
100 Acalabrutinib:Ibrutinib Acalabrutinib

Cumulative Event Rate (%)

Cumulative Event Rate (%)
HR (95% CI): 0.52 (0.32 to 0.86) HR (95% CI): 0.34 (0.21 to 0.54)
Ibrutinib Ibrutinib

80 80

60 60

40 40

20 20

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60

Time (months) Time (months)

No. at risk: No. at risk:
Acalabrutinib 266 255 240 231 228 218 206 197 188 183 172 167 142 115 89 58 35 19 8 0 Acalabrutinib 266 246 229 220 216 205 193 184 176 169 157 153 136 114 89 60 34 17 5 0 0
Ibrutinib 263 241 224 208 199 185 176 166 156 143 136 128 117 96 73 56 36 18 8 0 Ibrutinib 263 230 203 183 170 153 141 130 120 111 104 98 85 69 48 40 27 15 7 1 0

FIG 4. (Continued).
Downloaded from [Link] by [Link] on April 23, 2026 from [Link]

Cancer Network guidelines,35 although the value of patients, particularly in those with pre-existing cardiovas-
Copyright © 2026 American Society of Clinical Oncology. All rights reserved.

del(11)(q22.3) as a prognostic factor is questionable with cular complications.

BTKi therapies.36 However, these findings are potentially In summary, in this first directly comparative phase III trial of
even more relevant to individuals earlier in the disease ibrutinib with acalabrutinib in CLL, acalabrutinib is non-
course. Patients with previously untreated disease have inferior in PFS and provides improved safety with fewer atrial
longer expected survival times37 and therefore potentially fibrillation events and discontinuations because of AEs
longer time on BTKi therapy. The improved tolerability of versus ibrutinib. These clinical trial findings demonstrate that
acalabrutinib suggests that it would be an equally effective acalabrutinib is better tolerated and has similar efficacy to
yet safer initial treatment than ibrutinib in treatment-naive ibrutinib in previously treated patients with CLL.

AFFILIATIONS CORRESPONDING AUTHOR

1
The Ohio State University Comprehensive Cancer Center, Columbus, OH John C. Byrd, MD, The Ohio State University Comprehensive Cancer
2
St James’s University Hospital, Leeds, UK Center, 455B OSUCCC 410 West 12th Ave, Columbus, OH 43210;
3
Università Vita-Salute San Raffaele, Milano, Italy e-mail: [Link]@[Link].
4
IRCCS Ospedale San Raffaele, Milano, Italy
5
Amsterdam University Medical Centers, University of Amsterdam,
PRIOR PRESENTATION
on behalf of Hovon, Amsterdam, the Netherlands
6 Presented in part at the American Society of Clinical Oncology (ASCO)
Mayo Clinic Jacksonville, Jacksonville, FL
7 Virtual Annual Meeting, June 4-8, 2021; European Hematology
Weill Cornell Medicine, New York Presbyterian Hospital, New York, NY
8 Association (EHA) 2021 Virtual Congress, June 9-17, 2021; and the
Chao Family Comprehensive Cancer Center, University of California-
International Conference on Machine Learning (ICML) Virtual Meeting,
Irvine, Irvine, CA
9 July 18-24, 2021.
Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
10
University of Debrecen, Debrecen, Hungary
11
Mayo Clinic Rochester, Rochester, MN SUPPORT
12
Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain Supported by the National Cancer Institute R35 CA197734, Four Winds
13
University of Pennsylvania, Philadelphia, PA Foundation, Sullivan CLL Foundation, and the D. Warren Brown
14
Moffitt Cancer Center, Tampa, FL Foundation.
15
Peter MacCallum Cancer Centre, Royal Melbourne Hospital and
University of Melbourne, Melbourne, Victoria, Australia
16
CLINICAL TRIAL INFORMATION
Centre Henri Becquerel, Rouen, France
17 NCT02477696
Normandie University UNIROUEN, Rouen, France
18
Internal Medicine III, University of Ulm, Ulm, Germany
19
Medical University of Lodz, Lodz, Poland AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF
20
Acerta, South San Francisco, CA INTEREST
21
AstraZeneca, South San Francisco, CA Disclosures provided by the authors are available with this article at DOI
22
Maria Sklodowska-Curie National Research Institute of Oncology, [Link]
Krakow, Poland

3450 © 2021 by American Society of Clinical Oncology Volume 39, Issue 31

 Acalabrutinib Versus Ibrutinib in Chronic Lymphocytic Leukemia

AUTHOR CONTRIBUTIONS Neil Kay, Jose A. Garcia-Marco, Anthony Mato, Javier Pinilla-Ibarz, John
Conception and design: John C. Byrd, Peter Hillmen, Paolo Ghia, Arnon P. F. Seymour, Stephan Stilgenbauer, Tadeusz Robak, Priti Patel, Kara
Kater, Susan O’Brien, Tadeusz Robak, Wayne Rothbaum, Raquel Izumi, Higgins, Sophia Sohoni, Wojciech Jurczak
Ahmed Hamdy, Sophia Sohoni, Wojciech Jurczak Manuscript writing: All authors
Administrative support: Ahmed Hamdy Final approval of manuscript: All authors
Provision of study materials or patients: John C. Byrd, Peter Hillmen, Paolo Accountable for all aspects of the work: All authors
Ghia, Arnon P. Kater, Asher Chanan-Khan, Arpad Illés, Jose A. Garcia-
Marco, John F. Seymour, Stephane Lepretre, Stephan Stilgenbauer, ACKNOWLEDGMENT
Tadeusz Robak The authors would like to thank the investigators and coordinators at each
Collection and assembly of data: John C. Byrd, Peter Hillmen, Paolo Ghia, of the clinical sites and the patients who participated in this trial and their
Arnon P. Kater, Asher Chanan-Khan, Susan O’Brien, Mustafa Nuri families. Medical writing assistance, funded by AstraZeneca, was
Yenerel, Arpad Illés, Jose A. Garcia-Marco, Anthony Mato, Javier Pinilla- provided by Allison Green, PhD, and Cindy Gobbel, PhD, of Peloton
Ibarz, John F. Seymour, Stephane Lepretre, Stephan Stilgenbauer, Advantage, LLC, an OPEN Health Company.
Tadeusz Robak, Raquel Izumi, Priti Patel, Sophia Sohoni, Wojciech
Jurczak
Data analysis and interpretation: John C. Byrd, Peter Hillmen, Paolo Ghia,
Arnon P. Kater, Asher Chanan-Khan, Richard R. Furman, Susan O’Brien,

REFERENCES
Downloaded from [Link] by [Link] on April 23, 2026 from [Link]

1. Wen T, Wang J, Shi Y, et al: Inhibitors targeting Bruton’s tyrosine kinase in cancers: Drug development advances. Leukemia 35:312-332, 2021
2. Kil LP, de Bruijn MJ, van Hulst JA, et al: Bruton’s tyrosine kinase mediated signaling enhances leukemogenesis in a mouse model for chronic lymphocytic
Copyright © 2026 American Society of Clinical Oncology. All rights reserved.

leukemia. Am J Blood Res 3:71-83, 2013

3. de Rooij MF, Kuil A, Geest CR, et al: The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in
chronic lymphocytic leukemia. Blood 119:2590-2594, 2012
4. Burger JA, Tedeschi A, Barr PM, et al: Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med 373:2425-2437, 2015
5. Byrd JC, Brown JR, O’Brien S, et al: Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 371:213-223, 2014
6. Ghia P, Pluta A, Wach M, et al: ASCEND: Phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed
or refractory chronic lymphocytic leukemia. J Clin Oncol 38:2849-2861, 2020
7. Sharman JP, Egyed M, Jurczak W, et al: Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic
lymphocytic leukaemia (ELEVATE TN): A randomised, controlled, phase 3 trial. Lancet 395:1278-1291, 2020
8. Barf T, Covey T, Izumi R, et al: Acalabrutinib (ACP-196): A covalent Bruton tyrosine kinase inhibitor with a differentiated selectivity and in vivo potency profile.
J Pharmacol Exp Ther 363:240-252, 2017
9. Imbruvica [package insert]. Sunnyvale, CA; Horsham, PA, Pharmacyclics; Janssen Biotech, 2020
10. Byrd JC, Hillmen P, O’Brien S, et al: Long-term follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab. Blood 133:2031-2042, 2019
11. Burger JA, Barr PM, Robak T, et al: Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3
RESONATE-2 study. Leukemia 34:787-798, 2020
12. Caldeira D, Alves D, Costa J, et al: Ibrutinib increases the risk of hypertension and atrial fibrillation: Systematic review and meta-analysis. PLoS One 14:
e0211228, 2019
13. McMullen JR, Boey EJ, Ooi JY, et al: Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signaling. Blood 124:
3829-3830, 2014
14. Xiao L, Salem JE, Clauss S, et al: Ibrutinib-mediated atrial fibrillation attributable to inhibition of C-terminal Src kinase. Circulation 142:2443-2455, 2020
15. Salem JE, Manouchehri A, Bretagne M, et al: Cardiovascular toxicities associated with ibrutinib. J Am Coll Cardiol 74:1667-1678, 2019
16. Chen J, Kinoshita T, Sukbuntherng J, et al: Ibrutinib inhibits ERBB receptor tyrosine kinases and HER2-amplified breast cancer cell growth. Mol Cancer Ther
15:2835-2844, 2016
17. Byrd JC, Harrington B, O’Brien S, et al: Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med 374:323-332, 2016
18. Bond DA, Woyach JA: Targeting BTK in CLL: Beyond ibrutinib. Curr Hematol Malig Rep 14:197-205, 2019
19. Patel V, Balakrishnan K, Bibikova E, et al: Comparison of acalabrutinib, a selective Bruton tyrosine kinase inhibitor, with ibrutinib in chronic lymphocytic
leukemia cells. Clin Cancer Res 23:3734-3743, 2017
20. Caron F, Leong DP, Hillis C, et al: Current understanding of bleeding with ibrutinib use: A systematic review and meta-analysis. Blood Adv 1:772-778, 2017
21. Calquence [package insert]. Wilmington, DE, AstraZeneca Pharmaceuticals, 2019
22. Byrd JC, Woyach JA, Furman RR, et al: Acalabrutinib in treatment-naı̈ve chronic lymphocytic leukemia. Blood 137:3327-3328, 2021
23. Byrd JC, Wierda WG, Schuh A, et al: Acalabrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia: Updated phase 2 results.
Blood 135:1204-1213, 2020
24. Awan FT, Schuh A, Brown JR, et al: Acalabrutinib monotherapy in patients with chronic lymphocytic leukemia who are intolerant to ibrutinib. Blood Adv 3:
1553-1562, 2019
25. Hallek M, Cheson BD, Catovsky D, et al: Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: A report from the International Workshop
on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 111:5446-5456, 2008
26. Non-inferiority Clinical Trials to Establish Effectiveness. Guidance for Industry. Silver Spring, MD, US Department of Health and Human Services; Food and Drug
Administration, 2016
27. Eichhorst B, Goede V, Hallek M: Treatment of elderly patients with chronic lymphocytic leukemia. Leuk Lymphoma 50:171-178, 2009
28. Brown JR, Moslehi J, O’Brien S, et al: Characterization of atrial fibrillation adverse events reported in ibrutinib randomized controlled registration trials.
Haematologica 102:1796-1805, 2017
29. Wiczer TE, Levine LB, Brumbaugh J, et al: Cumulative incidence, risk factors, and management of atrial fibrillation in patients receiving ibrutinib. Blood Adv 1:
1739-1748, 2017

Journal of Clinical Oncology 3451

 Byrd et al

30. Mato AR, Nabhan C, Barr PM, et al: Outcomes of CLL patients treated with sequential kinase inhibitor therapy: A real world experience. Blood 128:2199-2205,
2016
31. Benjamin EJ, Wolf PA, D’Agostino RB, et al: Impact of atrial fibrillation on the risk of death: The Framingham heart study. Circulation 98:946-952, 1998
32. Chai KL, Rowan G, Seymour JF, et al: Practical recommendations for the choice of anticoagulants in the management of patients with atrial fibrillation on
ibrutinib. Leuk Lymphoma 58:2811-2814, 2017
33. Tam CS, Opat S, D’Sa S, et al: A randomized phase 3 trial of zanubrutinib versus ibrutinib in symptomatic Waldenström macroglobulinemia:the ASPEN study.
Blood 136:2038-2050, 2020
34. Dickerson T, Wiczer T, Waller A, et al: Hypertension and incident cardiovascular events following ibrutinib initiation. Blood 134:1919-1928, 2019
35. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Version 3.2021. Plymouth Meeting, PA, National Comprehensive Cancer Network, 2021
36. Kipps TJ, Fraser G, Coutre SE, et al: Long-term studies assessing outcomes of ibrutinib therapy in patients with del(11q) chronic lymphocytic leukemia. Clin
Lymphoma Myeloma Leuk 19:715-722.e6, 2019
37. O’Brien S, Furman RR, Coutre S, et al: Single-agent ibrutinib in treatment-naive and relapsed/refractory chronic lymphocytic leukemia: A 5-year experience.
Blood 131:1910-1919, 2018

n n n
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3452 © 2021 by American Society of Clinical Oncology Volume 39, Issue 31

 Acalabrutinib Versus Ibrutinib in Chronic Lymphocytic Leukemia

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia: Results of the First Randomized Phase III Trial
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted.
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John C. Byrd Arpad Illés

Stock and Other Ownership Interests: Vincerx Pharma Consulting or Advisory Role: Janssen, Takeda, Novartis, Pfizer, Roche, Celgene
Honoraria: Pharmacyclics, AstraZeneca, Novartis, Syndax, Trillium Research Funding: Takeda, Seattle Genetics
Therapeutics Travel, Accommodations, Expenses: Novartis, Janssen, Pfizer, Roche
Consulting or Advisory Role: Acerta Pharma, Janssen, Kura Oncology, Novartis,
Neil Kay
Syndax, AstraZeneca
Consulting or Advisory Role: MorphoSys, Celgene, Agios, CytomX Therapeutics,
Research Funding: Acerta Pharma, Pharmacyclics, Zencor
AstraZeneca, Pharmacyclics, DAVA Pharmaceuticals, Juno Therapeutics, Rigel,
Patents, Royalties, Other Intellectual Property: OSU Patents
Oncotracker, Bristol Myers Squibb, AbbVie, Targeted Oncology, Acerta Pharma/
Travel, Accommodations, Expenses: Gilead Sciences, Janssen, Novartis,
AstraZeneca, MEI Pharma, Sunesis Pharmaceuticals, TG Therapeutics, Tolero
Pharmacyclics, TG Therapeutics
Pharmaceuticals, Janssen Biotech, Genentech/AbbVie
Peter Hillmen Research Funding: Pharmacyclics/Janssen, Tolero Pharmaceuticals, Acerta
Honoraria: Janssen, AbbVie, Roche Pharma, MEI Pharma, Celgene, Genentech, Sunesis Pharmaceuticals, AbbVie,
Research Funding: Janssen, Pharmacyclics, Roche, Gilead Sciences, AbbVie TG Therapeutics, Bristol Myers Squibb
Travel, Accommodations, Expenses: Janssen, AbbVie
Jose A. Garcia-Marco
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Paolo Ghia Consulting or Advisory Role: AbbVie, Janssen, AstraZeneca Spain

Honoraria: AbbVie, BeiGene, Janssen Oncology, Gilead Sciences, Juno Speakers’ Bureau: AbbVie, Janssen, AstraZeneca Spain
Therapeutics, Sunesis Pharmaceuticals, ArQule, Adaptive Biotechnologies, Research Funding: AbbVie, Janssen
Copyright © 2026 American Society of Clinical Oncology. All rights reserved.

Dynamo Therapeutics, MEI Pharma, Acerta Pharma/AstraZeneca, Juno/ Travel, Accommodations, Expenses: AbbVie, Janssen
Celgene/Bristol Myers Squibb, MSD, Lilly, Roche
Anthony Mato
Consulting or Advisory Role: AbbVie, BeiGene, Janssen, Gilead Sciences,
Consulting or Advisory Role: TG Therapeutics, AbbVie/Genentech, Celgene,
Sunesis Pharmaceuticals, Juno Therapeutics, ArQule, Adaptive
Pharmacyclics, Adaptive Biotechnologies, Verastem, Johnson & Johnson,
Biotechnologies, Dynamo Therapeutics, MEI Pharma, Acerta Pharma/
Acerta Pharma/AstraZeneca, DTRM, Loxo/Lilly, Curio/Vaniam Group, Merck,
AstraZeneca, MSD, Lilly, Roche
Bristol Myers Squibb/Pfizer
Research Funding: AbbVie, Janssen Oncology, Gilead Sciences, Sunesis
Research Funding: Regeneron, TG Therapeutics, Sunesis Pharmaceuticals,
Pharmaceuticals, Novartis, AstraZeneca
LOXO, AbbVie/Genentech, Pharmacyclics, Adaptive Biotechnologies, Johnson
Arnon P. Kater & Johnson, Acerta Pharma/AstraZeneca, DTRM, Genmab, Nurix
Consulting or Advisory Role: Janssen Oncology, AbbVie/Genentech,
Javier Pinilla-Ibarz
AstraZeneca, Bristol Myers Squibb/Celgene, Lava Therapeutics
Honoraria: Novartis, Pharmacyclics, Janssen, AbbVie, Takeda, AstraZeneca
Research Funding: Janssen Oncology, Roche/Genentech, Bristol Myers Squibb/
Consulting or Advisory Role: Novartis, Pharmacyclics, Janssen, AbbVie
Celgene, AbbVie, AstraZeneca
Speakers’ Bureau: Pharmacyclics/Janssen, AbbVie, Takeda, AstraZeneca
Travel, Accommodations, Expenses: Acerta Pharma/AstraZeneca, Roche/
Patents, Royalties, Other Intellectual Property: From a WT vaccine patent by
Genentech
Memorial Sloan Kettering Cancer Center
Asher Chanan-Khan
John F. Seymour
Stock and Other Ownership Interests: Matthew & Asher Inc, NanoDev
Honoraria: AbbVie, Acerta Pharma, Janssen, Roche, Sunesis Pharmaceuticals,
Therapeutics, STARTON Therapeutics
Takeda
Honoraria: BeiGene, Ascentage Pharma
Consulting or Advisory Role: AbbVie, Acerta Pharma, Janssen, Roche, Sunesis
Research Funding: Ascentage Pharma
Pharmaceuticals, Takeda, AstraZeneca, BMS, Gilead Sciences, MEI Pharma,
Patents, Royalties, Other Intellectual Property: Patent on PSMB9 biomarker
MorphoSys
Richard R. Furman Speakers’ Bureau: AbbVie, Roche
Honoraria: Janssen, AstraZeneca Research Funding: AbbVie, Celgene, Janssen, Roche
Consulting or Advisory Role: Pharmacyclics, Janssen Biotech, Genentech/ Expert Testimony: Roche
Roche, Loxo, TG Therapeutics, Verastem, Acerta Pharma, AstraZeneca, Travel, Accommodations, Expenses: AbbVie, Roche
Beigene, Incyte, OncoTracker, AbbVie, MorphoSys, Sanofi
Stephan Stilgenbauer
Research Funding: Acerta Pharma, TG Therapeutics
Honoraria: AbbVie, AstraZeneca, Celgene, Gilead Sciences, GlaxoSmithKline,
Expert Testimony: AbbVie, Janssen Oncology
Roche, Janssen
Travel, Accommodations, Expenses: TG Therapeutics, Janssen Oncology
Consulting or Advisory Role: AbbVie, AstraZeneca, Celgene, Gilead Sciences,
Other Relationship: Incyte, Janssen Biotech
GlaxoSmithKline, Roche, Janssen
Susan O’Brien Speakers’ Bureau: AbbVie, AstraZeneca, Celgene, Gilead Sciences,
Employment: University of California, Irvine GlaxoSmithKline, Roche, Janssen
Honoraria: Celgene, Janssen, Pharmacyclics, Gilead Sciences, Pfizer, Amgen, Research Funding: AbbVie, AstraZeneca, Celgene, Gilead Sciences,
Astellas Pharma, GlaxoSmithKline, Aptose Biosciences, Vaniam Group, AbbVie, GlaxoSmithKline, Roche, Janssen
Sunesis Pharmaceuticals, Alexion Pharmaceuticals, Eisai, TG Therapeutics, Travel, Accommodations, Expenses: AbbVie, AstraZeneca, Celgene, Gilead
Nova Research Company Sciences, GlaxoSmithKline, Roche, Janssen
Consulting or Advisory Role: Amgen, Celgene, GlaxoSmithKline, Janssen
Tadeusz Robak
Oncology, Aptose Biosciences, Vaniam Group, AbbVie/Genentech, Sunesis
Honoraria: AbbVie
Pharmaceuticals, Alexion Pharmaceuticals, Astellas Pharma, Gilead Sciences,
Consulting or Advisory Role: AbbVie
Pharmacyclics, TG Therapeutics, Pfizer, Sunesis Pharmaceuticals
Research Funding: AbbVie/Genentech
Research Funding: Acerta Pharma, Regeneron, Gilead Sciences, Pfizer, TG
Therapeutics, Pharmacyclics, Kite, a Gilead company, Sunesis Pharmaceuticals
Travel, Accommodations, Expenses: Celgene, Janssen, Gilead Sciences,
Regeneron, Janssen Oncology
Mustafa Nuri Yenerel
Consulting or Advisory Role: Pfizer, Alexion Pharmaceuticals
Speakers’ Bureau: Janssen Oncology
Travel, Accommodations, Expenses: Pfizer

Journal of Clinical Oncology

 Byrd et al

Wayne Rothbaum Priti Patel

Leadership: Iovance Biotherapeutics Employment: AstraZeneca, Neoleukin Therapeutics
Stock and Other Ownership Interests: Acerta Pharma/AstraZeneca, Telios, Leadership: Neoleukin Therapeutics
Kartos Therapeutics Stock and Other Ownership Interests: AstraZeneca, Neoleukin Therapeutics
Patents, Royalties, Other Intellectual Property: Telios Pharma and Kartos
Kara Higgins
Therapeutics
Employment: AstraZeneca, PROMETRIKA LLC
Travel, Accommodations, Expenses: Iovance Biotherapeutics, Kartos
Therapeutics Sophia Sohoni
Uncompensated Relationships: Kartos Therapeutics, Telios Employment: AstraZeneca, Portola Pharmaceuticals
Stock and Other Ownership Interests: Theravance
Raquel Izumi
Employment: Acerta Pharma, Vincerx Pharma Wojciech Jurczak
Stock and Other Ownership Interests: Acerta Pharma, Vincerx Pharma Consulting or Advisory Role: Janssen-Cilag, Roche, AstraZeneca, Debiopharm
Patents, Royalties, Other Intellectual Property: Patents pending for Acerta Group, Epizyme
Pharma Research Funding: Acerta Pharma, TG Therapeutics, Incyte, Bayer, Sandoz-
Expert Testimony: Diablo Valley Oncology Novartis, Roche, Takeda, Epizyme, Janssen-Cilag, BeiGene, Debiopharm
Group, MorphoSys, MEI Pharma
Ahmed Hamdy
Employment: Acerta Pharma/AstraZeneca No other potential conflicts of interest were reported.
Stock and Other Ownership Interests: Acerta Pharma
Patents, Royalties, Other Intellectual Property: Acalabrutinib multiple patents
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Copyright © 2026 American Society of Clinical Oncology. All rights reserved.

© 2021 by American Society of Clinical Oncology Volume 39, Issue 31