Overview of Blood and Marrow Transplantation

Introduction/Overview History of BMT Rationale Definitions Stem cell sources Specific Diseases AML ALL MDS Breast cancer Multiple Myeloma NHL Hodgkins disease Alternative Stem Cell Transplantation Supportive Measures

HEMATOPOIETIC STEM CELL DIFFERENTIATION

Immunologic Marker Expression In Hematopoiesis

36

Erythrocyte BFU-E
33,61

CFU-E
9,36,41,42,61

Reticulocyte Platelet

Myeloid SC

CFU-Mega
13,15,33,38

Megakaryocyte
13,16,33 13,16,11b

Neutrophil 10 Eosinophil Basophil

11b,13,14,15,33,36

Myeloblast

Promyelocyte

Myelocyte

Pluripotent Stem Cell

13,14,15,33

13,14,15,33

Monocyte Monoblast Promonocyte

56 11b,16,56

NK Cell Lymphoid SC
10,19,24,38

NK Precursor
9,10,19,20,24,38 19,20,22

B Progenitor
7

Pre-B
2,3,5,7,38

B-Cell
2,3,5,7
2,3,5,7

CD34+ T Progenitor Sub Cortical Cortical Thymocyte Medullary Thymocyte

T-Cell

HISTORY OF STEM CELL TRANSPLANTATION

Turn of the 20th century, scientists began to formulate the idea that a small number of cells in the marrow, referred to as stem cells, might be responsible for the development of all blood cells. Marrow injury was an important and potentially lethal side effect of exposure to the atomic bomb or to industrial accidents in the atomic weapons industry. Spurred by the Atomic Energy Commission's and the militarys concern about the spread of nuclear technology and weapons, studies of bone marrow transplantation were initiated.

Lethal TBI Syndromes

Cerebral Syndrome Intestinal Syndrome

12,000-1,000,000 cGy 1,200-10,000 cGy 500-700 cGy

Bone Marrow Syndrome

Effects of Spleen Shielding on Mice After Total Body Irradiation

TBI Dose (cGy) 700 700 1050 1050 1200 Spleen Shielding Yes No Yes No Yes Survival 96.3% 0.0% 30.4% 0.0% 0.0%

Rationale for High Dose Therapy and Hematopoietic Stem Cell Transplantation
Death due to other organ toxicity

Increasing Dose

Death due to Marrow toxicity

Treatment Necessary for Cure

CONDITIONING (PREPARATIVE) REGIMEN

To suppress the patients immune system from rejecting the stem cells.

To eliminate the cancer

Stem Cell Sources

Bone Marrow Blood Umbilical Cord Fetal Liver

TYPES OF STEM CELL TRANSPLANTS

AUTOLOGOUS TRANSPLANTS - Patients receive their own stem cells. SYNGENEIC TRANSPLANTS - Patients receive stem cells from their identical twin. ALLOGENEIC TRANSPLANTS - Patients receive stem cells from someone other than the patient or an identical twin.

Potential Stem Cell Sources

Autologous stem cells HLA-matched related donors HLA-matched unrelated donors Haploidentical related donors

Umbilical cord blood

Autologous Bone Marrow Transplantation

Criteria
Tumor with dose response curve Tumor sensitive to myelosuppressive agents Purging techniques if marrow is contaminated with tumor - Preserve stem cells - Eradicate tumor Technique for peripheral stem cell collections Minimal tumor burden Marrow ablation

Allogeneic Engraftment
Host
Immunosuppression Preparative regimen Post-transplant Rx Disease effects Sensitization

Graft
Stem cell dose T-cell dose (CD8) Graft facilitating cells Stromal stem cells?

With reduced immunosuppression in current NST regimen, we rely on graft cells (stem, Tand accessories cells) to overcome rejection.

Allogeneic Engraftment
Host
Immunosuppression Preparative regimen Post-transplant Rx Disease effects Sensitization

Graft
Stem cell dose T-cell dose (CD8) Graft facilitating cells Stromal stem cells?

With reduced immunosuppression in current NST regimen, we rely on graft cells (stem, Tand accessories cells) to overcome rejection.

Engraftment
Host
Immunosuppression Preparative regimen Post-transplant Rx Disease effects Sensitization

Graft
Stem cell dose T-cell dose (CD8) Graft facilitating cells Stromal stem cells?

With reduced immunosuppression in current NST regimen, we rely on graft cells (stem, Tand accessories cells) to overcome rejection.

Graph Rejection/ GVHD

Recurrent Disease

HUMAN LEUKOCYTE-ASSOCIATED (HLA) ANTIGENS

A set of proteins on the surface of their cells. A set of HLA proteins are inherited equally from patients. Chances of having a full match are ~ 1 in 3. The higher the number of matching HLA antigens, the greater the chance that the patients body will accept the donors stem cells.

HUMAN LEUKOCYTE ANTIGEN INHERRITANCE

IDENTIFICATION OF A RELATED ALLOGENEIC DONOR

Identical Twin HLA-matched Sibling 6 antigen 5 antigen 4 antigen 3 antigen < 1%
25 - 30% 10 - 20% 50 - 60% > 90%

Stem Cell Source

Allogeneic Donor Availability Tumor Content GVHD/GVL Tx-related Mortality Limited None Possible 10-40% Autologous Majority Possible None 0-10%

Alternatives to HLA-matched Related Donors

HLA-matched unrelated donors Cord Blood Transplantation -Related -Unrelated HLA-mismatched related Donors (Haplo-identical) (Autologous stem cell transplantation)

Stem Cell Source

Allogeneic Donor Availablity Tumor Content GVHD/GVL Tx-related Mortality Limited None Possible 10-40%

Autologous Majority Possible None 0-10%

Advancements in Allogeneic Stem Cell Transplantation

Alternative donors - Unrelated bone marrow donors - Stored cord blood Ganciclovir Hematopoietic growth factors Blood as stem cell product Donor lymphocyte infusions

Stem Cell Donor Availability

HLA-matched relative Unrelated donor Cord blood HLA-mismatched relative 1 Ag 2 Ag 3 Ag 25-30% 10-40% 50% 10% 50% 90%

Alternatives to HLA-matched Related Donors

HLA-matched unrelated donors Cord blood transplantation - Related - Unrelated HLA-mismatched related donors (Haplo-identical) Autologous stem cell transplantation

The NMDP Network

98 Donor Center (8 foreign)

114 Collection Centers (15 foreign)

Coordinating Center Minneapolis, MN

112 Transplant Centers (23 foreign)

ASCO 1998

Volunteer Marrow Donors

40 Volunteers in Registry (Millions)
Total Donors 3,134,601

30

20
Fully Typed Donors

10

88 89

90 91 92 93 94 Year

95 96 97 98
ASCO 1998

Probability of Finding a Six-antigen HLA Matched Donor

Pool Size
100 1000 10,000 100,000 500,000 1,000,000

Japanese
0.0% 11.9% 54.2% 90.6% 99.9% 99.9%

North America Caucasian

0.0% 3.3% 20.7% 60.0% 85.7% 93.7%

Preliminary Search
54.7% 25.6%

Formal Search
43.5%

DR Typing
7.2%

Confirmatory Typing
20.2%

Confirmatory Typing
2.1%

Work-Up

Work-Up

15.8%

1.6%

Transplant

Beatty et al., 1995

Cord Blood Transplantation

Advantages
Waste product of normal deliveries

Disadvantages
One unit rescues one patient/no DLI

Readily available
Increased availability for minorities Decreased transmission of viruses (e.g. CMV)

Theoretical risk of genetic disease transmission

Theoretical risk of maternal cell contamination (GVHD) Efficacy in adults unknown

Haplo-identical HSCT
Advantages
Nearly all patients have a donor Share major (e.g. HLA-C) and minor hitocompatibility antigens Immediate donor availability

Disadvantages
HLA Barriers: -Graft rejection -GVHD -Immune dysregulation

Strategy for Donor Selection

Referral

Simultaneous Search URD, BM and UCB Non-urgent or Non-malignant Diagnosis Urgent

6/6 HLA-matched BM Donor Available?

4-6 HLA-matched UCB(s) Identified with Cell Dose >1.5 x 107 NC/kg? No Yes

Yes

BMT

UCBT

Choice of Stem Cell Source

Diagnosis Urgency of transplant HLA typing Cell dose available in UC units(s) Age Chemo-sensitivity

Diseases Treated by Bone Marrow Transplantation

Aplastic anemia Thalassemia Sickle cell anemia Immunodeficiency disorders Acute myelogenous leukemia Myelodysplastic syndrome Multiple myeloma Acute lymphocytic leukemia Chronic myelogenous leukemia Chronic lymphocytic leukemia Non-Hodgkins lymphoma Hodgkins disease
Armitage, NEJM 1994

Indications for Blood and Marrow Transplantation in North America

(2000)
4,500 4,000 3,500 Transplants 3,000 2,500
Allogeneic (Total N=67,000) Autologous (Total N=11,000)

2,000
1,500 1,000 500 0
NonHodgkin Lymphoma AML Hodgkin Disease Breast Cancer Other Cancer CML MDS/ CLL Other Leukemia ALL NonOvarian Malignant Cancer Disease

Multiple Myeloma

Annual Numbers of Blood and Marrow Transplants Worldwide

(1970-2000)
40 Number of Transplants (Thousands)

30

Autologous

20

10

Allogeneic

0 1970

1975

1980

1985 Year

1990

1995

2000

Advancements in Allogeneic Stem Cell Transplantation

Alternative donors Unrelated bone marrow donors Stored cord blood Ganciclovir Hematopoietic growth factors Blood as a stem cell product Donor lymphocyte infusions

Donor Lymphocyte Infusions

Efficacy varies: CML = 50-90% AML = 25-50% High incidence of GVHD (40-60%) High correlation of GVHD and response Optimal dose, frequency and timing remain undetermined

Allogeneic Hematopoietic Stem Cell Transplantation

Old Paradigm The allograft is a rescue product to replace the defective stem cells following ablation with cytotoxic therapy. New Paradigm Main therapeutic component of an allogeneic stem cell transplant is the graft vs. leukemia effect mediated by Tcells in the allograft.

Non-myeloablative Regimens in Allo SCT

Advantages: -Decreased acute toxicity -Application to older and/or morbid patients -Application to broader spectrum of diseases Disadvantages: -Toxicity of the procedure (GVHD) -Loss/decrease in anti-tumor activity from cytotoxic chemotherapy/radiation

Non-myeloablative Hematopoietic Cell Transplant

Preparative Regimen

B B
B B HSCT

B
B B

A Host B Donor

DLI

A A A AL AL A

B B AL A B

A B

B B

B B B

Recipient

Donor

Mixed Chimera

Complete Chimera

CLINICAL COURSE ON ABP1 (CC 00-C-0119)

Hematopoetic Stem Cell Transplantation for Auto-immune Diseases

Multiple Sclerosis Rheumatoid Arthritis Scleroderma

ETIB RESEARCH HEMATOPOIETIC STEM CELL TRANSPLANTATION

Strategy Rejection Tactic Immune-depleting chemo Tc2 cells

GVHD
GVL Immune reconstitution

Th2 cells
Tc2 cells Id vaccines Cytokines (IL-7)

Diseases desperate grown By disparate appliance Are relievd, Or not at all

After Shakespeare