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Introduction/Overview Specific Diseases Alternative Stem Cell Transplantation Supportive Measures

History of BMT Definitions AML ALL Breast cancer NHL. Rationale Stem cell sources MDS Multiple Myeloma Hodgkin’s disease. Overview of Blood and Marrow Transplantation. Introduction/Overview Specific Diseases Alternative Stem Cell Transplantation Supportive Measures.

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Introduction/Overview Specific Diseases Alternative Stem Cell Transplantation Supportive Measures

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  1. History of BMT Definitions AML ALL Breast cancer NHL Rationale Stem cell sources MDS Multiple Myeloma Hodgkin’s disease Overview of Blood and Marrow Transplantation • Introduction/Overview • Specific Diseases • Alternative Stem Cell Transplantation • Supportive Measures

  2. HEMATOPOIETIC STEM CELL DIFFERENTIATION

  3. 36 Erythrocyte 33,61 9,36,41,42,61 Platelet Neutrophil 10 13,15,33,38 13,16,33 13,16,11b Eosinophil Basophil 11b,13,14,15,33,36 13,14,15,33 13,14,15,33 Monocyte 11b,16,56 NK Cell 19,20,22 9,10,19,20,24,38 10,19,24,38 B-Cell 2,3,5,7 2,3,5,7 7 2,3,5,7,38 T-Cell Immunologic Marker Expression In Hematopoiesis BFU-E CFU-E Reticulocyte Myeloid SC CFU-Mega Megakaryocyte Myeloblast Promyelocyte Myelocyte Pluripotent Stem Cell Monoblast Promonocyte 56 NK Precursor Lymphoid SC Pre-B B Progenitor CD34+ T Progenitor Sub Cortical Cortical Thymocyte Medullary Thymocyte

  4. 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 military’s concern about the spread of nuclear technology and weapons, studies of bone marrow transplantation were initiated.

  5. Lethal TBI Syndromes • Cerebral Syndrome • Intestinal Syndrome • Bone Marrow Syndrome 12,000-1,000,000 cGy 1,200-10,000 cGy 500-700 cGy

  6. Effects of Spleen Shielding on Mice After Total Body Irradiation • TBI Dose • (cGy) Spleen Shielding Survival 700 700 1050 1050 1200 Yes No Yes No Yes 96.3% 0.0% 30.4% 0.0% 0.0%

  7. 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

  8. CONDITIONING (PREPARATIVE) REGIMEN • To suppress the patient’s immune system from rejecting the stem cells. • To eliminate the cancer

  9. Stem Cell Sources • Bone Marrow • Blood • Umbilical Cord • Fetal Liver

  10. 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.

  11. Potential Stem Cell Sources • Autologous stem cells • HLA-matched related donors • HLA-matched unrelated donors • Haploidentical related donors • Umbilical cord blood

  12. 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

  13. Host Graft Immunosuppression Preparative regimen Post-transplant Rx Disease effects Sensitization Stem cell dose T-cell dose (CD8) Graft facilitating cells Stromal stem cells? Allogeneic Engraftment With reduced immunosuppression in current NST regimen, we rely on graft cells (stem, T- and accessories cells) to overcome rejection.

  14. Host Graft Immunosuppression Preparative regimen Post-transplant Rx Disease effects Sensitization Stem cell dose T-cell dose (CD8) Graft facilitating cells Stromal stem cells? Allogeneic Engraftment With reduced immunosuppression in current NST regimen, we rely on graft cells (stem, T- and accessories cells) to overcome rejection.

  15. Host Graft Immunosuppression Preparative regimen Post-transplant Rx Disease effects Sensitization Stem cell dose T-cell dose (CD8) Graft facilitating cells Stromal stem cells? Engraftment With reduced immunosuppression in current NST regimen, we rely on graft cells (stem, T- and accessories cells) to overcome rejection.

  16. Graph Rejection/ GVHD Recurrent Disease

  17. 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 patient’s body will accept the donor’s stem cells.

  18. HUMAN LEUKOCYTE ANTIGEN INHERRITANCE

  19. IDENTIFICATION OF A RELATED ALLOGENEIC DONOR • Identical Twin < 1% • HLA-matched Sibling • 6 antigen 25 - 30% • 5 antigen 10 - 20% • 4 antigen 50 - 60% • 3 antigen > 90%

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

  21. 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)

  22. Allogeneic Autologous Majority Possible None 0-10% Donor Availablity Tumor Content GVHD/GVL Tx-related Mortality Limited None Possible 10-40% Stem Cell Source

  23. 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

  24. HLA-matched relative Unrelated donor Cord blood HLA-mismatched relative 25-30% 10-40% 50% 1 Ag 2 Ag 3 Ag 10% 50% 90% Stem Cell Donor Availability

  25. 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

  26. The NMDP Network 98 Donor Center (8 foreign) Coordinating Center Minneapolis, MN 114 Collection Centers (15 foreign) 112 Transplant Centers (23 foreign) ASCO 1998

  27. 88 89 90 91 92 93 94 95 96 97 98 Volunteer Marrow Donors 40 Total Donors 3,134,601 30 Volunteers in Registry (Millions) 20 Fully Typed Donors 10 0 Year ASCO 1998

  28. Probability of Finding a Six-antigen HLA Matched Donor North America Caucasian Pool Size Japanese 100 1000 10,000 100,000 500,000 1,000,000 0.0% 11.9% 54.2% 90.6% 99.9% 99.9% 0.0% 3.3% 20.7% 60.0% 85.7% 93.7%

  29. Preliminary Search 54.7% 25.6% Formal Search DR Typing 43.5% 7.2% Confirmatory Typing Confirmatory Typing 20.2% 2.1% Work-Up Work-Up 15.8% 1.6% Transplant Beatty et al., 1995

  30. Waste product of normal deliveries Readily available Increased availability for minorities Decreased transmission of viruses (e.g. CMV) One unit rescues one patient/no DLI Theoretical risk of genetic disease transmission Theoretical risk of maternal cell contamination (GVHD) Efficacy in adults unknown Cord Blood Transplantation Advantages Disadvantages

  31. Nearly all patients have a donor Share major (e.g. HLA-C) and minor hitocompatibility antigens Immediate donor availability HLA Barriers: -Graft rejection -GVHD -Immune dysregulation Haplo-identical HSCT Advantages Disadvantages

  32. 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? Yes No Yes UCBT BMT Strategy for Donor Selection

  33. Diagnosis Urgency of transplant HLA typing Cell dose available in UC units(s) Age Chemo-sensitivity Choice of Stem Cell Source

  34. Diseases Treated by Bone Marrow Transplantation Acute lymphocytic leukemia Chronic myelogenous leukemia Chronic lymphocytic leukemia Non-Hodgkin’s lymphoma Hodgkin’s disease • Aplastic anemia • Thalassemia • Sickle cell anemia • Immunodeficiency disorders • Acute myelogenous leukemia • Myelodysplastic syndrome • Multiple myeloma Armitage, NEJM 1994

  35. Indications for Blood and Marrow Transplantation in North America (2000) 4,500 4,000 Allogeneic (Total N=67,000) Autologous (Total N=11,000) 3,500 3,000 2,500 Transplants 2,000 1,500 1,000 500 0 Non- Hodgkin Lymphoma AML Hodgkin Disease CML MDS/ Other Leukemia CLL Multiple Myeloma Breast Cancer Other Cancer ALL Non- Malignant Disease Ovarian Cancer

  36. Annual Numbers of Blood and Marrow Transplants Worldwide (1970-2000) 40 30 Autologous Number of Transplants (Thousands) 20 10 Allogeneic 0 1970 1975 1980 1985 1990 1995 2000 Year

  37. Alternative donors Unrelated bone marrow donors Stored cord blood Ganciclovir Hematopoietic growth factors Blood as a stem cell product Donor lymphocyte infusions Advancements in Allogeneic Stem Cell Transplantation

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

  39. Allogeneic Hematopoietic Stem Cell Transplantation Old Paradigm New Paradigm The allograft is a rescue product to replace the defective stem cells following ablation with cytotoxic therapy. Main therapeutic component of an allogeneic stem cell transplant is the “graft vs. leukemia” effect mediated by T-cells in the allograft.

  40. 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 Regimens in Allo SCT

  41. Preparative Regimen A Host Donor B B B B B B B B ± DLI HSCT A A A B B A B B B AL AL AL A B B B A B Mixed Chimera Complete Chimera Recipient Donor Non-myeloablative Hematopoietic Cell Transplant

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

  43. Hematopoetic Stem Cell Transplantation for Auto-immune Diseases • Multiple Sclerosis • Rheumatoid Arthritis • Scleroderma

  44. ETIB RESEARCH HEMATOPOIETIC STEM CELL TRANSPLANTATION • StrategyTactic •  Rejection Immune-depleting chemo • Tc2 cells • GVHD Th2 cells • GVL Tc2 cells • Id vaccines • Immune reconstitution Cytokines (IL-7)

  45. “Diseases desperate grown • By disparate appliance • Are reliev’d, • Or not at all” After Shakespeare

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