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Introduction/Overview Specific Diseases Alternative Stem Cell Transplantation Supportive Measures Overview of Blood and Marrow Transplantation History.

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Presentation on theme: "Introduction/Overview Specific Diseases Alternative Stem Cell Transplantation Supportive Measures Overview of Blood and Marrow Transplantation History."— Presentation transcript:

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

2 HEMATOPOIETIC STEM CELL DIFFERENTIATION

3 Immunologic Marker Expression In Hematopoiesis CD34+ Pluripotent Stem Cell T Progenitor BFU-E B Progenitor Lymphoid SC Myeloid SC CFU-Mega ReticulocyteCFU-E Myeloblast Megakaryocyte MyelocytePromyelocyte PromonocyteMonoblast NK Precursor Pre-B Sub Cortical Cortical Thymocyte Medullary Thymocyte Erythrocyte NK Cell Platelet Monocyte B-Cell T-Cell Eosinophil Basophil Neutrophil ,19,24,38 33, ,15,33,38 9,36,41,42,61 13,16,11b13,16,33 13,14,15,33 9,10,19,20,24,38 2,3,5,7,38 2,3,5,7 19,20,22 11b,16,56 11b,13,14,15,33,36

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 militarys 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 cGy

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

7 Rationale for High Dose Therapy and Hematopoietic Stem Cell Transplantation Increasing Dose Treatment Necessary for Cure Death due to other organ toxicity Death due to Marrow toxicity

8 CONDITIONING (PREPARATIVE) REGIMEN To suppress the patients 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 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 Autologous Bone Marrow Transplantation

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

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

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

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 patients body will accept the donors stem cells.

18 HUMAN LEUKOCYTE ANTIGEN INHERRITANCE

19 IDENTIFICATION OF A RELATED ALLOGENEIC DONOR Identical Twin< 1% HLA-matched Sibling 6 antigen % 5 antigen % 4 antigen % 3 antigen> 90%

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

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

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

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 114 Collection Centers (15 foreign) Coordinating Center Minneapolis, MN 112 Transplant Centers (23 foreign) ASCO Donor Center (8 foreign)

27 Volunteer Marrow Donors ASCO Year Volunteers in Registry (Millions) Total Donors 3,134,601 Fully Typed Donors

28 Probability of Finding a Six-antigen HLA Matched Donor , , ,000 1,000, % 11.9% 54.2% 90.6% 99.9% 0.0% 3.3% 20.7% 60.0% 85.7% 93.7% Pool SizeJapanese North America Caucasian

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

30 Cord Blood Transplantation AdvantagesDisadvantages 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

31 Haplo-identical HSCT AdvantagesDisadvantages 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

32 Strategy for Donor Selection BMT No Urgent Referral Simultaneous Search URD, BM and UCB Non-urgent or Non-malignant Diagnosis Yes UCBT 6/6 HLA-matched BM Donor Available? 4-6 HLA-matched UCB(s) Identified with Cell Dose >1.5 x 10 7 NC/kg?

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

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

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

36 Annual Numbers of Blood and Marrow Transplants Worldwide ( ) Year Number of Transplants (Thousands) Autologous Allogeneic

37 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

38 Donor Lymphocyte Infusions 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%

39 Allogeneic Hematopoietic Stem Cell Transplantation 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. Old ParadigmNew Paradigm

40 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

41 Non-myeloablative Hematopoietic Cell Transplant ± DLI HSCT A B B BBBB B B BB AB ALAL A AA ALAL ALAL AA BBB BBB RecipientDonor Mixed Chimera Complete Chimera Host Donor Preparative Regimen

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

43 Multiple SclerosisMultiple Sclerosis Rheumatoid ArthritisRheumatoid Arthritis SclerodermaScleroderma Hematopoetic Stem Cell Transplantation for Auto-immune Diseases

44 ETIB RESEARCH HEMATOPOIETIC STEM CELL TRANSPLANTATION StrategyTactic RejectionImmune-depleting chemo RejectionImmune-depleting chemo Tc2 cells GVHDTh2 cells GVHDTh2 cells GVLTc2 cells GVLTc2 cells Id vaccines Immune reconstitutionCytokines (IL-7)

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


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