Overview of Hematopoietic Stem Cell Transplantation (HSCT)

1. Overview of Hematopoietic Stem Cell Transplantation (HSCT) Daniel R Couriel, MD Sarah Cannon Blood and Marrow Transplant Program

2. Hematopoiesis T-lymphocytes Stem Cells B-lymphocytes Granulocytes Monocytes Eosinophils Basophils Erythrocytes Megakaryocytes Platelets

3. Hematopoietic Stem Cell Transplantation D D D D D D D D HSCT Allogeneic Autologous R R Preparative Regimen R R R R R R R RL RL R Allogeneic hematopoietic is an effective, but toxic treatment for hematologic malignancies, associated with a high risk of morbidity and mortality (10->50%), restricting its use to young patients without comorbidities

8. Types of HCT: Histocompatibility Autologous HCT Allogeneic HCT • HLA-identical sibling • HLA-matched unrelated donor (MUD) • HLA-mismatched donor Patient’s own cells • Choice of Transplant Type • Disease susceptibility to chemotherapy • Ability to eradicate malignant clones

9. Autologous High dose therapy with reinfusion of own cryopreserved cells Safer, TRM <5% Possible contamination with malignant cells No Graft-vs-malignancy effect Higher risk of relapse Allogeneic Immunosuppressive Rx with infusion of cells from another person Risk of rejection, GVHD Higher risk, TRM 10-40% Graft-vs-malignancy (GVM) occurs Lower risk of relapse Can perform in diseases in which blood and BM involved Autologous vs. Allogeneic

10. Sensitivity/resistance to GVM • Indolent diseases (CML, CLL, LGL) • Intrinsic sensitivity +/or time for development of GVM • Rapidly proliferating disease may outpace immune response • Effective antigen presentation, costimulation (capacity to generate an immune response) • CML dendritic cells, LGL • ALL ineffective costimulation • Chemotherapy resistance • Chemorresistance may also affect sensitivity to immune mediated cytotoxicity

11. Nonablative/Reduced Intensity Regimens Nonablative Reduced Intensity Ablative TBI/CyT TMF F-TBI 2Gy BuF BuCy Immunosuppression* MF FCR TC TBI 2Gy FlagIda Myelosuppression

12. General Eligibility Criteria • Autotransplant: Physiologic age 70, minimal comorbidities • Allotransplant: Physiologic age 65, although patients with comorbidities or elderly (to chronologic age of 75) can be considered for reduced intensity HSCT • Comorbidities: To be evaluated in the context of risk/benefit ratio • Chemosensitivity: Precondition in the majority of diagnoses, particularly in DLCL, ALL, BC of CML.

13. Transplant Patient Flow in a Nutshell • Pretransplant Evaluation and donor search and collection • Inpatient: Admission for chemotherapy, preparative regimen, acute GVHD • Ambulatory treatment Center (allo)/Outpatient (auto): From D/C to Day 100 (or beyond if complications occur) • LTFU phase in the outpatient clinic (cGVHD and other long term, survivorship issues)

14. 45,000 40,000 35,000 30,000 25,000 20,000 15,000 10,000 5,000 0 ANNUAL NUMBERS OF BLOOD AND MARROW TRANSPLANTS WORLDWIDE1970-2002 Autologous NUMBER OF TRANSPLANTS Allogeneic 1970 1975 1980 1985 1990 1995 2000 YEAR 1

15. Non-myeloablative (N=7532) Traditional (N=36,543) INDICATIONS FOR ALLOGENEIC BLOOD AND MARROW TRANSPLANTS REGISTERED WITH THE IBMTR, 1997-2002- Worldwide - 14,000 12,000 10,00 8,000 TRANSPLANTS 6,000 4,000 2,000 0 AML CML ALL MDS/MPSOtherLeukemia NHL MultipleMyeloma CLL HodgkinDisease RenalCell OtherCancer SAA OtherNon-MalignantDisease 17

16. 100 80 60 40 20 0 0 1 2 3 4 5 PROBABILITY OF SURVIVAL AFTER HLA-IDENTICAL SIBLING MYELOABLATIVE TRANSPLANTS FOR LEUKEMIA- Registered with the IBMTR, 1975-2002 - ³1995 (N=15,126) 1985-1994 (N=14,755) PROBABILITY, % 1975-1984 (N=2,334) P = 0.0001 YEARS Mln04_3.ppt

17. Complications after HSCT (non-immunologic) • Short and long term toxicities of preparative regimen • Secondary malignancies

18. Immune Reactivity with BMT • Graft-rejection • Recipient (host) immune cells react against donor cells • T-cells, NK cells • Graft-vs-host disease • Donor cells react against host tissues • T-cells • Immune deficiency • Profound deficiency of T-cells and B cells (CD4 slower recovery than CD8), • Most severe in first 100 days • Slow recovery during first year • Graft-vs-malignancy effects • T-cells or NK cells react against residual malignancy

19. Human Leukocyte Antigens • Histocompatibility antigens are cell surface determinants that mediate immune reactions and graft rejection after transplantation between genetically diverse individuals. • T cells will recognize antigens presented as peptide fragments associated to HLA molecules.

20. HLA complex on chromosome 6

21. HLA Matching • A, B, C, DRB1, DQB1 - 10 out of 10 match • Molecular typing (allele level) - eg for class II (DRB1, DQB1)

22. Engraftment Graft Host Stem cell dose T-cell dose (CD8) Graft-facilitating cells Stromal stem cells? Immunosuppression Preparative Regimen Post transplant Rx Disease effects Sensitization Histocompatibility With reduced immunosuppression in current NST regimens, graft cells (stem, T-, NK- and accessory cells) important to overcome rejection

23. Acute GVHD Due to reactivity of mature T-cells in the graft vs. recipient (host) tissues, augmented by inflammatory cytokines • Targets- Skin, liver, GI tract • Immune system and marrow also a target • Usually occurs within the first 100 days

28. Chronic GVHD • Most frequent late complication of allogeneic BMT • Occurs in 1/3 to 1/2 of patients • Most frequent in patients with acute GVHD, but 1/3 of cases develop de novo • More frequent with older age • More frequent with PBSC transplants • Treatment- steroids +/- other agents • Trade off immunosuppression improves manifestations of GVHD, but increases risk of infection

29. Lichenoid GVHD

30. Sclerosis

31. Sclerosis/Ulcer

32. Lichenoid changes, Lichen sclerosus, Sclerosis/Morphea, Poikiloderma, Dyspigmentation

33. Fasciitis Deep sclerosis

34. Lichenoid GVHD of the lips

35. Lichenoid GVHD with hyperkeratotic changes and ulcerations

36. Late Complications of BMT • Secondary Malignancies • Cirrhosis (multifactorial, transfusions, toxicity of prior chemo, alcohol, GVHD) • Late infections (CMV, fungi if on steroids or cGVHD, encapsulated bacteria,) • EBV lymphoproliferative disease • Most patients return to normal or near normal performance status

37. Conclusions • HCT is an effective therapy for several types of hematologic malignancies • Autologous transplants are associated with a transplant-related mortality (TRM) similar to that of chemotherapy, but has the disadvantage of no GVM and therefore the potential for a higher relapse rate • Allogeneic transplants have a comparatively higher TRM, and GVHD is a major complication. The risk and commitment is substantially higher, but it is the price we have to pay for GVM and a long-term remission in select situations