1. Allogeneic “Mini” Transplantation Mark B. Juckett M.D. June 4, 2004

2. Problems with BMT Relapse –CML chronic phase – 10% –High risk AML/ALL – 50% Toxicity –Non-relapse mortality of 10 – 40% –Graft vs. Host disease (GVHD) of 40 – 60% Cost

3. 100-DAY MORTALITY AFTER HLA-IDENTICAL SIBLING TRANSPLANTS 1999-2000 SUM02_39.ppt MORTALITY, % 100 0 20 40 60 80 464 359 1,267 90 67 952 AMLALLCMLMDSAplastic Anemia Immune Deficiency Numbers on bars = numbers of patients evaluable CR1 CR2+ Other 386 173 212 433 437 258 CP AP BP

4. What is GVHD? An cell mediated reaction of donor origin against recipient tissues It requires: –a donor graft with immunologically competent cells –a recipient unable to mount immune response –recipient expresses tissue antigens that are not present in the donor.

5. Pathogenesis of GVHD Recipient Donor Donor T cells Recipient APC Present self Ags to Donor React to Recipient Ags

6. Why Does allogeneic BMT Work? “Roundup” theory – eradicate all hematopoeitic tissue

7. Rescue patient with healthy stem cells Graft vs. Host reactions a nuisance Why Does allogeneic BMT Work?

8. Past Approaches used to Improve Outcome Intensify regimen (More Roundup) Better matching (twin donor best?) Improve immune suppression –i.e. “GVHD prophylaxis” Remove immune cells capable of GVHD –“T cell depletion” started at UW

9. Clift, Blood, 76, 1867,1990 Intensified Regimen Randomized trial of 12.0 Gy vs. 15.75 Gy Total Body Irradiation & cyclophosphamide Lower risk of relapse… 12.0 Gy vs. 15.75 Gy

10. …BUT Higher rate of aGVHD 12.0 Gy vs. 15.75 Gy Higher non-relapse mortality 12.0 Gy vs. 15.75 Gy

11. GVHD Prophylaxis - How much? Aggressive Prophylaxis LESS GVHD MORE infection MORE relapse Minimal Prophylaxis MORE GVHD LESS infection LESS relapse SURVIVAL

12. Non-selective T cell depletion Relative Risk Grade 2-4 AGVHD0.50 Graft Rejection3.37 Relapse (5yr)1.87 Transplant Mortality1.60 Champlin, Blood, 95, 3996, 2000

13. Gale, Ann Intern Med 120:646, 1994 Twin – Best Donor?

14. Chronic GVHD marks long-term disease control Overall survival best with mild cGVHD Horowitz, Blood 75:555, 1990

15. Porter, NEJM 330:100, 1994 Donor Lymphocyte Infusion for relapse after allogeneic BMT Patient relapsing after allogeneic BMT for CML received donor lymphocyte infusions

16. Porter, BBMT 5:253, 1999 DLI for relapse after allogeneic BMT

17. Learning Points Preparative regimen provides short-term disease control – not cure. Preparative regimen toxicity increases risk of acute GVHD (“cytokine storm”) A “graft vs. disease” response exists –Varies with respect to disease Long term disease control related to immunological effects from the donor –Correlates with chronic GVHD

18. New Paradigm Hematopoeitic stem cell transplantation succeeds when a chronic “allo”immune process is created that is specific to the disease/diseased tissue. The “preparative regimen” is necessary to provide: –Sufficient immune suppression for donor engraftment And – Short-term disease control sufficient to allow the autoimmune process to develop.

19. Strategies for Improvement Reduce the intensity of the preparative regimen –Use agents specific to the disease & immunosuppressive Speed neutrophil engraftment –Peripheral blood stem cell collection Improve lymphoid immune reconstitution –Donor lymphocyte infusion

20. Spectrum of Preparative Regimens Immunosuppresion Myelosuppression 2Gy TBI FC Flag 2Gy TBI/Flu Cy/12Gy TBI MF Bu/Cy Bu/F/ATG Human LD 50 = 4Gy Myeloablative dose = 8Gy

21. Non-myeloablative Transplantion Seattle Study McSweeney, Blood 97:3390, 2001 Chimerism Analyses = “DNA fingerprinting” “Mini-transplant”

22. Patients – Seattle Study MM41 MDS26 CLL19 CML17 AML17 NHL19 HD12 Other5 Eligibility –Age greater than 50 Or –Ineligible for Conventional BMT Aspergillis infection Liver/cardiac/pulm disease Previous BMT McSweeney, Blood 97:3390, 2001

23. Neutrophil/Platelet changes after transplant McSweeney, Blood 97:3390, 2001

24. Graft vs. Host Disease McSweeney, Blood 97:3390, 2001 Lower risk of severe aGVHD Delayed onset Similar risk of cGVHD

25. Survival after Non-myeloablative Stem cell Transplant McSweeney, Blood 97:3390

26. Grade 3-5 toxicity by day 100 Organ systemNonmyeloablativeMyeloablative Cardiovascular47%74% Gastrointenstinal12%76% Hepatic37%57% Infection56%84% Pulmonary6%21% Diaconescu, Blood, 102:261a, 2003

27. Non-myeloablative transplant for Chronic Myeloid Leukemia Disease Free SurvivalChronic GVHD Or, Blood 101:441, 2003 N = 24

28. Overall and EFS Chronic GVHD Non-myeloablative transplant for Myelodysplastic Syndrome N = 16 Taussig, JCO 21:3060, 2003

29. Non-myeloablative transplant for Renal Cell Cancer Childs, NEJM 343:750, 2000 Time to responseOverall Survival N = 19

30. Problem: Early Disease Control Patient GN - IgA myeloma 2Gy TBI PBSCT DLI IgA CSA

31. Findings from NST trials Early toxicity reduced –Heme toxicity much shortened Outpatient management feasible Engraftment successful –with fludarabine added to regimen Risk of aGVHD reduced and delayed Risk of cGVHD unchanged but delayed Early disease progression common

32. Disease Sensitivity to “Graft vs. Malignancy” Sensitive –CML –Follicular lymphoma –Mantle cell lymphoma –CLL Insensitive –ALL –High-grade NHL Intermediate –AML –Diffuse large NHL –Multiple myeloma –Hodgkin disease –Renal cell –Breast cancer

33. Strategies to Improve NST Treat to remission prior to transplant Use disease specific chemotherapy in regimen Incorporate monoclonal antibodies Infuse engineered lymphocytes Use Auto followed by Allo strategy –Allow recovery/healing prior to allo transplant

34. “Auto/Allo” strategy for Myeloma High dose Melphalan Auto PBSCT Recovery 2 Gy TBI Allogeneic PBSCT Immune suppression BMT CTN 0102 60 – 90 days

35. “Auto/Allo” - Results 54 patients (median age 52) Overall 1-year survival 78% at 18 months Event Free Survival 2-year 55% Day-200 mortality 7% GVHD –Acute 39% –Chronic 46% Response Rate 81% (CR 52%, PR 29%) Maloney, Blood 98:1822a

36. Problem: Need for phase III trials! Blood and Marrow Transplant Clinical Trials Network (BMT CTN) –NCI sponsored cooperative trials group –Composed of 14 Core Transplant Centers –Goal to complete high-quality clinical trials in BMT

37. BMT CTN Protocol 0102 Myeloma

38. BMT CTN Protocol 0202 Follicular Lymphoma

39. Conclusions Allogeneic transplantation works due to a “Graft vs. Malignancy” immune response. NST approaches have improved the safety of transplantation. NST allows transplantation of patients not eligible for standard approaches. Phase III studies are need to determine place in therapy.