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Allogeneic “Mini” Transplantation

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

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Allogeneic “Mini” Transplantation

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  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 100 CR1 CR2+ Other CP AP BP 80 60 MORTALITY, % 173 40 464 67 437 212 20 258 359 386 952 433 1,267 90 0 AML ALL CML MDS AplasticAnemia ImmuneDeficiency Numbers on bars = numbers of patients evaluable SUM02_39.ppt

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

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

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

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

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

  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 Champlin, Blood, 95, 3996, 2000

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

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

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

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

  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 Cy/12Gy TBI Bu/F/ATG 2Gy TBI/Flu Bu/Cy MF Immunosuppresion FC Human LD50 = 4Gy 2Gy TBI Flag Myeloablative dose = 8Gy Myelosuppression

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

  22. MM 41 MDS 26 CLL 19 CML 17 AML 17 NHL 19 HD 12 Other 5 Eligibility Age greater than 50 Or Ineligible for Conventional BMT Aspergillis infection Liver/cardiac/pulm disease Previous BMT Patients – Seattle Study McSweeney, Blood 97:3390, 2001

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

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

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

  26. Grade 3-5 toxicity by day 100 Diaconescu, Blood, 102:261a, 2003

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

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

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

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

  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. 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 Disease Sensitivity to “Graft vs. Malignancy”

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

  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 0102Myeloma

  38. BMT CTN Protocol 0202Follicular 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.

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