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Avichai Shimoni, MD Chaim Sheba Medical Center, Tel-Hashomer

Allogeneic hematopoietic stem cell transplantation when a matched sibling donor is not available: unrelated donors. Avichai Shimoni, MD Chaim Sheba Medical Center, Tel-Hashomer. INA06_1.ppt. HLA Genotypical matched sibling is the best donor for HSC transplantation

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Avichai Shimoni, MD Chaim Sheba Medical Center, Tel-Hashomer

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  1. Allogeneic hematopoietic stem cell transplantation when a matched sibling donor is not available: unrelated donors Avichai Shimoni, MD Chaim Sheba Medical Center, Tel-Hashomer INA06_1.ppt

  2. HLA Genotypical matched sibling is the best donor for HSC transplantation • Only 30% of patients have a matched sibling donor • 50-70% can find a suitable match in the unrelated donor registries, depending on ethnic origin • The median time from the start of search to transplant is 4 months.

  3. Results of MUD transplants • Results have markedly improved over the last decade • Better matching of donors high resolution DNA typing • Larger registries • Better supportive care, more tolerable conditioning regimens

  4. BMDW 4/2009

  5. Results of MUD transplants • Results have markedly improved over the last decade • Better matching of donors high resolution DNA typing • Larger registries • Better supportive care, more tolerable conditioning regimens

  6. Probability of Survival after Transplantation, 2000-2003- by Donor Type - 100 100 90 90 80 80 70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 0 Probability, % HLA-sib (N = 16,789) URD (N = 11,127) 0 1 2 3 4 5 6 Years

  7. 1-year Survival over Time, 1988 – 2005Data from NMDP and CIBMTR for patients <50 yrs, receiving HCT with myeloablative regimens for acute leukemias in any remission, CML or MDS

  8. Seattle data MUD Vs Sib

  9. Sheba experience • 325 pts with AML/MDS (n=256), ALL (n=69) transplanted between 2000-8 • Donor: HLA-matched sibling - 187 Matched unrelated - 138 • Median follow-up 44 months (range, 10-112 months)

  10. 5-yr OS MUD 37 (28-45) Sib37 (29-44)

  11. Alternative donor vs. Sib. Donor transplant • With modern HLA typing and supportive treatments the results of transplant from alternative donors (mainly unrelated donors) are not statistically significant different than transplant from sibling donors • The more GVHD and infections are somewhat balanced by stronger GVL effect • However hospitalization period and costs are much higher

  12. How Should We Select a Donor to Optimize Outcomes?

  13. Donor Selection – HLA Matching • General agreement that fully HLA-matched related or unrelated donor is the goal – but not every patient who needs a transplant will have one. • Prior large studies suggest conflicting strategies for choosing the best partially matched donor: • Antigens vs. alleles • Class I vs. class II • Specific loci

  14. Study Population • N = 3,860 US transplants, 1988-2003 • AML, ALL, CML, MDS • Myeloablative conditioning • Calcineurin inhibitor-based GVHD prophylaxis, T replete grafts (79%) • Bone marrow (94%) • Median follow-up 6 years

  15. Any Single Locus Mismatch 9/10 associated with worse survival, DFS, TRM, AGVHD

  16. Single Antigen vs Allele MM No statistical difference if mismatched at antigen or allele level, except for C

  17. Specific Single Locus Mismatches Considering 8/8 as “fully matched” Survival: Mismatch at A or DRB1 vs. B or C, RR 1.18 (1.10-1.38), p=0.04

  18. Survival 9-10% lower overall survival with each additional mismatch

  19. 50% 39% 28%

  20. 32% 27% 22%

  21. 17% 15% 10%

  22. Transplants Today are Using Better Matched Donors

  23. Sheba acute leukemia series mismatched MUD(≤9/10) 46% (n=50) Sibling 37% (n=187) matched MUD (10/10) 32% (n=85)

  24. Non-relapse mortality Non relapse mortality mismatched MUD 30% MUD (10/10)18% Sibling 20%

  25. relapse mortality Relapsemortality MUD (10/10) 51% Sibling 47% mismatched MUD 24%

  26. 10/10 MUD transplant has identical outcome as sibling transplants in patients with AML.

  27. Sheba MUD transplants 2000-9 • 260 pts • Diagnoses: • Matching: 10/10 165 pts 9/10 56 pts ≤ 8/10 37 pts

  28. Non-relapse mortality (all MUDs) mismatched MUD ≤ 9/10 MUD (10/10)

  29. relapse mortality (All MUDs) MUD (10/10) mismatched MUD ≤ 9/10

  30. MUD ≤ 10/10 MUD 10/10

  31. Mismatched Vs matched MUD • Mismatched MUD is associated with increased risk of non-relapse mortality, predominantly due to GVHD • Mismatched MUD is associated with potent graft-versus malignancy effect

  32. Mismatched Vs matched MUD –Cont.Why different than the NMDP study? • Kroger at al Biol Blood Marrow Transplant 4/2009 • 110 pts 10/10, 91 pts 9/10, 67 pts 6-8/10 • No difference in OS; 45%, 43%, 39% • No difference in TRM, relapse, GVHD • May be related to high dose ATG given in the conditioning ATG in NMDP study? • Other differences: study size, PBSC, RIC, % advanced disease

  33. BUT . . . Requiring a Fully Matched Donor Limits Access to HCT • HLA-matched unrelated adult donors are found for only ~1/2 of patients without an HLA-identical sibling • Time to identify a suitable donor is too long for some patients

  34. The only way to substantially improve access to (and outcome of) transplantation is to tolerate a certain amount of HLA-mismatching and avoid undue delays in treatment MUD search should be started early in the course of disease

  35. Conclusions (1) • Overall probability of survival after unrelated donor transplantation is 40-50% • Higher in young patients with early disease, fully matched donors • Worse in older patients with advanced disease, mismatched donors • Although 8/8 matched donors are preferred, using a partially mismatched donor may be preferable to delaying HCT • Decisions depend on predicted efficacy of HCT and alternative treatments, given patient’s constellation of risk factors

  36. Conclusions (2) • When selecting among mismatched donors: • Mismatching at HLA-DQ and HLA-DP are not associated with worse survival • The adverse effects of allele and antigen mismatches appear equivalent (except C) • When selecting among equivalently matched donors, consider: • Younger age • CMV negativity (for CMV – recipients) • Avoiding F to M transplants • To optimize outcomes, donor search should be initiated early in patient’s treatment course (increase the chance of finding a matched donor and decrease the chance of disease progression before HCT)

  37. 0 1 2 3 4 5 Adjusted Probability of Survival After Umbilical Cord Blood Transplantation in Adults 1.0 1.0 0.8 0.8 0.6 0.6 Adjusted Probability 0.4 0.4 BM, matched (n=367) CB, 1-2 Ag MM (n=150) 0.2 0.2 BM, 1 Ag MM (n=83) 0.0 0.0 Years

  38. 100 80 60 40 20 0 Leukemia-free Survival After Unrelated Donor Transplants by Graft Source CB matched (n=35) 60% CB 1-Ag MM high (n=157) 45% BM matched (n=116) 38% Adjusted Probability, % CB 2-Ag MM (n=267) 33% CB 1-Ag MM low (n=44) 36% 0 12 24 36 48 60 Months

  39. MUD vs. Haplo in AML • AML / ALL; age > 18y; 1st transplant1997 – 2007 • Haplo: 243 (Cicceri et al)AML ALL MUD* Haplo MUD Haplo CR1 1360 32 974 18 CR2 764 47 415 23 CR3 55 14 79 5 advanced 949 78 347 26 Total 3128 171 1815 72 • The European Group for Blood and Marrow Transplantation

  40. Haplo vs. MUD: 1y LFS AML all pts Haplo 23+/-4 MUD 12/12 42+/-7 0.02 MAC only Haplo 24+/-4 MUD 12/12 39+/-10 0.16 ALL all pts Haplo 26+/-6 MUD 12/12 58+/-9 0.1 MAC only Haplo 27+/-6 MUD 12/12 51+/-11 0.38 The European Group for Blood and Marrow Transplantation

  41. Haplo-identical transplants: results by disease status

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