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UNRELATED DONOR TRANSPLANTS A Bacigalupo, Ospedale San Martino, Genova, Italy

UNRELATED DONOR TRANSPLANTS A Bacigalupo, Ospedale San Martino, Genova, Italy. Donor Safety . death BM 27770 1 PB 23254 4 5/36317 RELATED 0/14706 UNRELATED . One additional death in Unrelated Donor Age = Gender=

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UNRELATED DONOR TRANSPLANTS A Bacigalupo, Ospedale San Martino, Genova, Italy

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  1. UNRELATED DONOR TRANSPLANTS A Bacigalupo, Ospedale San Martino, Genova, Italy

  2. Donor Safety

  3. death BM 27770 1 PB 23254 4 5/36317 RELATED 0/14706 UNRELATED

  4. One additional death in Unrelated Donor Age = Gender= Cause = repiratory insufficiency after attempted insertion of CVC , and bilateral pneumothorax

  5. SAE BM 27770 12 PB 23254 25

  6. DONOR SAFETY 1.HSC donationscarries a small, butprovenhazard: wemustbecautious (VERY) in selecting HSC donor 2. PB donations are notsaferthan BM Higherdeath rate and signficantlyhigher SAE rate for PB vs BM donations. Informedconsentshouldsay so 3. Accurate donor screening will reduce riskoflethalcomplications Lowerdeathriskoccurred in UNRELATED donations

  7. DonorSafety Graft versus HostDisease

  8. Preventing acute GvHD II-IV Blood 2000 BBMT 2008; BJH 2011 96:2062 14:920 Lancet Onc 2009:10 march 8

  9. Reduction of GvHD in alternative donor TX for 402 Myeloid Leukemias: Genova San Martino P<0.0001 P<0.0001

  10. Preventing Chronic GvHD Blood 2000 BBMT 2008; BJH 2011 96:2062 14:920 march 8

  11. Biol Blood Marrow Transpl ; 2006 ; 12: 560 Chronic GvHD P<0.0001 Lancet Oncol 2009; 10:855 P<0.0001 Same results with ATG Thymo Or ATG Fresenius

  12. UD or SIB BM Tx CY 50 mg/kg x2 CY 50 mg/kg CY 50 mg/kg BU 3.2 mg/kg x4 Day -7 -6 -5 -4 -3 -2 -1 0 +3 +4

  13. GvHD 1.Prophylaxis with 2 drugs (C+M, T+M) isassociatedwithsignificantacute+chronicGvHD 2. A thirdagent (ATG or CAMPATH or SIROLIMUS) signifanctly REDUCES acute +GvHD 3. ATG significantlyreduceschronicGvHD 4. High dose CY post-Transplantmaybe a promisingnewoption with or withoutC+M

  14. DonorSafety Graft versus HostDisease DoesreductionofGvHDtranslate in better OS?

  15. OS not significantly different (not inferior) with ATG vs no ATG GITMO trial (Thymo) BBMT 2006; 12:560 German trial (Thymo) Lancet Onc ; 2009

  16. Very long follow up (over 10 years) , may allow for late complications of chronic GvHD (in particular lung complications) to become clinically relevant

  17. DonorSafety Graft versus HostDisease DoeseductionofGvHDtranslate in better OS? HLA matchingcriteria

  18. Worse outcomes with

  19. Early Stage Disease: Adverse impact of HLA mismatch HLA-A ,B, C, DR Lee et al, 2007 Each mm yield 10-11% worse survival

  20. Advanced Disease: Limited impact of HLA mismatch HLA-A ,B, C, DR Delay had worse consequences than MM Lee et al, 2007

  21. KIR genes on Chromosome 19 Segregate indep. From HLA A group (inhibitory receptors) B group (activating receptors) A/A= homozygous for A B/x (at least one B)

  22. Lancet February 15, 2012

  23. HLA 10/10 match DP permiss mm # same TRM as DP= # lower TRM as DP non perm mm # lower Relapse as DP=

  24. V V

  25. Faster Registration on International Donor Registries and Shorter Time to Allogeneic Hematopoietic Stem Cell Transplantation After Having Found a Donor Confers Better Outcome In Acute Leukemia Patients Mauricette Michallet1, Lyon Abstract 2371 ASH 2010; Patients = 251 with acute leukemia and active donor search 2000-2008 The 3years OS for SD allo-HSCT 59% UD allo-HSCTearly registration: 47% UD allo-HSCTlate registration: 29%

  26. Donorselection EARLY DISEASE 1.Choose 8/8 = A,B,C,DRB1 donors 2. permissive DP mm shouldbepreferredof non permissive mm 3.In AML patients , ifpossible, with a NK -B cent haplotype ADVANCED DISEASE The earlier, the better

  27. DonorRegistries DonorSafety Graft versus HostDisease DoeseductionofGvHDtranslate in better OS? HLA matchingcriteria Stemcell source

  28. Patient Selection • Transplants in 2000-2003 • PB = 451 • BM = 781 • Age, 18-60 yrs • ALL, AML, MDS and CML • Excluded: • T-cell depleted grafts • Reduced Intensity Conditioning • Median follow-up: • PB, 34 months • BM, 38 months Eapen et al, Biol Blood Marrow Transplant, 2007 PBG05_3.ppt

  29. 100 80 60 BM (N=781; 46%) Cumulative Incidence, % 40 PB (N=451; 45%) 20 0 0 12 24 36 Months Transplant-Related Mortality Eapen et al, Biol Blood Marrow Transplant, 2007

  30. 100 80 60 Cumulative Incidence, % 40 PB (N=451; 26%) 20 BM (N=781; 24%) 0 0 12 24 36 Months Relapse Eapen et al, Biol Blood Marrow Transplant, 2007

  31. 100 80 60 Probability, % BM (N=781; 31%) 40 PB (N=451; 29%) 20 0 Months: 0 12 24 36 No at Risk PB: 451 179 127 48 BM: 781 306 230 146 Leukemia-free Survival Eapen et al, Biol Blood Marrow Transplant, 2007

  32. Randomized CTN trial (Anasetti et al ASH 2011) Median follow up 36 months Peripheral BLOOD MARROW P 273 278 Overall survival 51% 46% 0.3 OS transplanted 52% 48% 0.3 DFS transplanted 47% 44% 0.6 Relapse 28% 28% 0.8 NRM 26% 27% 0,6 ANC 500 day 100 95% 86% 0.09 aGvHD II-IV 47% 46% 0.8 aGvHD III-IV 16% 14% 0.3 cGvHD 53% 40% 0.02 Ext cGvHD 46% 31% 0.01

  33. Stemcell source 1.Same TRM /relapse / LFS 2.More chronicGvHD Both in retrospective and prospectivetrials

  34. PERIPHERAL BLOOD TRANSPLANTS DONORS # more SAE for PB donations (significant) # more deaths (ns) # shouldbestated in the informedconsent PATIENTS # no protectionagainstrelapse # same TRM; same LFS # more chronicGvHD Shouldwe continue touse PB graftsroutinely? ??

  35. DonorRegistries DonorSafety Graft versus HostDisease HLA matchingcriteria Stemcell source Outcome

  36. ACUTE LEUKAEMIA REGISTRY ADULTS TRANSPLANTED FROM 2000 TO 2010MATCHED UNRELATED DONOR / OS at 5 years AMLn=2901 ALLn=1655 50%±1 46%±2 CR1 (n=1117) 40%±2 CR1 (n=804) CR2 (n=879) 28%±2 CR2 (n=510) 21%±2 ADV (n=905) 13%±2 ADV (n=341)

  37. Matched Unrelated Transplants for SAA Effect of transplant era 10 year OS >2000 (752) 67% >1990 (230) 44% >1980 (27) 29% 1971-80 (1) 0% >2000 P<0.0001 1991-00 P=0.1 1981-90 1971-80 days from transplant

  38. Conclusions 1.Caution requiredfordonorharvest (BM and especially PB) 2.Several optionsfor HLA /non HLA donorselection 3.Three agents (C+M+other) for appropriate GvHDprophylaxis 4.Time totransplant=crucialfactor 5. Shouldwe continue touse PB??

  39. Donor Registries

  40. 2009 2010 WMDA 2012 Activations 44201 46919 BMT Tx 3445 (8%) 3574 (8%) PB Tx 8162 (18%) 9248 (20%) CB 3792 (9%) 4036 (9%) TOT transpl 15399 (35%) 16858 (37%)

  41. REGISTRIES: LargeDonor pool SearchesActivated : UD Transplants = 44201 : 12822 = We are transplanting 1/3 ofpatientswhoactivate a donorsearch (optimistically 50%)

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