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

2. Donor Safety

4. death BM 277701 PB 232544 5/36317 RELATED 0/14706 UNRELATED

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

6. SAE BM 2777012 PB 2325425

7. DONOR SAFETY 1.HSC donations carries a small, but proven hazard: we must be cautious (VERY) in selecting HSC donor 2. PB donations are not safer than BM Higher death rate and signficantly higher SAE rate for PB vs BM donations. Informed consent should say so 3. Accurate donor screening will reduce risk of lethal complications Lower death risk occurred in UNRELATED donations

8. Donor Safety Graft versus Host Disease

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

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

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

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

13. Day -7-6-5-4-3-2-10+3+4 BU 3.2 mg/kg x4 CY 50 mg/kg x2 UD or SIB BM Tx CY 50 mg /kg

15. GvHD 1.Prophylaxis with 2 drugs (C+M, T+M) is associated with significant acute+chronic GvHD 2. A third agent (ATG or CAMPATH or SIROLIMUS) signifanctly REDUCES acute +GvHD 3. ATG significantly reduces chronic GvHD 4. High dose CY post-Transplant may be a promising new option with or without C+M

16. Donor Safety Graft versus Host Disease Does reduction of GvHD translate in better OS?

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

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

19. Donor Safety Graft versus Host Disease Does eduction of GvHD translate in better OS? HLA matching criteria

20. Worse outcomes with

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

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

23. StudyReferenceN.patientsDiagnosis Survival disadvantage in mismatched pairs Type of mismatch One should avoid Seattlle Petersdorf Blood 2004; 104: 2976 1249LeukemiaEarly disC locus NMDP CIBMTR Lee Blood 2007 3860 AML ALL MDS CML Early disA or DRB1 JMDP Takakazu Blood 2007 110; 2235 5210 Malignant and non malignant All patients C locus Non permissive mismatches positions 9,77,80,99,116,156 Seattle Petersdorf Plos Med 2007; 4: 59 246LeukemiaAll patients Haplotype Mismatched GITMO Crocchiolo, Blood 2009, 114:1437 537LeukemiaAll patients DP non permissive mismacth CIBMTRCooley, Blood 2010, 116:2411 1409LeukemiaAMLDonor B gene content <2

24. 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)

25. Lancet February 15, 2012

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

27. V V

28. 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 Michallet 1, Lyon Abstract 2371 ASH 2010; Patients = 251 with acute leukemia and active donor search 2000-2008 The 3years OS for SD allo-HSCT59% UD allo-HSCT early registration: 47% UD allo-HSCT late registration: 29%

29. Donor selection EARLY DISEASE 1.Choose 8/8 = A,B,C,DRB1 donors 2. permissive DP mm should be preferred of non permissive mm 3.In AML patients, if possible, with a NK -B cent haplotype ADVANCED DISEASE The earlier, the better

30. Donor Registries Donor Safety Graft versus Host Disease Does eduction of GvHD translate in better OS? HLA matching criteria Stem cell source

31. 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 PBG05_3.ppt Eapen et al, Biol Blood Marrow Transplant, 2007

32. Months Cumulative Incidence, % 100 0 20 40 60 80 0361224 PB (N=451; 45%) BM (N=781; 46%) Transplant-Related Mortality Eapen et al, Biol Blood Marrow Transplant, 2007

33. Months Cumulative Incidence, % 100 0 20 40 60 80 0361224 BM (N=777; 40%) PB (N=447; 54%) Chronic GVHD

34. Months Cumulative Incidence, % 100 0 20 40 60 80 0361224 BM (N=781; 24%) PB (N=451; 26%) Relapse Eapen et al, Biol Blood Marrow Transplant, 2007

35. Probability, % 100 0 20 40 60 80 PB (N=451; 29%) BM (N=781; 31%) Months:0122436 No at Risk PB:45117912748 BM:781306230146 Leukemia-free Survival Eapen et al, Biol Blood Marrow Transplant, 2007

36. Randomized CTN trial (Anasetti et al ASH 2011) Median follow up 36 months Peripheral BLOODMARROWP 273278 Overall survival51%46%0.3 OS transplanted52%48%0.3 DFS transplanted47%44%0.6 Relapse28%28%0.8 NRM26%27%0,6 ANC 500 day 10095%86%0.09 aGvHD II-IV47%46%0.8 aGvHD III-IV16%14%0.3 cGvHD53%40%0.02 Ext cGvHD46%31%0.01

37. Stem cell source 1.Same TRM /relapse / LFS 2.More chronic GvHD Both in retrospective and prospective trials

38. PERIPHERAL BLOOD TRANSPLANTS DONORS # more SAE for PB donations (significant) # more deaths (ns) # should be stated in the informed consent PATIENTS # no protection against relapse # same TRM; same LFS # more chronic GvHD Should we continue to use PB grafts routinely? ??

39. Donor Registries Donor Safety Graft versus Host Disease HLA matching criteria Stem cell source Outcome

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

41. 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% P=0.1 P<0.0001 >2000 1991-00 1971-80 1981-90 days from transplant

42. Conclusions 1.Caution required for donor harvest (BM and especially PB) 2.Several options for HLA /non HLA donor selection 3.Three agents (C+M+other) for appropriate GvHD prophylaxis 4.Time to transplant= crucial factor 5. Should we continue to use PB??

43. Donor Registries

44. 2009 2010 Activations 44201 46919 BMT Tx 3445 (8%) 3574 (8%) PB Tx 8162 (18%) 9248 (20%) CB 3792 (9%) 4036 (9%) TOTtranspl 15399 (35%) 16858 (37%) WMDA 2012

45. REGISTRIES: Large Donor pool Searches Activated : UD Transplants = 44201 : 12822 = We are transplanting 1/3 of patients who activate a donor search (optimistically 50%)