1. Le malattie onco-ematologiche ed i trapianti di cellule staminali ematopoietiche Venezia14 maggio 2016 Università Cà Foscari Il Trapianto di cellule staminali emopoietiche in pazienti adulti Il ruolo del trapianto allogenico nel paziente con linfoma, mieloma, aplasia, malattie mieloproliferative croniche e malattie congenite dell’adulto Fabio Benedetti - CTMO Verona

2. Teams: 656 Transplants: 40.829 Allo Tx: 16.946 AutoTx:23.883

3. THALASSEMIA

4. malattia genetica (beta, alfa) malattia non neoplastica diffusa in Italia, medio oriente, Asia, India, Indonesia, Georgia, Armenia… In Italia 3 milioni di portatori primo trapianto in Seattle 1981 primo trapianto a Pesaro 1981 Allotrapianto nella Thalassemia

5. Lucarelli G, Blood Rev 2008 Allo BMT in Thalassemia: the Italian Experience

6. 01234567 0 0.2 0.4 0.6 0.8 1 PROBABILITY YEARS TRANSPLANT-RELATED MORTALITY REJECTION 67% 27% 8% THALASSEMIA-FREE SURVIVAL median follow-up: 4 years (1.7-6.8) BMT in Adult Thalassemia (BU14 CY90) Blood, 2002

7. Unrelated BMT for Thalassemia La Nasa et al. Bone Marrow Transplant, 2005 Class 3 adult patients, age >17 years; n=27

8. Copyright ©2010 American Society of Hematology. Copyright restrictions may apply. Sodani, P. et al. Blood 2010;115:1296-1302 Figure 2 Hemopoietic Stem Cell Transplant from related haploidentical donor. MIH experience on 22 patients of different classes.

9. Blood, 2013

11. Retrospective study Period 1968-2005 SCID699 Non-SCID783 J Allergy Clin Immune, 2010

13. Multiple Myeloma

14. What’s the role of transplant in MM? Results by myloablative conditioning TxRM: 20-60% OS at 3 y: 30-40%

15. What’s the role of transplant in MM? Results by non-myloablative conditioning TxRM: 15-40% OS at 3 y: 25-70%

16. JCO, 2012

17. OSDFS RELAPSE RATE: 45-54% Biol Blood Marrow Transplant, 2013

19. BMT, 2016

20. SAA

21. HLA identical sibling transplatation for SAA: the effect of age

22. Conditioning Regimen Cy 50 mg/Kg over 4 days GVHD prophylaxis CSA: 3 mg Kg ev MTX: 8 mg/m2,+1 6mg/m +2, +3, +6, +11 Pts: 71 (34 CSA vs 37 CSA+MTX) Conditioning: Cy 200 mg/Kg Age 19 y (range 4-46) IS pre-BMT 40% GFailure 6/7 1 (8%) 1 y TxRM: 15% with CSA 3% with CSA+MTX

23. Bacigalupo A, et al, Haematologica, 2010 13 y 27 y Graft failure 17% In both groups

24. NHL

25. BMT, 2014

26. Ann Hemat, 2012 b/w 1998-2008 93 italian centers 3449 Autologous Tx for DLBL 884 relapsed 165 Allo Tx (19%)

27. Ann Hemat, 2012 DFS

28. JCO, 2008

29. 62 pts (34 Sibli/28 MUD) Long-term DFS Good immunologic control Related donor

32. Reduced intensity conditioning (RIC) Allogeneic stem cell transplants

33. relatedunrelated (MUD) Mohamed L. Sorror, J Clin Oncol June 2005, 23:3819-3829 Donors: related/unrelated Hematopoietic Cell Transplantation After Nonmyeloablative Conditioning for Advanced Chronic Lymphocytic Leukemia

34. GvL activity in CLL wide circumstantial evidences that GvL is effective in CLL - long-term molecular responses can be obtained with allo- SCT but not with auto-SCT (Mattsson J et al., Leukemia 2000; Esteve J et al. Blood 2002) - reduced relapse risk in the presence of chronic GvHD (Dreger P et al., Leukemia 2005) - increased relapse risk associated with the use of T-cell- depleted allografts (Gribben JG et al., Blood 2005) - reports on the efficacy of donor lymphocyte infusion (Schetelig J et al., J Clin Oncol 2003; Gribben JG et al., Blood 2005; Caballero D et al., Clin Cancer Res 2005; I Ben-Bassat et al BMT 2007) I Ben-Bassat, Bone Marrow Transplantation, 2007

36. What is the impact of new drugs?

37. NHL-T

38. Vose, JCO 2008

39. JCO, 2014 treatmentn0RRCR1 y PFS sequential1385%6277 combination26100%8871

40. Leukemia, 2014 Age < 60 CHOP- HyperCHiDAM Auto/Allo No difference b/w Auto and Allo

41. Reduced Intensity conditioning in relapsed peripheral T-cell NHL: Kaplan-Meier curves P.Corradini, et al. JCO, 2004, 22: 2172-2177

42. HD

48. BMT, 2014

50. CML/MFI

51. Giralt SA et al, BJH, 2007 Impact of Imatinib on Allogeneic transplant activity in Nord America for CML: 1998-2003 1st CP62%44% 2nd CP/AP24%41% BC14%15%

53. First chronic phase (n = 695) Log-rank p-value < 0.0001 Blast phase (n = 45) Second chronic phase / Accelerated phase (n = 273) Chronic Myelogenous Leukemia Survival of Adult (Age  18 Years) Marrow Recipients with Myeloablative Preparative Regimens, by Disease Stage 1998–2006

54. Allo SCT in CML: guideline Allo SCT is recommended for the following pts: CP if refractory disease AP or BC at diagnosis (TKIs first as bridge to Tx) Progressive disease to AP or BC (2nd,3rd generation TKIs first as bridge to Tx)

55. Primary myelofibrosis:transplant with MA and RIC regimens BJH, 2012 TRM 10-42% OS 14-45%

56. BMT, 2014 9/14 engraft OS 78% EFS 64% TRM 7% GVHD ≥ II 43% GVHD > III 14%

57. thank you for your attention

58. BMT, 2014

59. Oncol Hematol. 2014

60. JCO, 2009 Prospective studies

61. JCO, 2009 Low Response rate pre HSCT 18 primary refractory 10 left study 3 y PFS 36%

67. Trapianto allogenico: indicazioni Malattie acquisiteMalattie congenite Neoplasie Aplasie Leucemia Acuta MieloideAnemia AplasticaErrori congeniti Mielodisplasie Anemia di FanconiImmunodeficienze Leucemie Acuta Linfoide Linfomi Leucemia Mieloide cronica Leucemia Linfatica cronica Tumori solidi pediatrici adulti

69. Trapianto allogenico: indicazioni Malattie acquisiteMalattie congenite Neoplasie Aplasie Leucemia Acuta MieloideAnemia AplasticaErrori congeniti Mielodisplasie Anemia di FanconiImmunodeficienze Leucemie Acuta Linfoide Linfomi Leucemia Mieloide cronica Leucemia Linfatica cronica Tumori solidi pediatrici adulti

71. First chronic phase (n = 105) Log-rank p-value = 0.004 Blast phase (n = 28) Second chronic phase / Accelerated phase (n = 117) Chronic Myelogenous Leukemia Survival of Adult (Age  18 Years) PBSC Recipients with Myeloablative Preparative Regimens, by Disease Stage 1998–2006 NMDP

72. Quality of life after IS or HSCT: a single center study III IS HSCT Voillier et al, Ann Hematol, 2005 transfusionslonger period free from symptoms medical care medications

73. BMT, 2014 13/14 engraft OS 78% EFS 64% TRM 7% GVHD ≥ II 43% GVHD > III 14%

74. HSCT from alternative donors for patients with SAA: conclusions Should be adopted after 1st line IS failure for patients 50 consider PS etc) High resolution HLA typing is mandatory A 10/10 or 9/10 matched is recommended Bone Marrow preferred The unrelated search should be started early

75. Allo SCT in CML: guideline Allo SCT is no longer recommended as 1st line treatment in CP (may be in very young pts?) Allo SCT is an alternative treatment for the following pts: CP if refractory disease Loss of CHR or MCyR (secondary resistance)?

76. Biol Blood Marrow Tranplant, 2012

77. Bacigalupo A, et al, Haematologica, 2010 For pts transplanted after 2004 and within 2 years: OS 92% Open questions:EBV LPD Graft failure (about 17%)

78. Thank to Velardi group work….. Blood, 2011

79. Biol Blood Marrow Tranplant, 2012

80. JCO, 2012

82. The ongoing phase III trial on upfront Brentuximab Vedotin in mature TCL