Il trapianto allogenico nelle SMD ad alto rischio

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1 Il trapianto allogenico nelle SMD ad alto rischio Stella Santarone Unità di Terapia Intensiva Ematologica per il Trapianto Emopoietico Pescara

2 AGENDA 1) QUANTI pazienti con MDS vengono allotrapiantati? 1) QUANDO trapiantare la MDS? 2) QUALI sono i candidati per la tipizzazione HLA? 3) Esperienza di Pescara 4) Fattori prognostici post-trapianto Studio GITMO 5) Terapia di condizionamento al TMO: Mieloablativo o non-mieloablativo? 6) Impatto prognostico della storia trasfusionale e del sovraccarico di ferro 7) Impatto prognostico del grado di fibrosi midollare 8) Impatto prognostico del disease tumor burden 9) CONCLUSIONI

3 La domanda Perche si trapiantano più leucemie se l incidenza delle MDS è la stessa se non superiore?...

4 HSCT in PESCARA n = 723 OTHER 18 AML % ALL 128 TM 132 SAA 42 LYMPH 35 MM 36 MDS 36 5% CML 108

5 GITMO ALLOTRAPIANTI n= 6869 LY: 880 ST: 363 MDS/MPS: 566 8,2% AA: 219 ID: 144 Thal: 329 IE: 52 AD: 6 LMA: % MM/PCD: 644 LMC: 548 LLC: 147 LLA: 1186 Leucemia Mieloide Acuta Leucemia Linfa5ca Cronica MielMult/Plasmacell Tumori Solidi Anemia Aplas5ca Talassemia MalaDe Autoimmuni Leucemia Linfa5ca Acuta Leucemia Mieloide Cronica Linfomi MDS/MPS Immunodeficienze Errori gene5ci

6 Myelodysplastic Syndromes Most common hematopoietic malignancy in the elderly Age years Incidence ( adults) > ,3 <50 0,6 PEDIATRICS Annual incidence: ~ 1.8 per million <14 yrs 4-5% of all childhood leukemia Comorbid diseases significantly impact treatment option and outcome

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8 Age at HSCT, by year

9 QUANDO trapiantare la MDS?

10 When to transplant? Intermediate 2/high-risk patients: immediate transplantation Intermediate 1/low risk: delayed transplantation at progress Characteristics of progression clinically important cytopenia increase of % marrow blasts or/and new chromosomal abnormality

11 QUALI sono i candidati per la tipizzazione HLA?

12 Which patients are candidates for HLA typing? Evidence and consensus-based practice guidelines for the therapy of primary MDS A statement from the Italian Society of Hematology Patients under 55 years old: HLA typing of the patient and siblings is recommended, irrispectively of the former s risk class or performance status Patients more than 55 years old but less than 65 years old: HLA typing is recommended only for those with a good performance status (ECOG 1-2)

13 Esperienza di Pescara

14 HSCT in MYELODISPLASTIC SYNDROME Pescara N. of patients 36 (M 25 - F 11) Median age, yr 50 (6 71) Diagnosis HSCT, mo 11 (5 105) IPSS Low INT-1 INT-2 High AML-MDS WPSS Low INT High Very High Unavailable

15 HSCT in MYELODISPLASTIC SYNDROME Pescara DONOR RELATED 28 HLA-id 23 1 ant. mm 2 Haploid. 3 MUD 8 A,B,DR id 7 1 ant. mm 1 SOURCE BM 25 PBSC 11 CONDITIONING MAC 22 BU 16 TREO 5 TBI 1 RIC 14 CTX 1 TH+MEL± FLU 11 TH+MEL+TBI 2

16 HSCT in MYELODISPLASTIC SYNDROME Pescara DISEASE-FREE 20 years All patients n = 36 Median follow-up mo 80 (12-230) 41%

17 HSCT in MYELODISPLASTIC SYNDROME Pescara Patient age IPSS <50 yr n=17 51% Low/INT 1 n=15 47% >50 yr n=19 32% INT 2/High n=21 35% P=NS P=NS

18 HSCT in MYELODISPLASTIC SYNDROME Pescara Conditioning Intensity Stem Cell Source RIC n=14 36% MAC n=22 48% BM n=25 41% PBSC n=11 39% P=NS P=NS

19 Registro GITMO MDS Allo ( ) N= 783 Median age 42 (0-71) Source of HSC Conditioning BM 396 Standard 331 PBSC 343 Reduced 174 BM+PBSC BM+CB PBSC+CB CB Unk Unk 2 Donor relation TBI Yes/No/Unk 219/531/1 Related 582 Alive Yes/No/Unk 364/412/7 Unrelated 195 Unk 6

20 Overall Survival: All patients Overall Survival: Related vs Unrelated donor 36% Unrelated 40% p=0.85 Related 32% days from BMT days from BMT

21 Fattori prognostici post-trapianto Studio GITMO

22 WHO CLASSIFICATION AND WPSS PREDICT POSTTRANSPLANTATION OUTCOME IN PATIENTS WITH MDS: A STUDY FROM THE GITMO Alessandrino EP et al. BLOOD 2008;112: MDS AML-MDS No. of patients Median age, yr 48 (17-67) 47 (23-72) Time Dx-HCT, mo Type of donor Sibling MUD Source of HCT PBSC / CB BM Conditioning MA RIC 9,5 (1-189) 8,3 (1-15) 166 (70%) 72 (30%) 139 (58%) 99 (42%) 156 (66%) 82 (34%) 83 (65%) 44 (35%) 61 (48%) 66 (52%) 89 (70%) 38 (30%) All patients (n=365) were classified according to: WHO IPSS - WPSS

23 WHO category TRM IPSS category WPSS category

24 WHO category Overall Survival IPSS category WPSS category

25 WHO CLASSIFICATION AND WPSS PREDICT POSTTRANSPLANTATION OUTCOME IN PATIENTS WITH MDS: A STUDY FROM THE GITMO Alessandrino EP et al. BLOOD 2008;112: CONCLUSIONS WHO classification and WPSS show a relavant prognostic value in posttransplantation outcome and might help decision making in transplantation; BIAS: retrospective study on a national transplantation registry, patient selection, missing data, long period of recruitment, different types of transplantation; A prospective validation of these results is needed

26 Terapia di condizionamento al TMO: Mieloablativo o non-mieloablativo?

27 REDUCED-INTENSITY vs CONVENTIONAL CONDITIONING FOR ALLO SCT USING HLA-IDENTICAL DONORS IN MDS Total number of patients 836 (IBMTR) Conventional conditioning 621 median age 45 (18-67) Reduced intensity conditioning 215 median age 56 (27-72) Martino R et al. Blood 2006;108:

28 REDUCED-INTENSITY vs CONVENTIONAL CONDITIONING FOR ALLO SCT USING HLA-IDENTICAL DONORS IN MDS NON RELAPSE MORTALITY and 36 months

29 REDUCED-INTENSITY vs CONVENTIONAL CONDITIONING FOR ALLO SCT USING HLA-IDENTICAL DONORS IN MDS OVERALL 36 months FROM A MULTIVARIATE COX MODEL

30 REDUCED-INTENSITY vs CONVENTIONAL CONDITIONING FOR ALLO SCT USING HLA-IDENTICAL DONORS IN MDS CONCLUSIONS The reduction in 3-year NRM after a heterogeneous group of RIC indicates that the goal of reducing early NRM with RICs has been accomplished, BUT at coast of a significantly higher risk of relapse. Thus, patients with no controindications for conventional conditioning should NOT receive RIC outside of prospective randomized trials.

31 CONVENTIONAL TRANSPLANT vs REDUCED INTENSITY CONDITIONING THE OPTIMAL BALANCE OCCURS WHEN THE COMBINATION OF CT and GVL OUTWHEIGHS THE RISK OF RELAPSE, GVHD AND TRM Porter DL Blood 2006;108:

32 Impatto prognostico della storia trasfusionale e del sovraccarico di ferro

33 PROGNOSTIC IMPACT OF PRE-TRANSPLANTATION TRANSFUSION HISTORY AND SECONDARY IRON OVERLOAD IN PATIENTS WITH MDS UNDERGOING ALLOGENIC SCT Alessandrino EP et al. HAEMATOLOGICA 2010;95: TRANSFUSION INDEPENDENT TRANSFUSION DEPENDENT No. of patients Hemoglobin (g/dl) 9,7 (7,9-11,2) 8,6 (7,1-9,6) Platelets (x10 9 /L) 64 (29-577) 46 (3-686) Ferritin (ng/ml) 426 (7-2260) 1326 ( )

34 PROGNOSTIC IMPACT OF PRE-TRANSPLANTATION TRANSFUSION HISTORY AND SECONDARY IRON OVERLOAD IN PATIENTS WITH MDS UNDERGOING ALLOGENIC SCT Alessandrino EP et al. HAEMATOLOGICA 2010;95: Overall Survival Non-relapse Mortality The curves were esnmated from mulnvariable Cox regression analysis

35 PROGNOSTIC IMPACT OF PRE-TRANSPLANTATION TRANSFUSION HISTORY AND SECONDARY IRON OVERLOAD IN PATIENTS WITH MDS UNDERGOING ALLOGENIC SCT Alessandrino EP et al. HAEMATOLOGICA 2010;95: Overall Survival Non-relapse Mortality The curves were esnmated from mulnvariable Cox regression analysis

36 PROGNOSTIC IMPACT OF PRE-TRANSPLANTATION TRANSFUSION HISTORY AND SECONDARY IRON OVERLOAD IN PATIENTS WITH MDS UNDERGOING ALLOGENIC SCT Alessandrino EP et al. HAEMATOLOGICA 2010;95: CONCLUSIONS Pre-transplantation transfusion history and serum ferritin have a significant prognostic value in MAC transplants inducing a significant increase of TRM; Patients with a long history of transfusion and evidence of iron overload at time of transplantation might benefit for a RIC regimen in order to reduce TRM; The possible role of pre-transplant chelation therapy is mandatory in a prospective study.

37 Impatto prognostico del grado di fibrosi midollare

38 Allogeneic stem cell transplantation for myelodysplastic syndromes with bone marrow fibrosis N. Kroger, Haematologica, 2011; 96 (2)

39 Allogeneic stem cell transplantation for myelodysplastic syndromes with bone marrow fibrosis CUMULATIVE INCIDENCE ENGRAFTMENT TREATMENT RELATED MORTALITY P= P= 0.34 RELAPSE P= 0.04 N. Kroger, Haematologica, 2011; 96 (2),

40 Allogeneic stem cell transplantation for myelodysplastic syndromes with bone marrow fibrosis Disease-Free Survival Overall Survival none none severe mild/mod severe mild/mod Months after SCT Months after SCT N. Kroger, Haematologica, 2011; 96 (2),

41 CONCLUSION Bone marrow fibrosis in MDS patients influences engraftment after allogeneic SCT BUT ONLY SEVERE bone marrow fibrosis affects survival because of a higher risk of relapse, while MDS patients with mild or moderate bone marrow fibrosis have an outcome COMPARABLE to that of MDS patients without bone marrow fibrosis.

42 Impatto prognostico del disease tumor burden

43 Allogeneic stem cell transplantation for Adults with Myelodysplastic Syndromes: importance of Pretransplant disease Burden Erica D. Warlick Biol. Blood Marrow Transplant, 15: 30-38,2009

44 Cumulative incidence of 1 year <5% blasts versus 5-20% blasts p= % blasts= 35% <5% blasts= 18%

45 Cumulative incidence of 1 year MAC conditioning versus NMA conditioning p=.07 NMA= 35% MA= 16%

46 Cumulative incidence of 1 year CR or <5% blasts at HCT MAC conditioning versus NMA conditioning p=.04 NMA= 31% MA= 9%

47 Disease-Free 1 year CR - <5% blasts % blasts CR= 80% p=.12 <5% blasts= 42% 5-20% blasts= 19%

48 Allogeneic stem cell transplantation for Adults with Myelodysplastic Syndromes: importance of Pretransplant disease Burden CONCLUSIONS Blast percentage <5% at HSCT is the major predictor of improved DFS and relapse and prior treatment to reach this disease status may have value in leading to improved DFS; MA conditioning is associated with lower relapse risk, particularly in patients with CR or <5% blasts, but is not able to overcome increased disease burden; NMA conditioning yields equivalent TRM, DFS, and OS, and is reasonable in patients unsuited for MA conditioning; The donor sources tested (PBSC, BM or CB) yielded similar outcomes. Erica D. Warlick Biol. Blood Marrow Transplant, 15: 30-38,2009

49 CONCLUSIONS HSCT in MDS (1) Allogeneic HSCT is a potentially curative treatment for MDS HSCT remains a high-risk treatment, however, and careful selection of patients is mandatory to ensure that this treatment approach is justified First choice therapy for patients < 55 yr with HLAid sibling donor MUD transplant feasible in patients whitout family donor

50 CONCLUSIONS HSCT in MDS (2) Relapse, GvHD and regimen-related toxicity still remain problems, although a significant reduction of TRM has been observed Patients with INT-2 or HIGH RISK: HSCT as soon as possible Patients with LOW or INT-1 RISK: HSCT may be postponed RIC transplant to be reserved to patients older than 55 yr or for patients with significative comorbidities

51 CASO CLINICO Uomo di 65 anni MDS LMMoC: anemia leucocitosi piastrinopenia Idrossiurea, AzaciNdina, Trasfusioni (RBC 20 PLT 82) Al trapianto: IPSS Intermedio 1 WPSS Intermedio Comorbidità (Sorror): 5 (obesità, fibrillazione atriale, aspergillosi polmonare, FEV1 76%)

52 CASO CLINICO Non donatore familiare HLA idennco Donatore MUD non indicato (età >65 anni) Un figlio 40 anni APLOIDENTICO (3/6) BlasN midollari al trapianto 5% Splenomegalia 18 cm FerriNna 983 Paziente fortemente monvato

53 Trapianto di midollo osseo non manipolato da donatore familiare aploidentico CONDIZIONAMENTO PROFILASSI GvHD CELLULE INFUSE TBF-RIC (Thiotepa 5 mg/kg+busilvex 6.4 mg/kg+fludarabina 150 mg/sq) ATG-F, CSA, MTX, MMF, Basiliximab MNC 0.69 x10 8 /Kg CD34 2,3 x10 6 /Kg CD3 33,7 x10 6 /Kg

54 Trapianto di midollo osseo non manipolato da donatore familiare aploidentico RISULTATI ATTECCHIMENTO PMN>500 g +27 PLT> g +23 GvHD acuta e cronica Follow-Up ASSENTE vivo in remissione completa +15 mesi post-tmo Ultimo emocromo Hb 15, 7 GB 8620 PMN 4000 PLT

55 TAKE HOME MESSAGE TUTTI I PAZIENTI < 70 ANNI DOVREBBERO ESSERE CONSIDERATI PER UNA PROCEDURA TRAPIANTOLOGICA