MSD HSCT for AA indications, conditioning, GVHD prophylaxis

Transcription

1 MSD HSCT for AA indications, conditioning, GVHD prophylaxis André Tichelli Special thanks to - Jakob Passweg - Régis Peffault de Latour - Gérard Socié

2 The aim for this presentation At the end of this presentation you should know when and why to use matched sibling donor HSCT in aplastic anemia what we can expect from MSD HSCT - Prognosis what is the best stem cell source, conditioning regimen and GVHD prophylaxis in MSD HSCT 2 2

3 First-line treatment options for SAA: Indications for MSD Matched sibling donor BMT Exchanges the whole lymphohematopoietic system Curative treatment But risk of GVHD Immunosuppression Attacks or modulates immunereactive T cells Not curative treatment Risk of clonal evolution SAA EBMT Registry, updated

4 How to decide whether initial treatment is BMT or immunosuppression? Difference between BMT (HLA-id sibling) and Immunosuppression in 5-Year Failure Free Survival (%) after initial treatment Neutrophil AGE (years) Count (x 10 9 /L) Positive values: Negative values: Advantage BMT Advantage Immunosuppresion A.Bacigalupo et al., Seminars in Hematology.2000;37:

5 Survival Severity of the disease does not influence outcome in HSCT % 5-year overall survival 0.50 vsaa (n=1183) SAA (n=1526) 0.25 p= 0, Days since Transplantation SAA-EBMT registry, update July

6 Algorithm for first-line treatment in aplastic anemia SAA Age < 40yr > 40yr HLA identical sibling donor Yes No HSCT IS Marsh J. ASH

7 First-line treatment with MSD HSCT in acquired AA 1. What are the main obstacles? 2. Which is the optimal source of stem cells? 3. Which is the standard conditioning regimen? 4. Which is the standard prophylaxis for GVHD? 5. What is the influence of the age of the patient? 7 7

8 Graft rejection and GVHD are the main obstacles of HSCT in SAA - related to age <=10 <=20 <=30 <=40 >40 0 GvHD rejection p< p<

9 CUMULATIVE INCIDENCE, % Stem cell source and platelet recovery PB median = 15d BM median = 25d DAYS Frl03_11.ppt Schrezenmeier al Blood 2007; 110:

10 SURVIVAL PROBABILITY, % Bone marrow has to be preferred to peripheral blood in any case 100 BM (N = 722) PB (N = 151) P = MONTHS Schrezenmeier al Blood 2007; 110:

11 CUMULATIVE INCIDENCE, % Stem cell source and chronic GVHD PB (N = 114) P = MONTHS BM (N = 620) Schrezenmeier al Blood 2007; 110:

12 Survival advantage for BM versus PB sibling transplants in all age groups 20 years Retrospective analysis of the SAA-WP 1886 patients First matched sibling transplant Acquired aplastic anemia > 20 years Bacigalupo A. et al. Haematologica. 2012;97:

13 Centers attitude in respect of stem cell source over the years SAA Database 13 13

14 Probability of Overall Survival, % Randomized study on the conditioning: Cyclophosphamide with or without ATG Addition of ATG to preparative regiment did not significantly improve the outcome; advances in supportive care Cy (n=60) Cy + ATG (n=70) P= Champlin R et al. Blood. 2007;109: Years sfgm-tc.com 14 14

15 Conditioning with Cy and ATG improves survival in MSD HSCT ATG is a favorable predictor of outcome For BMT and PBPC Especially in patients >20 years Bacigalupo A. Et al. Haematologica. 2012;97:

16 Alemtuzumab vs ATG-based conditioning without irradiation for MSD HSCT OS all patients (MSD, 87; other 68) OS only MSD Retrospective study from the British Society for BMT Alemtuzumab -based conditioning 1oo patients ATG-based conditioning 55 patients Donor type MSD 87 patients MUD or other donor type 68 patients No survival advantage for MSD Marsh J. et al. BMT 2013;49:

17 Prophylaxis of GVHD: CSA and MTX versus CSA alone The use of CSA and MTX is associated with improved survival in patients with SAA who receive transplant from a matched sibling donor Locatelli F et al. From GITMO/EBMT. Blood. 2000;96:

18 Influence of age on 10-year survival in MSD HSCT with acquired SAA SAA-EBMT registry, update July

19 The problem of age causes of death according to age at HSCT survival 1,000 0,750 0,500 0,250 0,000 < 40 years, n=273 70% > 40 years, n=44 54% Interval Diagnosis/HSCT;240 days Previous IST (?) 0,0 1500,0 3000,0 4500,0 days from transplant % causes death rejection GvHD infection hemorr MOF heart <40 years >40 years Unpublished data; by courtesy of Gérard Socié and Régis Peffault de la Tour 19 19

20 Improved outcome in patients older than 30 years receiving MSD HSCT for SAA n = 30; median age 46 (31-66) n = 239; median age 39 (30-67) Trend of lower graft failure: 0% vs 11%, p=0.09) No difference in incidence of GVHD Overall survival Maury et al. Haematologica. 2009;94:

21 Can we improve the results in the elderly SAA with MSD Transplant Multicenter retrospective study: conditioning with Alemtuzumab + Fludara + Cyclophosph. 50 patients (21 MSD), median age 35 years (8-62), 12 patients 50 years Median time interval to HSCT: MSD 6 months Marsh J. et al. Blood. 2011;118:

22 Progressive mixed chimerism is at high risk of graft rejection McCann S et al. BMT. 2007; 39: Lawler M et al Br J Haematol. 2008;144:

23 What to do in case of mixed chimerism? Monitoring of chimeric status during cyclosporine withdrawal Myeloid Donor- derived T Ly. Increase CsA! this is not a Leukemia Recipient-derived 23 23

24 What is the influence of chimerism in HSCT for SAA? 21 patients with sequential split chimerism results In unfractionated peripheral blood, full donor chimerism In CD3 fraction stable mixed chimerism No rejection 1 patient with acute GVHD Marsh J. et al. Blood. 2011;118: Deeg J. Comment of Marsh et al. Blood 2011;118:

25 Outcome of patients with autologous recovery after BMT for aplastic anemia SAA Working Party, EBMT Autologous reconstitution (AR): 45 Graft failure (GF): 136 Stable engraftment (Control): 1024 Patient with autologous reconstitution More often peripheral blood Conditioning with Cy and ATG Risk factors for graft failure and autologus reconstitution Older age T cell depletion Longer interval from diagnosis to HSCT More transfusions Piccin A. et la. BMT 2010: 45;

26 Syngeneic HSCT in patients with aplastic anemia Patients characteristics N=88 Median age 21 (2-69) Second transplant, n=21 With conditioning, n=65 No conditioning, n=18 Treatment bevor syngeneic HSCT ATG (6) Cyclosporine (3) Other treatment (29) Gerull S. et al. Haematologica. 2013;98:

27 Outcome of first transplant with and without conditioning With conditioning (except 1) Gerull S. et al. Haematologica. 2013;98:

28 Risk of graft failure after syngeneic HSCT Gerull S. et al. Haematologica. 2013;98:

29 Failure-free survival for patients treated first with IS or BMT Bacigalupo A. Sem. Hematol. 2000; (37)

30 Take home message HSCT is the first-line treatment of choice for patients with SAA <40 years with an available MSD Bone marrow and not peripheral blood should be used as far as possible Cyclophosphamide and ATG belongs to the standard conditioning New conditioning regimens are under investigation Immunosuppression with MTX and CSA improves the outcome Age at HSCT has a major impact on outcome in SAA Improvement of the results in elderly patients (>40 years) with new conditioning regimens including fludarabine, and or alemtuzumab 30 30

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