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Is allo-SCT first line option for AA if sibling donor available?

Is allo-SCT first line option for AA if sibling donor available?. Surapol Issaragrisil Division of Hematology, Department of Medicine Siriraj Hospital, Mahidol University Bangkok, Thailand. Incidence and Etiologic Fraction of Aplastic Anemia. “ The Beggar” of Hematology

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Is allo-SCT first line option for AA if sibling donor available?

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  1. Is allo-SCT first line option for AA if sibling donor available? Surapol Issaragrisil Division of Hematology, Department of Medicine Siriraj Hospital, Mahidol University Bangkok, Thailand

  2. Incidence and Etiologic Fraction of Aplastic Anemia “The Beggar” of Hematology 1888 - First described by Paul Ehrlich 1904 - Vagues and Aubertin – used term “Aplastic anemia”

  3. Outline of The Talk • Guideline for management of AA • HSCT vs IST • Improvement of MSD HSCT outcome

  4. UK Guideline For Management of Severe Aplastic Anemia Marsh JC et all. Br J Haematol. 2009;147:43-70.

  5. UK Guideline For Management of Non Severe Aplastic Anemia Marsh JC et all. Br J Haematol. 2009;147:43-70.

  6. Is allo-SCT first line option for AA if sibling donor available?

  7. First Line BMT vs IST • N = 2,479 • Better 10 year survival in BMT group vs IST • Favorable predictors : • Younger age - Transplant after 1996 • Matched sibling donor - Short diagnosis-transplant interval • No irradiation SAA-WP, BMT. Haematologica. 2007; 92:11-18

  8. First Line BMT vs IST • Meta analysis; N= 26 Non-RCT; N=7,955 ; 1970-2001 • Heterogeneity of non RCT studies did not justify a pooled estimate Peinemann F et al. Plos One. 2011;6(4):e18572.

  9. First-line Treatment Strategy • Results of MSD HSCT have improved overtime • Results of IST seem to be unchanged during the past decade HSCT IST EBMT Database. 2009.

  10. BMT vs ISTQuality Adjusted Analysis in Aplastic Anemia • BMT (n=52) or IST (n=155) • Survival, event-free survival, and Q-TWiST (Time without symptom and toxic ity) are similar • BMT-treated patients had longer periods free from symptoms, while IST-treated patients needed closer medical care, transfusion support, and medications BMT IST IST BMT Viollier R, et al. Ann Hematol. 2005 Jan;8 4(1):47-55.

  11. BMT vs ISTQuality Adjusted Analysis in Aplastic Anemia • TOX = treatment-related toxicity • TRANS = transfusion dependency • PR = partial remission • CLON = secondary clonal disorder • GVHD = extensive chronic graft-versus-host disease (GvHD) Viollier R, et al. Ann Hematol. 2005 Jan;8 4(1):47-55.

  12. Can We Improve The Result of MSD HSCT?

  13. Factors Predicting HSCT Outcome • Age • Interval from diagnosis to transplantation • Conditioning • Bone marrow cell dose • Stem cell source

  14. Allogeneic HSCT in SAA • Improved outcomes were seen overtime • Less so, in the last decade with OS rates close 80% <20 vs 21-30 p<0.0001 21-30 vs 31-40 p=0.1 31-40 vs 41-50 p=0.3 41-50 vs >50 p=0.005 • Young patients less than 20 years have best outcome • Those over 50 years do poorest • Those with 21-50 years have intermediate outcome

  15. HLA-identical Sibling HSCT in age > 40 years • Retrospective; n=23; median age = 49 (40-68) • High dose Cy + horse ATG; BMSC = 21, PBSC = 2; CSA+MTX • Acute GVHD 30%; Chronic GVHD 26% • Risk of early TRM: documented infection within 1 mo • Median FU 9.1 yr (0.9-19.2) OS 65% Seattle, Sangiolo D et al. Biol Blood Marrow Transplant. 2010 Oct;16(10):1411-8.

  16. Impact of Age on Outcomes After BMT Acute GVHD Chronic GVHD Overall Survival • N = 1,307 Toronto, Gupta V et al. Haematologica. 2010;95(12):2119-25.

  17. The Interval From Diagnosis to Transplant and Pretransplant IST ≤ 1998 >1998 ≤ 1998 >1998

  18. Cyclophosphamide Alone as Conditioning ≤1998 >1998 Seattle and EBMT 2009.

  19. Cy/ATG as Conditioning • In non-RCT, Cy + ATG is well tolerated and effective in heavily pretreated aplastic anemia patients • Lower incidence of chronic GVHD • Overall survival 88% with long term follow-up Year after HSCT Storb R et al. Biol Blood Marrow Transplant. 2001;7(1):39-44. Kahl et al. Br J Haematol. 2005 Sep;130(5):747-51.

  20. ATG in Conditioning Regimen

  21. ATG in Conditioning Regimen • ATG is a favorable predictor of outcome  both for BM and PB; especially for patients >20 years • ATG reduces chronic GvHD (and its consequence , BOS) • ATG improves survival Bacigalupo A et al.Biol Blood Marrow Transplant. 2006;12: 560-5.

  22. Cy vs Cy/ATG as Conditioning • A randomized controlled study • No difference in graft failure, GVHD and survival • The addition of ATG to conditioning regimen did not significant improve outcome P = 0.44 Champlin RE et al. Blood. 2007;109: 4582-4585.

  23. Cy/ATG as Conditioning: Long Term Follow Up • n=61; median age 21 years (4-43) • Median duration of the disease before HSCT 93 days • Cyclophosphamide 200mg/kg + antithymocyte globulin 2.5 mg/kg/day x 5 days  HLA matched sibling HSCT  CsA and MTX (days 1,3,6 11) • BMSC 97%; Primary graft failure 3% • acute grade II-IV GvHD 23%; chronic GvHD 32%  associated with higher number of infused CD3 cells (p=0.017) 6yr OS 87% Paris, Konopacki J, et al. Haematologica. 2011 Dec 29.

  24. Cy/ATG as Conditioning: Long Term Follow Up Risk Factors for AVN • Long term complication: • AVN 21% • Endocrine dysfunction 19% (3 had diabetes, 4 hypothyroidism, 4 dyslipidemia, 1 Cushing’s syndrome and 1 hypogonadism) • EBV associated HL 1% 61% 25% 8% Konopacki J, et al. Haematologica. 2011 Dec 29.

  25. Fludarabine Based as Conditioning in Patients over 30 years Retrospective; n = 30; median 46 (31-66) BMSC = 20, PBSC = 10 Reduced incidence of graft failure (0 vs 11 %, p = 0.09) No difference in GVHD Higher probability of overall survival when adjusting for recipient’s age Maury S et al. EBMT-SAAWP. Haematologica. 2009;94:1312-1315.

  26. Fludarabine Based as Conditioning • Prospective study; n = 38, median age = 20 yr (14-36); median FU = 43 mo • Flu/Cy  CSA + MTX; Unmanipulated BM stem cell • aGVHD grade ≥ II 11%; extensive cGVHD 25% • Graft rejection 3% ; D+100 TRM 16% 83% OS 79% 71% Al-Zahrani H et al. Biol Blood Marrow Transplant. 2011;17: 717-722.

  27. Alemtuzumab Based as Conditioning • Fludarabine 30 mg/m2 x 4 days, cyclophosphamide 300 mg/m2 x 4 days, and alemtuzumab median total dose of 60 mg • Cumulative incidence of graft failure was 9.5% • Acute GVHD 13.5% and chronic GVHD 4% • Low incidence of viral infection 2 yr OS 95% vs 83% Marsh JC et al. Blood2011 ;118(8):2351-7.

  28. Bone Marrow Cell Dose, Chronic GVHD and Survival Deeg HJ. Unpublished data.

  29. BM vs PB Stem Cell Source Chronic GVHD Overall survival • N = 692 (134 PBPC, 558 BM); HLA-matched siblings • Similar rates of hematopoietic recovery and grades 2 to 4 chronic GVHD • Higher chronic GVHD (RR 2.82; P = .002) and overall mortality (RR 2.04; P = .024) in patient < 20 years who received PBPC • BM grafts are preferred to PBPC grafts in young patients Schrezenmeier H et al. Blood 2007;110: 1397-1400.

  30. BM vs PB Stem Cell Source Bacigalupo A. Haematologica. 2012. Feb 7.

  31. BMSC Gives Survival Advantage in All Age Group Bacigalupo A. Haematologica. 2012. Feb 7.

  32. G-CSF stimulated BMSC vs BMSC vs PBSC • N = ( 78 G-BM, 547 BM, 134 PBPC) • No difference in neutrophil and platelet recovery rate • aGVHD and cGVHD were significantly higher in PBPC group • aGVHD and cGVHD were similar after G-BM and BM • Mortality risks were lower after transplantation of BM compared to G-BM (RR = 0.63, P = .05) • No advantage to using G-BM • BM is the preferred graft for HLA-matched sibling transplants for SAA Chu R et al. Biol Blood Marrow Transplant. 2011 Jul;17(7):1018-24.

  33. Negative Predictors for HLA identical HSCT in SAA Patients Bacigalupo A. Haematologica. 2012. Feb 7.

  34. Negative Predictors for HLA identical HSCT in SAA Patients • Interval ≥114 days • Age ≥20 years • Conditioning other than Cy 200 • No ATG in conditioning Bacigalupo A. Haematologica. 2012. Feb 7.

  35. CSA/MTX vs CSA alone as GVHD Prophylaxis • RCT; N = 71; median age 19 years (4-46) • HLA-identical BMT; Cy 200 mg/kg • Faster median time for neutrophil engraftment in CSA alone group (12 vs 17 days, p = 0.01) • Better 1 year TRM (3% vs 15%, p = 0.07) and 5 year survival (94% vs 78 %, p = 0.05) in CSA/MTX Locatelli F et al. Blood 2000; 96: 1690-1697.

  36. Effect of Serial Chimerism in SAA • N = 45 (72% Complete donor chimerism, 11% stable mixed chimerism, 17% progressive mixed chimerism) • The overall 5-year survival probability was 82% with a significant survival advantage (P = 0.0009) in CDC or SMC compared to those with PMC • Chronic GvHD was more frequent in CDC; no patient with SMC developed cGvHD • Graft failure occurred in 50% of the PMC McCann S et al. Bone Marrow Transplantation (2007) 39, 109–114

  37. Post-Transplantation Cyclophosphamide for GVHD Prophylaxis in SAA • 2 cases; age 54 and 55 years old • Myeloablative regimen in older, heavily pretreated and transfusion dependent • Successful engraftment, transfusion independent and no GVHD • Follow up time 12 months Dezern AE et al. Bone Marrow Transplant. 2011 Jul;46(7):1012-3.

  38. Post-Transplantation Cyclophosphamide for GVHD Prophylaxis in SAA - Thailand Cy 60 mg/day Unmanipulated BMSC ATG 2.5 mg/kg/day Cy 50 mg/day • 25-year-old female; median transfusion 30 unit; Positive for allo Ab • ANC engraftment = 15 days; Platelet engraftment = 24 days • CMV reactivation at D+33 • Post HSCT 1 mo = full donor chimerism • Acute skin GVHD gr I  well response to steroid • Follow up time 6 months Issaragrisil S. Unpublished data. 2012

  39. Second HLA-Matched Sibling Transplantion • N = 166 ( Primary graft failure 16%, secondary graft failure 84%) • Second HLA matched sibling HSCT with 88% use the same donor • BMSC 84% • non-engraftment 43%  early 100 day mortality rate 30% • Acute GVHD 9%, Chronic GVHD 16% Horan JT et al. Biol Blood Marrow Transplant. 2009 ;15(5):626-31.

  40. HLA Matched Sibling Transplatation in SAA: Comparison for Results in Asia

  41. Immunosuppressive Therapy in SAA:Comparison for Results in Asia

  42. Conclusion (1) • HSCT in younger patients give better outcome • HSCT may be performed in patients age 41-50 years with comparable outcome to those age below 40 years • Early transplant improves survival • Previous IST seems to have less effect on survival • Standard conditioning is high dose cyclophosphamide with or without ATG • Fludarabine based conditioning gives better outcome in patients age over 30 years

  43. Conclusion (2) • Marrow cell dose of 2.1-2.5 x108/kg is most appropriate to be transplanted • BMT is the standard therapy • PBSC should not be performed because of more incidence of GVHD and having a neagtive impact on survival and quality of life • Cyclosporin and short course methotrexate is the standard GVHD prophylaxis

  44. Acknowledgements • Andrea Bacigalupo • HJ Deeg • Simrit Parmar

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