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

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Presentation on theme: "Is allo-SCT first line option for AA if sibling donor available? Surapol Issaragrisil Division of Hematology, Department of Medicine Siriraj Hospital,"— Presentation transcript:

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 No. of Cases Rate/10 6 yr Etiologic Fraction DrugsOther factors IAAAS2082.0*45%27%18% Thailand † 20-30%3%15-29% “ The Beggar” of Hematology First described by Paul Ehrlich 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 ; 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 IST HSCT EBMT Database

10 BMT vs IST Quality 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 Viollier R, et al. Ann Hematol Jan;8 4(1): BMT IST BMT

11 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 Jan;8 4(1): BMT vs IST Quality Adjusted Analysis in Aplastic Anemia

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% Young patients less than 20 years have best outcome Those over 50 years do poorest Those with years have intermediate outcome <20 vs 21-30p< vs 31-40p= vs 41-50p= vs >50p=0.005

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 ( ) Seattle, Sangiolo D et al. Biol Blood Marrow Transplant Oct;16(10): OS 65%

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

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

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

19 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 Cy/ATG as Conditioning Kahl et al. Br J Haematol Sep;130(5): Storb R et al. Biol Blood Marrow Transplant. 2001;7(1): Year after HSCT

20 ATG in Conditioning Regimen

21 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 ATG in Conditioning Regimen Bacigalupo A et al.Biol Blood Marrow Transplant. 2006;12:

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

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 Dec 29.

24 Cy/ATG as Conditioning: Long Term Follow Up 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% Konopacki J, et al. Haematologica Dec % 8% 25% Risk Factors for AVN

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:

26

27 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% Al-Zahrani H et al. Biol Blood Marrow Transplant. 2011;17: OS 79% 83% 71%

28 Alemtuzumab Based as Conditioning Fludarabine 30 mg/m 2 x 4 days, cyclophosphamide 300 mg/m 2 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 Marsh JC et al. Blood2011 ;118(8): Factors influencing OS2-year OSP value HSCT comorbidity index 0-1 vs ≥292% vs 42%<.001 Age (years) <50 vs ≥5092% vs 71%< yr OS 95% vs 83%

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

30 BM vs PB Stem Cell Source Schrezenmeier H et al. Blood 2007;110: Chronic GVHDOverall 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

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

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

33 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 Jul;17(7):

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

35 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 Feb 7.

36 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:

37 Effect of Serial Chimerism in SAA McCann S et al. Bone Marrow Transplantation (2007) 39, 109–114 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 = ) 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

38 Post-Transplantation Cyclophosphamide for GVHD Prophylaxis in SAA Dezern AE et al. Bone Marrow Transplant Jul;46(7): 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

39 Post-Transplantation Cyclophosphamide for GVHD Prophylaxis in SAA - Thailand 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 ATG 2.5 mg/kg/day Cy 50 mg/day Cy 60 mg/day Unmanipulated BMSC Issaragrisil S. Unpublished data. 2012

40 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 ;15(5): yr OS 2 nd HSCT within 3 mo 2 nd HSCT after 3 mo Good PS56%76% Poor PS33%61%

41 HLA Matched Sibling Transplatation in SAA: Comparison for Results in Asia StudyYearsN Median Age (years) Median transfusion units Conditioning Stem cell Graft rejection GVHDRelapseSurvival Japan Inamoto Cy/TLI 85%BMSC4.1% Acute 23%, chronic 29% No 81% at 7 yrs China Cheng NA Cy/ATG G- BMSC+ G-PBSC No Acute 16%, Chronic 36% No 82.5% at 1.5 yrs Taiwan Bai (MSD 84%) 22 NACy/TBI3.6% Acute 6.8%, Chronic 35% 3.8% 74% at 5 yrs Korea Kim Cy/ATG/PCB PBSC+ BMSC 5.6% Acute gr %, Chronic 11.9% 11.5% 89% at 6 yrs Korea Cho Cy/ATG/PCB 59%, Cy/ATG/Flu 31% PBSC + BMSC No Acute 9.4%, Chronic 18% NA 87.5% at 5 yrs Korea Ahn NA 12.5 Acute gr %, Chronic 18.8% NA 79% at 6 yrs Thailand Issaragrisil Cy 91% Cy/ATG 6% Flu/Cy/ATG 3 PBSC 78% BMSC 22% 6% Acute 12% Chronic 40% 15% 87% at 5 yrs Overall survival 83%

42 StudyYearsN Median Age (years) ResponseRelapse Clonal Evolution Survival Japan %22%6% 88% at 3 yrs Korea Ahn %7.1%NA69% at 6 yrs China Zheng %NA 81% at 5 yrs Japan Teramura % vs 76% (G-CSF vs no) 15% vs 42% 15 vs 6% 94% vs 88% at 4 yrs Japan Hattori survey %NA 80% at 3 yr Thailand Issaragrisil % NA 60% at 5 yrs Korea Chang MH % NANo 74.9% at 4 yrs China Wang W %NA 74% at 5 yrs Overall survival Immunosuppressive Therapy in SAA: Comparison for Results in Asia

43 Conclusion (1) HSCT in younger patients give better outcome HSCT may be performed in patients age 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

44 Conclusion (2) Marrow cell dose of x10 8 /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

45 Acknowledgements Andrea Bacigalupo HJ Deeg Simrit Parmar


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