Pacientes jovens sem doador com anemia aplástica grave devem receber TMO de fonte alternativa de CTH NO!

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1 Pacientes jovens sem doador com anemia aplástica grave devem receber TMO de fonte alternativa de CTH NO! Phillip Scheinberg, MD Head, Clinical Hematology Hospital A Beneficência Portuguesa de Sao Paulo

2 Conflitos de Interese Novartis Speaker, Advisory Pfizer Speaker Alexion Speaker, Advisory

4 Therapeutic options for SAA Allogeneic BMT Age < years HLA-matched donor (+) Severe or very severe AA Immunosuppressive therapy Hematological recovery in 60~70% of patients1,2 Supportive care Blood transfusions, management of infections, iron chelation therapy 1. Rosenfeld SJ, et al. Blood. 1995;85: Bacigalupo A, et al. Blood. 1995;85:

5 Guidelines for the diagnosis and management of adult aplastic anaemia British Journal of Haematology Volume 172, Issue 2, pages , 16 NOV 2015 DOI: /bjh

6 10-year survival of patients receiving the first-line immunosuppressive treatment (IST) or bone marrow transplantation from an HLA identical sibling (BMT) Int J Hematol 104: 168, 2016

7 Comparison of IST versus BMT in patients aged 1 20 years, before or after 1999 Int J Hematol 104: 168, 2016

8 Probability of overall survival adjusted for performance score, waiting time to transplantation and transplant conditioning regimen 2010 by Ferrata Storti Foundation Vikas Gupta et al. Haematologica 2010;95:

9 Overall survival and transplant era. Sabrina Giammarco et al. Blood 2018;131: by American Society of Hematology

10 (A) Cumulative incidence of acute GVHD. (B) Cumulative incidence of chronic GVHD. A B 2010 by Ferrata Storti Foundation Vikas Gupta et al. Haematologica 2010;95:

11 Guidelines for the diagnosis and management of adult aplastic anaemia British Journal of Haematology Volume 172, Issue 2, pages , 16 NOV 2015 DOI: /bjh IF

12 Peripheral blood vs bone marrow HSCT in SAA PBSC vs BMT Study N Acute GVHD II-IV Chronic GVHD Mortality Comment Schrezenmeie r (2007) 692 RR 1.42 (p=0.436) RR 2.82 (p=0.002) RR 2.04 (p=0.024) Related HSCT < 20 yrs Chu (2011) 759 RR 2.90 (P<0.001) RR 3.26 (p<0.001) RR 1.28 (P=0.212) Related HSCT All ages Eapen (2011) 296 RR 1.68 (p=0.02) RR 1.39 (p=0.14) RR 1.62 (p=0.04) MUD Bacigalupo (2012) % vs 11% (p=0.001) 22% vs 11% (p<0.001) RR 2.1 (p<0.001) Related HSCT all ages Schrezenmeier et al. Blood 110: 1397, 2007 Chu et al. Biol Blood Marrow Transplant 17: 1018, 2011 Eapen et al. Blood 118: 2618, 2011 Bacigalupo et al. Haematologica 97: 1142, 2012

1998 and 1999 2004 N=89 Median age 17 years Graft failure: 10% agvhd III IV: 22% cgvhd: 26%

13 Improved probability of survival after HSCT from unrelated donor with time Probability of survival after HSCT from unrelated donors for SAA according to period of transplantation: and N=89 Median age 17 years Graft failure: 10% agvhd III IV: 22% cgvhd: 26% Survival: 50% (n=52) (n=37) agvhd, acute GVHD; cgvhd, chronic GVHD Maury S et al. Haematologica 2007;92:

14 Survival by conditioning regimen dose in unrelated BMT Deeg HJ et al. Blood 2006;108:

15 Actuarial survival in patients with acquired SAA undergoing alternative donor transplants without radiation: the EBMT trial Actuarial survival of patients stratified according to age Median age 14 years Non-myeloablative MUD: Flu, Cy, ATG Bacigalupo A et al. Bone Marrow Transplant 2005;36:

16 Unrelated donor HSCT in severe aplastic anemia Study (year) N Conditioning Graft failure agvhd (II IV) cgvhd Survival Kim (2007) 40 Cy/TBI 5% 30% 38% 75% at 3 years Maury (2007) 89 Various 14% 50% 28% 42% at 5 years Viollier (2008) 349 Various 11% 28% 22% 57% at 5 years Kosaka (2008) 31 Cy/ATG/TBI Flu/Cy/ATG/TBI 16% 13% 13% 93% at 3 years Perez (2008) 195 Various 15% 43% 35% 51% at 5 years Bacigalupo (2010) 100 Flu/Cy/ATG Flu/Cy/ATG-TBI 17% 18% 27% (no TBI) 50% (TBI) 75% at 5 years Kang (2010) 28 Flu/Cy/ATG 0% 46% 35% 68% at 3 years Lee (2010) 50 Cy/ATG 0% 46% 50% 88% at 5 years Yagasaki (2010) 31 Various 3% 37% 27% 94% at 5 years Szpecht (2012) 38 Flu/Cy/ATG Treo/Cy/ATG 20% 64% at 5 years Marsh (2011) 29 FCC 15% 17% 7% 83% at 2 years Samarasinghe (2012) 44 FCC 0% 38.4% 6.8% 95% at 5 years FCC, cyclophosphamide and alemtuzumab; TBI, total body irradiation; Treo, treosulfan Scheinberg P et al. Blood 2012;120:

17 Increased cumulative incidence of acute and chronic GVHD in patients grafted from unrelated sibling donors Acute GVHD Chronic GVHD Bacigalupo A et al. Haematologica 2015;100:

18 Upfront MUD in children Br J Haematol 2015;171(4):590

19 Probability of response according Probability to age of response according to age Scheinberg P et al. J Pediatrics 2008

20 Survival Probability in Children witg ATG/CsA Overall Responders to IST

21 Survival (%) Survival (%) A randomised trial of hatg versus ratg in SAA: overall survival greater with hatg Censored for stem cell transplantation 100 Horse ATG Not censored for stem cell transplantation 100 Horse ATG Rabbit ATG Rabbit ATG P= P= Days 0 Horse ATG Rabbit ATG Days Horse ATG Rabbit ATG Median follow-up, all patients = 839 days (range, ) Median follow-up, surviving patients = 891 days (range, ) Scheinberg P et al. N Engl J Med 2011;365:

22 Proportion surviving Proportion surviving Prospective study of rabbit ATG and cyclosporine for aplastic anaemia from the EBMT Severe Aplastic Anaemia Working Party Phase II pilot study ratg + CSA (n=35) Retrospective matched comparison (pair-matched) with hatg + CSA (n=105) Pilot ratg + CSA study: OR 40% at 6 months (CR 3%, PR 37%) Overall survival for all patients hatg; n=105 ratg; n=35 86% 68% Transplant-free survival for all patients: transplant is considered an event hatg ratg 76% 52% This slide is already being used in Dr Townsley s slides, so will not need to be covered in detail P= Days from ATG P= Days from ATG ratg is inferior to hatg in first-line treatment of SAA, as indicated by haematologic response and survival Marsh JC et al. Blood 2012;119: CSA, cyclosporine A; hatg, horse antithymocyte globulin; ratg, rabbit antithymocyte globulin 22

23 Studies comparing horse and rabbit ATG as first therapy in SAA Study (year) hatg (N) ratg (N) hatg resp (%) ratg resp (%) Design Zheng (2006) 47 (LG) 32 (Fr) Prospective, randomized Atta (2010) 42 (LG) 29 (Thymo) Retrospective Afable (2011) 67 (ATGAM) 20 (Thymo) Retrospective Scheinberg (2011) 60 (ATGAM) 60 (Thymo) Prospective, randomized Marsh (2012) 105 (LG) 35 (Thymo) Prospective Shin (2013) 46 (LG) 53 (Thymo) Retrospective Yoshimi (2013) 96 (LG) 32 (Thymo) Retrospective Vallejo (2015) 62 (LG) 162 (Thymo) Retrospective *Only complete manuscripts that include a comparative analysis between the two ATG formulations are shown. Abstracts are not included ATGAM, lymphocyte immune globulin, Genzyme Corporation; LG, Lymphoglobulin, IMTIX SangStat Afable MG II et al. Haematologica 2011;96: ; Atta EH et al. Ann Hematol 2010;89: ; Marsh JC et al. Blood 2012;119: ; Scheinberg P et al. N Engl J Med 2011;365: ; Shin SH et al. Ann Hematol 2013;92: ; Vallejo C et al. Ann Hematol 2015;94: ; Yoshimi A et al. Blood 2013;121: ; Zheng Y et al. Exp Hematol 2006;34:

24 Rabbit ATG dose does affect survival (N=255) Clé, D, et al. Ann Hematol Jul 5. doi: /s [Epub ahead of print] 24

25 Cumulative incidence of acute and chronic GVHD Adjusted cumulative incidence HLA-matched sibling transplant Unrelated donor transplant Acute GVHD Chronic GVHD hatg, horse-derived ATG; ratg, rabbit-derived ATG Kekre N et al. Haematologica 2017;102: Atta, EH. PLoS One Sep 4;9(9):e107155

26 Treatment of refractory severe aplastic anaemia Refractory aplastic anaemia is defined as lack of response with persistence of severe pancytopenia at 6 months after one course of IST 1 Approximately one-third of patients with severe aplastic anaemia fail to respond to IST 2 HSCT should be considered if pancytopenia persists 6 months after IST 3 First choice in older and younger patients: matched sibling donor HSCT 3 Unrelated donor (UD) HSCT may be considered in younger patients 3 Survival rates have improved over time 4 Group 1: patients treated from 1989 to 1996 Group 2: patients treated from 1996 to 2002 Group 3: patients treated from 2002 to 2008 Five-year survival of patients with IST-refractory severe aplastic anaemia has improved over time, but is still below that observed for HSCT 4 1. Marsh JWC & Kulasekararaj AG. Blood 2013;122:3561; 2. Young NS, et al. Blood 2006;108:2509; 3. Scheinberg P. Hematology ASH Educ Program 2012;292; 4. Valdez JM, et al. Clin Infect Dis 2011;52: Non-responders to 1st (N=174) p<0.001 Group 3 5-year survival = 57% Time (years) Group 2 5-year survival = 35% Group 1 5-year survival = 23%

$receptor Breakthrough therapy designation for refractory SAA, FDA approval 2014 FDA (2014) and EMA (2015) approved for treatment of SAA MAPK/ERK EMA, European Medicines Agency; FDA, US Food and Drug$

27 ELTROMBOPAG: synthetic TPO-R agonist TPO-R JAK2 kinase Stat Eltrombopag & Transmembrane domain RAS/RAF MEK Orally administered non-peptide mimetic Interacts with the transmembrane domain of TPO receptor Breakthrough therapy designation for refractory SAA, FDA approval 2014 FDA (2014) and EMA (2015) approved for treatment of SAA MAPK/ERK EMA, European Medicines Agency; FDA, US Food and Drug Administration; Erickson-Miller C, et al. Exp Hematol 2005;33:85; Bussel JB and Pinheiro MP. In Hematopoietic Growth Factors in Oncology. 2011; Kuter D, et al. Seminars Hematol 2010;47:243; Kuter DJ. Blood 2007;109:4607;

$NEJM Original Article Eltrombopag and improved hematopoiesis in refractory$

28 NEJM Original Article Eltrombopag and improved hematopoiesis in refractory aplastic anemia Olnes MJ, Scheinberg P, et al. N Engl J Med 2012;367:11 19

29 Phase II study showed improved hematological responses in patients with refractory SAA Censure date 11/1/2011 Median follow up 13 months (range 4 28 months) 26 patients enrolled 11 responders (44%) Nine platelet responses Two hemoglobin responses additional four at >16 weeks Four neutrophil responses Additional five at >16 weeks 25 evaluable patients One patient ineligible, not treated 14 non-responders 10 stable disease Two died of progression Two clonal evolution to MDS One died One HSCT Olnes MJ, et al. N Engl J Med 2012;367:11 19

30 Eltrombopag and AA: extended cohort Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug Desmond R et al. Blood 2014;123: % (17/43) response rate Durable tri- and bilineage responses Platelet transfusion independence Well-tolerated

31 Bone marrow cellularity is sustained after discontinuation of eltrombopag Patient 1 Patient 2 Baseline 39 months on eltrombopag 6 months off drug Baseline 33 months on eltrombopag 6 months off drug Desmond R, et al. Blood 2014;123:

32 A Phase I II clinical trial of eltrombopag added to standard immunosuppression for AA Hematologic response hatg Days months 6 months CSA x 6 months Cohort 1 Cohort 2 Eltrombopag 150 mg Day 14 to 6 months Eltrombopag 150 mg Day 14 to 3 months 5-year follow-up Cohort 3 Eltrombopag 150 mg Day 1 to 6 months Primary endpoints: Complete response (CR) rate at 6 months and safety Secondary endpoints: Overall response (OR), partial response (PR), survival, clonal evolution and relapse CR = ANC 1x10 9 /L, hemoglobin 10 g/dl and platelets 100x10 9 /L PR = Blood counts no longer meeting criteria for SAA or CR CSA, cyclosporine A; hatg, horse anti-thymocyte globulin Townsley DM, Scheinberg P, et al. N Engl J Med 2017;376:

33 Hematologic response rate (%) Hematologic response rate (%) Eltrombopag added to IST improves hematologic response among patients with SAA Hematologic response at 3 months 1 Hematologic response at 6 months 1 OR CR PR OR CR PR Cohort 1 (N=30) Cohort 2 (N=31) Cohort 3 (N=31) All cohorts (N=92) Cohort 1 (N=30) Cohort 2 (N=31) Cohort 3 (N=31) All cohorts (N=92) Historical IST hematologic response at 6 months: OR 60 70%; CR ~10% 2,3 1. Townsley DM et al. N Engl J Med 2017;376: ; 2. Scheinberg P et al. Haematologica 2009;94: ; 3. Scheinberg P et al. N Engl J Med 2011;365:

34 Probability (%) Probability (%) Eltrombopag added to IST improves overall survival Survival Censored for HSCT Overall Survival (not censored for HSCT) % % Median follow-up 18 months (range 1 42 months) Time (days) Time (days) No. at risk: No. at risk: Townsley DM, Scheinberg P, et al. N Engl J Med 2017;376:

35 Eltrombopag as a first-line therapy for SAA without ATG SOAR trial FPFV May months 6 months Hematologic response CSA 12 months 12 months Eltrombopag 150 mg Day 0 to 6 months Phase II, open-label, single-arm trial to assess efficacy and safety of eltrombopag combined with CSA as first-line therapy in patients with SAA Primary endpoints: OR rate at 6 months Secondary endpoints: OR rate at 3 and 12 months, survival and safety FPFV, first patient first visit NCT

36 Haploidentical HSCT in SAA Bone Marrow Transplantation (2015) 50,

37 Sobrevida global da população de 384 pacientes com anemia aplástica (AA) tratados com CSA e PRD (HC-UFPR Courtesy of Larissa Medeiros Personal communication

MUD HSCT as first line Treatment in Idiopathic SAA. Dr Sujith Samarasinghe Great Ormond Street Hospital for Children, London, UK

MUD HSCT as first line Treatment in Idiopathic SAA Dr Sujith Samarasinghe Great Ormond Street Hospital for Children, London, UK No Financial Disclosures Guidelines for management of aplastic anaemia British