Management of idiopathic aplastic anemia in 2018 Rgis Peffault de - PowerPoint PPT Presentation

Management of idiopathic aplastic anemia in 2018 Régis Peffault de Latour, MD, PhD French reference center for aplastic anemia & PNH French network for rare immunological & hematological disorders (MaRIH) Severe aplastic anemia working party of EBMT (SAAWP EBMT) Hôpital Saint-Louis, Paris, France

Treatment (guidelines) Idiopathic aplastic anemia needed to be treated HLA-identical sibling donor No sibling donor and age < 40 or age 40 or more HSCT hATG + CSA Refractory/relapse Marrow / Cy + ATG / CSA MTX 10/10 (8/8 matched UD) Young (<30 years) First year YES: NO: Unrelated Eltrombopag matched BMT Repeated IST Alternative (mismatch BMT)

Treatment (guidelines) Idiopathic aplastic anemia needed to be treated HLA-identical sibling donor No sibling donor and age < 40 or age 40 or more HSCT hATG + CSA Refractory/relapse Marrow / Cy + ATG / CSA MTX 10/10 (8/8 matched UD) Young (<30 years) First year YES: NO: Unrelated Eltrombopag matched BMT Repeated IST Alternative (mismatch BMT)

Sibling transplantation Long-term Marrow / Cy-ATG / CSA + MTX (standard) As soon as possible (<100 days) 1.0 No of Survival probability 0.8 Event events 6yr-CI (%) Secondary cancer 1 2 (0-9) 0.6 87,5 % (CI 95%, 78-97) Osteonecrosis 10 21 (10-36) 0.4 Cardiovascular 61 patients 1 2 (0-9) 0.2 complications Median follow-up 77 months Endocrine 0.0 7 19 (9-31) dysfunctions 0 12 24 36 48 60 72 Time (months) N. at risk 61 53 38 35 33 30 28 Saint Louis experience. Konopacki J, et al. Haematologica. 2012;97:710-6.

Sibling transplantation Age is still a limitation Probability of overall survival, % Survival Years Days from transplant Bacigalupo A. Blood. 2017;129:1428-36. Gupta V, et al. Haematologica. 2010;95:2119-25.

Treatment (guidelines) Idiopathic aplastic anemia needed to be treated HLA-identical sibling donor No sibling donor and age < 40 or age 40 or more HSCT hATG + CSA Refractory/relapse Marrow /Cy + ATG / CSA MTX 10/10 (8/8 matched UD) Young (<30 years) First year YES: NO: Unrelated Eltrombopag matched BMT Repeated IST Alternative (mismatch BMT)

Horse ATG + Cyclosporine The French experience – response characteristics • Response characteristics • Responders • 40% at months 3 & 60% at months 6 Time to response Cum incidence (overall) Peffault de Latour R, et al. Am J Hematol. 2018;93:635-42.

Horse ATG + Cyclosporine The French experience – response characteristics • Response characteristics • Responders • 40% at months 3 & 60% at months 6 Time to response Cum incidence (overall) Peffault de Latour R, et al. Am J Hematol. 2018;93:635-42.

Horse ATG + Cyclosporine The French experience – response characteristics • Response characteristics • Responders • 40% at months 3 & 60% at months 6 • Better & quicker response for patients with moderate aplastic anemia Time to response Time to response Cum incidence (overall) Cum incidence (severity) Peffault de Latour R, et al. Am J Hematol. 2018;93:635-42.

Horse ATG + Cyclosporine The French experience – response characteristics • Response characteristics • Responders • 40% at months 3 & 60% at months 6 • Better & quicker response for patients with moderate aplastic anemia • Complete response is exceptional (!) Time to response Time to response Cum incidence (overall) Cum incidence (severity) Peffault de Latour R, et al. Am J Hematol. 2018;93:635-42.

Horse ATG + Cyclosporine The French experience – response characteristics • Response characteristics • Responders • 40% at months 3 & 60% at months 6 • Better & quicker response for patients with moderate aplastic anemia • Complete response is exceptional (!) • Refractory patients (about 30-40%) Time to response Time to response Cum incidence (overall) Cum incidence (severity) Refractory patients Peffault de Latour R, et al. Am J Hematol. 2018;93:635-42.

Any progress since 40 years? Anti-thymocyte globuline • Add androgens to ATG • No increase in response rate (Champlin, Blood 1985) • Add to or replace ATG with megadose corticosteroids • No increase in response; high toxicity (Marmontl, Prog Clin Biol Res 1984) • Replace ATG with high dose cyclophosphamide • Toxicity (Tisdale, Lancet 2001; Blood 2002) • Replace ATG with moderate dose cyclophosphamide • Excessive toxicity secondary to neutropenia (Scheinberg, Blood 2014) • Add mycophenolate mofetil to ATG/CsA • No improvement in response/survival (Scheinberg, Br J Haematol 2006) • Add sirolimus to ATG/CsA • No improvement in response/survival (Scheinberg, Haematologica 2009) • Add G-CSF to ATG/CsA • No improvement in response/survival (Locasciulli, Haematologica 2004) • Prolonged CsA (2 years) to prevent relapse • Delayed but ultimately equivalent rate (Scheinberg, Am J Hematol 2014)

Horse ATG + Cyclosporine The French experience – response characteristics • Response characteristics • Responders • 40% at months 3 & 60% at months 6 • Better & quicker response for patients with moderate aplastic anemia • Complete response is exceptional (!) • Refractory patients (about 30-40%) Time to response Cum incidence (overall) Refractory • Refractory patients = 2 questions: patients - Is it really acquired? - Clonal evolution? Peffault de Latour R, et al. Am J Hematol. 2018;93:635-42.

Treatment (guidelines) Idiopathic aplastic anemia needed to be treated HLA-identical sibling donor No sibling donor and age < 40 or age 40 or more HSCT hATG + CSA Refractory/relapse Marrow / Cy + ATG / CSA MTX 10/10 (8/8 matched UD) Unrelated Young (<30 years) transplantation? First year YES: NO: Unrelated Eltrombopag matched BMT Repeated IST Alternative (mismatch BMT)

Unrelated transplantation Guidelines & role of age Marrow as source of stem cells In the first year after diagnosis for refractory patients Flu Cy ATG Low dose TBI (EBMT / BMT CTN / Japan) <10 years (85%) 11-30 years (77%) Overall survival 30-40 years (66%) >40 years (49%) Time (day) Anderlini P et al , Lancet Hematol. 2015;2:e367-75. Bacigalupo, Blood 2016 In press; Bacigalupo A, et al. Haematologica. 2010;95:976-82. Devillier R, et al. Haematologica. 2016; 101:884-90. Eapen M, et al. Blood. 2011;118:2618-21. Marsh J, et al. Blood. 2011;118:2351-7.

Unrelated transplantation Decision making process 3 Risk factors - Age (30) - MUD versus mismatch UD - BMT in the first year post AA versus after French cohort Validation cohort (EBMT) (n=131) (n=751) Years post BMT Bacigalupo, Blood 2016; Devillier R, et al. Haematologica. 2016;101:884-90.

Treatment (guidelines) Idiopathic aplastic anemia needed to be treated HLA-identical sibling donor No sibling donor and age < 40 or age 40 or more HSCT hATG + CSA Refractory/relapse Marrow / Cy + ATG / CSA MTX 10/10 (8/8 matched UD) Young (<30 years) First year YES: NO: Unrelated Eltrombopag matched BMT Repeated IST Alternative (mismatch BMT)

Treatment (guidelines) Idiopathic aplastic anemia needed to be treated HLA-identical sibling donor No sibling donor and age < 40 or age 40 or more HSCT hATG + CSA Refractory/relapse Marrow / Cy + ATG / CSA MTX 10/10 (8/8 matched UD) Young (<30 years) First year YES: NO: Unrelated Eltrombopag matched BMT Repeated IST Alternative (mismatch BMT)

Treatment (guidelines) Idiopathic aplastic anemia needed to be treated HLA-identical sibling donor No sibling donor and age < 40 or age 40 or more HSCT hATG + CSA Refractory/relapse Marrow / Cy + ATG / CSA MTX 10/10 (8/8 matched UD) Young (<30 years) First year YES: NO: Unrelated Eltrombopag matched BMT Repeated IST Alternative (mismatch BMT)

TPO receptor agonist and refractory aplastic anemia Response rate 47 patients screened 26 patients enrolled (cohort 1) Four patients Response rate = 44% 25 patients received discontinued (11/25) eltrombopag treatment An additional six patients met the 18 patients (cohort 2) hematological received treatment response criteria = 40% (17/43) Overall response rate = 40% (17/43) Successful taper off eltrombopag and sustained multilineage response in five patients Adapted from Olnes M, et al. N Engl J Med. 2012;367:11-9. Desmond R, et al. Blood. 2014;123:1818-25.

TPO receptor agonist and refractory aplastic anemia Response rate 47 patients screened Olnes et al NEJM 2012 26 patients enrolled (cohort 1) Four patients Response rate = 44% 25 patients received discontinued (11/25) eltrombopag treatment An additional six patients met the 18 patients (cohort 2) hematological received treatment response criteria = 40% (17/43) Overall response rate = 40% (17/43) Successful taper off eltrombopag and sustained multilineage response in five patients Adapted from Olnes M, et al. N Engl J Med. 2012;367:11-9. Desmond R, et al. Blood. 2014;123:1818-25.