Predicting response of severe aplastic anemia to immunosuppression combined with eltrombopag

Yoshitaka Zaimoku, Bhavisha A Patel, Ruba Shalhoub, Emma M Groarke, Xingmin Feng, Colin O Wu, Neal S Young, Yoshitaka Zaimoku, Bhavisha A Patel, Ruba Shalhoub, Emma M Groarke, Xingmin Feng, Colin O Wu, Neal S Young

Abstract

Pretreatment blood counts, particularly an absolute reticulocyte count ≥25×109/L, correlate with response to immunosuppressive therapy in severe aplastic anemia. In recent trials, eltrombopag combined with standard immunosuppressive therapy yielded superior responses than those to immunosuppressive therapy alone. Our single institution retrospective study aimed to elucidate whether historical predictors of response to immunosuppressive therapy alone were also associated with response to immunosuppressive therapy plus eltrombopag. We sought correlations of blood counts, thrombopoietin levels and the presence of paroxysmal nocturnal hemoglobinuria clones with both overall and complete responses in 416 patients with severe aplastic anemia, aged 2-82 years (median, 30 years), initially treated with immunosuppressive therapy plus eltrombopag between 2012 and 2019 (n=176) or with immunosuppressive therapy alone between 1999 and 2010 (n=240). Compared to non-responders, patients in the group of overall responders to immunosuppressive therapy plus eltrombopag had significantly higher pretreatment absolute reticulocyte counts, higher neutrophil counts and reduced thrombopoietin levels, as also observed for the group treated with immunosuppressive therapy alone. Addition of eltrombopag markedly improved the overall response in subjects with an absolute reticulocyte count between 10-30×109/L from 60% (54 of 90) to 91% (62 of 68). Absolute lymphocyte count correlated with complete response in the groups treated with immunosuppressive therapy with or without eltrombopag, especially in adolescents aged ≥10 years and adults, but the correlation was reversed in younger children. Platelet count and the presence of a paroxysmal nocturnal hemoglobinuria clone did not correlate with responses to immunosuppressive therapy. Blood counts remain the best predictors of response to nontransplant therapies in severe aplastic anemia. Addition of eltrombopag to immunosuppressive therapy shifted patients with a lower absolute reticulocyte count into a better prognostic category.

Trial registration: ClinicalTrials.gov NCT01623167.

Figures

Figure 1.
Figure 1.
Pretreatment blood counts and overall response. Absolute reticulocyte count, absolute neutrophil count, absolute lymphocyte count and plasma thrombopoietin level at baseline were compared between patients who achieved a response and those who did not at 6 months according to whether they were treated with immunosuppressive therapy plus eltrombopag or immunosuppressive therapy alone. ARC: absolute reticulocyte count; ANC: absolute neutrophil count; ALC: absolute lymphocyte count; TPO: thrombopoietin; NR: no response; OR: overall response; IST: immunosuppressive therapy; EPAG: eltrombopag.
Figure 2.
Figure 2.
Pretreatment absolute reticulocyte count and response rates to immunosuppressive therapy. (A) The overall response rates and their 90% confidence interval of individuals with an initial absolute reticulocyte count between X and (X+10) ×109/L in the group treated with immunosuppressive therapy (IST) plus eltrombopag (EPAG) and in the group treated with IST alone. (B) The overall response rates and the complete response rates were compared between the IST plus EPAG group and IST alone group according to initial absolute reticulocyte count. Overall response includes complete responses and partial responses. OR: overall response; ARC: absolute reticulocyte count; PR: partial response; CR: complete response.
Figure 3.
Figure 3.
Blood counts and complete response. Pretreatment absolute reticulocyte count, absolute neutrophil count, absolute lymphocyte count and plasma thrombopoietin level of patients in the groups treated with immunosuppressive therapy (IST) plus eltrombopag (EPAG) and IST alone are shown according to responses (complete, partial and none) at 6 months. Initial absolute lymphocyte count tended to be elevated in patients who achieved complete response after IST both with and without EPAG, but absolute reticulocyte count, absolute neutrophil count and thrombopoietin, could not discriminate who would go on to have a complete response. ARC: absolute reticulocyte count; ANC: absolute neutrophil count; ALC: absolute lymphocyte count; TPO: plasma thrombopoietin; NR: no response; PR: partial response; CR: complete response.

References

    1. Young NS. Aplastic anemia. N Engl J Med. 2018;379(17):1643-1656.
    1. Bacigalupo A. How I treat acquired aplastic anemia. Blood. 2017;129(11):1428-1436.
    1. Scheinberg P, Young NS. How I treat acquired aplastic anemia. Blood. 2012;120(6):1185-1196.
    1. Townsley DM, Scheinberg P, Winkler T, et al. . Eltrombopag added to standard immunosuppression for aplastic anemia. N Engl J Med. 2017;376(16):1540-1550.
    1. Peffault de Latour R, Marsh J, Iacobelli S, et al. . Results of the EBMT SAAWP phase III prospective randomized multicenter RACE study of horse ATG and ciclosporin with or without eltrombopag in naïve SAA patients [abstract]. In: 46th Annual Meeting of the EBMT. 2020 Aug 31-Sep 1; Virtual: 2020. Abstract O018.
    1. Olnes MJ, Scheinberg P, Calvo KR, et al. . Eltrombopag and improved hematopoiesis in refractory aplastic anemia. N Engl J Med. 2012;367(1):11-19.
    1. Desmond R, Townsley DM, Dumitriu B, et al. . Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug. Blood. 2014;123(12):1818-1825.
    1. Assi R, Garcia-Manero G, Ravandi F, et al. . Addition of eltrombopag to immunosuppressive therapy in patients with newly diagnosed aplastic anemia. Cancer. 2018;124(21):4192-4201.
    1. Lengline E, Drenou B, Peterlin P, et al. . Nationwide survey on the use of eltrombopag in patients with severe aplastic anemia: a report on behalf of the French Reference Center for Aplastic Anemia. Haematologica. 2018;103(2):212-220.
    1. Lee JW, Lee SE, Jung CW, et al. . Romiplostim in patients with refractory aplastic anaemia previously treated with immunosuppressive therapy: a dose-finding and long-term treatment phase 2 trial. Lancet Haematol. 2019;6(11):e562-e572.
    1. Ecsedi M, Lengline É, Knol-Bout C, et al. . Use of eltrombopag in aplastic anemia in Europe. Ann Hematol. 2019;98(6):1341-1350.
    1. Scheinberg P, Wu CO, Nunez O, Young NS. Predicting response to immunosuppressive therapy and survival in severe aplastic anaemia. Br J Haematol. 2009;144(2):206-216.
    1. Afable MG 2nd, Shaik M, Sugimoto Y, et al. . Efficacy of rabbit anti-thymocyte globulin in severe aplastic anemia. Haematologica. 2011;96(9):1269-1275.
    1. Shin SH, Yoon JH, Yahng SA, et al. . The efficacy of rabbit antithymocyte globulin with cyclosporine in comparison to horse antithymocyte globulin as a first-line treatment in adult patients with severe aplastic anemia: a single-center retrospective study. Ann Hematol. 2013;92(6):817-824.
    1. Narita A, Muramatsu H, Sekiya Y, et al. . Paroxysmal nocturnal hemoglobinuria and telomere length predicts response to immunosuppressive therapy in pediatric aplastic anemia. Haematologica. 2015;100(12):1546-1552.
    1. Elmahdi S, Muramatsu H, Narita A, et al. . Markedly high plasma thrombopoietin (TPO) level is a predictor of poor response to immunosuppressive therapy in children with acquired severe aplastic anemia. Pediatr Blood Cancer. 2016;63(4):659-664.
    1. Vaht K, Goransson M, Carlson K, et al. . Low response rate to ATG-based immunosuppressive therapy in very severe aplastic anaemia - a Swedish nationwide cohort study. Eur J Haematol. 2018;100(6):613-620.
    1. Cabannes-Hamy A, Boissel N, Peffault De Latour R, et al. . The effect of age in patients with acquired aplastic anaemia treated with immunosuppressive therapy: comparison of Adolescents and Young Adults with children and older adults. Br J Haematol. 2018;183(5):766-774.
    1. Chang MH, Kim KH, Kim HS, et al. . Predictors of response to immunosuppressive therapy with antithymocyte globulin and cyclosporine and prognostic factors for survival in patients with severe aplastic anemia. Eur J Haematol. 2010;84(2):154-159.
    1. Zhao X, Zhang L, Jing L, et al. . The role of paroxysmal nocturnal hemoglobinuria clones in response to immunosuppressive therapy of patients with severe aplastic anemia. Ann Hematol. 2015;94(7):1105-1110.
    1. Yoshida N, Yagasaki H, Hama A, et al. . Predicting response to immunosuppressive therapy in childhood aplastic anemia. Haematologica. 2011;96(5):771-774.
    1. Boddu P, Garcia-Manero G, Ravandi F, et al. . Clinical outcomes in adult patients with aplastic anemia: a single institution experience. Am J Hematol. 2017;92(12):1295-1302.
    1. Yoshizato T, Dumitriu B, Hosokawa K, et al. . Somatic mutations and clonal hematopoiesis in aplastic anemia. N Engl J Med. 2015;373(1):35-47.
    1. Sugimori C, Chuhjo T, Feng X, et al. . Minor population of CD55-CD59- blood cells predicts response to immunosuppressive therapy and prognosis in patients with aplastic anemia. Blood. 2006;107(4):1308-1314.
    1. Kulagin A, Lisukov I, Ivanova M, et al. . Prognostic value of paroxysmal nocturnal haemoglobinuria clone presence in aplastic anaemia patients treated with combined immunosuppression: results of two-centre prospective study. Br J Haematol. 2014;164(4):546-554.
    1. Sakaguchi H, Nishio N, Hama A, et al. . Peripheral blood lymphocyte telomere length as a predictor of response to immunosuppressive therapy in childhood aplastic anemia. Haematologica. 2014;99(8): 1312-1316.
    1. Kordasti S, Costantini B, Seidl T, et al. . Deep phenotyping of Tregs identifies an immune signature for idiopathic aplastic anemia and predicts response to treatment. Blood. 2016;128(9):1193-1205.
    1. Zaimoku Y, Patel BA, Kajigaya S, et al. . Deficit of CD19+ CD24hi CD38hi regulatory B cells in severe aplastic anaemia. Br J Haematol. 2020;190(4):610-617.
    1. Rosenfeld S, Follmann D, Nunez O, Young NS. Antithymocyte globulin and cyclosporine for severe aplastic anemia: association between hematologic response and long-term outcome. JAMA. 2003;289(9):1130-1135.
    1. Scheinberg P, Nunez O, Wu C, Young NS. Treatment of severe aplastic anaemia with combined immunosuppression: anti-thymocyte globulin, ciclosporin and mycophenolate mofetil. Br J Haematol. 2006;133(6):606-611.
    1. Scheinberg P, Wu CO, Nunez O, Boss C, Sloand EM, Young NS. Treatment of severe aplastic anemia with a combination of horse antithymocyte globulin and cyclosporine, with or without sirolimus: a prospective randomized study. Haematologica. 2009;94(3):348-354.
    1. Scheinberg P, Nunez O, Weinstein B, Biancotto A, Wu CO, Young NS. Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. N Engl J Med. 2011;365(5):430-438.
    1. Feng X, Scheinberg P, Wu CO, et al. . Cytokine signature profiles in acquired aplastic anemia and myelodysplastic syndromes. Haematologica. 2011;96(4):602-606.
    1. Kanda Y. Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant. 2013;48(3): 452-458.
    1. Bacigalupo A, Brand R, Oneto R, et al. . Treatment of acquired severe aplastic anemia: bone marrow transplantation compared with immunosuppressive therapy-- the European Group for Blood and Marrow Transplantation experience. Semin Hematol. 2000;37(1):69-80.
    1. Yoshida N, Kobayashi R, Yabe H, et al. . Firstline treatment for severe aplastic anemia in children: bone marrow transplantation from a matched family donor versus immunosuppressive therapy. Haematologica. 2014;99(12):1784-1791.
    1. Schrezenmeier H, Griesshammer M, Hornkohl A, et al. . Thrombopoietin serum levels in patients with aplastic anaemia: correlation with platelet count and persistent elevation in remission. Br J Haematol. 1998;100(3):571-576.
    1. Zhao X, Feng X, Wu Z, et al. . Persistent elevation of plasma thrombopoietin levels after treatment in severe aplastic anemia. Exp Hematol. 2018;58:39-43.
    1. Dunn DE, Tanawattanacharoen P, Boccuni P, et al. . Paroxysmal nocturnal hemoglobinuria cells in patients with bone marrow failure syndromes. Ann Intern Med. 1999;131(6): 401-408.
    1. Katagiri T, Sato-Otsubo A, Kashiwase K, et al. . Frequent loss of HLA alleles associated with copy number-neutral 6pLOH in acquired aplastic anemia. Blood. 2011;118(25):6601-6609.
    1. Zaimoku Y, Takamatsu H, Hosomichi K, et al. . Identification of an HLA class I allele closely involved in the autoantigen presentation in acquired aplastic anemia. Blood. 2017;129(21):2908-2916.
    1. Babushok DV, Duke JL, Xie HM, et al. . Somatic HLA mutations expose the role of class I-mediated autoimmunity in aplastic anemia and its clonal complications. Blood Adv. 2017;1(22):1900-1910.
    1. Katagiri T, Kawamoto H, Nakakuki T, et al. . Individual hematopoietic stem cells in human bone marrow of patients with aplastic anemia or myelodysplastic syndrome stably give rise to limited cell lineages. Stem Cells. 2013;31(3):536-546.
    1. Maruyama H, Katagiri T, Kashiwase K, et al. . Clinical significance and origin of leukocytes that lack HLA-A allele expression in patients with acquired aplastic anemia. Exp Hematol. 2016;44(10):931-939.
    1. Lee-Six H, Obro NF, Shepherd MS, et al. . Population dynamics of normal human blood inferred from somatic mutations. Nature. 2018;561(7724):473-478.
    1. Admiraal R, van Kesteren C, Jol-van der Zijde CM, et al. . Association between antithymocyte globulin exposure and CD4+ immune reconstitution in paediatric haemopoietic cell transplantation: a multicentre, retrospective pharmacodynamic cohort analysis. Lancet Haematol. 2015;2(5): e194-203.
    1. Admiraal R, Nierkens S, de Witte MA, et al. . Association between anti-thymocyte globulin exposure and survival outcomes in adult unrelated haemopoietic cell transplantation: a multicentre, retrospective, pharmacodynamic cohort analysis. Lancet Haematol. 2017;4(4):e183-e191.
    1. Soiffer RJ, Kim HT, McGuirk J, et al. . Prospective, randomized, double-blind, phase III clinical trial of anti-T-lymphocyte globulin to assess impact on chronic graftversus- host disease-free survival in patients undergoing HLA-matched unrelated myeloablative hematopoietic cell transplantation. J Clin Oncol. 2017;35(36):4003-4011.
    1. Kennedy VE, Chen H, Savani BN, et al. . Optimizing antithymocyte globulin dosing for unrelated donor allogeneic hematopoietic cell transplantation based on recipient absolute lymphocyte count. Biol Blood Marrow Transplant. 2018;24(1):150-155.
    1. Shearer WT, Rosenblatt HM, Gelman RS, et al. . Lymphocyte subsets in healthy children from birth through 18 years of age: the Pediatric AIDS Clinical Trials Group P1009 study. J Allergy Clin Immunol. 2003;112(5): 973-980.
    1. McCarron M, Osborne Y, Story CJ, Dempsey JL, Turner DR, Morley AA. Effect of age on lymphocyte proliferation. Mech Ageing Dev. 1987;41(3):211-218.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner