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Eltrombopag for post-transplant cytopenias due to poor graft function

Bone Marrow Transplantation volume 54, pages 1346–1353 (2019)Cite this article

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Abstract

Persistent cytopenia due to poor graft function (PoGF) is a relatively common complication which may affect up to 20% of patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Treatment options for PoGF remain limited, and reinfusion of additional HSC is often the only way to rescue hematopoiesis. Here we describe a retrospective single-center experience with the thrombopoietin-mimetic agent eltrombopag for the treatment of PoGF. Thirteen patients have received eltrombopag for either PoGF (n = 12) or primary graft failure (n = 1). In the 12 PoGF patients eltrombopag was started at the median time of 79 days after HSCT, due to persistent thrombocytopenia, with concomitant anemia and neutropenia in 7 and 3 patients, respectively. The treatment was started at the dose of 50 mg per day, and eventually increased up to 150 mg in case of lack of response. Hematological response was seen in 7 patients, with 6 complete responses. Hematological responses were seen both in patients with evidence of immune-mediated pathophysiology, and with possible infectious/iatrogenic causes. In responding patients, eltrombopag was discontinued in 6/7 patients without further relapse. These results suggest that eltrombopag is safe and possibly effective in the setting of the treatment of PoGF, and pave the way for future prospective studies.

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References

  1. Olsson R, Remberger M, Schaffer M, Berggren DM, Svahn BM, Mattsson J, et al. Graft failure in the modern era of allogeneic hematopoietic SCT. Bone Marrow Transplant. 2013;48:537–43. https://doi.org/10.1038/bmt.2012.239

    Article  CAS  PubMed  Google Scholar 

  2. Lee KH, Lee JH, Choi SJ, Lee JH, Kim S, Seol M, et al. Failure of trilineage blood cell reconstitution after initial neutrophil engraftment in patients undergoing allogeneic hematopoietic cell transplantation—frequency and outcomes. Bone Marrow Transplant. 2004;33:729–34. https://doi.org/10.1038/sj.bmt.1704428

    Article  PubMed  Google Scholar 

  3. Kong Y, Chang YJ, Wang YZ, Chen YH, Han W, Wang Y, et al. Association of an impaired bone marrow microenvironment with secondary poor graft function after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2013;19:1465–73. https://doi.org/10.1016/j.bbmt.2013.07.014

    Article  PubMed  Google Scholar 

  4. Dominietto A, Raiola AM, van Lint MT, Lamparelli T, Gualandi F, Berisso G, et al. Factors influencing haematological recovery after allogeneic haemopoietic stem cell transplants: graft-versus-host disease, donor type, cytomegalovirus infections and cell dose. Br J Haematol. 2001;112:219–27.

    Article  CAS  PubMed  Google Scholar 

  5. Weaver CH, Hazelton B, Birch R, Palmer P, Allen C, Schwartzberg L, et al. An analysis of engraftment kinetics as a function of the CD34 content of peripheral blood progenitor cell collections in 692 patients after the administration of myeloablative chemotherapy. Blood. 1995;86:3961–9.

    Article  CAS  PubMed  Google Scholar 

  6. Davies SM, Kollman C, Anasetti C, Antin JH, Gajewski J, Casper JT, et al. Engraftment and survival after unrelated-donor bone marrow transplantation: a report from the national marrow donor program. Blood. 2000;96:4096–102.

    Article  CAS  PubMed  Google Scholar 

  7. Petersdorf EW, Mickelson EM, Anasetti C, Martin PJ, Woolfrey AE, Hansen JA. Effect of HLA mismatches on the outcome of hematopoietic transplants. Curr Opin Immunol. 1999;11:521–6.

    Article  CAS  PubMed  Google Scholar 

  8. Anasetti C, Amos D, Beatty PG, Appelbaum FR, Bensinger W, Buckner CD, et al. Effect of HLA compatibility on engraftment of bone marrow transplants in patients with leukemia or lymphoma. N Eng J Med. 1989;320:197–204. https://doi.org/10.1056/NEJM198901263200401

    Article  CAS  Google Scholar 

  9. Larocca A, Piaggio G, Podesta M, Pitto A, Bruno B, Di Grazia C, et al. Boost of CD34 + -selected peripheral blood cells without further conditioning in patients with poor graft function following allogeneic stem cell transplantation. Haematologica. 2006;91:935–40.

    PubMed  Google Scholar 

  10. Stasia A, Ghiso A, Galaverna F, Raiola AM, Gualandi F, Luchetti S, et al. CD34 selected cells for the treatment of poor graft function after allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2014;20:1440–3. https://doi.org/10.1016/j.bbmt.2014.05.016

    Article  CAS  PubMed  Google Scholar 

  11. Bussel JB, Cheng G, Saleh MN, Psaila B, Kovaleva L, Meddeb B, et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Eng J Med. 2007;357:2237–47. https://doi.org/10.1056/NEJMoa073275

    Article  CAS  Google Scholar 

  12. Desmond R, Townsley DM, Dumitriu B, Olnes MJ, Scheinberg P, Bevans M, et al. Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug. Blood. 2014;123:1818–25. https://doi.org/10.1182/blood-2013-10-534743

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Olnes MJ, Scheinberg P, Calvo KR, Desmond R, Tang Y, Dumitriu B, et al. Eltrombopag and improved hematopoiesis in refractory aplastic anemia. N Eng J Med. 2012;367:11–19. https://doi.org/10.1056/NEJMoa1200931

    Article  CAS  Google Scholar 

  14. Townsley DM, Scheinberg P, Winkler T, Desmond R, Dumitriu B, Rios O, et al. Eltrombopag added to standard Immunosuppression for aplastic anemia. N Eng J Med. 2017;376:1540–50. https://doi.org/10.1056/NEJMoa1613878

    Article  CAS  Google Scholar 

  15. Marsh JC, Mufti GJ. Eltrombopag: a stem cell cookie? Blood. 2014;123:1774–5. https://doi.org/10.1182/blood-2014-02-553404

    Article  CAS  PubMed  Google Scholar 

  16. Marsh JC, Gupta V, Lim Z, Ho AY, Ireland RM, Hayden J, et al. Alemtuzumab with fludarabine and cyclophosphamide reduces chronic graft-versus-host disease after allogeneic stem cell transplantation for acquired aplastic anemia. Blood. 2011;118:2351–7. https://doi.org/10.1182/blood-2010-12-327536

    Article  CAS  PubMed  Google Scholar 

  17. Raiola AM, Dominietto A, Ghiso A, Di Grazia C, Lamparelli T, Gualandi F, et al. Unmanipulated haploidentical bone marrow transplantation and posttransplantation cyclophosphamide for hematologic malignancies after myeloablative conditioning. Biol Blood Marrow Transplant. 2013;19:117–22. https://doi.org/10.1016/j.bbmt.2012.08.014

    Article  CAS  PubMed  Google Scholar 

  18. Oliva EN, Alati C, Santini V, Poloni A, Molteni A, Niscola P, et al. Eltrombopag versus placebo for low-risk myelodysplastic syndromes with thrombocytopenia (EQoL-MDS): phase 1 results of a single-blind, randomised, controlled, phase 2 superiority trial. Lancet Haematol. 2017;4:e127–e136. https://doi.org/10.1016/S2352-3026(17)30012-1

    Article  PubMed  Google Scholar 

  19. Selleri C, Maciejewski JP, De Rosa G, Raiola A, Risitano AM, Picardi M, et al. Long-lasting decrease of marrow and circulating long-term culture initiating cells after allogeneic bone marrow transplant. Bone Marrow Transplant. 1999;23:1029–37. https://doi.org/10.1038/sj.bmt.1701759

    Article  CAS  PubMed  Google Scholar 

  20. Raiola AM, Risitano A, Sacchi N, Giannoni L, Signori A, Aquino S, et al. Impact of HLA disparity in haploidentical bone marrow transplantation followed by high-dose cyclophosphamide. Biol Blood Marrow Transplant. 2018;24:119–26. https://doi.org/10.1016/j.bbmt.2017.10.002

    Article  CAS  PubMed  Google Scholar 

  21. Luzzatto L, Risitano AM. Advances in understanding the pathogenesis of acquired aplastic anaemia. Br J Haematol. 2018. https://doi.org/10.1111/bjh.15443

    Article  PubMed  Google Scholar 

  22. Marsh JC, Chang J, Testa NG, Hows JM, Dexter TM. The hematopoietic defect in aplastic anemia assessed by long-term marrow culture. Blood. 1990;76:1748–57.

    Article  CAS  PubMed  Google Scholar 

  23. Maciejewski JP, Kim S, Sloand E, Selleri C, Young NS. Sustained long-term hematologic recovery despite a marked quantitative defect in the stem cell compartment of patients with aplastic anemia after immunosuppressive therapy. Am J Hematol. 2000;65:123–31.

    Article  CAS  PubMed  Google Scholar 

  24. Busca A, Dellacasa C, Giaccone L, Manetta S, Biale L, Godio L, et al. Eltrombopag for the Treatment of Refractory Pure RBC Aplasia after Major ABO Incompatible Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2018. https://doi.org/10.1016/j.bbmt.2018.04.022

    Article  CAS  PubMed  Google Scholar 

  25. Tang C, Chen F, Kong D, Ma Q, Dai H, Yin J, et al. Successful treatment of secondary poor graft function post allogeneic hematopoietic stem cell transplantation with eltrombopag. J Hematol Oncol. 2018;11:103 https://doi.org/10.1186/s13045-018-0649-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Li S, Wu R, Wang B, Fu L, Zhu G, Zhou X, et al. Eltrombopag for delayed platelet recovery and secondary thrombocytopenia following allogeneic stem cell transplantation in children. J Pediat Hematol. 2018. https://doi.org/10.1097/MPH.0000000000001263

    Article  CAS  PubMed  Google Scholar 

  27. Master S, Dwary A, Mansour R, Mills GM, Koshy N. Use of Eltrombopag in Improving Poor Graft Function after Allogeneic Hematopoietic StemCell Transplantation. Case Rep Oncol. 2018;11:191–5. https://doi.org/10.1159/000487229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ali S, Gassas A, Kirby-Allen M, Krueger J, Ali M, Schechter T. Eltrombopag for secondary failure of platelet recovery post-allogeneic hematopoietic stem cell transplant in children. Pediat Transplant. 2017; 21. https://doi.org/10.1111/petr.13017

    Article  Google Scholar 

  29. Ma YR, Huang XJ, Mo XD, Han W, Yan CH, Chen Y, et al. [Eltrombopag for refractory thrombocytopenia in patients with allogeneic hematopoietic stem cell transplantation]. Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi. 2016;37:1065–9. https://doi.org/10.3760/cma.j.issn.0253-2727.2016.12.011

    Article  CAS  PubMed  Google Scholar 

  30. Dyba J, Tinmouth A, Bredeson C, Matthews J, Allan DS. Eltrombopag after allogeneic haematopoietic cell transplantation in a case of poor graft function and systematic review of the literature. Transfus Med. 2016;26:202–7. https://doi.org/10.1111/tme.12300

    Article  CAS  PubMed  Google Scholar 

  31. Tanaka T, Inamoto Y, Yamashita T, Fuji S, Okinaka K, Kurosawa S, et al. Eltrombopag for treatment of thrombocytopenia after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2016;22:919–24. https://doi.org/10.1016/j.bbmt.2016.01.018

    Article  CAS  PubMed  Google Scholar 

  32. Raut SS, Shah SA, Sharanangat VV, Shah KM, Patel KA, Anand AS, et al. Safety and Efficacy of Eltrombopag in Post-hematopoietic Stem Cell Transplantation (HSCT) Thrombocytopenia. Indian J Hematol Blood Transfus. 2015;31:413–5. https://doi.org/10.1007/s12288-014-0491-0

    Article  PubMed  Google Scholar 

  33. Rivera D, Bastida JM, Lopez-Corral L, Sanchez-Guijo F, Cabrero M, Martin A, et al. Usefulness of eltrombopag for treating thrombocytopenia after allogeneic stem cell transplantation. Bone Marrow Transplant. 2018. https://doi.org/10.1038/s41409-018-0368-1

    Article  PubMed  Google Scholar 

  34. Popat UR, et al. Eltrombopag for post-transplant thrombocytopenia: results of phase II randomized double blind placebo controlled trial. Blood. 2015;126:738.

    Article  Google Scholar 

  35. Liu W, Wang M, Tang DC, Ding I, Rodgers GP. Thrombopoietin has a differentiative effect on late-stage human erythropoiesis. Br J Haematol. 1999;105:459–69.

    Article  CAS  PubMed  Google Scholar 

  36. Bao W, Bussel JB, Heck S, He W, Karpoff M, Boulad N, et al. Improved regulatory T-cell activity in patients with chronic immune thrombocytopenia treated with thrombopoietic agents. Blood. 2010;116:4639–45. https://doi.org/10.1182/blood-2010-04-281717

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Alvarado LJ, Andreoni A, Huntsman HD, Cheng H, Knutson JR, Larochelle A. Heterodimerization of TPO and IFNγ impairs human hematopoietic stem/progenitor cell signaling and survival in chronic inflammation. Blood. 2017;130:4.

    Article  Google Scholar 

  38. Fujimi A, Kamihara Y, Hashimoto A, Kanisawa Y, Nakajima C, Hayasaka N, et al. Identification of anti-thrombopoietin receptor antibody in prolonged thrombocytopenia after allogeneic hematopoietic stem cell transplantation treated successfully with eltrombopag. Int J Hematol. 2015;102:471–6. https://doi.org/10.1007/s12185-015-1806-0

    Article  PubMed  Google Scholar 

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Author notes

  1. These authors contributed equally: Serena Marotta, Luana Marano.

Authors and Affiliations

  1. Hematology, Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy

    Serena Marotta, Luana Marano, Patrizia Ricci, Fabiana Cacace, Camilla Frieri, Luigia Simeone, Fabio Trastulli, Selenia Vitiello, Flora Cardano, Fabrizio Pane & Antonio M Risitano

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Contributions

SM, LM, and AMR conceived the study; PR performed hematopoietic progenitor cell in vitro cultures. Al the remaining authors contributed with SM, LM and AMR to the clinical management of the patients, and collected the clinical data from their clinical records. SM, LM, and AMR wrote the manuscript, which was critically revised by all the other authors.

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Correspondence to Antonio M Risitano.

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Conflict of interest

AMR is involved in the clinical development of eltrombopag for the treatment of aplastic anemia, serving as Principal Investigator of a phase III trial (NCT02099747), as a member of an advisory board and as a consultant for Novartis; AMR has also received lecture fees from Novartis. The paper describes an off-label use of eltrombopag. The remaining authors declare that they have no conflict of interest.

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Marotta, S., Marano, L., Ricci, P. et al. Eltrombopag for post-transplant cytopenias due to poor graft function. Bone Marrow Transplant 54, 1346–1353 (2019). https://doi.org/10.1038/s41409-019-0442-3

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