Thrombopoietin receptor agonists: ten years later

Waleed Ghanima, Nichola Cooper, Francesco Rodeghiero, Bertrand Godeau, James B Bussel, Waleed Ghanima, Nichola Cooper, Francesco Rodeghiero, Bertrand Godeau, James B Bussel

Abstract

The two thrombopoietin receptor agonists (TPO-RA), eltrombopag and romiplostim, were licensed in the US for treatment of immune thrombocytopenia (ITP) in 2008 and, since then, their use has progressively increased around the world; they are currently used in more than 100 countries. The six largest randomized controlled trials conducted in ITP have used one of these two agents. All studies have demonstrated a platelet response rate between 50-90%, depending on the criteria used, with good safety and tolerability. TPO-RA were shown to be effective in reducing bleeding and the need for concomitant or rescue medication. Many other investigations of their mechanism of effect, prospective and retrospective trials, and studies focusing on toxicity have been performed widening our knowledge of these two agents. Initial concerns on issues such as myelofibrosis have not been confirmed. Only a small number of patients develop moderate-severe reticulin fibrosis and/or collagen fibrosis; however, these are usually reversed after discontinuation of TPO-RA. Studies indicate, however, that TPO-RA may increase the risk of venous thromboembolism. Both TPO-RA are currently approved in patients with chronic ITP aged >1-year who are refractory to at least one other treatment. Eltrombopag has acquired two additional indications: severe aplastic anemia refractory to first-line treatment and hepatitis C patients undergoing treatment with interferon-ribavirin. Despite these wide-ranging studies, important questions still need to be answered. This summary review on TPO-RA will summarize what is known regarding efficacy in ITP, evaluate safety concerns in more depth, and focus on the questions that remain.

Copyright© 2019 Ferrata Storti Foundation.

Figures

Figure 1.
Figure 1.
Cellular mechanisms of action of thrombopoietin (TPO) and of thrombopoietin receptor agonists (TPO-RA). Binding of the ligand (TPO/TPO-RA) to the c-MPL receptor on the megakaryocyte causes conformational change in the receptor, resulting in downstream activation of the various signaling pathways including JAK2/STAT5, PI3K/AKT, ERK, ultimately resulting in increased platelet production. Various pathways can be activated by the different substances (see also Table 1). GRB2: growth factor receptor-binding protein 2; JAK: Janus kinase; MAPK: mitogen-activated protein kinase; P: phosphorylation; RAF: rapidly accelerated fibrosarcoma kinase; RAS: rat sarcoma GTPase; SHC: Src homology collagen protein; STAT: signal transducer and activator of transcription; PI3K: phosphatidylinositol 3-kinases; ERK: extracellular-signal-regulated kinase.

References

    1. Rodeghiero F. A critical appraisal of the evidence for the role of splenectomy in adults and children with ITP. Br J Haematol. 2018;181(2):183–195.
    1. Patel VL, Mahevas M, Lee SY, et al. Outcomes 5 years after response to rituximab therapy in children and adults with immune thrombocytopenia. Blood. 2012;119(25):5989–5995.
    1. Ghanima W, Godeau B, Cines DB, Bussel JB. How I treat immune thrombocytopenia: the choice between splenectomy or a medical therapy as a second-line treatment. Blood. 2012;120(5):960–969.
    1. Erickson-Miller CL, Delorme E, Tian SS, et al. Preclinical activity of eltrombopag (SB-497115), an oral, nonpeptide thrombopoietin receptor agonist. Stem Cells. 2009;27(2):424–430.
    1. Broudy VC, Lin NL. AMG531 stimulates megakaryopoiesis in vitro by binding to Mpl. Cytokine. 2004;25(2):52–60.
    1. Will B, Kawahara M, Luciano JP, et al. Effect of the nonpeptide thrombopoietin receptor agonist Eltrombopag on bone marrow cells from patients with acute myeloid leukemia and myelodysplastic syndrome. Blood. 2009;114(18):3899–3908.
    1. Sun H, Tsai Y, Nowak I, Liesveld J, Chen Y. Eltrombopag, a thrombopoietin receptor agonist, enhances human umbilical cord blood hematopoietic stem/primitive progenitor cell expansion and promotes multi-lineage hematopoiesis. Stem Cell Res. 2012;9(2):77–86.
    1. Di Buduo CA, Currao M, Pecci A, Kaplan DL, Balduini CL, Balduini A. Revealing eltrombopag’s promotion of human megakaryopoiesis through AKT/ERK-dependent pathway activation. Haematologica. 2016;101(12):1479–1488.
    1. Vlachodimitropoulou E, Chen YL, Garbowski M, et al. Eltrombopag: a powerful chelator of cellular or extracellular iron(III) alone or combined with a second chelator. Blood. 2017;130(17):1923–1933.
    1. Roth M, Will B, Simkin G, et al. Eltrombopag inhibits the proliferation of leukemia cells via reduction of intracellular iron and induction of differentiation. Blood. 2012;120(2):386–394.
    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. D’Arena G, Guariglia R, Mansueto G, et al. No cross-resistance after sequential use of romiplostim and eltrombopag in chronic immune thrombocytopenic purpura. Blood. 2013;121(7):1240–1242.
    1. Bao W, Bussel JB, Heck S, et al. Improved regulatory T-cell activity in patients with chronic immune thrombocytopenia treated with thrombopoietic agents. Blood. 2010;116(22):4639–4645.
    1. Wan YY, Flavell RA. ‘Yin-Yang’ functions of transforming growth factor-beta and T regulatory cells in immune regulation. Immunol Rev. 2007;220:199–213.
    1. Schifferli A, Kuhne T. Thrombopoietin receptor agonists: a new immune modulatory strategy in immune thrombocytopenia? Semin Hematol. 2016;53 Suppl 1:S31–4.
    1. Zufferey A, Kapur R, Semple JW. Pathogenesis and Therapeutic Mechanisms in Immune Thrombocytopenia (ITP). J Clin Med. 2017;6(2).
    1. Kuter DJ, Rummel M, Boccia R, et al. Romiplostim or standard of care in patients with immune thrombocytopenia. N Engl J Med. 2010;363(20):1889–1899.
    1. Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet. 2008;371(9610):395–403.
    1. Bussel JB, Provan D, Shamsi T, et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet. 2009;373(9664):641–648.
    1. Bussel JB, Kuter DJ, Pullarkat V, Lyons RM, Guo M, Nichol JL. Safety and efficacy of long-term treatment with romiplostim in thrombocytopenic patients with chronic ITP. Blood. 2009;113(10):2161–2171.
    1. Bussel JB, Kuter DJ, George JN, et al. AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP. N Engl J Med. 2006;355(16):1672–1681.
    1. Bussel JB, Cheng G, Saleh MN, et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med. 2007;357(22):2237–2247.
    1. Bussel JB, Buchanan GR, Nugent DJ, et al. A randomized, double-blind study of romiplostim to determine its safety and efficacy in children with immune thrombocytopenia. Blood. 2011;118(1):28–36.
    1. Wong RSM, Saleh MN, Khelif A, et al. Safety and efficacy of long-term treatment of chronic/persistent ITP with eltrombopag: final results of the EXTEND study. Blood. 2017;130(23):2527–2536.
    1. Cheng G, Saleh MN, Marcher C, et al. Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study. Lancet. 2011;377:393–402.
    1. Wang L, Gao Z, Chen XP, et al. Efficacy and safety of thrombopoietin receptor agonists in patients with primary immune thrombocytopenia: A systematic review and meta-analysis. Sci Rep. 2016;6:39003.
    1. Kuter DJ, Bussel JB, Newland A, et al. Long-term treatment with romiplostim in patients with chronic immune thrombocytopenia: safety and efficacy. Br J Haematol. 2013;161(3):411–423.
    1. McMillan R, Bussel JB, George JN, Lalla D, Nichol JL. Self-reported health-related quality of life in adults with chronic immune thrombocytopenic purpura. Am J Hematol. 2008;83(2):150–154.
    1. Mathias SD, Gao SK, Miller KL, et al. Impact of chronic Immune Thrombocytopenic Purpura (ITP) on health-related quality of life: a conceptual model starting with the patient perspective. Health Qual Life Outcomes. 2008;6:13.
    1. Kuter DJ, Mathias SD, Rummel M, et al. Health-related quality of life in nonsplenectomized immune thrombocytopenia patients receiving romiplostim or medical standard of care. Am J Hematol. 2012;87(5): 558–561.
    1. Saleh MN, Bussel JB, Khelif A, et al. Improvements in Patient Health-Related Quality of Life (HRQoL) with Clinical Efficacy in Patients Treated with Eltrombopag: Final Results from the Long-Term, Open-Label Extend Study. Blood. 2016;128(22):3742.
    1. Steurer M, Quittet P, Papadaki HA, et al. A large observational study of patients with primary immune thrombocytopenia receiving romiplostim in European clinical practice. Eur J Haematol. 2017;98(2):112–120.
    1. Grainger JD, Locatelli F, Chotsam -pancharoen T, et al. Eltrombopag for children with chronic immune thrombocytopenia (PETIT2): a randomised, multicentre, placebo-controlled trial. Lancet. 2015;386(10004):1649–1658.
    1. Bussel JB, de Miguel PG, Despotovic JM, et al. Eltrombopag for the treatment of children with persistent and chronic immune thrombocytopenia (PETIT): a randomised, multicentre, placebo-controlled study. Lancet Haematol. 2015;2(8):e315–325.
    1. Tarantino MD, Bussel JB, Blanchette VS, et al. Romiplostim in children with immune thrombocytopenia: a phase 3, randomised, double-blind, placebo-controlled study. Lancet. 2016;388(10039):45–54.
    1. Khellaf M, Michel M, Quittet P, et al. Romiplostim safety and efficacy for immune thrombocytopenia in clinical practice: 2-year results of 72 adults in a romiplostim compassionate-use program. Blood. 2011;118(16):4338–4345.
    1. Khellaf M, Viallard JF, Hamidou M, et al. A retrospective pilot evaluation of switching thrombopoietic receptor-agonists in immune thrombocytopenia. Haematologica. 2013;98(6):881–887.
    1. Cantoni S, Carpenedo M, Mazzucconi MG, et al. Alternate use of thrombopoietin receptor agonists in adult primary immune thrombocytopenia patients: A retrospective collaborative survey from Italian hematology centers. Am J Hematol. 2018;93(1):58–64.
    1. Kuter DJ, Macahilig C, Grotzinger KM, et al. Treatment patterns and clinical outcomes in patients with chronic immune thrombocytopenia (ITP) switched to eltrombopag or romiplostim. Int J Hematol. 2015;101(3): 255–263.
    1. Mahevas M, Fain O, Ebbo M, et al. The temporary use of thrombopoietin-receptor agonists may induce a prolonged remission in adult chronic immune thrombocytopenia. Results of a French observational study. Br J Haematol. 2014;165(6):865–869.
    1. Newland A, Godeau B, Priego V, et al. Remission and platelet responses with romiplostim in primary immune thrombocytopenia: final results from a phase 2 study. Br J Haematol. 2016;172(2):262–273.
    1. Gonzalez-Lopez TJ, Pascual C, Alvarez-Roman MT, et al. Successful discontinuation of eltrombopag after complete remission in patients with primary immune thrombocytopenia. Am J Hematol. 2015;90(3):E40–43.
    1. Ghadaki B, Nazi I, Kelton JG, Arnold DM. Sustained remissions of immune thrombocytopenia associated with the use of thrombopoietin receptor agonists. Transfusion. 2013;53(11):2807–2812.
    1. Gibiansky E, Zhang J, Williams D, Wang Z, Ouellet D. Population pharmacokinetics of eltrombopag in healthy subjects and patients with chronic idiopathic thrombocytopenic purpura. J Clin Pharmacol. 2011;51(6):842–856.
    1. Gonzalez-Lopez TJ, Alvarez-Roman MT, Pascual C, et al. Use of eltrombopag for secondary immune thrombocytopenia in clinical practice. Br J Haematol. 2017;178(6):959–970.
    1. Cines DB, Gernsheimer T, Wasser J, et al. Integrated analysis of long-term safety in patients with chronic immune thrombocytopaenia (ITP) treated with the thrombopoietin (TPO) receptor agonist romiplostim. Int J Hematol. 2015;102(3):259–270.
    1. Kuter DJ, Mufti GJ, Bain BJ, Hasserjian RP, Davis W, Rutstein M. Evaluation of bone marrow reticulin formation in chronic immune thrombocytopenia patients treated with romiplostim. Blood. 2009;114(18): 3748–3756.
    1. Ghanima W, Geyer JT, Lee CS, et al. Bone marrow fibrosis in 66 Immune Thrombocytopenia patients treated with thrombopoietin receptor agonists: a single center long-term follow-up. Haematologica. 2014;99(5):937–944.
    1. Brynes RK, Wong RS, Thein MM, et al. A 2-Year, Longitudinal, Prospective Study of the Effects of Eltrombopag on Bone Marrow in Patients with Chronic Immune Thrombocytopenia. Acta Haematol. 2017;137(2):66–72.
    1. Janssens A, Rodeghiero F, Anderson D, et al. Changes in bone marrow morphology in adults receiving romiplostim for the treatment of thrombocytopenia associated with primary immune thrombocytopenia. Ann Hematol. 2016;95(7):1077–1087.
    1. Brynes RK, Orazi A, Theodore D, et al. Evaluation of bone marrow reticulin in patients with chronic immune thrombocytopenia treated with eltrombopag: Data from the EXTEND study. Am J Hematol. 2015;90(7):598–601.
    1. Imbach P, Crowther M. Thrombopoietin-receptor agonists for primary immune thrombocytopenia. N Engl J Med. 2011;365(8):734–741.
    1. Rodeghiero F, Stasi R, Giagounidis A, et al. Long-term safety and tolerability of romiplostim in patients with primary immune thrombocytopenia: a pooled analysis of 13 clinical trials. Eur J Haematol. 2013;91(5): 423–436.
    1. Mittelman M, Platzbecker U, Afanasyev B, et al. Eltrombopag for advanced myelodysplastic syndromes or acute myeloid leukaemia and severe thrombocytopenia (ASPIRE): a randomised, placebo-controlled, phase 2 trial. Lancet Haematol. 2018;5(1):e34–e43.
    1. Fenaux P, Muus P, Kantarjian H, et al. Romiplostim monotherapy in thrombocytopenic patients with myelodysplastic syndromes: long-term safety and efficacy. Br J Haematol. 2017;178(6):906–913.
    1. Platzbecker U, Wong RS, Verma A, et al. Safety and tolerability of eltrombopag versus placebo for treatment of thrombocytopenia in patients with advanced myelodysplastic syndromes or acute myeloid leukaemia: a multicentre, randomised, placebo-controlled, double-blind, phase 1/2 trial. Lancet Haematol. 2015;2(10):e417–426.
    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. Severinsen MT, Engebjerg MC, Farkas DK, et al. Risk of venous thromboembolism in patients with primary chronic immune thrombocytopenia: a Danish population-based cohort study. Br J Haematol. 2011;152(3):360–362.
    1. Sarpatwari A, Bennett D, Logie JW, et al. Thromboembolic events among adult patients with primary immune thrombocytopenia in the United Kingdom General Practice Research Database. Haematologica. 2010;95(7):1167–1175.
    1. Norgaard M, Severinsen MT, Lund Maegbaek M, Jensen AO, Cha S, Sorensen HT. Risk of arterial thrombosis in patients with primary chronic immune thrombocytopenia: a Danish population-based cohort study. Br J Haematol. 2012;159(1):109–111.
    1. Norgaard M, Cetin K, Maegbaek ML, et al. Risk of arterial thrombotic and venous thromboembolic events in patients with primary chronic immune thrombocytopenia: a Scandinavian population-based cohort study. Br J Haematol. 2016;174(4):639–642.
    1. Enger C, Bennett D, Forssen U, Fogarty PF, McAfee AT. Comorbidities in patients with persistent or chronic immune thrombocytopenia. Int J Hematol. 2010;92(2):289–295.
    1. Rodeghiero F. Is ITP a thrombophilic disorder? Am J Hematol. 2016;91(1):39–45.
    1. Ramaswamy K, Hsieh L, Leven E, Thompson MV, Nugent D, Bussel JB. Thrombopoietic agents for the treatment of persistent and chronic immune thrombocytopenia in children. J Pediatr. 2014;165(3): 600–6055.e4.
    1. Elalfy MS, Abdelmaksoud AA, Eltonbary KY. Romiplostim in children with chronic refractory ITP: randomized placebo controlled study. Ann Hematol. 2011;90(11): 1341–1344.
    1. Cines DB, Wasser J, Rodeghiero F, et al. Safety and efficacy of romiplostim in splenectomized and nonsplenectomized patients with primary immune thrombocytopenia. Haematologica. 2017;102(8):1342–1351.
    1. Rodeghiero F. ITP and thrombosis: an intriguing association. Blood Adv. 2017;1(24):2280.
    1. Psaila B, Bussel JB, Linden MD, et al. In vivo effects of eltrombopag on platelet function in immune thrombocytopenia: no evidence of platelet activation. Blood. 2012;119(17): 4066–4072.
    1. Haselboeck J, Kaider A, Pabinger I, Panzer S. Function of eltrombopag-induced platelets compared to platelets from control patients with immune thrombocytopenia. Thromb Haemost. 2013;109(4):676–683.
    1. Garabet L, Ghanima W, Monceyron Jonassen C, et al. Effect of thrombopoietin receptor agonists on markers of coagulation and P-selectin in patients with immune thrombocytopenia. Platelets. 2017:1–7.
    1. Alvarez Roman MT, Fernandez Bello I, Arias-Salgado EG, et al. Effects of thrombopoietin receptor agonists on procoagulant state in patients with immune thrombocytopenia. Thromb Haemost. 2014;112(1):65–72.
    1. Justo Sanz R, Monzon Manzano E, Fernandez Bello I, et al. Platelet Apoptosis and PAI-1 are Involved in the Pro-Coagulant State of Immune Thrombocytopaenia Patients Treated with Thrombopoietin Receptor Agonists. Thromb Haemost. 2019. February 11 [Epub ahead of print]
    1. Bussel JB, Saleh MN, Vasey SY, Mayer B, Arning M, Stone NL. Repeated short-term use of eltrombopag in patients with chronic immune thrombocytopenia (ITP). Br J Haematol. 2013;160(4):538–546.
    1. Gonzalez-Porras JR, Mingot-Castellano ME, Andrade MM, et al. Use of eltrombopag after romiplostim in primary immune thrombocytopenia. Br J Haematol. 2015;169(1):111–116.
    1. Carpenedo M, Cantoni S, Coccini V, Pogliani EM, Cairoli R. Response loss and development of neutralizing antibodies during long-term treatment with romiplostim in patients with immune thrombocytopenia: a case series. Eur J Haematol. 2016;97(1):101–103.
    1. Afdhal NH, Dusheiko GM, Giannini EG, et al. Eltrombopag increases platelet numbers in thrombocytopenic patients with HCV infection and cirrhosis, allowing for effective antiviral therapy. Gastroenterology. 2014;146(2):442–452.e1.
    1. Zhang X, Chuai Y, Nie W, Wang A, Dai G. Thrombopoietin receptor agonists for prevention and treatment of chemotherapy-induced thrombocytopenia in patients with solid tumours. Cochrane Database Syst Rev. 2017;11:CD012035.
    1. Pecci A, Gresele P, Klersy C, et al. Eltrombopag for the treatment of the inherited thrombocytopenia deriving from MYH9 mutations. Blood. 2010;116(26): 5832–5837.
    1. Gerrits AJ, Leven EA, Frelinger AL, 3rd, et al. Effects of eltrombopag on platelet count and platelet activation in Wiskott-Aldrich syndrome/X-linked thrombocytopenia. Blood. 2015;126(11):1367–1378.
    1. Rodeghiero F, Pecci A, Balduini CL. Thrombopoietin receptor agonists in hereditary thrombocytopenias. J Thromb Haemost. 2018;16(9):1700–1710.
    1. Bussel JB, Kuter DJ, Aledort LM, et al. A randomized trial of avatrombopag, an investigational thrombopoietin-receptor agonist, in persistent and chronic immune thrombocytopenia. Blood. 2014;123(25):3887–3894.
    1. Jurczak W, Chojnowski K, Mayer J, et al. Phase 3 randomised study of avatrombopag, a novel thrombopoietin receptor agonist for the treatment of chronic immune thrombocytopenia. Br J Haematol. 2018;183(3):479–490.
    1. Kong Z, Qin P, Xiao S, et al. A novel recombinant human thrombopoietin therapy for the management of immune thrombocytopenia in pregnancy. Blood. 2017;130(9): 1097–1103.
    1. Huang Y, Liu X, Xue F, et al. [Efficacy and safety of rhTPO in the treatment of pediatric primary immune thrombocytopenia]. Zhonghua Xue Ye Xue Za Zhi. 2015;36(6): 511–514.
    1. Bussel J, Arnold DM, Grossbard E, et al. Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: Results of two phase 3, randomized, placebo-controlled trials. Am J Hematol. 2018;93(7):921–930.
    1. Robak T, Jarque I, Musteata V, et al. Phase II, Multiple-Dose Study of Anti-FcRn Antibody, Rozanolixizumab (UCB7665), in Patients with Primary Immune Thrombocytopenia: Interim Analysis. Blood. 2017;130(Suppl 1):15.
    1. Kiessling P, Lledo-Garcia R, Watanabe S, et al. The FcRn inhibitor rozanolixizumab reduces human serum IgG concentration: A randomized phase 1 study. Sci Transl Med. 2017;9(414).
    1. Shirasugi Y, Ando K, Miyazaki K, et al. Romiplostim for the treatment of chronic immune thrombocytopenia in adult Japanese patients: a double-blind, randomized Phase III clinical trial. Int J Hematol. 2011;94(1):71–80.
    1. Tomiyama Y, Miyakawa Y, Okamoto S, et al. A lower starting dose of eltrombopag is efficacious in Japanese patients with previously treated chronic immune thrombocytopenia. J Thromb Haemost. 2012;10(5):799–806.
    1. Janssens A, Tarantino M, Bird RJ, et al. Romiplostim Treatment in Adults with Immune Thrombocytopenia of Varying Duration and Severity. Acta Haematol. 2015;134(4):215–228.

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