THROMBOCYTOPENIA IN PATIENTS WITH MYELODYSPLASTIC SYNDROMES - STILL AN UNSOLVED PROBLEM
Main Article Content
Keywords
Myelodysplastic Syndrome, Thrombocythopenia, Thrombomimetics,
Abstract
The myelodysplastic syndromes (MDS) are a group of clonal bone marrow (BM) stem cell disorders, characterized by ineffective hematopoiesis, peripheral cytopenias and hematologic cellular dysfunction, as well as potential transformation to acute leukemia.
Thrombocytopenia is common in MDS and is associated with bleeding complications, occasionally life threatening. Low platelet count (PLT), as well declining PLT also serves as a prognostic marker. Understanding thrombopoiesis led to the cloning of thrombopoietin, resulting in the development of platelet stimulating agents, thrombomimetics, romiplostim and eltrombopag.
Both agents have been shown to increase PLT, decrease the need for platelet transfusions and reduce the number of bleeding episodes, with a reasonable tolerance. They are already approved for immune thrombocytopenia and thrombocytopenia related to liver disease.
Romiplostim and eltrombopag have proven efficacy in lower- and higher-risk MDS with thrombocytopenia, as monotherapy, as well as a part of a combination, either with lenalidomide, and mainly combined with hypomethylating agents. However, safety concerns have been raised: while several trials have been completed with no evidence of disease progression, others have been early terminated due to increased number of BM blasts and possible leukemic transformation in treated-patients. The jury is still out regarding this safety concern, although recent publications are more encouraging.
Keywords: Myelodysplastic syndrome, Thrombocytopenia, Thrombomimetics,
Romiplostim, Eltrombopag.
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References
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2. Malcovati L, Hellström-Lindberg E, Bowen D, et al. Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood. 2013;122(17):2943 LP-2964.
3. Mittelman M. The myelodysplastic syndromes-1990. Israel Journal ofMmedical Sciences. 1990;26(8):468-478.
4. de Swart L, Smith A, Johnston TW, et al. Validation of the revised international prognostic scoring system (IPSS?R) in patients with lower?risk myelodysplastic syndromes: a report from the prospective European LeukaemiaNet MDS (EUMDS) registry. British Journal of Haematology. 2015;170(3):372-383. doi:10.1111/bjh.13450.
5. Platzbecker U, Wong RSM, 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. The Lancet Haematology. 2018;2(10):e417-e426. doi:10.1016/S2352-3026(15)00149-0.
6. Kantarjian HM, Giles F, List AF, et al. The Incidence and Impact of thrombocytopenia in Myelodysplastic Syndrome (MDS). Blood. 2006;108(11):2617 LP-2617.
7. Gonzalez-Porras JR, Cordoba I, Such E, et al. Prognostic impact of severe thrombocytopenia in low-risk myelodysplastic syndrome. Cancer. 2011;117(24):5529-5537. doi:10.1002/cncr.26173.
8. Zeidman A, Sokolover N, Fradin Z, Cohen A, Redlich O, Mittelman M. Platelet function and its clinical significance in the myelodysplastic syndromes. The Hematology Journal. 2004;5(3):234-238. doi:10.1038/sj.thj.6200364.
9. Neukirchen J, Blum S, Kuendgen A, et al. Platelet counts and haemorrhagic diathesis in patients with myelodysplastic syndromes. European Journal of Haematology. 2009;83(5):477-482. doi:10.1111/j.1600-0609.2009.01299.x.
10. Nachtkamp K, Stark R, Strupp C, et al. Causes of death in 2877 patients with myelodysplastic syndromes. Annals Of Hematology. 2016;95(6):937-944. doi:10.1007/s00277-016-2649-3.
11. Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89(6):2079 LP-2088.
12. Greenberg PL, Tuechler H, Schanz J, et al. Revised International Prognostic Scoring System for myelodysplastic syndromes. Blood. 2012;120(12):2454-2465. doi:10.1182/blood-2012-03-420489.
13. Itzykson R, Smith A, Fenaux P, et al. Prognostic value of early drop in platelets in lower-risk MDS. A sub-study from the European Leukemianet Lower-Risk MDS (EUMDS) Registry. Leukemia Research. 2017;55:S10-S11. doi:10.1016/S0145-2126(17)30132-7.
14. List A, Dewald G, Bennett J, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. New England Journal of Medicine. 2006;355(14):1456-1465. doi:10.1056/NEJMoa061292.
15. Fenaux P, Giagounidis A, Selleslag D, et al. A randomized phase 3 study of lenalidomide versus placebo in RBC transfusion-dependent patients with Low-/Intermediate-1-risk myelodysplastic syndromes with del5q. Blood. 2011;118(14):3765-3776. doi:10.1182/blood-2011-01-330126.
16. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. The Lancet Oncology. 2009;10(3):223-232. doi:10.1016/S1470-2045(09)70003-8.
17. Kantarjian H, Issa J-PJ, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer. 2006;106(8):1794-1803. doi:10.1002/cncr.21792.
18. Lee RE, Young RH, Castleman B, et al. : A biography of the enigmatic creator of the Wright stain on the occasion of its centennial. The American Journal of Surgical Pathology. 2002;26(1):88-96.
19. Kelemen E, Cserháti I, Tanos B. Demonstration and some properties of human thrombopoietin in thrombocythaemic Sera. Acta Haematologica. 1958;20(6):350-355. doi:10.1159/000205503.
20. Metcalf D. Thrombopoietin - at last. Nature. 1994;369:519.
21. Kaushansky K, Lichtman MA, Prchal JT, et al. Williams - Hematology, 9th Edition.Chapter 18-Hematopoietic stems cells, progenitors and cytokins. K.Kaushansky, 2016:2505.
22. Eaton, DL. Thrombopoietin?: the primary regulator of megakaryocytopoiesis and thrombopoiesis. Exp Hematol. 1997;25:1-7.
23. Ramsfjell V, Borge OJ, Veiby OP, et al. Thrombopoietin, but not erythropoietin, directly stimulates multilineage growth of primitive murine bone marrow progenitor cells in synergy with early acting cytokines: distinct interactions with the ligands for c-kit and FLT3. Blood. 1996;88(12):4481 LP-4492.
24. Alexander WS, Roberts AW, Nicola NA, et al. Deficiencies in progenitor cells of multiple hematopoietic lineages and defective megakaryocytopoiesis in mice lacking the thrombopoietic receptor c-Mpl. Blood. 1996;87(6):2162 LP-2170.
25. Kuter DJ, Begley CG. Recombinant human thrombopoietin: basic biology and evaluation of clinical studies. Blood. 2002;100(10):3457 LP-3469.
26. Li J, Yang C, Xia Y, et al. Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood. 2001;98(12):3241 LP-3248.
27. Rodeghiero F, Carli G. Beyond immune thrombocytopenia: the evolving role of thrombopoietin receptor agonists. Annals of Hematology. 2017;96(9):1421-1434. doi:10.1007/s00277-017-2953-6.
28. 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. European Journal of Haematology. 2013;91(5):423-436. doi:10.1111/ejh.12181.
29. Saleh MN, Bussel JB, Cheng G, et al. Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: results of the long-term, open-label EXTEND study. Blood. 2013;121(3):537-545. doi:10.1182/blood-2012-04-425512.
30. Wang B, Nichol J, Sullivan J. Pharmacodynamics and pharmacokinetics of AMG 531, a novel thrombopoietin receptor ligand. Clinical Pharmacology & Therapeutics. 2004;76(6):628-638. doi:10.1016/j.clpt.2004.08.010.
31. Kantarjian H, Fenaux P, Sekeres MA, et al. Safety and efficacy of romiplostim in patients with lower-risk myelodysplastic syndrome and thrombocytopenia. Journal of Clinical Oncology. 2010;28(3):437-444. doi:10.1200/JCO.2009.24.7999.
32. Giagounidis A, Mufti GJ, Fenaux P, et al. Results of a randomized, double-blind study of romiplostim versus placebo in patients with low/intermediate-1-risk myelodysplastic syndrome and thrombocytopenia. Cancer. 2014;120(12):1838-1846. doi:10.1002/cncr.28663.
33. Kantarjian HM, Fenaux P, Sekeres MA, et al. Long-term follow-up for up to 5 years on the risk of leukaemic progression in thrombocytopenic patients with lower-risk myelodysplastic syndromes treated with romiplostim or placebo in a randomised double-blind trial. The Lancet Haematology. February 2018. doi:10.1016/S2352-3026(18)30016-4.
34. Fenaux P, Muus P, Kantarjian H, et al. Romiplostim monotherapy in thrombocytopenic patients with myelodysplastic syndromes: long-term safety and efficacy. British Journal of Haematology. 2017;178(6):906-913. doi:10.1111/bjh.14792.
35. Mittelman M. Good news for patients with myelodysplastic syndromes and thrombocytopenia. The Lancet Haematology. February 2018. doi:10.1016/S2352-3026(18)30017-6.
36. Sekeres MA, Kantarjian H, Fenaux P, et al. Subcutaneous or intravenous administration of romiplostim in thrombocytopenic patients with lower risk myelodysplastic syndromes. Cancer. 2011;117(5):992-1000. doi:10.1002/cncr.25545.
37. Prica A, Sholzberg M, Buckstein R. Safety and efficacy of thrombopoietin-receptor agonists in myelodysplastic syndromes: a systematic review and meta-analysis of randomized controlled trials. British Journal of Haematology. 2014;167(5):626-638. doi:10.1111/bjh.13088.
38. Sekeres MA, Giagounidis A, Kantarjian H, et al. Development and validation of a model to predict platelet response to romiplostim in patients with lower-risk myelodysplastic syndromes. British Journal of Haematology. 2014;167(3):337-345. doi:10.1111/bjh.13037.
39. Kantarjian HM, Giles FJ, Greenberg PL, et al. Phase 2 study of romiplostim in patients with low- or intermediate-risk myelodysplastic syndrome receiving azacitidine therapy. Blood. 2010;116(17):3163 LP-3170.
40. Greenberg PL, Garcia-Manero G, Moore M, et al. A randomized controlled trial of romiplostim in patients with low- or intermediate-risk myelodysplastic syndrome receiving decitabine. Leukemia & Lymphoma. 2013;54(2):321-328. doi:10.3109/10428194.2012.713477.
41. Wang ES, Lyons RM, Larson RA, et al. A randomized, double-blind, placebo-controlled phase 2 study evaluating the efficacy and safety of romiplostim treatment of patients with low or intermediate-1 risk myelodysplastic syndrome receiving lenalidomide. Journal of Hematology & Oncology. 2012;5(1):71. doi:10.1186/1756-8722-5-71.
42. Erickson-Miller C, Delorme E, Giampa L, et al. Biological activity and selectivity for Tpo receptor of the orally bioavailable, small molecule Tpo receptor agonist, SB-497115. Blood. 2004;104(11):2912 LP-2912.
43. 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 LP-394.
44. Vlachodimitropoulou E, Chen Y-L, Garbowski M, et al. Eltrombopag: a powerful chelator of cellular or extracellular iron(III) alone or combined with a second chelator. Blood. 2017 130: 1923-1933.
45. Oliva EN, Alati C, Santini V, 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. The Lancet Haematology. 2017;4(3):e127-e136. doi:10.1016/S2352-3026(17)30012-1.
46. Platzbecker U, Wong RSM, 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. The Lancet Haematology. 2015;2(10):e417-e426. doi:10.1016/S2352-3026(15)00149-0.
47. 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. The Lancet Haematology. 2018;5(1):e34-e43. doi:10.1016/S2352-3026(17)30228-4.
48. Mittelman M, Platzbecker U, Afanasyev B V, et al. Phase 3, placebo-controlled, ASPIRE study (TRC114968) of eltrombopag (EPAG) treatment of thrombocytopenia (TCP) in advanced myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML): Assessment of clinical benefit, safety, and tolerability. Blood (Suppl). 2015;126(23).
49. Svensson T, Chowdhury O, Garelius H, et al. A pilot phase I dose finding safety study of the thrombopoietin-receptor agonist, eltrombopag, in patients with myelodysplastic syndrome treated with azacitidine. European Journal of Haematology. 2014;93(5):439-445. doi:10.1111/ejh.12383.
50. Dickinson MJ, Cherif H, Fenaux P, et al. Thrombopoietin (TPO) receptor agonist eltrombopag in combination with azacitidine (AZA) for primary treatment of myelodysplastic syndromes (MDS) patients with thrombocytopenia: Outcomes from the randomized, placebo-controlled, phase III support study. Blood (Suppl). 2016;128(22):163 LP-163.
51. Dodillet H, Kreuzer K-A, Monsef I, Skoetz N. Thrombopoietin mimetics for patients with myelodysplastic syndromes. The Cochrane database of systematic reviews. 2017;9:CD009883. doi:10.1002/14651858.CD009883.pub2.
2. Malcovati L, Hellström-Lindberg E, Bowen D, et al. Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood. 2013;122(17):2943 LP-2964.
3. Mittelman M. The myelodysplastic syndromes-1990. Israel Journal ofMmedical Sciences. 1990;26(8):468-478.
4. de Swart L, Smith A, Johnston TW, et al. Validation of the revised international prognostic scoring system (IPSS?R) in patients with lower?risk myelodysplastic syndromes: a report from the prospective European LeukaemiaNet MDS (EUMDS) registry. British Journal of Haematology. 2015;170(3):372-383. doi:10.1111/bjh.13450.
5. Platzbecker U, Wong RSM, 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. The Lancet Haematology. 2018;2(10):e417-e426. doi:10.1016/S2352-3026(15)00149-0.
6. Kantarjian HM, Giles F, List AF, et al. The Incidence and Impact of thrombocytopenia in Myelodysplastic Syndrome (MDS). Blood. 2006;108(11):2617 LP-2617.
7. Gonzalez-Porras JR, Cordoba I, Such E, et al. Prognostic impact of severe thrombocytopenia in low-risk myelodysplastic syndrome. Cancer. 2011;117(24):5529-5537. doi:10.1002/cncr.26173.
8. Zeidman A, Sokolover N, Fradin Z, Cohen A, Redlich O, Mittelman M. Platelet function and its clinical significance in the myelodysplastic syndromes. The Hematology Journal. 2004;5(3):234-238. doi:10.1038/sj.thj.6200364.
9. Neukirchen J, Blum S, Kuendgen A, et al. Platelet counts and haemorrhagic diathesis in patients with myelodysplastic syndromes. European Journal of Haematology. 2009;83(5):477-482. doi:10.1111/j.1600-0609.2009.01299.x.
10. Nachtkamp K, Stark R, Strupp C, et al. Causes of death in 2877 patients with myelodysplastic syndromes. Annals Of Hematology. 2016;95(6):937-944. doi:10.1007/s00277-016-2649-3.
11. Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89(6):2079 LP-2088.
12. Greenberg PL, Tuechler H, Schanz J, et al. Revised International Prognostic Scoring System for myelodysplastic syndromes. Blood. 2012;120(12):2454-2465. doi:10.1182/blood-2012-03-420489.
13. Itzykson R, Smith A, Fenaux P, et al. Prognostic value of early drop in platelets in lower-risk MDS. A sub-study from the European Leukemianet Lower-Risk MDS (EUMDS) Registry. Leukemia Research. 2017;55:S10-S11. doi:10.1016/S0145-2126(17)30132-7.
14. List A, Dewald G, Bennett J, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. New England Journal of Medicine. 2006;355(14):1456-1465. doi:10.1056/NEJMoa061292.
15. Fenaux P, Giagounidis A, Selleslag D, et al. A randomized phase 3 study of lenalidomide versus placebo in RBC transfusion-dependent patients with Low-/Intermediate-1-risk myelodysplastic syndromes with del5q. Blood. 2011;118(14):3765-3776. doi:10.1182/blood-2011-01-330126.
16. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. The Lancet Oncology. 2009;10(3):223-232. doi:10.1016/S1470-2045(09)70003-8.
17. Kantarjian H, Issa J-PJ, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer. 2006;106(8):1794-1803. doi:10.1002/cncr.21792.
18. Lee RE, Young RH, Castleman B, et al. : A biography of the enigmatic creator of the Wright stain on the occasion of its centennial. The American Journal of Surgical Pathology. 2002;26(1):88-96.
19. Kelemen E, Cserháti I, Tanos B. Demonstration and some properties of human thrombopoietin in thrombocythaemic Sera. Acta Haematologica. 1958;20(6):350-355. doi:10.1159/000205503.
20. Metcalf D. Thrombopoietin - at last. Nature. 1994;369:519.
21. Kaushansky K, Lichtman MA, Prchal JT, et al. Williams - Hematology, 9th Edition.Chapter 18-Hematopoietic stems cells, progenitors and cytokins. K.Kaushansky, 2016:2505.
22. Eaton, DL. Thrombopoietin?: the primary regulator of megakaryocytopoiesis and thrombopoiesis. Exp Hematol. 1997;25:1-7.
23. Ramsfjell V, Borge OJ, Veiby OP, et al. Thrombopoietin, but not erythropoietin, directly stimulates multilineage growth of primitive murine bone marrow progenitor cells in synergy with early acting cytokines: distinct interactions with the ligands for c-kit and FLT3. Blood. 1996;88(12):4481 LP-4492.
24. Alexander WS, Roberts AW, Nicola NA, et al. Deficiencies in progenitor cells of multiple hematopoietic lineages and defective megakaryocytopoiesis in mice lacking the thrombopoietic receptor c-Mpl. Blood. 1996;87(6):2162 LP-2170.
25. Kuter DJ, Begley CG. Recombinant human thrombopoietin: basic biology and evaluation of clinical studies. Blood. 2002;100(10):3457 LP-3469.
26. Li J, Yang C, Xia Y, et al. Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood. 2001;98(12):3241 LP-3248.
27. Rodeghiero F, Carli G. Beyond immune thrombocytopenia: the evolving role of thrombopoietin receptor agonists. Annals of Hematology. 2017;96(9):1421-1434. doi:10.1007/s00277-017-2953-6.
28. 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. European Journal of Haematology. 2013;91(5):423-436. doi:10.1111/ejh.12181.
29. Saleh MN, Bussel JB, Cheng G, et al. Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: results of the long-term, open-label EXTEND study. Blood. 2013;121(3):537-545. doi:10.1182/blood-2012-04-425512.
30. Wang B, Nichol J, Sullivan J. Pharmacodynamics and pharmacokinetics of AMG 531, a novel thrombopoietin receptor ligand. Clinical Pharmacology & Therapeutics. 2004;76(6):628-638. doi:10.1016/j.clpt.2004.08.010.
31. Kantarjian H, Fenaux P, Sekeres MA, et al. Safety and efficacy of romiplostim in patients with lower-risk myelodysplastic syndrome and thrombocytopenia. Journal of Clinical Oncology. 2010;28(3):437-444. doi:10.1200/JCO.2009.24.7999.
32. Giagounidis A, Mufti GJ, Fenaux P, et al. Results of a randomized, double-blind study of romiplostim versus placebo in patients with low/intermediate-1-risk myelodysplastic syndrome and thrombocytopenia. Cancer. 2014;120(12):1838-1846. doi:10.1002/cncr.28663.
33. Kantarjian HM, Fenaux P, Sekeres MA, et al. Long-term follow-up for up to 5 years on the risk of leukaemic progression in thrombocytopenic patients with lower-risk myelodysplastic syndromes treated with romiplostim or placebo in a randomised double-blind trial. The Lancet Haematology. February 2018. doi:10.1016/S2352-3026(18)30016-4.
34. Fenaux P, Muus P, Kantarjian H, et al. Romiplostim monotherapy in thrombocytopenic patients with myelodysplastic syndromes: long-term safety and efficacy. British Journal of Haematology. 2017;178(6):906-913. doi:10.1111/bjh.14792.
35. Mittelman M. Good news for patients with myelodysplastic syndromes and thrombocytopenia. The Lancet Haematology. February 2018. doi:10.1016/S2352-3026(18)30017-6.
36. Sekeres MA, Kantarjian H, Fenaux P, et al. Subcutaneous or intravenous administration of romiplostim in thrombocytopenic patients with lower risk myelodysplastic syndromes. Cancer. 2011;117(5):992-1000. doi:10.1002/cncr.25545.
37. Prica A, Sholzberg M, Buckstein R. Safety and efficacy of thrombopoietin-receptor agonists in myelodysplastic syndromes: a systematic review and meta-analysis of randomized controlled trials. British Journal of Haematology. 2014;167(5):626-638. doi:10.1111/bjh.13088.
38. Sekeres MA, Giagounidis A, Kantarjian H, et al. Development and validation of a model to predict platelet response to romiplostim in patients with lower-risk myelodysplastic syndromes. British Journal of Haematology. 2014;167(3):337-345. doi:10.1111/bjh.13037.
39. Kantarjian HM, Giles FJ, Greenberg PL, et al. Phase 2 study of romiplostim in patients with low- or intermediate-risk myelodysplastic syndrome receiving azacitidine therapy. Blood. 2010;116(17):3163 LP-3170.
40. Greenberg PL, Garcia-Manero G, Moore M, et al. A randomized controlled trial of romiplostim in patients with low- or intermediate-risk myelodysplastic syndrome receiving decitabine. Leukemia & Lymphoma. 2013;54(2):321-328. doi:10.3109/10428194.2012.713477.
41. Wang ES, Lyons RM, Larson RA, et al. A randomized, double-blind, placebo-controlled phase 2 study evaluating the efficacy and safety of romiplostim treatment of patients with low or intermediate-1 risk myelodysplastic syndrome receiving lenalidomide. Journal of Hematology & Oncology. 2012;5(1):71. doi:10.1186/1756-8722-5-71.
42. Erickson-Miller C, Delorme E, Giampa L, et al. Biological activity and selectivity for Tpo receptor of the orally bioavailable, small molecule Tpo receptor agonist, SB-497115. Blood. 2004;104(11):2912 LP-2912.
43. 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 LP-394.
44. Vlachodimitropoulou E, Chen Y-L, Garbowski M, et al. Eltrombopag: a powerful chelator of cellular or extracellular iron(III) alone or combined with a second chelator. Blood. 2017 130: 1923-1933.
45. Oliva EN, Alati C, Santini V, 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. The Lancet Haematology. 2017;4(3):e127-e136. doi:10.1016/S2352-3026(17)30012-1.
46. Platzbecker U, Wong RSM, 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. The Lancet Haematology. 2015;2(10):e417-e426. doi:10.1016/S2352-3026(15)00149-0.
47. 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. The Lancet Haematology. 2018;5(1):e34-e43. doi:10.1016/S2352-3026(17)30228-4.
48. Mittelman M, Platzbecker U, Afanasyev B V, et al. Phase 3, placebo-controlled, ASPIRE study (TRC114968) of eltrombopag (EPAG) treatment of thrombocytopenia (TCP) in advanced myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML): Assessment of clinical benefit, safety, and tolerability. Blood (Suppl). 2015;126(23).
49. Svensson T, Chowdhury O, Garelius H, et al. A pilot phase I dose finding safety study of the thrombopoietin-receptor agonist, eltrombopag, in patients with myelodysplastic syndrome treated with azacitidine. European Journal of Haematology. 2014;93(5):439-445. doi:10.1111/ejh.12383.
50. Dickinson MJ, Cherif H, Fenaux P, et al. Thrombopoietin (TPO) receptor agonist eltrombopag in combination with azacitidine (AZA) for primary treatment of myelodysplastic syndromes (MDS) patients with thrombocytopenia: Outcomes from the randomized, placebo-controlled, phase III support study. Blood (Suppl). 2016;128(22):163 LP-163.
51. Dodillet H, Kreuzer K-A, Monsef I, Skoetz N. Thrombopoietin mimetics for patients with myelodysplastic syndromes. The Cochrane database of systematic reviews. 2017;9:CD009883. doi:10.1002/14651858.CD009883.pub2.