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

Platzbecker, Uwe; Wong, Raymond; Verma, Amit; Abboud, Camille N.; Araújo, Sérgio Schusterschitz da Silva; Chiou, Tzeon Jye; Feigert, John; Yeh, Shih-Peng; Götze, Katharina; Gorin, Norbert Claude; Greenberg, Peter L.; Kambhampati, Suman; Kim, Yoo Jin; Lee, Je Hwan; Lyons, Roger M.; Ruggeri, Marco; Santini, Valeria; Cheng, Gregory; Jang, Jun Ho; Chen, Chien Yuan; Johnson, Brendan M.; Bennett, John M.; Mannino, Frank; Kamel, Yasser Mostafa; Stone, Nicole L.; Dougherty, Souria; Chan, Geoffrey; Giagounidis, Aristoteles

doi:10.1016/s2352-3026(15)00149-0

Cited by 67 publications

(47 citation statements)

References 28 publications

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“…Of particular interest would be use of eltrombopag in combination with less toxic immunosuppressive regimens that omit antithymocyte globulin, particularly in older patients, in patients with coexisting conditions, and in developing countries where aplastic anemia is prevalent and conventional therapies extremely costly. Eltrombopag has shown some efficacy beyond aplastic anemia, including myelodysplastic syndromes, 31 unilineage cytopenias, or moderate aplastic anemia (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia

et al. 2017

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Background Acquired aplastic anemia results from immune-mediated destruction of bone marrow. Immunosuppressive therapies are effective, but reduced numbers of residual stem cells may limit their efficacy. In patients with aplastic anemia that was refractory to immunosuppression, eltrombopag, a synthetic thrombopoietin-receptor agonist, led to clinically significant increases in blood counts in almost half the patients. We combined standard immunosuppressive therapy with eltrombopag in previously untreated patients with severe aplastic anemia. Methods We enrolled 92 consecutive patients in a prospective phase 1–2 study of immunosuppressive therapy plus eltrombopag. The three consecutively enrolled cohorts differed with regard to the timing of initiation and the duration of the eltrombopag regimen (cohort 1 received eltrombopag from day 14 to 6 months, cohort 2 from day 14 to 3 months, and cohort 3 from day 1 to 6 months). The cohorts were analyzed separately. The primary outcome was complete hematologic response at 6 months. Secondary end points included overall response, survival, relapse, and clonal evolution to myeloid cancer. Results The rate of complete response at 6 months was 33% in cohort 1, 26% in cohort 2, and 58% in cohort 3. The overall response rates at 6 months were 80%, 87%, and 94%, respectively. The complete and overall response rates in the combined cohorts were higher than in our historical cohort, in which the rate of complete response was 10% and the overall response rate was 66%. At a median follow-up of 2 years, the survival rate was 97%; one patient died during the study from a nonhematologic cause. Marked increases in bone marrow cellularity, CD34+ cell number, and frequency of early hematopoietic progenitors were noted. Rates of relapse and clonal evolution were similar to our historical experience. Severe rashes occurred in two patients, resulting in the early discontinuation of eltrombopag. Conclusions The addition of eltrombopag to immunosuppressive therapy was associated with markedly higher rates of hematologic response among patients with severe aplastic anemia than in a historical cohort. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT01623167.)

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Section: Discussionmentioning

confidence: 99%

Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia

et al. 2017

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“…15,16,36,37 Despite the wide spectrum of conditions where eltrombopag has been used, little is known about the mechanisms of action of this drug on human HSCs. The results of our study demonstrated that eltrombopag promoted successful in vitro human cord and peripheral blood-derived HSCs differentiation towards the megakaryocytic lineage, as assessed by the maturation of high ploidy megakaryocytes expressing the lineage-speEx vivo inquiry on Eltrombopag mechanism of action haematologica | 2016; 101 (12) 1485 27,28 stimulated the activation of all the main biochemical pathways downstream of the c-Mpl receptor.…”

Section: Discussionmentioning

confidence: 99%

“…[12][13][14] Moreover, improvement of thrombocytopenia has been obtained in patients with acute myeloid leukemia (AML) and MDS. 15,16 Interestingly, promising clinical results have also demonstrated multi-lineage responses and the maintenance of normalized hematopoiesis in several patients suffering from AA, [17][18][19] suggesting that eltrombopag may exert a beneficial effect on HSCs recovery by yet unexplored ways. Unfortunately, the use of traditional animal models for studies on the mechanisms of action of eltrombopag is not possible due to its selective activity only in humans and chimpanzees.…”

Section: Introductionmentioning

confidence: 99%

Revealing eltrombopags promotion of human megakaryopoiesis through AKT/ERK-dependent pathway activation

et al. 2016

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“…In kleineren Studien konnten TPO-RA dieses Risiko und die Abhängigkeit von ThrombozytenTransfusionen reduzieren [24,25]. In einer randomisierten Doppelblindstudie (Phase I/II) konnte mit Eltrombopag bei Hochrisiko-MDS/AML ein nicht signifikanter Überlebensvorteil gegenüber Placebo erreicht werden [26]. Die Phase-III-Studie SUPPORT (NCT02158936), so Platzbecker, prüft derzeit randomisiert die Zugabe von Eltrombopag zu Azacitidin (gegen Placebo + Azacitidin).…”

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

Cited by 67 publications

References 28 publications

Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia

Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia

Revealing eltrombopags promotion of human megakaryopoiesis through AKT/ERK-dependent pathway activation

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