Induction of short-term remission with single agent eltrombopag in refractory nucleophosmin-1-mutated acute myeloid leukemia

Platzbecker, Uwe; Sockel, Katja; Schönefeldt, Claudia; Nowak, Daniel; Helas, Susann; Röllig, Christoph; Mossner, Maximilian; Jann, Johann Christoph; Ehninger, Gerhard; Hofmann, Wolf‐Karsten; Bornhäuser, Martin; Thiede, Christian; Wermke, Martin

doi:10.3324/haematol.2014.111948

Cited by 7 publications

(3 citation statements)

References 6 publications

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“…The cytotoxicity of EP, unlike its ability to promote megakaryopoiesis, does not depend on c-Mpl 17. This anti-leukemic effect was also observed in an AML patient with a NPM1 mutation 19. Consistent with those studies,15–18,24 our results reveal that continuous EP (5–30 μg/mL) or DAC (>0.5 μmol/L) single-agent treatment suppresses the proliferation of K562 and THP-1 cells.…”

Section: Discussionsupporting

confidence: 90%

“…This anti-leukemic effect was also observed in an AML patient with nucleophosmin 1 (NPM1) mutation. After 2 months of treatment with EP, that patient achieved short-term remission of AML 19. A preclinical study also showed that EP in combination with lenalidomide suppresses leukemia cell growth while preserving the advantageous effect of stimulating megakaryocyte growth 20…”

Section: Introductionmentioning

confidence: 95%

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<p>The synergistic antileukemic effects of eltrombopag and decitabine in myeloid leukemia cells</p>

Shi

Yang

et al. 2019

CMAR

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BackgroundHypomethylating agents (HMAs), such as decitabine (DAC), are currently used as first-line therapy for patients with high-risk myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML) not eligible for standard chemotherapies. Exacerbation of thrombocytopenia is one of the prevalent complications after HMA treatment. Eltrombopag (EP), an oral thrombopoietin receptor agonist, can efficiently stimulate megakaryopoiesis and elevate platelet counts in MDS/AML patients. However, the significance of combining EP with HMAs in patients with high-risk MDS/AML has not been determined.PurposeTo explore the impacts and mechanisms of EP and/or DAC on leukemia cell growth and to explore whether EP exhibits antileukemic effects in the context of DAC treatment in human myeloid leukemia cell lines.MethodsIn our study, we assessed the anti-leukemic effect of EP in the context of DAC treatment by measuring cell proliferation, apoptosis, cell-cycle distribution, and intracellular reactive oxygen species (ROS) levels.ResultsOur results showed that the combination of EP and DAC had a more obvious antiproliferative effect than that of DAC as a single agent. EP mainly induced S or G0/G1 phase cell cycle arrest, and DAC arrested the cell cycle in the S or G2/M phase. The combination of EP and DAC had a synergistic effect on cell cycle arrest. Furthermore, single-agent treatment with EP or DAC induced a change in intracellular ROS levels, and the combination of EP and DAC had a synergistic effect on ROS levels, exacerbating leukemia cell death.ConclusionOur study provides in vitro evidence of the synergistic antileukemic effect and potential mechanisms of the combination of DAC and EP on myeloid leukemia cells.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 95%

<p>The synergistic antileukemic effects of eltrombopag and decitabine in myeloid leukemia cells</p>

Shi

Yang

et al. 2019

CMAR

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“…[15][16][17]32 There were no indicators that would predict the outcome of this phase 3 trial. 18,19 Preclinical and single-agent clinical studies of eltrombopag suggest that as a single agent, eltrombopag suppresses malignant myeloid blast proliferation [33][34][35][36] ; hence, the findings of this trial were unexpected. One hypothesis for our findings is a potential inhibition of the effects of azacitidine by eltrombopag when given concomitantly.…”

Section: Discussionmentioning

confidence: 92%

Azacitidine with or without eltrombopag for first-line treatment of intermediate- or high-risk MDS with thrombocytopenia

Dickinson

Cherif

Fenaux

et al. 2018

Blood

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Abstract Azacitidine treatment of myelodysplastic syndromes (MDSs) generally exacerbates thrombocytopenia during the first treatment cycles. A Study of Eltrombopag in Myelodysplastic Syndromes Receiving Azacitidine (SUPPORT), a phase 3, randomized, double-blind, placebo-controlled study, investigated the platelet supportive effects of eltrombopag given concomitantly with azacitidine. International Prognostic Scoring System intermediate-1, intermediate-2, or high-risk MDS patients with baseline platelets <75 × 109/L were randomized 1:1 to eltrombopag (start, 200 mg/d [East Asians, 100 mg/d], maximum, 300 mg/d [East Asians, 150 mg/d]) or placebo, plus azacitidine (75 mg/m2 subcutaneously once daily for 7 days every 28 days). The primary end point was the proportion of patients platelet transfusion-free during cycles 1 through 4 of azacitidine therapy. Based on planned interim analyses, an independent data monitoring committee recommended stopping the study prematurely because efficacy outcomes crossed the predefined futility threshold and for safety reasons. At termination, 28/179 (16%) eltrombopag and 55/177 (31%) placebo patients met the primary end point. Overall response (International Working Group criteria; complete, marrow, or partial response) occurred in 20% and 35% of eltrombopag and placebo patients, respectively, by investigator assessment. There was no difference in hematologic improvement in any cell lineage between the 2 arms. There was no improvement in overall or progression-free survival. Adverse events with ≥10% occurrence in the eltrombopag vs placebo arm were febrile neutropenia and diarrhea. Compared with azacitidine alone, eltrombopag plus azacitidine worsened platelet recovery, with lower response rates and a trend toward increased progression to acute myeloid leukemia. This trial was registered at www.clinicaltrials.gov as #NCT02158936.

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Thrombopoietin Receptor Agonists

Kuter

2019

Platelets

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Induction of short-term remission with single agent eltrombopag in refractory nucleophosmin-1-mutated acute myeloid leukemia

Cited by 7 publications

References 6 publications

<p>The synergistic antileukemic effects of eltrombopag and decitabine in myeloid leukemia cells</p>

<p>The synergistic antileukemic effects of eltrombopag and decitabine in myeloid leukemia cells</p>

Azacitidine with or without eltrombopag for first-line treatment of intermediate- or high-risk MDS with thrombocytopenia

Thrombopoietin Receptor Agonists

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