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

Dickinson, Michael; Cherif, Honar; Fenaux, Pierre; Mittelman, Moshe; Verma, Amit; Portella, Maria Socorro O; Burgess, Paul; Ramos, Pedro Marques; Choi, Jeea; Platzbecker, Uwe

doi:10.1182/blood-2018-06-855221

Cited by 78 publications

(61 citation statements)

References 36 publications

(45 reference statements)

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“…[29][30][31] Concerningly, a recent large study comparing azacytidine with or without EPAG for patients with intermediate-or high-risk MDS was terminated prematurely due to a lower response rate in the EPAG arm, in addition to a trend toward a higher rate of progression to AML. 32 Characteristics of clonal progression in patients with rSAA and severely reduced persistent HSPC reserve may not apply to EPAG treatment in other clinical settings.…”

Section: Discussionmentioning

confidence: 99%

Treatment optimization and genomic outcomes in refractory severe aplastic anemia treated with eltrombopag

Winkler¹,

Fan²,

Cooper

et al. 2019

Blood

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Eltrombopag (EPAG) received approval from the US Food and Drug Administration for the treatment of refractory severe aplastic anemia (rSAA) based on treatment of 43 patients with doses escalating from 50 to 150 mg daily for 12 weeks. Response kinetics suggested that more prolonged administration of EPAG at a dose of 150 mg could speed and improve response rates. We enrolled 40 patients with rSAA in a study of EPAG 150 mg daily, with a primary end point of response at 24 weeks. Twenty (50%) of 40 patients responded at 24 weeks; 5 (25%) of 20 would have been deemed nonresponders at 12 weeks, the end point of the previous study. Fifteen of the 19 responding patients continuing on EPAG had drug discontinued for robust response; 5 of the 15 required EPAG re-initiation for relapse, with all recovering response. To analyze risk of clonal progression, we combined long-term data from the 83 patients with rSAA enrolled in both studies. Evolution to an abnormal karyotype occurred in 16 (19%), most within 6 months of EPAG initiation. Targeted deep sequencing/whole-exome sequencing was performed pre-EPAG and at primary response end point and/or time of clonal evolution or longest follow-up. Cytogenetic evolution did not correlate with mutational status, and overall mutated allele fractions of myeloid cancer genes did not increase on EPAG. In summary, extended administration of EPAG at a dose of 150 mg for 24 weeks rescued responses in some patients with rSAA not responding at 12 weeks. The temporal relationship between clonal evolution and drug exposure suggests that EPAG may promote expansion of dormant preexisting clones with an aberrant karyotype. The studies were registered at www.clinicaltrials.gov as #NCT00922883 and #NCT01891994.

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Section: Discussionmentioning

confidence: 99%

Treatment optimization and genomic outcomes in refractory severe aplastic anemia treated with eltrombopag

Winkler¹,

Fan²,

Cooper

et al. 2019

Blood

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“…However, there is still much controversy about the application of EP in patients simultaneously treated with HMAs. One phase III clinical trial (NCT02158936) that examined the capability of EP in intermediate or high-risk MDS patients using azacytidine treatment was terminated because of the slower platelet and increased risk of developing AML, and the usage of EP combined with HMAs in patients with MDS is, therefore, contraindicated 32. Although that clinical study did not observe a synergistic effect of azacytidine and EP in MDS patients, concerns about concomitant treatment with EP and HMAs have been raised.…”

Section: Discussionmentioning

confidence: 99%

<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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“…Several promising drugs, such as vorinostat, lenalinomide, and eltrombopag, have been combined with azacitidine in an attempt to improve its efficacy; however, none of these combinations has shown a significant benefit compared with azacitidine alone. 68,69 In general, the combinations increased hematological toxicity, suggesting that a lower dose of azacitidine, when combined with other agents, could be worthy of study.…”

Section: Hmasmentioning

confidence: 99%

In MDS, is higher risk higher reward?

Sanz

2019

Hematology

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Patients with higher-risk myelodysplastic syndrome (HR-MDS) are defined by the original or revised International Prognostic Scoring System and specific genetic features. Treatment of HR-MDS is challenging. Allogeneic hematopoietic stem cell transplantation, the only curative approach, is feasible in a minority of fit or intermediate fitness patients aged <70 to 75 years who are willing to face the risks of the procedure. Response to azacitidine and decitabine, the only approved drugs for HR-MDS and considered the standard of care, is partial and transient in most patients. The development of novel more personalized and efficient drugs is an unmet medical need. During the last decade, there have been substantial advances in understanding the multiple molecular, cellular, and immunological disturbances involved in the pathogenesis of myelodysplastic syndrome. As a result, a number of clinical and translational studies of new more focused treatment approaches for HR-MDS patients are underway. In contrast to acute myeloid leukemia, they have not resulted in any new drug approval. This review addresses the benefits and limitations of current treatment alternatives, offers a practical individualized treatment approach, and summarizes the clinical trials in progress for HR-MDS.

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

Cited by 78 publications

References 36 publications

Treatment optimization and genomic outcomes in refractory severe aplastic anemia treated with eltrombopag

Treatment optimization and genomic outcomes in refractory severe aplastic anemia treated with eltrombopag

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

In MDS, is higher risk higher reward?

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