Eltrombopag for patients with moderate aplastic anemia or uni-lineage cytopenias

Abstract

There is no standard or widely effective treatment of patients with moderate aplastic anemia (MAA) or hypo-productive uni-lineage cytopenias (UC). Eltrombopag (EPAG), a small molecule thrombopoietin mimetic, has previously been shown to result in durable multi-lineage hematologic responses with low toxicity in patients with refractory severe aplastic anemia (SAA). Its safety and efficacy in MAA are unknown. This prospective phase 2 study enrolled previously untreated and treated MAA and UC patients with clinically relevant cytopenias. EPAG was administered at doses escalating from 50 to 300 mg/d. Hematologic responses were assessed at 16 to 20 weeks. Responding patients were continued on EPAG until reaching defined robust or stable blood counts. EPAG was reinstituted for relapse. Thirty-four patients were enrolled between 2012 and 2017, including 31 with MAA and 3 with UC. Seventeen patients responded in at least 1 eligible lineage by the primary end point. A striking improvement in anemia was observed in a patient with Diamond-Blackfan anemia. EPAG was well tolerated, and it was discontinued for robust or stable blood counts in 12 of 17 patients after a median of 8 months. A majority required re-initiation of EPAG for declining counts, and all regained response. Two of 34 patients developed non–chromosome 7 bone marrow cytogenetic abnormalities while taking EPAG, without dysplasia or increased blasts. Somatic mutation allele frequencies in cancer genes did not increase overall on EPAG. EPAG is a well-tolerated oral treatment of cytopenias in patients with MAA/UC. This trial was registered at www.clinicaltrials.gov as #NCT01328587.

Current evidence and the emerging role of eltrombopag in severe aplastic anemia

“…Consequently, the NIH performed a dose-escalating study in MAA and unilineage cytopenic syndromes. 25 Eltrombopag was given at doses from 50 mg up to 300 mg and hematologic response was assessed after 14–20 weeks. Half of the study population responded in at least one previously affected lineage and the treatment could be stopped in the majority of the responding patients.…”

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“…However, in the age-matched subgroup, in which patients were younger, there was less relapse as well as clonal evolution implying an age-related effect. Although no evidence for the increase of clone evolution rate has been identified when EPAG+IST was compared with the history controls of IST alone as the frontline therapy so far (23,29), we do see the relapse when EPAG or IST was tapered or withdrawn (36,42). VSAA patients usually exhibit higher chances of relapse and clonal evolution when compared with SAA patients (43).…”

“…Aged patients usually exhibit poor response to treatment when compared with the younger ones, for either IST or HSCT (35)(36)(37). Under this circumstance, we found that EPAG+IST had a very similar ORR (lower in absolute number) than the haplo-HSCT (81% in the EPAG+IST group and 86% in the haplo-HSCT group, p = 0.23).…”

Eltrombopag Improves Erythroid Differentiation in a Human Induced Pluripotent Stem Cell Model of Diamond Blackfan Anemia

“…We present evidence that addition of EPAG during DBA iPSC differentiation rescues at least in part the block in erythroid maturation recapitulated in this model. These findings and the recent report of a robust erythroid response to EPAG in a steroid-refractory DBA patient with a de novo mutation in RPS19 [42] suggest that EPAG may represent an alternative therapeutic modality for subjects with DBA. A single-arm phase I/II pilot trial (NCT04269889) has recently received approval at our institution to further assess safety and efficacy of EPAG in DBA patients.…”