Induces Acute Myeloid Leukemia Cell Differentiation to Promote Clinical Response

One Sentence Summary: Enasidenib promotes hematopoietic differentiation to induce clinical responses in IDH2 -mutant Acute Myeloid Leukemia that are modulated by co-occurring mutations. Abstract: Recurrent mutations at R140 and R172 in isocitrate dehydrogenase 2 ( IDH2 ) occur in many cancers, including ~12% of acute myeloid leukemia (AML). In preclinical models these mutations cause accumulation of the oncogenic metabolite R-2-hydroxyglutarate (2-HG) and induce hematopoietic differentiation block. Single-agent enasidenib (AG-221/CC-90007), a selective mutant IDH2 (mIDH2) inhibitor, produced an overall response rate of 40.3% in relapsed/refractory AML patients with mIDH2 in a phase 1 trial. However, its mechanism of action and biomarkers associated with response remain unclear. Here, we measured 2-HG, mIDH2 allele burden, and co-occurring somatic mutations in sequential patient samples from the clinical trial and correlated these with clinical response. Furthermore, we used flow cytometry to assess inhibition of mIDH2 on hematopoietic differentiation. We observed potent 2-HG suppression in both R140- and R172 AML subtypes, with different kinetics, which preceded clinical response. Suppression of 2-HG alone did not predict response, as most non-responding patients also exhibited 2-HG suppression. In a subset of patients, m IDH2 allele burden decreased with response. Conversely, complete remission with persistence of mIDH2 and normalization of hematopoietic stem and progenitor compartments with emergence of functional m IDH2 neutrophils was more commonly observed. Co-occurring mutations in NRAS and other MAPK pathway effectors were enriched in non-responding patients, consistent with RAS signaling contributing to primary therapeutic resistance. Together, these data support differentiation as the main mechanism of enasidenib efficacy in relapse/refractory AML patients and provide insights into resistance mechanisms to inform future mechanism-based combination treatment studies.

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