Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response Journal Article

Authors: Amatangelo, M. D.; Quek, L.; Shih, A.; Stein, E. M.; Roshal, M.; David, M. D.; Marteyn, B.; Farnoud, N. R.; de Botton, S.; Bernard, O. A.; Wu, B.; Yen, K. E.; Tallman, M. S.; Papaemmanuil, E.; Penard-Lacronique, V.; Thakurta, A.; Vyas, P.; Levine, R. L.
Article Title: Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response
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 (rrAML) 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 mIDH2 AML subtypes, with different kinetics, which preceded clinical response. Suppression of 2-HG alone did not predict response, because most nonresponding patients also exhibited 2-HG suppression. Complete remission (CR) with persistence of mIDH2 and normalization of hematopoietic stem and progenitor compartments with emergence of functional mIDH2 neutrophils were observed. In a subset of CR patients, mIDH2 allele burden was reduced and remained undetectable with response. Co-occurring mutations in NRAS and other MAPK pathway effectors were enriched in nonresponding patients, consistent with RAS signaling contributing to primary therapeutic resistance. Together, these data support differentiation as the main mechanism of enasidenib efficacy in relapsed/refractory AML patients and provide insight into resistance mechanisms to inform future mechanism-based combination treatment studies. © 2017 by The American Society of Hematology.
Keywords: mitogen activated protein kinase; controlled study; treatment response; unclassified drug; human cell; somatic mutation; genetics; mutation; leukemia, myeloid, acute; clinical trial; antineoplastic agents; flow cytometry; antineoplastic agent; metabolism; allele; cell compartmentalization; enzyme inhibition; neutrophil count; neoplasm recurrence, local; cohort analysis; gene frequency; cell differentiation; pathology; retrospective study; tumor marker; neutrophil; drug mechanism; tumor recurrence; thrombocyte count; hematopoiesis; ras protein; hematopoietic stem cell; phase 1 clinical trial; phagocytosis; peripheral blood mononuclear cell; leukemia remission; isocitrate dehydrogenase; transcription factor runx1; molecularly targeted therapy; glutarates; 2 hydroxyglutaric acid; alpha-hydroxyglutarate; glutaric acid derivative; oncogene n ras; acute myeloid leukemia; additional sex comb like 1; triazines; drug effects; isocitrate dehydrogenase 2; isocitrate dehydrogenase 2, human; humans; human; male; female; priority journal; article; antagonists and inhibitors; aminopyridines; aminopyridine derivative; bone marrow derived mononuclear cell; enasidenib; serine arginine rich splicing factor; serine arginine rich splicing factor 2; ag-221; triazine derivative; acute myeloid leukemia cell line
Journal Title: Blood
Volume: 130
Issue: 6
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2017-08-10
Start Page: 732
End Page: 741
Language: English
DOI: 10.1182/blood-2017-04-779447
PUBMED: 28588019
PROVIDER: scopus
PMCID: PMC5553578
Notes: Article -- Export Date: 2 October 2017 -- Source: Scopus
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MSK Authors
  1. Eytan Moshe Stein
    134 Stein
  2. Martin Stuart Tallman
    461 Tallman
  3. Alan H Shih
    56 Shih
  4. Ross Levine
    508 Levine
  5. Mikhail Roshal
    79 Roshal