Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response

Abstract

• Enasidenib inhibits mIDH2, leading to leukemic cell differentiation with emergence of functional mIDH2 neutrophils in rrAML patients.• RAS pathway mutations and increased mutational burden overall are associated with a decreased response rate to mIDH2 inhibition.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. (Blood. 2017;130(6):732-741)

Hypomethylating agents for treatment and prevention of relapse after allogeneic blood stem cell transplantation

“…This small molecule mediates its effect rather by differentiation than by a direct cytotoxic effect against myeloid blasts and induces a promising response rate of 40% [76,77]. Enasidenib has just recently been approved in the USA for the treatment of patients with IDH2-mutated relapsed/refractory AML.…”

The role of targeted therapy in the management of patients with AML

“…The IDH2 mutation allele burden at study entry had no effect on response rate. 29 Similarly, reduction in 2HG concentration was profound and nearly uniform across the trial. Accordingly, a reduction in 2HG did not predict response to enasidenib.…”

“…However, the majority did not show a significant reduction in IDH2 mutation burden because the primary mechanism of response appears to be induction of terminal differentiation. 29 As well, ;12% of enasidenib-treated patients experienced a differentiation syndrome variably characterized by fever, dyspnea/lung infiltrates, pleural effusions, leukocytosis, and kidney injury. 30 Similar to the management of APL differentiation syndrome, systemic corticosteroids led to the resolution of these symptoms.…”

“…Certain co-mutations, specifically N-or K-ras, but also a number of mutations that activate hematopoietic cytokine signal transduction (eg, PTPN11, NF1, and FLT3), were associated with relatively low response rates. 29 Patients with high numbers of co-mutations, generally a marker for clonal diversity, also had relatively low responses to enasidenib.…”

Hitting the target in IDH2 mutant AML

“…In a related paper, Amatangelo et al 2 investigate mechanisms of response in samples derived from the same patients.…”