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Enasidenib in acute myeloid leukemia: clinical development and perspectives on treatment.

ABSTRACT: Recently there has been a significant progression in the understanding of molecular mutations driving biochemical and cellular signaling changes leading to survival and proliferation of leukemia cells in patients with acute myeloid leukemia (AML). Preclinical studies have demonstrated a mutated enzyme in the citric acid cycle, isocitrate dehydrogenase (IDH), leads to the production of an oncogenic metabolite R-2-hydroxy-glutarate (R-2-HG). This causes the arrest in the differentiation of hematopoietic stem cells leading to the promotion of leukemia. Inhibitors of the IDH enzyme have been shown in preclinical studies to reduce the production of R-2-HG, resulting in terminal differentiation of leukemia blast cells. In recent phase I and II trials, the IDH2 inhibitor enasidenib has shown clinical activity in patients with relapsed and refractory (R/R) AML. This review will describe the preclinical and clinical developments of enasidenib and its Food and Drug Administration approval in R/R AML, treatment recommendations and management will be outlined.

SUBMITTER: Reed DR

PROVIDER: S-EPMC6724422 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Enasidenib in acute myeloid leukemia: clinical development and perspectives on treatment.

Reed Daniel R DR Elsarrag Ramey Z RZ Morris Amy L AL Keng Michael K MK

Cancer management and research 20190830

Recently there has been a significant progression in the understanding of molecular mutations driving biochemical and cellular signaling changes leading to survival and proliferation of leukemia cells in patients with acute myeloid leukemia (AML). Preclinical studies have demonstrated a mutated enzyme in the citric acid cycle, isocitrate dehydrogenase (IDH), leads to the production of an oncogenic metabolite R-2-hydroxy-glutarate (R-2-HG). This causes the arrest in the differentiation of hematop ...[more]

PMID: 31564968

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Project description:Recurrent mutations affecting cellular metabolism and epigenetic regulation are implicated in the pathogenesis of acute myeloid leukemia (AML). Isocitrate dehydrogenase 2 (IDH2) gene mutations are described in 12% of patients with AML and 5% of patients with myelodysplastic syndromes. IDH2 enzyme is involved in the Krebs cycle, catalyzing ?-ketoglutarate from isocitrate. Mutant IDH2 enzymes acquire a neomorphic enzymatic activity with the ability to produce 2-hydroxyglutarate from ?-ketoglutarate, inhibiting multiple ?-ketoglutarate-dependent dioxygenase reactions; leading to aberrant DNA hypermethylation and differentiation block in myeloid precursors and ultimately promoting leukemogenesis. Enasidenib (formerly AG-221) is an oral small molecule selective targeted inhibitor of the mutant IDH2 enzyme, approved in August 2017 by the United States Food and Drug Administration for the treatment of patients with relapsed or refractory (R/R) IDH2-mutated AML. Preclinical studies showed the effectiveness of enasidenib in inhibiting the production of 2-hydroxyglutarate with high potency, and alleviating the mutant IDH2-induced differentiation block. In the original AG221-001 phase I/II trial, patients with R/R AML were treated with enasidenib single agent therapy at escalating doses up to 650 mg daily, with the 100 mg dose level identified to be safe and effective for further evaluation. Overall, 113 patients were treated in the dose-escalation and 126 in the dose-expansion cohorts. The overall response rate for R/R patients was 40%, including a complete remission of 19%. At a median follow up of 7.7 months, the median overall survival was 9.3 months, and reached 19.7 months in responders. Enasidenib was well tolerated, although adverse events of clinical interest include indirect hyperbilirubinemia and IDH-inhibitor-induced differentiation syndrome, which can be life threatening if not identified and treated promptly. Ongoing clinical trials evaluating enasidenib in combination with intensive chemotherapy and hypomethylating agents in newly diagnosed AML, and in rational combinations for R/R AML patients are underway.

Project description:Opinion statementRelapse is still a common scenario in acute myeloid leukemia (AML) treatment and occurs in 40-50% of younger and the great majority of elderly patients. The prognosis in relapsed AML patients is generally poor but depends largely on the timing of relapse (early versus late) and the possibility of allogeneic hematopoietic stem cell transplantation (HSCT). At the time of relapse, we again perform a mutational screening and cytogenetic analysis in all AML patients as clonal evolution of disease is frequent. Clinical trials should be first priority in all relapsed patients. In fit patients without prior transplant, we aim to perform HSCT after salvage therapy. In AML patients relapsing after HSCT and good performance status, intensive therapy can be considered with subsequent cellular therapy such as donor lymphocyte infusion (DLI) or a second HSCT. However, less than 20% of these patients are alive after 5 years. For those patients that are unfit, the therapeutic aim is to prolong life with acceptable quality of life. Here, hypomethylating agents (HMA), low-dose AraC (LDAC), and solely cytoreductive therapy with hydroxurea are options depending on first-line therapy. For those patients that have not been treated with venetoclax in first line, the combination therapy of venetoclax with demethylating agents achieves encouraging response rates. Venetoclax is currently also studied in combination with intensive salvage therapy. Importantly, for patients with isocitrate dehydrogenase (IDH) 1/2-mutated AML, ivosidenib, an IDH1 inhibitor, and enasidenib, an IDH2 inhibitor, present well-tolerated options in the setting of refractory or relapsed (r/r) disease even in elderly and heavily pre-treated patients with response rates of 30-40%. Both substances have been approved by the U.S. Food and Drug Administration (FDA) for r/r AML patients with IDH1/2 mutations (but not yet by the European Medicines Agency (EMA)). For patients with FMS-like tyrosine kinase 3 (FLT3) mutations, treatment with the selective FLT3 inhibitor gilteritinib is well tolerated and leads to improved outcome compared with standard salvage therapy. The approval has been granted by the FDA and the EMA. Generally, we would recommend targeted therapy for IDH1/2- and FLT3-mutated AML if available. In order to improve outcome in relapsed AML, it will be important to intelligently combine novel substances with each other as well as chemotherapy in prospective clinical trials. The development of therapies with bispecific antibodies or chimeric antigen receptor T cells (CAR-T) are still in early development.

Dataset Information

Enasidenib in acute myeloid leukemia: clinical development and perspectives on treatment.

Publications

Enasidenib in acute myeloid leukemia: clinical development and perspectives on treatment.

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