Evolving Treatment Strategies for Elderly Leukemia Patients with IDH Mutations

Abstract

Acute myeloid leukemia (AML) is a debilitating and life-threatening condition, especially for elderly patients who account for over 50% of diagnoses. For over four decades, standard induction therapy with intensive cytotoxic chemotherapy for AML had remained unchanged. However, for most patients, standard therapy continues to have its shortcomings, especially for elderly patients who may not be able to tolerate the complications from intensive cytotoxic chemotherapy. New research into the development of targeted and alternative therapies has led to a new era in AML therapy. For the nearly 20% of diagnoses harboring a mutation in isocitrate dehydrogenase 1 or 2 (IDH1/2), potential treatment options have undergone a paradigm shift away from intensive cytotoxic chemotherapy and towards targeted therapy alone or in combination with lower intensity chemotherapy. The first FDA approved IDH2 inhibitor was enasidenib in 2017. In addition, IDH1 inhibitors are in ongoing clinical studies, and the oral BCL-2 inhibitor venetoclax shows preliminary efficacy in this subset of patients. These new tools aim to improve outcomes and change the treatment paradigm for elderly patients with IDH mutant AML. However, the challenge of how to best incorporate these agents into standard practice remains.

Differentiation of leukemic blasts is not completely blocked in acute myeloid leukemia

“…However, ATRA is not effective in AML outside of APL, suggesting that differentiation blocks do not have a uniform underlying mechanism and could be a reflection of the disease complexity in AML. The more recent advent of isocitrate dehydrogenase (IDH) inhibitors that are selectively effective only in IDH1 and IDH2 mutant tumors by inducing differentiation further reinforces this point (13).…”

Target Therapy in Acute Myeloid Leukemia

“…5-methylcytosine (5mC) coverts to 5-hydroxymethylcytosine (5hmc) as a result of interaction between α-KG and TET2 which promotes DNA and histone demethylation [58]. Approximately 8-19% of AML cases carry IDH2 mutations, with another 7-14% carrying IDH1 mutations [59]. IDH1/2 are found with higher frequency in older patients and patients with a normal karyotype [60,61].…”

Quantitative analysis of enasidenib in dried blood spots of mouse blood using an increased‐sensitivity LC–MS/MS method: Application to a pharmacokinetic study

“…Recent investigations have discovered isocitrate dehydrogenase 1 or 2 (IDH1/2) mutations in 20% of the AML population (Abou Dalle & DiNardo, ). Targeting mutant IDH1/2 is an option for the treatment of AML as a targeted therapy alone or in combination with other antileukemic agents (Buege, DiPippo, & DiNardo, ). Recently, the US Food and Drug Administration approved enasidenib (AG‐221, CC‐90007, Idhifa ® ; Figure ), a novel first‐generation, oral small‐molecule selective mIDH2 inhibitor for relapsed/refractory AML.…”