Efficacy and safety of FDA-approved IDH inhibitors in the treatment of IDH mutated acute myeloid leukemia: a systematic review and meta-analysis

Abstract

Objective To systematically evaluate the efficacy and safety of FDA-approved isocitrate dehydrogenase (IDH) inhibitors in the treatment of IDH-mutated acute myeloid leukemia (AML). Methods We used R software to conduct a meta-analysis of prospective clinical trials of IDH inhibitors in the treatment of IDH-mutated AML published in PubMed, Embase, Clinical Trials, Cochrane Library and Web of Science from inception to November 15th, 2022. Results A total of 1109 IDH-mutated AML patients from 10 articles (11 cohorts) were included in our meta-analysis. The CR rate, ORR rate, 2-year survival (OS) rate and 2-year event-free survival (EFS) rate of newly diagnosed IDH-mutated AML (715 patients) were 47%, 65%, 45% and 29%, respectively. The CR rate, ORR rate, 2-year OS rate, median OS and median EFS of relapsed or refractory (R/R) IDH-mutated AML (394 patients) were 21%, 40%, 15%, 8.21 months and 4.73 months, respectively. Gastrointestinal adverse events were the most frequently occurring all-grade adverse events and hematologic adverse events were the most frequently occurring ≥ grade 3 adverse events. Conclusion IDH inhibitor is a promising treatment for R/R AML patients with IDH mutations. For patients with newly diagnosed IDH-mutated AML, IDH inhibitors may not be optimal therapeutic agents due to low CR rates. The safety of IDH inhibitors is controllable, but physicians should always pay attention to and manage the differentiation syndrome adverse events caused by IDH inhibitors. The above conclusions need more large samples and high-quality RCTs in the future to verify.

Monocytic Differentiation in Acute Myeloid Leukemia Cells: Diagnostic Criteria, Biological Heterogeneity, Mitochondrial Metabolism, Resistance to and Induction by Targeted Therapies

“…IDH1 and IDH2 mutations are associated with the differentiated FAB-M2 phenotype [ 104 , 216 ]. Differentiation syndrome is seen in 15–20% of patients during IDH inhibitory treatment; the risk factors for its development are high leukemia cell burden and concomitant TET2 and SRS2 mutations, and the syndrome is characterized by leukocytosis with increased neutrophil and monocyte levels, but the syndrome is not associated with improved outcome [ 217 , 218 , 219 ]. Furthermore, enasidenib is an IDH2 mutant inhibitor that can increase the sensitivity to venetoclax; this sensitizing effect was observed both in vitro and in human AML xenograft models and seemed to depend on whether the leukemic cells differentiated (i.e., decreased c-kit/CD117 and increased granulocytic marker GR-1) in response to the enasidenib treatment [ 220 ].…”

Mitochondrial inhibitors: a new horizon in breast cancer therapy

“…It has been found that IDH inhibitors. Enasidenib and ivosidenib have been approved for the treatment of BC ( Chen et al, 2023 ). In addition, Dichloroacetate, a PDK inhibitor, contributes to the increase of PDH activity, and has been reported to have significant antimicrobial activity against NSCLC and metastatic breast cancer.…”

Role of Ubiquitination and Epigenetics in the Regulation of AhR Signaling in Carcinogenesis and Metastasis: “Albatross around the Neck” or “Blessing in Disguise”

“…Epigenetics is a highly complicated mechanism and phenomenal advancements have been made in the comprehensive characterization of methylation-associated machinery [89][90][91][92][93][94][95][96]. AhR has been shown to utilize different mechanisms to regulate epigenetics.…”