IDH1-mutated relapsed or refractory AML: current challenges and future prospects

Abstract

The prognosis of patients with relapsed or refractory acute myeloid leukemia (R/R AML) is discouraging with salvage standard approaches. Mutations of isocitrate dehydrogenase 1 (IDH1^mut), present in 7–14% of AML patients, have been discovered recently, opening the door to targeted agents aiming to improve the outcomes in this setting. Several oral selective IDH1^mut inhibitors are under investigation, ivosidenib being the first approved for R/R AML. We performed a systematic review to analyze the clinical outcomes and safety reported with IDH1^mut inhibitors and other agents in adult patients with IDH1^mut R/R AML. Ivosidenib in monotherapy achieved complete remission (CR) of 24%, overall response of 42%, and median overall survival of 9 months in R/R AML, and promising outcomes were reported with IDH305 and FT-2102. IDH1^mut inhibitors were generally well tolerated, but some therapy-related toxicities should be monitored, including IDH-differentiation syndrome, prolongation of the QT interval, and leukocytosis, all manageable and reversible. Also, venetoclax, CB-839, PARP inhibitors, and IDH1 peptide vaccine are being studied in IDH1^mut AML. The results of the ongoing and upcoming clinical trials will bring new evidence to establish the role of IDH1^mut inhibitors in therapeutic strategies of AML.

Keywords:

• isocitrate dehydrogenase 1
• acute myeloid leukemia
• relapsed/refractory
• ivosidenib
• FT-2102
• venetoclax

Acknowledgments

This study was supported in part by a grant from the “Instituto Carlos III” (PI16/00665).

Disclosure

Dr Pau Montesinos reports grants from Celgene and Daiichi Sankyo during the conduct of the study and is on the advisory board for AGIOS, Celgene and Daiichi Sankyo. The authors report no other conflicts of interest in this work.