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.

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Keywords: isocitrate dehydrogenase 1, acute myeloid leukemia, relapsed/refractory, ivosidenib, FT-2102, venetoclax

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INTRODUCTION

Despite improvements in chemotherapy over the last years, the majority of adult patients with acute myeloid leukemia (AML) will show primary refractory disease or relapse after achieving complete remission (CR).¹ The prognosis of relapsed/refractory (R/R) AML patients is particularly poor, but in a subset of patients salvage therapy followed by allogeneic hematopoietic stem cell transplantation (alloHSCT) was shown to be possibly curative.²

Whole-genome sequencing of AML has revealed some acquired mutations in such genes as isocitrate dehydrogenase 1 (IDH1) or 2 (IDH2) genes, encoding for two enzymes that catalyze the conversion of isocitrate to α-ketoglutarate (αKG) and reduce nicotinamide adenine dinucleotide phosphate (NADP⁺) to NADPH. In mutated IDH1 (IDH1^mut) and IDH2 (IDH2^mut), NADPH is oxidized to NADP+ and αKG transformed into the oncometabolite D-2-hydroxyglutarate (2HG). When levels of 2HG are increased, they interfere with cellular metabolism and epigenetic regulation and hence contribute to leukemogenesis. Somatic mutations of IDH1 and IDH2 genes are found in 7–14% and 8–19% of AML cases, respectively.^3,4

The recent discovery of new mutations in AML has opened the door to targeted agents that are actually in use or under investigation. This is the case for IDH1^mut and IDH2^mut inhibitors for patients with IDH mutations. Enasidenib was the first inhibitor of IDH2 to be approved by the US Food and Drug Administration (FDA) in August 2017 for R/R AML that carries IDH2^mut. More recently, in July 2018, ivosidenib which inhibits mutated cytosolic IDH1 was also approved for R/R AML. Following this path, there are other IDH1^mut and IDH2^mut inhibitors and their combinations with other therapies under investigation (ie, intensive chemotherapy and hypomethylating agents).⁵ Our aim was to perform a systematic review of the literature and to analyze the clinical outcomes reported with IDH1^mut inhibitors and other agents in adult patients with IDH1^mut R/R AML.

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