<p>IDH1-mutated relapsed or refractory AML: current challenges and future prospects</p>

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.

Mitochondrial metabolism as a target for acute myeloid leukemia treatment

“…Commonly, this results in neofunctionalization of IDH1 (cytoplasmic) and IDH2 (mitochondrial) enzymes, allowing them to convert α-ketoglutarate into 2-hydroxyglutarate. This onco-metabolite interferes with cellular metabolism and epigenetic regulation [ 50 ] and contributes to mitochondrial DNA instability [ 51 ]. It is believed that the ability of 2-hydroxyglutarate to interfere with processes that require α-ketoglutarate, such as histone and DNA demethylation, is also likely to interfere with the prolyl hydroxylases that regulate HIF-1α [ 52 ].…”

New agents in acute myeloid leukemia (AML)

“…As an adverse event of special interest, differentiation syndrome was observed in patients treated with enasidenib (7%) and ivosidenib (3.9%). Reportedly, the IDH-differentiation syndrome is manageable by interrupting medication and treatment with glucocorticoids, with or without hydroxyurea [ 39 , 40 ].…”

Assessing acquired resistance to IDH1 inhibitor therapy by full-exon IDH1 sequencing and structural modeling

“…The pan-IDH inhibitor AG-881 is being studied in clinical trials (Nassereddine et al 2017). Ivosidenib in monotherapy has achieved complete remission (CR) in 24% of cases, an overall response of 42%, and a median overall survival of 9 mo in patients with relapsed/refractory (R/R) IDH1 mutant AML (Megías-Vericat et al 2019). However, reports have already emerged describing cases of relapse during therapy and acquired resistance to these mutant IDH1/2 inhibitors (Harding et al 2018;Intlekofer et al 2018;Quek et al 2018;Choe et al 2020).…”