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.

Keywords: Acute myeloid leukemia; Enasidenib; IDH inhibitors; Ivosidenib; Meta-analysis.

Fig. 1

The PRISMA flowchart shows the selection process of the systematic review. The abstracts of all the studies were imported into Endnote from the indicated databases

Fig. 2

CR rate in IDH-mutant AML patients treated with IDH inhibitors. A Newly diagnosed AML patients treated with IDH inhibitors; B Newly diagnosed AML patients treated with IDH inhibitors in combination; C Newly diagnosed AML patients treated with IDH inhibitors alone; D Relapsed or refractory AML patients treated with IDH inhibitors; E Relapsed or refractory AML patients treated with IDH inhibitors alone. CR complete remission, AML acute myeloid leukemia, IDH isocitrate dehydrogenase genes, 95% CI 95% confidence interval

Fig. 3

ORR rate in IDH-mutant AML patients treated with IDH inhibitors. A Newly diagnosed AML patients treated with IDH inhibitors; B Newly diagnosed AML patients treated with IDH inhibitors in combination; C Newly diagnosed AML patients treated with IDH inhibitors alone; D Relapsed or refractory AML patients treated with IDH inhibitors. ORR overall response, AML acute myeloid leukemia, IDH isocitrate dehydrogenase genes, 95% CI 95% confidence interval

Fig. 4

OS in IDH-mutant AML patients treated with IDH inhibitors. A 2-year OS rate in newly diagnosed AML patients treated with IDH inhibitors; B 2-year OS rate in newly diagnosed AML patients treated with IDH inhibitors in combination; C 2-year OS rate in newly in newly diagnosed AML patients treated with IDH inhibitors alone; D 2-year OS rate in relapsed or refractory AML patients treated with IDH inhibitors alone; E Median OS in relapsed or refractory AML patients treated with IDH inhibitors alone. OS overall survival, AML acute myeloid leukemia, IDH isocitrate dehydrogenase genes, 95% CI 95% confidence interval

Fig. 5

EFS in IDH-mutant AML patients treated with IDH inhibitors. A 2-year EFS rate in newly diagnosed AML patients treated with IDH inhibitors; B 2-year EFS rate in newly diagnosed AML patients treated with IDH inhibitors in combination; C Median EFS in relapsed or refractory AML patients treated with IDH inhibitors alone. EFS event-free survival, AML acute myeloid leukemia, IDH isocitrate dehydrogenase genes, 95% CI 95% confidence interval