Efficacy and safety of IDH Inhibitors in AML: A systematic review of clinical trials

Background:

Isocitrate dehydrogenase (IDH) gene mutation leads to the accumulation of oncometabolite. IDH 1 and 2 gene mutations are associated with multiple malignancies including gliomas, leukemias, etc. Despite improving treatment for hematological malignancies, advanced acute myeloid leukemia is associated with a poor prognosis. In this systematic review, we assessed the efficacy and safety of IDH 1 and 2 inhibitors used alone or in combination with other drugs in IDH 1 and 2 mutated AML.

Methods:

We followed PRISMA guidelines to conduct this systematic review. A literature search was performed on PubMed, Web of Science, and Embase (Ovid) with mesh terms, "Acute Myeloid Leukemia" and "Isocitrate dehydrogenase" from the inception of data till 6/15/2022. We screened 3,263 articles and included 3 randomized clinical trials (RCTs, N=398) and 4 non-randomized clinical trials (nRCTs, N=609) measuring the efficacy and safety of IDH inhibitors in AML.

Results:

In 7 clinical trials, 1,007 adult patients with IDH mutated AML were included. 472 patients had IDH-2 mutation (mIDH-2) while 535 patients had IDH-1 mutation (mIDH-1). 582 patients had relapsed/refractory (R/R) disease while 425 patients had newly diagnosed (ND) disease. In a clinical trial on R/R mIDH-2 AML patients treated with enasidenib (N=280), overall response rate (ORR), complete response (CR), morphologic free state (MLFS), and median overall survival (mOS) were 39.6%, 18.9%, 5.7%, and 8.8 months, respectively. In two clinical trials (N=192) on ND mIDH-2 AML patients, ORR was 74%-89%, CR was 54%-55%, and MLFS was 4%-11% with enasidenib + chemotherapy/azacytidine as compared to ORR of 36%, CR of 12%, and MLFS of 0% with azacytidine alone. However, the mOS was not significantly different among the two groups. Table 1.

In two clinical trials (N=206) on ND mIDH-1 AML patients, ORR was 63%-87%, CR was 47%-68%, and MLFS was 7%-8% with ivosedanib + chemotherapy/azacytidine as compared to ORR of 19%, CR of 15%, and MLFS of 0% with azacytidine alone. The hazard ratio (HR) of OS was significantly in favor of ivosedanib + azacytidine as compared to azacytidine alone. In a clinical trial on R/R mIDH-1 AML patients treated with ivosedanib (N=179), ORR, CR, MLFS, and mOS were 39.1%, 21.8%, 5.6%, and 9.3 months, respectively. In two clinical trials, ORR with BAY1436032 (N=27) and olutasidenib (N=123) were 15% and 46% respectively. Table 1.

≥Grade 3 hyperbilirubinemia, thrombocytopenia, IDH differentiation syndrome, anemia, thrombocytopenia, neutropenia, diarrhea, and long QT syndrome were the common side effects reported in AML patients treated with IDH inhibitors. Table 1.

Conclusion:

IDH inhibitors were well tolerated by most of the patients with AML. Enasidenib significantly improved the response rates in patients with mIDH-2 AML. However, the OS was not improved with the addition of enasidenib in ND mIDH-2 AML patients in phase 2 RCT. Ivosedanib significantly improved the response rates and survival rates in patients with mIDH-1 AML. Olutasidenib was also effective in patients with R/R mIDH-1 AML. More randomized double-blind multicenter clinical trials are needed to confirm these results.