Efficacy and tolerability of isocitrate dehydrogenase inhibitors in patients with acute myeloid leukemia: A systematic review of clinical trials

by Selleckchem | Jul 23 2023

Background: Acute myeloid leukemia (AML) is a hematological malignancy due to anomalous differentiation and proliferation of hematopoietic stem cells with myeloid blast buildup. Induction chemotherapy is considered the first line of treatment in most patients with AML. However, targeted therapy in the form of FLT-3, IDH, BCL-2, and immune checkpoint inhibitors, can be considered as the first line depending on their molecular profile, resistance to chemotherapy, comorbidities, etc. This review aims to assess the tolerability and efficacy of isocitrate dehydrogenase (IDH) inhibitors in AML.

Methods: We searched Medline, WOS, Embase, and clinicaltrials.gov. PRISMA guidelines were followed in this systematic review. 3327 articles were screened, and 9 clinical trials (N = 1119) were included.

Results: In randomized clinical trials (RCTs), objective response (OR) was reported in 63-74% of the patients with IDH inhibitors + azacitidine as compared to 19-36 % of the patients with azacitidine monotherapy in newly diagnosed (ND) medically unfit patients. Survival rates were significantly improved with the use of ivosidenib. OR was reported in 39.1-46 % of the patients who relapsed/refractory to chemotherapy. ≥Grade 3 IDH differentiation syndrome and QT prolongation were reported in 3.9-10 % and 2-10 % of the patients, respectively.

Conclusion: IDH inhibitors (ivosidenib for IDH-1 and enasidenib for IDH-2) are safe and effective in treating ND medically unfit or relapsed refractory patients with IDH mutation. However, no survival benefit was reported with enasidenib. More randomized multicenter double-blinded clinical studies are needed to confirm these results and compare them with other targeting agents.

Comments:

This systematic review aimed to assess the tolerability and efficacy of isocitrate dehydrogenase (IDH) inhibitors in the treatment of acute myeloid leukemia (AML). The researchers conducted a comprehensive search of several databases and identified nine clinical trials involving a total of 1,119 patients for inclusion in the review. The PRISMA guidelines were followed to ensure the quality and transparency of the review process.

The results of the included randomized clinical trials (RCTs) indicated that the addition of IDH inhibitors to azacitidine resulted in objective responses (OR) in 63-74% of newly diagnosed (ND) medically unfit AML patients with IDH mutations. In comparison, only 19-36% of patients treated with azacitidine monotherapy achieved OR. Furthermore, the use of ivosidenib, an IDH-1 inhibitor, significantly improved survival rates.

For patients who had relapsed/refractory disease after chemotherapy, OR rates of 39.1-46% were reported with IDH inhibitors. However, it's worth noting that enasidenib, an IDH-2 inhibitor, did not demonstrate a survival benefit in the reviewed studies.

In terms of safety, ≥Grade 3 IDH differentiation syndrome and QT prolongation were reported in 3.9-10% and 2-10% of patients, respectively. These adverse events should be carefully monitored and managed during treatment with IDH inhibitors.

Based on the findings of this review, the researchers concluded that IDH inhibitors, specifically ivosidenib for IDH-1 and enasidenib for IDH-2 mutations, are both safe and effective in the treatment of ND medically unfit or relapsed/refractory AML patients with IDH mutations. However, further randomized multicenter double-blinded clinical studies are needed to confirm these results and compare the efficacy of IDH inhibitors with other targeted agents.