Prognostic Implications and Therapeutic Landscape of IDH1-Mutated AML: An Updated Review of Evidence and Indian...

Acute myeloid leukemia (AML) is a biologically heterogeneous hematologic malignancy in which cytogenetic and molecular abnormalities critically influence prognosis and treatment decisions. Since the identification of isocitrate dehydrogenase (IDH) mutations in AML in 2009, growing evidence has highlighted their role in leukemogenesis through aberrant cellular metabolism and epigenetic dysregulation. IDH1 mutations, occurring predominantly in cytogenetically normal AML and frequently co-existing with mutations such as NPM1 and DNMT3A, have demonstrated context-dependent prognostic implications rather than uniformly adverse outcomes.

Several studies associate IDH1 mutations with inferior clinical outcomes, including reduced remission rates, poorer overall survival, and global DNA hypermethylation, particularly in specific biological and therapeutic contexts influenced by co-mutational profiles and treatment era.

Recent therapeutic advancements have introduced selective IDH1 inhibitors targeting these mutations. Ivosidenib and Olutasidenib, have demonstrated efficacy in relapsed/refractory (r/r) AML and have received United States Food and Drug Administration (USFDA) approval for these indications. Notably, Ivosidenib has also been approved for newly diagnosed (ND) IDH1-mutated AML patients who are ineligible for intensive chemotherapy. These IDH1 inhibitors, often combined with agents like Azacitidine and Venetoclax, represent a promising shift toward personalized medicine, offering effective, less toxic alternatives for challenging AML cases, including those in elderly patients or individuals with comorbidities.

This review summarizes the prognostic implications of IDH1 mutations in AML and critically examines emerging IDH1 targeted therapies, highlighting their impact on disease biology and evolving treatment algorithms.