Clinical research round-up: Current and emerging treatments for IDH1-mutated AML

The AML Hub was pleased to speak with Eytan Stein, Memorial Sloan Kettering Cancer Center, New York, US. We asked, What are the latest data presented on current and emerging treatments for acute myeloid leukemia (AML)?

Stein starts by discussing therapies approved for the treatment of IDH1-mutated (IDH1m) AML, including ivosidenib and olutasidenib, and supporting data. He then considers strategies in development for IDH-mutated AML, such as combining IDH1 inhibitors with venetoclax, before concluding with areas of interest for future research. Stein talks about the potential of IDH1 inhibitors in precursor states of myeloid malignancies, such as clonal cytopenia of undetermined significance (CCUS), and the aims of ongoing studies. 

Key learnings 

• IDH1 and 2 mutations occur in approximately 20–25% of patients with newly diagnosed (ND) AML; recent research has focused predominantly on treatment of IDH1m AML.
• The IDH1 inhibitor ivosidenib was approved as monotherapy by the U.S. Food and Drug Administration (FDA) in 2018 for the treatment of relapsed/refractory (R/R) IDH1m AML,¹ and in 2019 for the treatment of patients with ND IDH1m AML aged ≥75 years or ineligible for intensive induction chemotherapy.²
• Ivosidenib, in combination with azacitidine, was also approved by the FDA in 2022 for the treatment of patients with ND IDH1m AML aged ≥75 years or ineligible for intensive induction chemotherapy, based on results from the phase III AGILE trial (NCT03173248),^3,4 and by the European Commission in 2023, for the treatment of adult patients with ND IDH1m AML ineligible for intensive induction chemotherapy.⁵
  • In the AGILE trial, median overall survival was significantly longer in the ivosidenib + azacitidine group (n = 72; 24.0 months) than in the azacitidine + placebo group (n = 74; 7.9 months; p = 0.001).⁴
  • Long-term data from the trial further demonstrated a significant overall survival benefit; after a median follow-up of 28.6 months, median overall survival in the ivosidenib + azacitidine group (n = 73) was 29.3 months, compared with 7.9 months in the azacitidine + placebo group (n = 75; p = <0.0001).⁶
• Olutasidenib, another IDH1 inhibitor, was approved by the FDA in 2022 for the treatment of relapsed/refractory (R/R) IDH1m AML. The approval was based on findings from a phase II study (NCT02719574) of olutasidenib with or without azacitidine or cytarabine in patients with IDH1m AML or myelodysplastic syndromes (MDS) in which favorable efficacy, in particular durable remissions, was demonstrated with olutasidenib treatment.⁷
• Triplet combinations are also being investigated for the treatment of ND IDH1m AML, combining using IDH1 inhibitors together with venetoclax and a hypomethylating agent such as azacitidine.
• An area of emerging interest is the investigation of strategies targeting IDH1m myeloid malignancies in their precursor state, as an increased risk of progression to MDS or AML has been demonstrated in patients with CCUS and IDH1 mutations.
  • Investigation of such strategies is ongoing, with data readouts expected within the next year. 

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