AML often presents with recurrent genetic mutations, particularly involving FLT3-ITD, NPM1, and DNMT3A, which frequently co-occur and portend a poor prognosis. DNMT3A mutations are known to disrupt DNA methylation patterns, aiding in the persistence of pre-leukemic clones, while mutations in genes like TET2, WT1, IDH1, and IDH2 impair cytosine hydroxymethylation and hematopoietic differentiation. Quizartinib (Quiz) is a selective FLT3 inhibitor that previously demonstrated significant OS benefit in FLT3-ITD+ newly diagnosed AML patients in the Phase III QuANTUM-First trial. This analysis explores whether co-occurring baseline mutations in FLT3-ITD, NPM1, and epigenetic regulators influence the efficacy of Quiz when used alongside standard chemotherapy and maintenance therapy.

Among 500 patients with available baseline mutational data, 54% had NPM1 mutations, and these patients experienced a marked survival benefit from Quiz compared to those without. Notably, the subgroup with triple mutations (FLT3-ITD, NPM1, DNMT3A)—associated with poor prognosis—had a median OS of only 9.6 months with placebo, but this improved significantly with Quiz (median OS not reached), including benefits in both younger and older patients.

Similarly, patients with NPM1mut combined with at least one epigenetic regulator mutation (DNMT3A, TET2, WT1, IDH1, or IDH2) showed minimal OS difference in the placebo arm (14.8 vs. 17.3 months) but demonstrated a robust survival improvement with Quiz (median OS not reached), consistent across age groups. These findings highlight the potential of Quiz to mitigate poor prognostic impacts of high-risk mutational profiles in ND FLT3-ITD+ AML.

KOL insights

“FLT3 mutations are present in approximately 25% to 30% AML cases, leading to aggressive disease and poor outcomes. FLT3 inhibitors encompass a diverse group of agents that target mutations in the FLT3 gene, which are implicated in the development of AML”– Expert Opinion

Conclusion

The treatment landscape of AML includes a mix of approved and emerging therapies, with approved options such as VANFLYTA (quizartinib), the first FLT3 inhibitor approved for FLT3-ITD+ AML across all treatment phases, and ONUREG (oral azacitidine), indicated for maintenance therapy post-remission. Emerging therapies in development include AbbVie’s pivekimab sunirine, a CD123-targeting ADC; SELLAS Life Sciences’ galinpepimut-S, a WT1-targeted immunotherapy in Phase III; and other targeted or immune-based candidates aimed at improving outcomes across AML subtypes and settings.

Quizartinib and gilteritinib are both highly potent and more FLT3-selective inhibitors, each with potential advantages. While they may delay blood count recovery and raise infection risk, they are also associated with deeper remissions and more effective clearance of FLT3-mutant clones. For patients whose disease is truly FLT3-driven, reducing clonal burden to minimal or undetectable levels before allogeneic transplant appears to significantly improve survival. This approach may also eliminate the need for post-transplant maintenance therapy, which was previously considered critical for preventing relapse in newly diagnosed FLT3-mutant AML.