Gilteritinib Plus Azacitidine Among Patients With FLT3-Mutated AML

Results from a Phase 3 Trial

According to findings of a phase 3 trial recently published in Blood, gilteritinib plus azacitidine yielded higher composite complete remission (CRc) rates than azacitidine treatment alone among patients with FLT3-mutated acute myeloid leukemia who were unable to receive intensive chemotherapy. 

Dr Eunice S. Wang, MD, Roswell Park Comprehensive Cancer Center, Buffalo, New York, and colleagues stated, “patients with newly diagnosed FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia who may be considered unfit for standard intensive induction chemotherapy have a poor prognosis characterized by worse survival or treatment response compared with their counterparts,” adding, “FLT3 mutations is also associated with worse survival.” 

To research safer and more effective treatment styles, Dr Wang et al aimed to study the combination of gilteritinib plus azacitidine treatment by measuring the primary endpoint of overall survival (OS), and secondary endpoints including event-free survival (EFS), CRc, and safety. 

123 patients with FLT3-mutated AML ineligible for intensive chemotherapy were enrolled in this open-label, phase 3 study. The patients were randomized 2 to 1 to receive either gilteritinib plus azacitidine (n=74) or azacitidine alone (n=49). Patients in the gilteritinib plus azacitidine arm received gilteritinib at 80 mg daily on days 1 to 28 and azacitidine at 75 mg/m2 daily on days 1 to 7. Before this trial began, 15 patients were set aside and enrolled in a safety cohort to evaluate the safety of the combination treatment in dose-escalation cohorts (gilteritinib from 80 to 120 mg). 

Results indicated that at a median follow-up of 9.76 months for the gilteritinib plus azacitidine arm and 17.96 months for the azacitidine alone arm, the median OS was 9.82 months vs 8.87 months, respectively. A total of 107 events occurred across all arms. Sensitivity analysis of EFS based on the CRc indicated that the median EFS was 4.53 months in the gilteritinib plus azacitidine arm and 0.03 months in the azacitidine alone arm. There was no significant difference in CR rates between arms (16.2% vs 14.3%). CRc rates were significantly higher in the gilteritinib plus azacitidine arm (58.1%) vs the azacitidine arm (26.5%), and the median time to CRc was 57 days for both arms.

Grade ≥3 adverse events occurred in 95.9% of patients in the gilteritinib plus azacitidine arm, with the most common events being pyrexia (47.9%), diarrhea, febrile neutropenia (35.6%), constipation (34.2%), and nausea (32.9%). Grade ≥3 adverse events occurred in 89.4% of patients in the azacitidine arm, with the most common events being pyrexia (34.0%), anemia (34.0%), neutropenia (27.7%), and thrombocytopenia (23.4%). In the safety cohort, 1 of 9 patients who received gilteritinib at 80 mg/d experienced dose-limiting toxicity, and none of the 6 patients receiving gilteritinib at 120 mg/d experienced dose-limiting toxicity. 

As both primary and secondary endpoints were reached, Dr Wang et al concluded, “these results support safety, tolerability, and activity of [gilteritinib plus azacitidine] in this patient population. Analysis in patients with FLT3-ITD–positive AML with high allelic burden or better PS indicates improved clinical activity in these subgroups, which may warrant further exploration.” 

Source: 

Wang ES, Montesinos P, Minden MD, et al. Phase 3 trial of gilteritinib plus azacitidine vs azacitidine for newly diagnosed FLT3mut+ AML ineligible for intensive chemotherapy. Blood. 2022;140(17):1845-1857. doi:https://doi.org/10.1182/blood.2021014586