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A Phase 3 Comparison of Azacitidine ± Gilteritinib for Newly Diagnosed FLT3-Mutated Acute Myeloid Leukemia Patients

Conference Correspondent

Gilteritinib is an oral FMS-like tyrosine kinase 3 (FLT3) inhibitor. An ongoing phase 3 open-label, randomized trial is investigating gilteritinib plus azacitidine (AZA) compared with AZA alone in adults with newly diagnosed FLT3-mutated (FLT3mut+) acute myeloid leukemia (AML) unfit for intensive induction chemotherapy (ICC).

Patients enrolled in this study were required to have newly diagnosed, FLT3mut+ AML (internal tandem duplication [ITD] or tyrosine kinase domain [TKD; D835/I836] mutations), be aged ≥65 years and unfit for IIC or 18 to 64 years of age and ineligible for IIC because of specific comorbidities. This study was initiated with a safety cohort. Patients in the safety cohort received an initial dose of oral gilteritinib 80 mg daily on days 1 to 28 (or 120 mg daily as the next dose level) plus AZA 75 mg/m2 daily on days 1 to 7. Patients in the randomization cohort were randomized (2:1) to receive oral gilteritinib on days 1 to 28, plus subcutaneous or intravenous AZA 75 mg/m2 daily on days 1 to 7 (arm AC) or AZA alone (arm C). Treatment continued in 28-day cycles until patients experienced a lack of efficacy, unacceptable toxicity, or an event leading to discontinuation. Approximately 250 patients were to be randomized per protocol. The primary end point is overall survival. Secondary end points include event-free survival (key secondary end point); best response; remission rates (complete remission [CR], CR with incomplete hematologic recovery [CRi], CR with partial hematologic remission [CRp], and composite CR [CRc; sum of CR, CRi, and CRp]) and duration; transfusion status conversion and maintenance rates; leukemia-free survival, and patient-reported fatigue, and safety and tolerability.

In the safety cohort, 15 patients were enrolled with a median age of 75 years (range, 65-86 years). Approximately half (53%) were female. Most patients had FLT3-ITD mutations (67%); 20% had FLT3-TKD mutations and 7% had both ITD and TKD mutations. Of 15 patients enrolled, 14 patients died and 1 continued treatment. The median treatment duration was 6 cycles (range, <1-34) and 40% received ≥12 cycles of treatment. Overall, a CRc of 67% was achieved. A total of 40% of patients experienced a treatment-emergent adverse event resulting in treatment discontinuation (only 1 deemed drug-related). Based on data from the safety cohort, a gilteritinib dose of 120 mg daily + AZA was selected for the randomization cohort. As of June 29, 2020, 136 patients had been randomized. At that time, the median treatment duration was 4 cycles (range, <1-31), with 40% receiving >6 cycles. In the randomization cohort, 83 patients have died (61%).

In summary, interim results from this study have not identified any new safety signals associated with gilteritinib 120 mg daily + AZA. A CRc rate of 67% was found for gilteritinib 80 mg to 120 mg plus AZA in the safety cohort. Patients continue to be randomized in the randomization cohort.

Reference

Abstract 27. ASH 2020. December 5, 2020. Phase 3, Multicenter, Open-Label Study of Gilteritinib, Gilteritinib Plus Azacitidine, or Azacitidine Alone in Newly Diagnosed FLT3 Mutated (FLT3mut+) Acute Myeloid Leukemia (AML) Patients Ineligible for Intensive Induction Chemotherapy.

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