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Gilteritinib + Azacitidine or Azacitidine Alone in Patients with Newly Diagnosed, FLT3-Mutated Acute Myeloid Leukemia

2020 Year in Review - AML

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

This study is enrolling patients with newly diagnosed FLT3mut+ AML (internal tandem duplication [ITD] or tyrosine kinase domain [TKD; D835/I836] mutations) who are either aged ≥65 years and deemed ineligible for intensive induction chemotherapy (IIC) or aged ≥18 to 64 years with specific comorbidities causing ineligibility for IIC. The study started with a safety cohort in which patients received oral gilteritinib 80 mg daily as the initial dose 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. For the randomization cohort, eligible patients will be enrolled and 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. Treatment will be administered in 28-day cycles (Arm C) until lack of efficacy, unacceptable toxicity, or a discontinuation event occurs. The protocol calls for approximately 250 patients to be randomized. The primary end point of this study is overall survival, with secondary end points of 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, as well as safety and tolerability.

Fifteen patients were enrolled in the safety cohort. Of these, 14 patients have died and 1 continued treatment. The median age was 75 years (range, 65-86 years) and 53% were female. The majority of patients (67%) had FLT3-ITD mutations; 20% had FLT3-TKD mutations and 7% had both ITD and TKD mutations. The median duration of treatment was 6 cycles (range, <1-34 cycles) with 40% receiving >12 cycles of treatment. Overall, a CRc of 67% was achieved. Forty percent of patients experienced a treatment-related adverse event that led to treatment withdrawal, but none of these were judged to be drug-related. A gilteritinib dose of 120 mg daily + AZA was adopted for the randomization cohort based on data from the safety cohort. As of June 29, 2020, 136 patients had been randomized. Median treatment duration at that time was 4 cycles (range, <1-31 cycles), with 40% having received >6 treatment cycles. Eighty-three (61%) patients in the randomization cohort have died.

In conclusion, no new safety signals associated with gilteritinib 120 mg daily + AZA have been observed to date. Data from the safety cohort showed a CRc rate of 67% for gilteritinib 80 mg to 120 mg plus AZA. Patients with newly diagnosed FLT3mut+ AML determined to be ineligible for intensive chemotherapy continue to be randomized to receive gilteritinib 120 mg daily + AZA or AZA alone in the randomization cohort.


Wang ES, Montesinos P, Minden MD, et al. 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. Presented at: 62nd American Society of Hematology Annual Meeting & Exposition, December 5-8, 2020. Abstract 27.

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