Azacitidine, Venetoclax, and Gilteritinib in Newly Diagnosed and Relapsed or Refractory <i>FLT3</i>-Mutated AML.

Abstract

Azacitidine plus venetoclax is a standard of care for patients with newly diagnosed AML who are unfit for intensive chemotherapy. However, <i>FLT3</i> mutations are a common mechanism of resistance to this regimen. The addition of gilteritinib, an oral FLT3 inhibitor, to azacitidine and venetoclax may improve outcomes in patients with <i>FLT3</i>-mutated AML. This phase I/II study evaluated azacitidine, venetoclax, and gilteritinib in two cohorts: patients with (1) newly diagnosed <i>FLT3</i>-mutated AML who were unfit for intensive chemotherapy or (2) relapsed/refractory <i>FLT3</i>-mutated AML (ClinicalTrials.gov identifier: NCT04140487). The primary end points were the maximum tolerated dose of gilteritinib (phase I) and the combined complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate (phase II). Fifty-two patients were enrolled (frontline [n = 30]; relapsed/refractory [n = 22]). The recommended phase II dose was gilteritinib 80 mg once daily in combination with azacitidine and venetoclax. In the frontline cohort, the median age was 71 years and 73% of patients had an <i>FLT3</i>-internal tandem duplication (ITD) mutation. The CR/CRi rate was 96% (CR, 90%; CRi, 6%). Sixty-five percent of evaluable patients achieved <i>FLT3</i>-ITD measurable residual disease <5 × 10^-5 within four cycles. With a median follow-up of 19.3 months, the median relapse-free survival (RFS) and overall survival (OS) have not been reached and the 18-month RFS and OS rates are 71% and 72%, respectively. In the relapsed/refractory cohort, the CR/CRi rate was 27%; nine additional patients (41%) achieved a morphologic leukemia-free state. The most common grade 3 or higher nonhematologic adverse events were infection (62%) and febrile neutropenia (38%), which were more frequent in the relapsed/refractory cohort. The combination of azacitidine, venetoclax, and gilteritinib resulted in high rates of CR/CRi, deep <i>FLT3</i> molecular responses, and encouraging survival in newly diagnosed <i>FLT3</i>-mutated AML. Myelosuppression was manageable with mitigative dosing strategies.