In a single-center phase I/II study reported in the Journal of Clinical Oncology, Nicholas J. Short, MD, and colleagues found that treatment with azacitidine, venetoclax, and gilteritinib produced a high response rate in newly diagnosed patients with FLT3-mutated acute myeloid leukemia (AML); responses were poorer in patients with relapsed or refractory disease.

Nicholas J. Short, MD

As stated by the investigators, “Azacitidine plus venetoclax is a standard of care for patients with newly diagnosed AML who are unfit for intensive chemotherapy. However, FLT3 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 FLT3-mutated AML.”

Study Details

The trial included 30 patients with newly diagnosed disease and 22 with relapsed or refractory disease treated at The University of Texas MD Anderson Cancer Center between October 2020 and January 2023. In cycle 1, patients received 75 mg/m² of azacitidine once daily intravenously or subcutaneously on days 1 to 7, venetoclax with a ramp-up to 400 mg once daily on days 1 to 28, and gilteritinib once daily on days 1 to 28 at 80 mg. The gilteritinib dose was selected as the recommend phase II dose. In cycle 2 and beyond, patients received azacitidine at 75 mg/m² once daily intravenously or subcutaneously on days 1 to 5, venetoclax at 400 mg once daily on days 1 to 7, and gilteritinib at 80 mg once daily on days 1 to 28. Treatment continued for up to 24 cycles.

Responses

Among 30 patients receiving frontline treatment (73% with FLT3-internal tandem duplication [ITD] mutation), complete remission/complete remission with incomplete hematologic recovery was observed in 29 (97%), with complete remission in 27 (90%); 1 additional patient achieved a morphologic leukemia-free state. Among patients with FLT3-ITD mutation, 65% achieved measurable residual disease at < 5 x 10⁵ by the end of cycle 4. With a median follow-up of 19.3 months, median relapse-free survival and overall survival were not reached; rates at 18 months were 71% and 72%, respectively.

Among 22 patients in the relapsed or refractory cohort, complete remission/complete remission with incomplete hematologic recovery was observed in 6 (27%), with complete remission in 4 (18%); an additional 9 patients (41%) achieved a morphologic leukemia-free state. With a median follow-up of 30.7 months, median relapse-free survival was 4.3 months and median overall survival was 5.8 months.

Adverse Events

The most common grade ≥ 3 nonhematologic adverse events were infection (53% of patients in the frontline cohort, 73% in the relapsed or refractory cohort), febrile neutropenia (33% and 45%), and sepsis (10% and 23%). Adverse events led to death in one patient in the frontline cohort (due to infection); adverse events led to death in five patients in the relapsed or refractory cohort, all in the setting of persistent AML, with causes consisting of infection in two patients and disseminated intravascular coagulopathy, intracranial hemorrhage, and multiorgan failure in one patient each.

The investigators concluded, “The combination of azacitidine, venetoclax, and gilteritinib resulted in high rates of complete remission/complete remission with incomplete hematologic recovery, deep FLT3 molecular responses, and encouraging survival in newly diagnosed FLT3-mutated AML. Myelosuppression was manageable with mitigative dosing strategies.”

Dr. Short, of the Department of Leukemia, The University of Texas MD Anderson Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the National Cancer Institute and Astellas. For full disclosures of the study authors, visit ascopubs.org.