Azacitidine Combo Shows High Response Rates in FLT3-Mutated AML


A phase 1/2 study found that using azacitidine, venetoclax, and gilteritinib for patients with FLT3-mutated acute myeloid leukemia yielded high rates of complete response and complete response with incomplete hematologic recovery.

The most common grade 3 or higher nonhematologic adverse effects (AEs) included infection (62%) and febrile neutropenia (38%).

The most common grade 3 or higher nonhematologic adverse effects (AEs) included infection (62%) and febrile neutropenia (38%).

Azacitidine (Vidaza), venetoclax (Venclexta), and gilteritinib (Xospata) evoked high response rates and improved survival in patients with newly diagnosed FLT3-mutated acute myeloid leukemia (AML), according to data from a phase 1/2 study (NCT04140487) published in the Journal of Clinical Oncology.

The complete response (CR)/CR with incomplete hematologic recovery (CRi) rate was 96%. Within 4 cycles, FLT3-ITD measurable residual disease (MRD) occurred in 65% of patients. The median relapse-free survival (RFS) and overall survival (OS) had not been reached, but at 18 months they were 71% and 72%, respectively.

The phase 1 portion of the study involved patients with relapsed/refractory FLT3-mutated AML, and phase 2 was the dose expansion portion. During cycle 1, patients were given azacitidine at 75 mg/m2 once daily intravenously or subcutaneously on days 1 to 7, venetoclax at ramp-up dosing of 400 mg once daily orally, and gilteritinib once daily at either 80 mg or 120 mg orally in phase 1 and 80 mg in phase 2 on days 1 to 28. Bone marrow biopsies were conducted during cycle 1, day 14, and if blasts were higher than 5%, venetoclax was held.

In cycle 2 and beyond, azacitidine was given at 75 mg/m2 once a day intravenously or subcutaneously on days 1 to 5, venetoclax daily on days 1 to 7 at 400 mg, and gilteritinib orally once daily on days 1 to 28. After venetoclax ramp-up, patients were given triazole fungal prophylaxis.

The primary end point was maximum tolerated dose of gilteritinib during phase 1 and the CR/CRi rate within 2 cycles during phase 2. Secondary end points included the CR rate, MRD negativity, RFS, OS, and safety.

In the phase 1 study, 10 patients were enrolled, of whom 6 were given gilteritinib at 80 mg and 4 at 120 mg. At the 80 mg dose, there were no dose-limiting toxicities observed. At 120 mg, 1 patient had prolonged grade 4 myelosuppression. Of note, 80 mg was chosen as the recommended phase 2 dose.

The Frontline Cohort

A total of 30 patients were enrolled between October 2020 and January 2023. Patients had a median age of 71 years old (range, 18-86).

A morphological remission was assessed in 70% of patients during cycle 1, day 14, with 6% having persistent morphological disease. By the end of cycle 1, 96% of patients achieved morphological remission. MRD negativity by multiparameter flow cytometry occurred in 93% of patients, and 90% achieved MRD negativity by FLT3 PCR with a sensitivity of 1%.

The median number of cycles given was 3 (range, 1-31), 30% received at least 6, and 20% received at least 12. Allogeneic hematopoietic stem cell transplant (HSCT) occurred in 43% of patients during the first remission after a median of 4.8 months (range, 2.7-8.0). After transplant, 17% of patients relapsed with a median time to relapse of 7.2 months (range, 6.2-19.9).

During cycle 1, 1 patient who had a CR died because of sepsis, and 1 who had a CRi did not want to receive additional treatment and died 4.5 months later. The median duration of follow-up was 19.3 months, and 27% of patients are still receiving therapy.

The Relapsed/Refractory Cohort

Between December 2019 and December 2022, 22 patients with relapsed/refractory FLT3-mutated AML or chronic myelomonocytic leukemia were enrolled. Of these patients, 45% had FLT3-ITD mutations, 32% had FLT3-TKD mutations, and 23% had both. The median number of prior therapies was 2 (range, 1-5), 36% had treatment with a previous FLT3 inhibitor, and 45% received a prior hypomethylating agent plus venetoclax.

A CR was achieved in 18% of patients, and a CRi was reported in 9%, with a composite CR/CRi rate of 27%. The median number of cycles of therapy was 2 (range, 1-9). Overall, 23% of all patients and 33% of those having a modified composite CR underwent HSCT with first remission, with a median duration of follow-up of 30.7 months (range, 1.1-41.8).

The median RFS was 4.3 months, and the median OS was 5.8 months. The mortality rate was 0% at 30 days and 14% at 60 days.


The most common grade 3 or higher nonhematologic adverse effects (AEs) included infection (62%) and febrile neutropenia (38%). For the frontline cohort, infection occurred in 53% of patients, and febrile neutropenia occurred in 33%, with rates of 73% and 45% in the relapsed/refractory cohort. In the relapsed/refractory cohort, 5 patients had grade 5 AEs.


Short NJ, Daver N, Dinardo CD, et al. Azacitidine, venetoclax, and gilteritinib in newly diagnosed and relapsed or refractory FLT3-mutated AML. J Clin Oncol. Published online January 26, 2024. doi:10.1200/JCO.23.01911

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