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ASTX727, Gilteritinib and Venetoclax Yielded High Remission Rates in Patients With R/R FLT3 Mutated AML Unfit for Chemotherapy
The combination of ASTX727, gilteritinib, and venetoclax as a treatment measure showed promising remission rates and safe results for patients with relapsed or refractory (R/R) FLT3-mutated acute myeloid leukemia (AML) and older patients unfit for chemotherapy, according to the findings from a phase 1/2 study.
Faustine Ong, MD, University of Texas MD Anderson Cancer Center, California, presented this data at the 2022 ASH Annual Meeting and Exposition in New Orleans, Louisiana.
“FLT3 gene mutations occur in approximately 30% of patients with AML and are associated with worse survival and higher relapse risk,” Ong and colleagues wrote, “Gilteritinib, a selective potent oral FLT3 tyrosine kinase inhibitor (FLT3i), improves survival in pts with relapsed FLT3 mutated AML.”
There were 8 patients with R/R FLT3-mutated AML (n=7) or high risk chronic myelomonocytic leukemia (HR-CMML) (n=1) enrolled in phase 1 of the study. The median age of the patients was 57 years old (range: 38 to -83), and the median number of prior lines of therapy was 1. 50% of patients (n=4) had a previous allogeneic hematopoietic stem cell transplant (HSCT), 75% of patients (n=6) had prior hypomethylating agent treatment (HMA)+VEN, and 27% of patients (n=3) had been administered FLT3 inhibitors in the past. All patients in phase 1 had FLT3-ITD and/or FLT3-TKD mutations. Before initiation of the combination therapy, hydroxyurea or one dose of cytarabine (≤1000 mg) was allowed to ensure safety of the study in higher-risk patients. 1 patient withdrew from the study in cycle 1, and therefore was not evaluable.
Patients were treated with 2 dosage levels of gilteritinib (80mg and 120mg daily) in phase 1, as well as set dosages of 35/100 mg ASTX727 (days 1-5) and 400 mg venetoclax (daily for up to 28 days). Treatment cycles were repeated every 28 days for up to 24 cycles and were followed by infinitive gilteritinib therapy as maintenance.
In cycle 1 of phase 1, venetoclax was prescribed at 100 mg on day 1, 200 mg on day 2, and 400 mg daily onwards. In cycles 2 to 24 of phase I, venetoclax was prescribed at 400 mg daily on days 1 to 21, but dose reductions were allowed depending on patient tolerance. In phase 2, newly diagnosed FLT3-mutated AML patients who were unfit for chemotherapy were also enrolled and received the same dosages.
This combination of treatments yielded an 87% overall remission rate (ORR). Patients achieved complete remission or complete remission with incomplete hematologic recovery (n=4) and morphologic leukemia-free state (n=3). The 30 and 60 day mortality rates were 0% and 13%, respectfully. The estimated 6-month overall survival (OS) rate was 70%.
Dr. Ong et al concluded “ASTX727, VEN, and gilteritinib appears to be effective and safe in R/R FLT3 mutated AML and HR-MDS,” adding, “continued accrual is anticipated to define the optimal triplet regimen in both R/R and newly diagnosed FLT3-mutated AML.”
Source:
Ong F, Short N, Daver N, et al. A Phase I/II Study of Combination of ASTX727, Gilteritinib and Venetoclax in Patients with Relapsed/Refractory FLT3¬ Mutated Acute Myeloid Leukemia (AML) and Frontline FLT3 Mutated AML Patients Unfit for Chemotherapy. ash.confex.com. Presented at ASH Annual Meeting and Exposition; December 10-13, 2023; New Orleans, LA. Abstract 4069.
