Venetoclax Plus Gilteritinib Shows High Rates of mCRC in Patients with AML

Gilteritinib was shown to improve survival outcomes in patients with FLT3-mutated (FLT3mut+) acute myeloid leukemia (AML). The FLT3 inhibitor demonstrated success in patients who were relapsed or refractory (R/R) to standard chemotherapy in the ongoing, phase 1b venetoclax plus gilteritinib trial presented at the EHA 2021 Virtual Congress.

Researchers evaluated various combinations of dose levels for venetoclax in combination with gilteritinib to expand upon prior reports of high rates of marrow blast elimination and a modified composite complete remission (mCRC) rate of 84%. However, relapses in FLT3mut+ are common and long-term survival remains poor.

Forty-three patients with R/R AML FLT3mut+ were enrolled and received venetoclax 400 mg with gilteritinib (80 mg or 120 mg) daily in 28-day cycles, following dose escalation of venetoclax.

FLT3 internal tandem duplications were identified in 37 patients (86%), and 6 patients (14%) were identified with only tyrosine kinase domain mutations. Baseline cytogenetic risk was favorable in 2 patients (5%), intermediate in 23 patients (55%), poor in 13 patients (31%), and 5 patients (12%) had no mitoses or missing data.

Median prior lines of therapy were 2, with 33 patients (77%) overall having 2 or more prior lines of therapy. Further, 28 patients (65%) had received at least 1 prior FLT3 inhibitor, and 3 patients (7%) received prior venetoclax. Fourteen patients (33%) had prior transplant.

The primary endpoint was mCRC, wherein a complete response (CR) rate with incomplete platelet recovery plus CR with incomplete blood count recovery plus morphologic leukemia-free state should align with CRC responses from the phase 3 ADMIRAL trial. Duration of response (DOR) of mCRC was a secondary endpoint with overall survival (OS) and changes in FLT3 allelic burden being exploratory.

Findings showed that mCRC was achieved by 86% of the FLT3mut+ population with a median time to first response of 1 month and by 86% of patients with prior FLT3 tyrosine kinase inhibitor exposure. FLT3 molecular clearance was observed in 69% of patients with mCRC who had PCR analyzed at baseline and at least 1 follow-up.

“These updates analyses show that venetoclax plus gilteritinib achieved high rates of mCRc in patients with heavily pretreated and prior TKI-exposed R/R FLT3mut+ AML with encouraging molecular clearance rates,” wrote Jessica K. Altman, MD, Robert H. Lurie Comprehensive Cancer Center, Northwest University, Chicago, Illinois, and co-investigators.

“Using similar response criteria to previously studied FTL3mut+ populations, the high mCRC rate with venetoclax plus gilteritinib reported here suggests strong antileukemic activity. Cytopenias were prominent but manageable,” Dr Altman et al concluded.—Alexa Stoia