Venetoclax Plus Gilteritinib Among Patients With FLT3-Mutated AML

Results from a Phase 1b Dose Escalation/Expansion Study

According to findings from a phase 1b dose escalation/expansion study recently published in the Journal of Clinical Oncology, venetoclax plus gilteritinib combination treatment resulted in a high modified composite complete response (mCRc) and molecular response rates among patients with relapsed/refractory (R/R) FLT3-mutated acute myeloid leukemia (AML). 

Dr Naval Daver, MD, MD Anderson Cancer Center, Houston, Texas, and coauthors stated “despite advances in frontline treatment with recently approved therapies for acute myeloid leukemia, most patients experience relapsed/refractory disease,” as the impetus of this study. They “reasoned that [venetoclax and gilteritinib] might induce earlier, deeper elimination of FLT3 [mutated] clones that drive chemotherapy-resistant disease.” 

In order to test the efficacy and safety of this combination, researchers aimed to study primary endpoints of safety, identification of the recommended phase 2 dose, and mCRc rate. The mCRc rate was described as the proportion of patients achieving complete response (CR), CR with blood count recovery, incomplete platelet recovery, or morphologic leukemia-free state. The secondary endpoints included FLT3 molecular response rate (proportion of patients with FLT3 mutation levels [< 10−2 at the time of achieved mCRc], duration of response, and overall survival (OS). 

61 patients with a median age of 63 years and FLT3-mutated AML (56 with FLT3 mutation and 5 with FLT3 wild-type) who failed at least 1 prior line of AML treatment were enrolled in this study. Patients received venetoclax at 400 mg once daily, starting on cycle 1 day 2 with a 3-day dose ramp-up and continued at 400 mg for cycles 2 and forward. Additionally, patients received gilteritinib at 80 or 120 mg once daily. Patients received this combination of treatment until disease progression, toxicity, or withdrawal. 

At a median follow-up of 17.5 months, results indicated that patients with FLT3-mutated AML treated at any dose had a mCRc rate of 75% and a duration of response of 4.9 months. Patients had a median OS of 10 months. The recommended phase 2 dose was venetoclax at 400 mg once daily and gilteritinib at 120 mg once daily. 97% (n=59) of patients had a grade 3 or 4 treatment-related adverse event, with 75% (n=46) experiencing a serious event. The most common adverse events were decreased white blood cell count, decreased platelet count, and anemia. Adverse events led 15% (n=9) of patients to withdraw from venetoclax treatment, and 13% (n=8) to withdraw from gilteritinib treatment. 

As results indicated that the combination of venetoclax and gilteritinib was safe and effective for patients with FLT3-mutated AML, Dr Daver et al concluded, “experience from this first data set of [venetoclax plus gilteritinib] could play a major role in efforts to redefine both R/R and frontline FLT3[mutated] AML treatment.” 

Source:

Daver N, Perl AE, Maly J, et al. Venetoclax plus gilteritinib for FLT3-mutated relapsed/refractory acute myeloid leukemia. J Clin Oncol. Published online July 18, 2022. doi:https://doi.org/10.1200/jco.22.00602