The combination of enasidenib, a mutant IDH2 inhibitor, plus venetoclax is safe and shows preliminary activity in patients with relapsed or refractory IDH2-mutated acute myeloid leukemia (AML), according to results from the ENAVEN-AML study published in The Lancet Haematology.
The ENAVEN-AML study was a single-arm, phase 1b/2 trial conducted at two centers in Canada. Patients were eligible to participate if they were 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0 to 2, had a confirmed IDH2 mutation, and had AML or myelodysplastic syndromes (MDS) that was refractory or had relapsed after at least one line of treatment.
The study enrolled 27 patients (13 in phase 1b, 14 in phase 2), of whom 26 had relapsed or refractory AML, and one had relapsed MDS. The median follow-up was 20.2 months at the data cutoff.
Patients were treated with venetoclax 400 mg orally daily with a three-day dose ramp-up starting on cycle 1 day 1 and enasidenib 100 mg orally daily starting on cycle 1 day 15.
The investigators, led by Guillaume Richard-Carpentier, MD, of the Princess Margaret Cancer Centre at the University Health Network in Toronto, Canada, reported that the most common grade 3 or worse treatment-emergent adverse event (TEAE)s were febrile neutropenia (n=11, 41%), infections (n=8, 30%), thrombocytopenia (n=7, 26%), pneumonia (n=6, 22%), sepsis (n=5, 19%), and anemia (n=5, 19%). One case of IDH inhibitor-associated differentiation syndrome was observed. Serious adverse events were reported in 17 (62%) of 27 patients, most commonly infections (n=11, 41%) and intracranial bleeding (n=5, 19%). No dose-limiting toxicities or treatment-related deaths were observed.
The recommended phase 2 dose was 400 mg daily for venetoclax and 100 mg daily for enasidenib.
Of the 26 patients with AML, the overall response rate was 62% (16 of 26), with 13 (50%) of 26 having complete remission. The only patient with MDS did not respond to enasidenib plus venetoclax, according to the investigators.
Funding for this study was provided by AbbVie and Bristol Myers Squibb.
Reference
Richard-Carpentier G, Gupta G, Koraksic C. Enasidenib plus venetoclax in patients with IDH2-mutated relapsed or refractory acute myeloid leukaemia or myelodysplastic syndrome (ENAVEN-AML): a multicentre, single-arm, phase 1b/2 trial. 2025. doi: 10.1016/S2352-3026(25)00254-6
