Enasidenib as treatment for AML with IDH2 mutation: multicenter real-life study of the early-access program in Spain

Enasidenib is an oral IDH2 inhibitor that reduces the production of the oncometabolite 2-hydroxyglutarate, differentiating IDH2 mutated leukemic cells with initial promising results for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients. We performed a retrospective study in Spain evaluating enasidenib in patients diagnosed with IDH2-mutated myeloid neoplasms (AML, MDS, myeloid sarcoma and chronic myelomonocytic leukemia (CMML). Twenty-three patients were included, with 20 having a refractory/relapsed (R/R) disease status. The median age was 73 years, and the majority patients were classified as adverse risk by the European LeukemiaNet 2022 criteria. The most frequent mutation was IDH2 R140 (69.6%), while 30.4% had R172 mutation. Enasidenib was administered as a single agent in 18 patients, in combination with azacitidine in four patients, and with low-dose cytarabine in another one. The median number of cycles administered was four, with an overall response rate (ORR) of 39.1% and a morphological complete remission (CR) rate of 26.1%. Median overall survival (OS) was 8.3 months. Patients who achieved a complete response had a better outcome than the rest of the patients in terms of OS (19.8 months (95%CI: 15.7-NR) vs. 4.2 (95%CI: 1.5-NR), p = 0.01). Drug-related events included leukocytosis in five patients (21.7%), hyperbilirubinemia in six patients (26.1%) and differentiation syndrome (DS) in four patients (17.4%), including one grade 3 DS and one death related to this latter adverse event (AE), similar to previous findings. Although enasidenib failed to demonstrate a clear overall survival advantage in phase 3 trials, the extended responses and long-term survivors observed herein underscore its therapeutic potential. Ultimately, our data support enasidenib's role as a targeted therapy for IDH2-mutated AML, indicating that expanded access to this agent is warranted to optimize outcomes in these challenging patient populations, especially for R/R AML patients.