Enasidenib Monotherapy Shows Promise for Patients With IDH2-mutated MDS

Preliminary findings from a phase 2 trial suggest that enasidenib, a selective isocitrate dehydrogenase 2 (IDH2) inhibitor, offers clinically meaningful responses and a manageable safety profile in participants with IDH2-mutated myelodysplastic syndrome (MDS), marking a potential advancement for this challenging-to-treat population.

Lionel Ades, MD, PhD, Hôpital Saint Louis, Paris, France, and colleagues shared results from the phase 2 collaborative trial (NCT03744390) of the Groupe Francophone des Myélodysplasies (GFM) and the European Myelodysplastic Syndrome Cooperative Group (EMSCO), which evaluated the efficacy and safety of enasidenib, an FDA-approved agent for relapsed or refractory IDH2-mutated acute myeloid leukemia (AML), for its potential benefits in the treatment of MDS.¹

Participants were enrolled in three groups of IDH2-mutated MDS, namely higher-risk MDS after hypomethylating agent failure (group A), untreated higher-risk MDS without severe cytopenia (group B), and lower-risk MDS  after erythropoiesis-stimulating agent failure (group C). Primary outcomes were overall hematologic response for groups A and B and safety for group C, and secondary outcomes included safety, survival, and duration of response. All participants received 100 mg of oral enasidenib daily in 28-day cycles.  In the absence of response after three cycles in the untreated higher-risk MDS group, azacitidine (75 mg/m²/d for 7 days) was added to enasidenib.

Overall response was achieved in 43% of groups A and B. In group A, complete response (CR) occurred in 18%, with a median duration of response of 6.9 months. Median overall survival (OS) was 14.9 months, and 57% of participants survived beyond 1 year. In the untreated group B, five participants (38%) presented with a CR, with a median duration of response of 12.2 months. Median OS extended to 25.5 months, with a 12-month survival rate of 85.8%. Among the 11 participants in the lower-risk MDS group C, 55% achieved a CR with durable responses and transfusion independence. The median OS was not reached, and the treatment showed minimal toxicity.

Enasidenib demonstrated tolerability across studied groups. Although cytopenia-related adverse events were common in higher-risk participants (groups A and B), no severe adverse events associated with treatment were observed. Differentiation syndrome, a known side effect of IDH inhibitors, occurred in 8.6% of high-risk patients (groups A and B) but was manageable.

These findings highlight the clinical benefits and safety profile of enasidenib. Although larger randomized studies are warranted, enasidenib represents a promising targeted therapy for patients with IDH2-mutated MDS.

REFERENCE:

Sebert M, Chevret S, Dimicoli-Salazar S, et al. Enasidenib (ENA) monotherapy in patients with IDH2 mutated myelodysplastic syndrome (MDS), the ideal phase 2 study by the GFM and Emsco groups. Abstract #1839. Presented at the ASH Annual Meeting; December 7-10, 2024; San Diego, California.