MDM2 antagonist idasanutlin in patients with polycythemia vera: results from a single-arm phase 2 study

Abstract

Idasanutlin, an MDM2 antagonist, showed clinical activity and rapid reduction in JAK2 V617F allele burden in patients with polycythemia vera (PV) in a phase 1 study. This open-label, phase 2 study evaluated idasanutlin in patients with hydroxyurea (HU)-resistant/intolerant PV, per the European LeukemiaNet criteria, and phlebotomy dependence; prior ruxolitinib exposure was permitted. Idasanutlin was administered once daily, days 1-5 of each 28-day cycle. The primary endpoint was composite response (hematocrit control and spleen volume reduction >35%) in patients with splenomegaly, and hematocrit control in patients without splenomegaly at week 32. Key secondary endpoints included safety, complete hematologic response (CHR), patient-reported outcomes, and molecular responses. All patients (n=27) received idasanutlin; 16 had response assessment (week 32). Among responders with baseline splenomegaly (n=13), 9 (69%) attained any spleen volume reduction and 1 achieved composite response. Nine patients (56%) achieved hematocrit control, and 8 patients (50%) achieved CHR. Overall, 43% of evaluable patients (n=6/14) showed a ≥50% reduction in the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (week 32). Nausea (93%), diarrhea (78%), and vomiting (41%) were the most common adverse events, with grade ≥3 nausea and vomiting experienced in 3 patients (11%) and 1 patient (4%), respectively. Reduced JAK2 V617F allele burden occurred early (after 3 cycles), with a median reduction of 76%, and associated with achieving CHR and hematocrit control. Overall, the idasanutlin dosing regimen showed clinical activity and rapidly reduced JAK2 allele burden in patients with HU-resistant/intolerant PV but was associated with low-grade gastrointestinal toxicity, leading to poor long-term tolerability. Registration: NCT03287245.