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

• DOI: 10.1182/bloodadvances.2021006043
• Publication Date: 2021-12-21T22:01:27Z
• Authors: John Mascarenhas; Francesco Passamonti; Kate Burbury; Tarec Christoffer...; Aaron Gerds; Vikas Gupta; Brian Higgins; Kathrin Wonde; Candice Jamois; Bruno Kovic; Ling-Yuh Huw; Sudhakar Katakam; Margherita Maffioli; Ruben Mesa; Jeanne Palmer; Marta Bellini; David M. Ross; Alessandro M. Van...; Abdulraheem Yacoub
• Keywords: Ruxolitinib; Regimen; Phlebotomy; Clinical endpoint

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