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

John Mascarenhas, Francesco Passamonti, Kate Burbury, Tarec Christoffer El-Galaly, 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. Vannucchi, Abdulraheem Yacoub

Research output: Contribution to journalArticlepeer-review


Idasanutlin, an MDM2 antagonist, showed clinical activity and a 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 on days 1 through 5 of each 28-day cycle. The primary end point 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 end points included safety, complete hematologic response (CHR), patient-reported outcomes, and molecular responses. All patients (n 5 27) received idasanutlin; 16 had response assessment (week 32). Among responders with baseline splenomegaly (n 5 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 (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 or vomiting experienced by 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 was 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.

Original languageEnglish (US)
Pages (from-to)1162-1174
Number of pages13
JournalBlood Advances
Issue number4
StatePublished - Feb 22 2022

ASJC Scopus subject areas

  • Hematology


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