The MDM2 antagonist idasanutlin in patients with polycythemia vera: results from a single-arm phase 2 study
- Author(s)
- Mascarenhas, J; Passamonti, F; Burbury, K; El-Galaly, TC; Gerds, A; Gupta, V; Higgins, B; Wonde, K; Jamois, C; Kovic, B; Huw, LY; Katakam, S; Maffioli, M; Mesa, R; Palmer, J; Bellini, M; Ross, DM; Vannucchi, AM; Yacoub, A;
- Details
- Publication Year 2022-02-22,Volume 6,Issue #4,Page 1162-1174
- Journal Title
- Blood Advances
- Publication Type
- Research article
- Abstract
- 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 = 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 (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. This trial was registered at www.clinincaltrials.gov as #NCT03287245.
- Keywords
- Humans; Hydroxyurea/pharmacology; Nausea/chemically induced; *Polycythemia Vera/drug therapy/genetics; Proto-Oncogene Proteins c-mdm2; *Pyrrolidines/adverse effects; Splenomegaly/chemically induced; Vomiting/chemically induced; *para-Aminobenzoates/adverse effects
- Department(s)
- Haematology
- PubMed ID
- 34933330
- Publisher's Version
- https://doi.org/10.1182/bloodadvances.2021006043
- Open Access at Publisher's Site
https://doi.org/10.1182/bloodadvances.2021006043- Terms of Use/Rights Notice
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Creation Date: 2025-01-31 03:38:55
Last Modified: 2025-01-31 03:40:50