According research published in Blood Advances, the MDM2 antagonist idasanutlin demonstrated clinical activity and rapidly reduced Janus kinase 2 (JAK2) allele burden in patients with hydroxyurea (HU)-resistant/-intolerant polycythemia vera (PV) but was associated with low-grade gastrointestinal toxicity that resulted in poor long-term tolerability.

The findings derive from a single-arm, open-label phase 2 study evaluating idasanutlin in patients with HU-resistant/-intolerant PV (according to the European LeukemiaNet criteria) and phlebotomy dependence ( Identifier: NCT03287245).

All patients received idasanutlin 150 mg once daily on days 1 through 5 of each 28-day cycle, for up to 24 treatment cycles. Dose reduction to 100 mg per day was permitted in cases of toxicity or in patients showing response at cycle 13.

Continue Reading

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 response.

 A total of 27 patients (20 ruxolitinib-naïve patients and 7 ruxolitinib-resistant/-intolerant patients) received idasanutlin. The patients had a median age of 56 years (range, 34-74) and 59% of patients were male. Baseline splenomegaly was reported in 21 patients (78%).

At the clinical cutoff date, the median follow-up duration was 41.3 weeks (range, 5.7-100.1), and the median number of treatment cycles was 8 (range, 1-22).

The primary endpoint was assessed in 16 evaluable patients at week 32. The investigators observed hematocrit control in 9 patients (56%) and CHR in 8 patients (50%). Of the 13 patients with baseline splenomegaly, 9 (69%) achieved spleen volume reduction, and 1 (8%) achieved composite response. Of 14 evaluable patients, 6 (43%) showed a ≥50% reduction in the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score at week 32.

The researchers reported an early reduction of JAK2 V617F allele burden after 3 cycles. The median reduction was 76% and was associated with CHR and hematocrit control.

All patients were evaluable for safety. At least 1 any grade treatment-emergent adverse event (TEAE) was reported in 100% of patients. The most common any-grade TEAEs were nausea (93%), diarrhea (78%), and vomiting (41%). Grade ≥3 nausea or vomiting occurred in 3 patients (11%) and 1 patient (4%), respectively.

“Because it is unclear whether modification of idasanutlin dosing would substantially improve its toxicity profile, there are no plans to further explore idasanutlin treatment in patients with PV,” the authors wrote in their report. “The early molecular response seen with idasanutlin therapy is promising, confirms that the MDM2 pathway is important in the pathogenesis of PV, and deserves further clinical evaluation.”

Disclosure: This research was supported by F. Hoffmann-La Roche Ltd. Please see the original reference for a full list of disclosures.


Mascarenhas J, Passamonti F, Burbury K, et al. The MDM2 antagonist idasanutlin in patients with polycythemia vera: results from a single-arm phase 2 study. Blood Adv. 2022;6(4):1162-1174. doi:10.1182/bloodadvances.2021006043