Idasanutlin Induces Responses in Polycythemia Vera, but GI AEs Lead to Frequent Dose Interruptions

December 22, 2020 - Idasanutlin, an investigational MDM2 antagonist that leads to increased p53 activity, led to hematologic responses in about two-thirds of patients with hydroxyurea-resistant polycythemia vera, but was associated with frequent discontinuation.

Idasanutlin, an investigational MDM2 antagonist that leads to increased p53 activity, led to hematologic responses in about two-thirds of patients with hydroxyurea (HU)-resistant polycythemia vera (PV), but was associated with frequent discontinuation most likely due to significant low-grade gastrointestinal toxicity, according to results presented at the 2020 ASH Annual Meeting and Exposition.

Findings showed an overall response rate (ORR) per modified European LeukemiaNet (ELN) criteria of 70%, lead study author John Mascarenhas, MD, said in a virtual presentation during the meeting. However, dose modifications/interruptions were common, with grade 1 to 3 nausea leading to dose interruptions in 22% of patients. Grade 1 to 2 nausea led to dose reductions in 19% of patients.

“These results iterate the importance of tolerability for novel therapies administered over the long term in patients with PV, and unfortunately with this active drug, long-term administration was not feasible for most patients,” said Mascarenhas, from the Icahn School of Medicine at Mount Sinai Health System. “Inhibiting the MDM2-p53 interaction is an appealing treatment strategy for p53 reactivation in cancers in which p53 is wild type or function,” he said, and phase 1 data showing promising activity led to this phase 2 study.

The study comprised 27 patients who met the revised 2016 World Health Organization criteria for the diagnosis of PV who were HU-resistant/intolerant and phlebotomy-dependent. Prior PV therapy with ruxolitinib (Jakafi) and/or interferon was permitted. All participants received idasanutlin at 150 mg/day for 5 days every 28 days, until treatment discontinuation or end of study, which was up to 2 years. The 150-mg starting dose could be escalated to 200 mg for those who demonstrated no hematocrit (Hct) control after cycle 3. Reduction to 100 mg was permitted for toxicity and treatment beyond cycle 12. Antiemetic prophylaxis was mandatory in cycle 1 throughout the study and later became mandatory in all cycles.

The primary endpoint was the composite response of Hct control and spleen volume reduction greater than 35% in patients with splenomegaly (> 450 cm3), and Hct control alone in patients without splenomegaly.

The median age was 56.0 years, 2 (7%) had prior thrombosis, HU discontinuation was due to intolerance in 89% of patients, prior cytoreductive therapy including ruxolitinib in 26%, and 78% had splenomegaly on imaging. Of the 27 patients, 20 were ruxolitinib-naïve and 7 patients had prior exposure to ruxolitinib. Eleven patients discontinued prior to week 32, 7 due to patient withdrawal. Sixteen patients discontinued following week 32.

The population for primary end point evaluation consisted of the 16 patients with response at week 32. Hct control was attained by 56% (9/16) at week 32, a complete hematologic response was attained by 50% (8/16), and 19% (3/16) had a complete ELN response while 50% (8/16) had a partial ELN response, for an overall response rate of 70%.

“Idasanutlin reduced spleen volume in some patients, but the spleen volume reduction threshold of 35% was rarely reached,” he said. “At week 32, only 2 patients achieved this endpoint.” Twenty-two of 24 (92%) evaluable patients had a reduction in spleen volume at any time and 9 of 13 (69%) evaluable patients had a reduction in spleen volume at week 32.

Idasanutlin also reduced the platelet and white blood cell counts. At week 32, there was a median reduction in platelet count of 23 x 109/L and a median reduction in the number of leukocytes of 4.8 x 109/L. “This suggests there was modulation of the disease at a level greater than the Hct, likely hitting the hematopoietic stem and progenitor cell level,” he said.

There were no deaths or transformation to acute myeloid leukemia, progression to myelofibrosis, or thrombotic events reported.

There were 3 serious adverse events (AEs): 1 each of atrial flutter, atrial fibrillation, and nausea/vomiting. Dose modification or interruption due to an AE, most commonly nausea, were required in 10 and 13 patients, respectively. There were no differences in the safety profiles of ruxolitinib-naïve and ruxolitinib-exposed patients.


Mascarenhas J, Higgins B, Anders D, et al. Safety and efficacy of idasanutlin in patients (pts) with hydroxyurea (HU)-resistant/intolerant polycythemia vera (PV): results of an International phase II study. Presented at: 2020 ASH Annual Meeting and Exposition; December 4-8, 2020; virtual. Abstract 479.