LAUSR

A limited number of drugs are available to treat patients with polycythemia vera (PV) and essential thrombocythemia (ET). We attempted to identify alternative agents that may target abnormalities within malignant hematopoietic stem and progenitor cells (HSC/HPC). Previously, MDM2 protein levels were shown to be up-regulated in PV/ET CD34+ cells and exposure to a nutlin, an MDM2 antagonist, induced activation of the TP53 pathway and selective depletion of PV HPC/HSCs. This anti-clonal activity was mediated by up-regulation of p53 and potentiated by the addition of interferon-alfa-2a. Therefore, we performed an investigator-initiated phase 1 trial of the oral MDM2 antagonist, idasanutlin (RG7388, Roche), in patients with high-risk PV/ET who had failed at least one prior therapy (NCT02407080). Patients failing to attain at least a partial response by EuropeanLeukemia Net criteria by 6 cycles were then allowed to receive combination therapy with low dose pegylated interferon-alfa-2a. 13 patients with JAK2V617F-positive PV/ET were enrolled and 12 (PV/ET 11/1) treated with idasanutlin at 100 mg and 150 mg daily for 5 consecutive days of a 28-day cycle. Idasanutlin was well tolerated, a dose limiting toxicity was not observed, but low grade gastrointestinal toxicity was common. The overall response rate after 6 cycles of idasanutlin monotherapy was 58% (7/12) and 50% (2/4) with combination therapy. Median duration of response was 16.8 months (range, 3.5 - 26.7). Hematologic, symptomatic, pathologic, and molecular responses were observed. These data indicate that idasanutlin is a promising novel agent for PV and is currently being evaluated in a global phase 2 trial.