Idasanutlin Well Tolerated in Patients With Polycythemia Vera and Essential Thrombocythemia

The MDM2 antagonist idasanutlin was well tolerated and demonstrated “clear clinical activity” in patients with polycythemia vera (PV) and essential thrombocythemia (ET) that was resistant or intolerant to standard therapy, according to results from a phase I study presented at the 2017 ASH Annual Meeting.

Standard treatment for this patient population includes hydroxyurea, interferon, and JAK2 inhibitors, explained John Mascarenhas, MD, from the Icahn School of Medicine at Mount Sinai in New York, and colleagues, but “hematopoietic stem cell-depleting therapies may result in an alternative mechanism to alter disease course and improve outcome.”

“MDM2, a negative regulator of p53, is overexpressed in CD34-positive myeloproliferative neoplasm cells harboring wild-type p53,” they added. Because PV CD34 cells contain higher levels of MDM2, compared with control cells, the researchers hypothesized that treatment with idasanutlin alone or in combination with low-dose pegylated interferon would reduce the number of JAK2-mutated primary cells in patients with PV.

Thirteen patients were enrolled in this dose-escalation study, with one patient withdrawing from the study prior to treatment (n=12; median age = 63.5 years; range not provided). All participants had JAK2-mutated PV or ET, were 60 years or older, had a history of thrombosis, and were previously treated with at least one other agent (excluding JAK inhibitors).

All participants previously received hydroxyurea. Baseline MDM2 levels were higher in study participants versus controls, and the median variant allele frequency (VAF) of JAK2 V617F was 40.6 percent (range not provided).

In part A of the study, patients received one of two doses of idasanutlin (100 mg and 150 mg; n=6 for each), administered daily for five consecutive days in 28-day cycles. Dose-limiting toxicities (DLTs; defined as any non-hematologic adverse event [AE] of grade ≥3 or a hematologic AE of grade ≥2) were assessed at 56 days.

Patients who did not achieve at least a partial response (PR; per modified European LeukemiaNet criteria) after cycle six were able to continue receiving idasanutlin in combination with pegylated interferon-alpha, 45 µg weekly (part B).

Participants received a median of nine cycles of idasanutlin (range not provided) and were followed for nearly one year (range = 8-107 weeks). Three discontinued treatment because of patient decision (n=2) or physician decision (n=1).

No DLTs were identified in either dose level. The only treatment-emergent AEs identified by the researchers as “significant” occurred in the 100 mg group: one case each of grade 3 fatigue and grade 3 headache.

Following six cycles of idasanutlin monotherapy in part A, four patients had non-responsive disease and were treated with concurrent pegylated interferon in part B. Of this group, three patients had PRs, and four had complete responses (CRs). Three of the patients in part B were evaluable. One patient had no response, one had PR, and one had CR, for a combined response rate of 75 percent in both study parts.

“Some patients didn’t even need to be treated every month; they got ‘treatment holidays,’” Dr. Mascarenhas said during his presentation, noting that one patient required no treatment for nine months following completion of the third cycle.

The median reduction in JAK2 V617F VAF was 43 percent (range not provided), with one patient achieving a 92 percent reduction, the authors observed. Seven of 10 patients achieved a ≥50 percent improvement in total symptom score from baseline.

Based on these results, an international, multicenter, single-arm, phase II trial evaluating idasanutlin 150 mg in patients with hydroxyurea-resistant or -intolerant PV is enrolling participants.

The study was limited by its small patient population, single-center design, and short duration of follow-up.

The authors report no conflicts of interest.


Mascarenhas J, Lu M, Virtgaym E, et al. Open label phase I study of single agent oral RG7388 (idasanutlin) in patients with polycythemia vera and essential thrombocythemia. Abstract 254. Presented at the 2017 American Society of Hematology Annual Meeting, December 9, 2017; Atlanta, GA.