Oral idasanutlin in patients with polycythemia vera

Abstract

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 (HSCs) and progenitor cells (HPCs). Previously, MDM2 protein levels were shown to be upregulated in PV/ET CD34+ cells, and exposure to a nutlin, an MDM2 antagonist, induced activation of the TP53 pathway and selective depletion of PV HPCs/HSCs. This anticlonal activity was mediated by upregulation of p53 and potentiated by the addition of interferon-α2a (IFN-α2a). Therefore, we performed an investigator-initiated phase 1 trial of the oral MDM2 antagonist idasanutlin (RG7388; Roche) in patients with high-risk PV/ET for whom at least 1 prior therapy had failed. Patients not attaining at least a partial response by European LeukemiaNet criteria after 6 cycles were then allowed to receive combination therapy with low-dose pegylated IFN-α2a. Thirteen patients with JAK2 V617F+ PV/ET were enrolled, and 12 (PV, n = 11; ET, n = 1) were treated with idasanutlin at 100 and 150 mg daily, respectively, for 5 consecutive days of a 28-day cycle. Idasanutlin was well tolerated; no dose-limiting toxicity was observed, but low-grade gastrointestinal toxicity was common. Overall response rate after 6 cycles was 58% (7 of 12) with idasanutlin monotherapy and 50% (2 of 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; it is currently being evaluated in a global phase 2 trial. This trial was registered at www.clinicaltrials.gov as #NCT02407080.

Conflict of interest statement

Conflict-of-interest disclosure: J.M. reports clinical trial research support paid to the institution from Incyte, Roche, Novartis, CTI Biopharma, Janssen, Merck, Promedior, and Celgene and has been a clinical trial steering committee and scientific advisory board member for Roche, CTI Biopharma, Incyte, and Celgene; R.R. reports research funding from Constellation, Incyte, and Stemline Therapeutics and consulting fees from Incyte, Celgene, Agios, Apexx, BeyondSpring, Partner Therapeutics, and Jazz Pharmaceuticals; R.M. reports research support from Incyte, Celgene, Genentech, and CTI Biopharma and consultant fees from Novartis, Sierra Oncology, and La Jolla Pharmaceuticals; and R.H. reports research support from Janssen, Merus, Dompe, Scholar Rock, Summer Road, Forbius, and Incyte and scientific advisory board fees from Novartis and La Jolla Pharmaceuticals. The remaining authors declare no competing financial interests.

© 2019 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Baseline genomic alterations. The genomic profiles of 11 patients as determined by next-generation sequencing studies are shown. Each column represents an individual patient. Bars at the top indicate the number of alterations identified per patient. Mutated genes are listed on the right. Frequency of each mutation in these 11 patients is listed on the left. Type of alteration is denoted by key. Additionally, prior hydroxyurea (HU) exposure qualified by intolerance or resistance is shown below, and this is further coupled to the clinical, pathologic, and molecular response by ELN criteria for each patient. HR, histologic response; N/E, not evaluable; NR, no response.

Figure 2.

Baseline MDM2 and day-5 plasma MIC-1 levels. (A) Baseline MDM2 levels were higher in patients with PV/ET compared with normal controls. The pretreatment MNC median MDM2 level was approximately fourfold higher in the PV/ET patients enrolled on the study compared with normal controls. (B) Plasma MIC-1 levels are increased on day 5 of idasanutlin therapy. p53 pathway activation is reflected by a 4.8-fold increase from baseline of MIC-1 protein levels by day 5 (P = .004).

Figure 3.

Maximum TSS response on study. Nine patients treated with idasanutlin attained at least a 50% reduction in TSS. The cycle in which the best percentage reduction was first noted is shown in association with each patient response. NE, not evaluable; NR, no response.

Figure 4.

JAK2 driver mutation response with idasanutlin therapy. The waterfall plots demonstrate the spectrum of molecular responses observed with idasanutlin therapy, and the cycle in which the maximal reduction in VAF was first noted is shown in association with the response bar. NE, not evaluable; NR, no response.