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.

New Perspectives on Polycythemia Vera: From Diagnosis to Therapy

“…Idasanutlin was well tolerated without dose-limiting toxicities. Five subjects (41.7%) experienced grade 3 non-hematologic AEs and grade 1/2 nausea occurred in 10 (83%) patients [106]. Idasanutlin is currently evaluated in a phase II trial (NCT03287245).…”

JAK2V617F myeloproliferative neoplasm eradication by a novel interferon/arsenic therapy involves PML

“…Although IFNα targets JAK2 V617F hematopoietic progenitors, in patient or mouse models its long-term efficacy remains modest ( Austin et al, 2020 ; Gisslinger et al, 2020 ; Hasan et al, 2013 ; Kiladjian et al, 2006 ; Mullally et al, 2012 ). Several clinical and preclinical studies have attempted to improve IFNα efficacy, for example, through combinations with MDM2 or JAK2 inhibitors ( Austin et al, 2020 ; Lu et al, 2014 ; Mascarenhas et al, 2019 ). We demonstrate that the IFNα+ATO combination specifically targets the Jak2 V617F disease-initiating cells in vivo, with a much higher potency than IFNα alone.…”

Targeting p53 in chronic lymphocytic leukemia

“…These non-genotoxic compounds bind to MDM2 in the p53-binding pocket and can release p53, leading to effective stabilization of the protein and activation of the Tp53 pathway (Figure 4) [82,83]. Initial preclinical and clinical studies have demonstrated promising efficacy of this class of drugs in a number of TP53 wild type adult and pediatric cancers, both as single agents and in combination with other targeted therapies [84][85][86][87][88][89][90].…”