Safety and efficacy of combination therapy of interferon‐α2 and ruxolitinib in polycythemia vera and myelofibrosis

Abstract

Interferon‐α2 reduces elevated blood cell counts and splenomegaly in patients with myeloproliferative neoplasms (MPN) and may restore polyclonal hematopoiesis. Its use is limited by inflammation‐mediated toxicity, leading to treatment discontinuation in 10‐30% of patients. Ruxolitinib, a potent anti‐inflammatory agent, has demonstrated benefit in myelofibrosis (MF) and polycythemia vera (PV) patients. Combination therapy (CT) with these two agents may be more efficacious than monotherapy with either, potentially improving tolerability of interferon‐α2 as well. We report the preliminary results from a phase II study of CT with pegylated interferon‐α2 and ruxolitinib in 50 MPN patients (PV, n = 32; low‐/intermediate‐1‐risk MF, n = 18), the majority (n = 47) being resistant and/or intolerant to interferon‐α2 monotherapy. Objectives included remission (2013 revised criteria encompassing histologic, hematologic, and clinical responses), complete hematologic response (CHR), molecular response, and toxicity. Follow‐up was 12 months. Partial remission (PR) and sustained CHR were achieved in 9% and 44% of PV patients, respectively. In MF patients, complete or partial remission was achieved in 39%, and sustained CHR in 58%. The median JAK2V617F allele burden declined significantly in both groups. Hematologic toxicity was the most common adverse event and was managed by dose reduction. Thirty‐seven serious adverse events were recorded in 23 patients; the discontinuation rate was 20%. We conclude that CT with interferon‐α2 and ruxolitinib is efficacious in patients with low‐/intermediate‐1‐risk MF and, to a lesser extent, in patients with PV. These preliminary results encourage phase III studies as well as a study with CT in newly diagnosed MPN patients.

Anti-Glucosylsphingosine Autoimmunity, JAK2V617F-Dependent Interleukin-1β and JAK2V617F-Independent Cytokines in Myeloproliferative Neoplasms

“…However, IFN-α also represses the expression of cytokines and receptors that do not signal via JAK/STAT, notably IL-1β, a major pro-inflammatory cytokine, as well as others that facilitate the survival of MPN progenitors, such as IL-11, hepatocyte growth factor (HGF) and its receptor, c-MET, and tumor growth factors β (TGF-β) [ 24 , 25 ]. Consistently, IFN-α and JAK inhibitors were reported to act in synergy in MPNs [ 26 , 27 , 28 ]. Hence, both chronic inflammation and the JAK2 / CALR / MPL mutants play major roles in the pathogenesis of MPNs, and inflammation cytokines act as stimulants of the mutated clone as well as mediators of clinical symptoms and complications [ 12 , 29 ].…”

B‐cell frequencies and immunoregulatory phenotypes in myeloproliferative neoplasms: Influence of ruxolitinib, interferon‐α2, or combination treatment

“…We studied three populations: (a) 42 patients with PV or MF included in the phase II COMBI trial investigating safety and efficacy of combination therapy with RUX and IFN‐α2 (EudraCT: 2013‐003295‐12) with measurements before and during therapy; (b) 29 MF patients with measurements before and during RUX therapy; and (c) reevaluation of the flow cytometry data on lymphocyte count and B‐cell frequency in 36 patients with MPNs, mainly ET or PV, included in a previous study on NK cells and 10 HDs. Of these 36 patients, 21 were treated with IFN‐α2 with measurements before and during treatment, and 15 patients were not receiving cytoreductive treatment .…”

MPN: The Molecular Drivers of Disease Initiation, Progression and Transformation and their Effect on Treatment

“…We have recently shown that this potential antagonism is avoided in vivo because of the relative sparing of LT-HSC from ruxolitinib-mediated JAK/STAT inhibition [172]. Initial combination phase 2 studies showed a complete haematological response was achieved in 44% of PV patients and 58% of low to intermediate-1 risk MF at 12 months of treatment, with both groups showing a significant reduction in JAK2 V617F allele burden with a median decrease in VAF from 47% to 23.5% for PV at 12 months and 45% to 18% for MF at 12 months [202].…”