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      Ruxolitinib and interferon-α2 combination therapy for patients with polycythemia vera or myelofibrosis: a phase II study

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          Abstract

          We report the final 2-year end-of-study results from the first clinical trial investigating combination treatment with ruxolitinib and low-dose pegylated interferon-α2 (PEG-IFNα2). The study included 32 patients with polycythemia vera and 18 with primary or secondary myelofibrosis; 46 patients were previously intolerant of or refractory to PEGIFNα2. The primary outcome was efficacy, based on hematologic parameters, quality of life measurements, and JAK2 V617F allele burden. We used the 2013 European LeukemiaNet and International Working Group- Myeloproliferative Neoplasms Research and Treatment response criteria, including response in symptoms, splenomegaly, peripheral blood counts, and bone marrow. Of 32 patients with polycythemia vera, ten (31%) achieved a remission which was a complete remission in three (9%) cases. Of 18 patients with myelofibrosis, eight (44%) achieved a remission; five (28%) were complete remissions. The cumulative incidence of peripheral blood count remission was 0.85 and 0.75 for patients with polycythemia vera and myelofibrosis, respectively. The Myeloproliferative Neoplasm Symptom Assessment Form total symptom score decreased from 22 [95% confidence interval (95% CI):, 16-29] at baseline to 15 (95% CI: 10-22) after 2 years. The median JAK2 V617F allele burden decreased from 47% (95% CI: 33-61%) to 12% (95% CI: 6-22%), and 41% of patients achieved a molecular response. The drop-out rate was 6% among patients with polycythemia vera and 32% among those with myelofibrosis. Of 36 patients previously intolerant of PEG-IFNα2, 31 (86%) completed the study, and 24 (67%) of these received PEG-IFNα2 throughout the study. In conclusion, combination treatment improved cell counts, reduced bone marrow cellularity and fibrosis, decreased JAK2 V617F burden, and reduced symptom burden with acceptable toxicity in several patients with polycythemia vera or myelofibrosis. #EudraCT2013-003295-12.

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          JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis.

          Claire Harrison, Jean-Jacques Kiladjian, Haifa Kathrin Al-Ali … (2012)
          Treatment options for myelofibrosis are limited. We evaluated the efficacy and safety of ruxolitinib, a potent and selective Janus kinase (JAK) 1 and 2 inhibitor, as compared with the best available therapy, in patients with myelofibrosis. We assigned 219 patients with intermediate-2 or high-risk primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis to receive oral ruxolitinib or the best available therapy. The primary end point and key secondary end point of the study were the percentage of patients with at least a 35% reduction in spleen volume at week 48 and at week 24, respectively, as assessed with the use of magnetic resonance imaging or computed tomography. A total of 28% of the patients in the ruxolitinib group had at least a 35% reduction in spleen volume at week 48, as compared with 0% in the group receiving the best available therapy (P<0.001); the corresponding percentages at week 24 were 32% and 0% (P<0.001). At 48 weeks, the mean palpable spleen length had decreased by 56% with ruxolitinib but had increased by 4% with the best available therapy. The median duration of response with ruxolitinib was not reached, with 80% of patients still having a response at a median follow-up of 12 months. Patients in the ruxolitinib group had an improvement in overall quality-of-life measures and a reduction in symptoms associated with myelofibrosis. The most common hematologic abnormalities of grade 3 or higher in either group were thrombocytopenia and anemia, which were managed with a dose reduction, interruption of treatment, or transfusion. One patient in each group discontinued treatment owing to thrombocytopenia, and none discontinued owing to anemia. Nonhematologic adverse events were rare and mostly grade 1 or 2. Two cases of acute myeloid leukemia were reported with the best available therapy. Continuous ruxolitinib therapy, as compared with the best available therapy, was associated with marked and durable reductions in splenomegaly and disease-related symptoms, improvements in role functioning and quality of life, and modest toxic effects. An influence on overall survival has not yet been shown. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT00934544.).
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            Ruxolitinib versus standard therapy for the treatment of polycythemia vera.

            Alessandro Vannucchi, Jean Kiladjian, Martin Griesshammer … (2015)
            Ruxolitinib, a Janus kinase (JAK) 1 and 2 inhibitor, was shown to have a clinical benefit in patients with polycythemia vera in a phase 2 study. We conducted a phase 3 open-label study to evaluate the efficacy and safety of ruxolitinib versus standard therapy in patients with polycythemia vera who had an inadequate response to or had unacceptable side effects from hydroxyurea.
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              Philadelphia chromosome-negative classical myeloproliferative neoplasms: revised management recommendations from European LeukemiaNet

              Guido Finazzi, Rüdiger Hehlmann, Gunnar Birgegård … (2018)
              This document updates the recommendations on the management of Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-neg MPNs) published in 2011 by the European LeukemiaNet (ELN) consortium. Recommendations were produced by multiple-step formalized procedures of group discussion. A critical appraisal of evidence by using Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methodology was performed in the areas where at least one randomized clinical trial was published. Seven randomized controlled trials provided the evidence base; earlier phase trials also informed recommendation development. Key differences from the 2011 diagnostic recommendations included: lower threshold values for hemoglobin and hematocrit and bone marrow examination for diagnosis of polycythemia vera (PV), according to the revised WHO criteria; the search for complementary clonal markers, such as ASXL1, EZH2, IDH1/IDH2, and SRSF2 for the diagnosis of myelofibrosis (MF) in patients who test negative for JAK2V617, CALR or MPL driver mutations. Regarding key differences of therapy recommendations, both recombinant interferon alpha and the JAK1/JAK2 inhibitor ruxolitinib are recommended as second-line therapies for PV patients who are intolerant or have inadequate response to hydroxyurea. Ruxolitinib is recommended as first-line approach for MF-associated splenomegaly in patients with intermediate-2 or high-risk disease; in case of intermediate-1 disease, ruxolitinib is recommended in highly symptomatic splenomegaly. Allogeneic stem cell transplantation is recommended for transplant-eligible MF patients with high or intermediate-2 risk score. Allogeneic stem cell transplantation is also recommended for transplant-eligible MF patients with intermediate-1 risk score who present with either refractory, transfusion-dependent anemia, blasts in peripheral blood > 2%, adverse cytogenetics, or high-risk mutations. In these situations, the transplant procedure should be performed in a controlled setting.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Haematologica
                Journal ID (iso-abbrev): Haematologica
                Journal ID (publisher-id): HAEMA
                Title: Haematologica
                Publisher: Fondazione Ferrata Storti
                ISSN (Print): 0390-6078
                ISSN (Electronic): 1592-8721
                Publication date (Electronic): 01 September 2020
                Publication date Collection: 01 September 2020
                Volume: 105
                Issue: 9
                Electronic Location Identifier: 235648
                Affiliations
                [1 ]Department of Hematology, Zealand University Hospital , Roskilde, Denmark
                [2 ]Institute for Inflammation Research , Center for Rheumatology and Spine Diseases, Copenhagen University Hospital Rigshospitalet , Copenhagen, Denmark
                [3 ]Department of Hematology, Copenhagen University Hospital Rigshospitalet , Copenhagen, Denmark
                [4 ]Biotech Research and Innovation Center, University of Copenhagen , Copenhagen, Denmark
                [5 ]Herlev University Hospital , Copenhagen, Denmark
                [6 ]Department of Public Health, Faculty of Health Sciences, University of Copenhagen , Copenhagen, Denmark
                [7 ]Department of Pathology, Zealand University Hospital , Roskilde, Denmark
                [8 ]Department of Clinical Genetics, Odense University Hospital , Odense, Denmark
                [9 ]Department of Hematology, Odense University Hospital , Odense, Denmark
                [10 ]Department of Hematology, South-West Jutlandic Hospital , Esbjerg, Denmark
                [11 ]Department of Laboratory Medicine, Boston Children’s Hospital , Harvard Medical School , Boston, MA, USA
                [12 ]Data and Development Support, Region Zealand , Sorø, Denmark
                Author notes
                Article
                DOI: 10.3324/haematol.2019.235648
                PMC ID: 7556624
                PubMed ID: 33054051
                SO-VID: a2177ed7-645a-4118-a3c5-1025486f6c33
                Copyright © Copyright© 2020 Ferrata Storti Foundation
                License:

                This article is distributed under the terms of the Creative Commons Attribution Noncommercial License ( by-nc 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

                History
                Date received : 18 August 2019
                Date accepted : 20 December 2019
                Date revision received : 16 January 2020
                Page count
                Figures: 4, Tables: 2, Equations: 0, References: 49, Pages: 11
                Categories
                Subject: Article

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