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Abstract: We report the 2-year end-of-study results from the phase 2 COMBI II clinical trial investigating the combination treatment of ruxolitinib and low-dose pegylated interferon alfa-2a in patients with newly diagnosed polycythemia vera (PV). The primary outcome was safety and key secondary endpoints were efficacy, based on hematologic parameters, quality-of-life measurements, and JAK2V617F variant allele frequency (VAF). We used the 2013 European LeukemiaNet and International Working Group-Myeloproliferative Neoplasms Research remission criteria. The remission criteria included remissions in symptoms, splenomegaly, peripheral blood counts, and bone marrow. We included 25 patients with PV with a median age of 70 years; 5 of those had prior thromboembolic events and 3 had computed tomography-verified splenomegaly. Two patients stopped both study drugs; 1 of these due to progression to post-PV myelofibrosis, the only one with a grade 3 infection. No events of herpes zoster infections were observed. None of the patients discontinued treatment due to psychiatric symptoms. The peripheral blood cell count remission rate was 92% at 24 months. Using the 2013 European LeukemiaNet and International Working Group-Myeloproliferative Neoplasms Research remission criteria, 14 (56%) achieved remission at 24 months; 3 (12%) achieved complete remission and 11 (44%) achieved partial remission. The following items from the Myeloproliferative Neoplasm Symptom Total Symptom Score were significantly reduced: abdominal discomfort, night sweats, itching, and bone pain. The median JAK2V617F VAF decreased from 47% (95% confidence interval [CI], 35-59) to 7% (95% CI, 3-15), and 60% of patients achieved molecular remission. In conclusion, combination treatment improved cell counts; bone marrow cellularity, and fibrosis; and decreased JAK2V617F VAF; with acceptable toxicity in patients with PV. The trial was registered at www.clinicaltrialsregister.eu as #EudraCT2018-004150-13., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Chronic inflammation is believed to play an important role in the development and disease progression of polycythemia vera (PV). Because an association between gut microbiota, hematopoiesis, and inflammation is well established, we hypothesized that patients with PV have a gut microbiota distinct from healthy control participants (HCs). Recombinant interferon alfa 2 (IFN-α2)-treatment of patients with PV is reportedly disease modifying in terms of normalization of elevated blood cell counts in concert with a reduction in the JAK2V617F allelic burden. Therefore, we hypothesized that patients treated with IFN-α2 might have a composition of the gut microbiota toward normalization. Herein, via amplicon-based next-generation sequencing of the V3 to V4 regions of the 16S ribosomal RNA gene, we report on an abnormal gut microbiota in 102 patients with PV compared with 42 HCs. Patients with PV had a lower alpha diversity and a lower relative abundance of several taxa belonging to Firmicutes (45%) compared with HCs (59%, P <.001). Furthermore, we report the composition of the gut microbiota to differ between the treatment groups (IFN-α2, hydroxyurea, no treatment, and combination therapy with IFN-α2 and ruxolitinib) and the HCs. These observations are highly interesting considering the potential pathogenetic importance of an altered gut microbiota for development of other diseases, including chronic inflammatory diseases. Our observations call for further gut microbiota studies to decipher potential causal associations between treatment and the gut microbiota in PV and related neoplasms., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)