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.
No other larger case-control study has described a positive association between the risk of MPN and a history of smoking in the general MPN population. This association might be explained by the chronic inflammatory state and oxidative stress in response to smoking, eliciting genomic instability in the stem cell compartment and ultimately clonal evolution resulting in MPNs.
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.
BackgroundFormer studies on smoking as a risk factor for Philadelphia‐negative myeloproliferative neoplasms (MPNs) have mainly been carried out in women's cohorts and studies with various definitions of MPNs. Herein, we conducted a cohort study with register‐based follow‐up of a general population from Denmark, to validate and substantiate prior observations.MethodsIn the Danish Health Examination Survey cohort, we used the Cox proportional‐hazards model adjusted for age, sex, body mass index, and level of education, to calculate hazard ratios (HRs), to investigate, whether daily smokers or occasional/ex‐smokers had an increased risk of MPNs compared to never‐smokers.ResultsFrom the time of data collection (September 2007 to October 2008) until 1 January 2015, 70 individuals were diagnosed with MPNs among 75 896 study participants. Similar results were observed in both the age and sex adjusted analysis and the multivariable analysis. The multivariable HR of any MPN diagnosis for daily smokers was 2.5 (95% CI: 1.3‐5.0). For essential thrombocytosis, polycythemia vera, myelofibrosis, and MPN‐unclassified, the HRs were 1.8 (95% CI: 0.5‐5.8), 1.7 (95% CI: 0.5‐5.8), 4.3 (95% CI: 0.9‐19), and 6.2 (95% CI: 1.5‐25), respectively. Among occasional/ex‐smokers the corresponding HRs were 1.9 (95% CI: 1.1‐3.3), 1.5 (95% CI: 0.6‐3.7), 0.8 (95% CI: 0.3‐2.4), 0.9 (95% CI: 0.2‐4.4), and 6.2 (95% CI: 1.8‐21). Participants, who smoked >15 g/day, had an overall HR of 3.4 (95% CI: 1.4‐8.2) for any MPN diagnosis, while participants who smoked ≤15 g/day, had an overall HR of 2.1 (95% CI: 0.9‐4.7).ConclusionSmoking was associated with MPN development when comparing smokers and never‐smokers. Further studies investigating smoking in MPNs are warranted to substantiate our findings.
Background While statins may have anti-inflammatory effects, anti-oxidative effects are controversial. We investigated if statin treatment is associated with differences in oxidatively generated nucleotide damage and chronic inflammation, and the relationship between nucleotide damage and chronic inflammation. Methods We included 19,795 participants from the Danish General Suburban Population Study. In 3420 participants, we measured urinary 8-oxodG and 8-oxoGuo by liquid chromatography-tandem mass spectrometry as markers of oxidatively generated damage to DNA and RNA, respectively. We used a composite score for chronic inflammation (INFLA score) of hsCRP, WBC, platelet count, and neutrophil granulocyte to lymphocyte ratio. Associations were assessed using multivariate linear regression models. Results Compared with non-users, statin users had 4.3–6.0% lower 8-oxodG in three separate models ( p < 0.05); there were no differences in 8-oxoGuo. Among participants aged > 60 y, statin users had 11.4% lower 8-oxodG (95%CI: 6.7–15.9%, p interaction <0.001) and 3.9% lower 8-oxoGuo (95%CI: 0.1–7.5%, p interaction = 0.002), compared with non-users. Compared with non-users, statin users had 11.1% (95%CI: 5.4–16.5%, p interaction <0.001) lower 8-oxodG in participants treated for hypertension, and 18.6% (95%CI: 6.8–28.9%, p interaction <0.001) lower 8-oxodG in participants with decreased renal function. Compared with non-users, statin users had significantly lower INFLA score ( p < 0.001). 8-oxodG and 8-oxoGuo associated positively with markers of chronic inflammation. Conclusions Oxidatively generated DNA damage and inflammatory burden are lower in statin users compared with non-users. Together, anti-oxidative and anti-inflammatory effects may contribute to the beneficial effects of statins.
We have found an increased risk of second malignancies in MPN patients treated with HU compared with patients treated with IFN.
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