Statins Enhance the Efficacy of Pegylated Interferon-alpha2 in Patients with Ph-Negative Chronic Myeloproliferative Neoplasms. Results from a Danish Single-Institution Cohort Study
Authors: Hansen Isabella Diana , Larsen Morten Kranker , Skov Vibe , Kjær Lasse , Ellervik Christina , Sørensen Anders Lindholm , Knudsen Trine Alma , Christensen Sarah Friis , Cordua Sabrina , Eickhardt-Dalbøge Christina Schjellerup , Wienecke Troels , Kristiansen Marie Hvelplund , Hasselbalch Hans C. 
Published: December 2024

Background: Chronic inflammation is an important driving force in the development and progression of myeloproliferative neoplasms (MPNs) in the biological continuum from the early MPN-stages - essential thrombocythemia (ET) and polycythemia vera (PV) - to the advanced myelofibrotic stage (MF). Statins are cholesterol-lowering drugs used for primary and secondary prevention of cardiovascular disease. In addition to cholesterol reduction, statins have demonstrated anti-proliferative, proapoptotic, anti-angiogenic, and anti-inflammatory properties. Several studies have investigated their impact on various types of cancer, including MPNs, demonstrating a reduction in the risk of cancer development and all-cause mortality. These pleiotropic effects of statins might be beneficial in the treatment of MPNs.

Aim: We aimed to investigate if statin use, in addition to standard cytoreductive treatment, entails a shorter time to obtain hematological and molecular responses, and with a lower dosage of cytoreductive drugs.

Method: The study was a single-institution, retrospective cohort study. We investigated a cohort of 126 patients diagnosed with MPNs at the Department of Hematology at Zealand University Hospital in Denmark from 2010-2023, including a JAK2V617F-subgroup consisting of all IFN-treated patients with the JAK2V617F mutation and ≥ 2 JAK2V617F variant allele frequency measurements (n = 34). All patients were diagnosed according to the WHO 2008 or 2016 classification of MPN. Data were collected from medical records, and the baseline was defined as the time of diagnosis. Blood sample values and changes in the cytoreductive treatment were collected at the time of diagnosis and afterward at approximately three-month intervals, depending on the frequency of outpatient clinic checkups. Cytoreductive therapy included pegylated-interferon-2alpha (IFN) or hydroxyurea (HU).

Hematological and molecular responses were assessed from the blood cell counts according to the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) criteria from 2013. A complete hematological response (CHR) was defined for ET as platelet count (PLT) &lt;400 x 109/L and leucocyte count (WBC) &lt;10 x 109/L, for PV as hematocrit &lt;0.45 without phlebotomy, PLT &lt;400 x 109/L and WBC &lt;10 x 109/L and for MF as hemoglobin ≥6,2 mmol/L and &lt; upper normal limit (UNL), neutrophil count ≥1 × 109/L and &lt; UNL and PLT ≥100 × 109/L and &lt; UNL. These criteria had to be maintained for 12 weeks to qualify as a response. A partial molecular response (PMR) was defined as a relative reduction of ≥50% from the JAK2V617F VAF at the time of diagnosis for patients with a baseline JAK2V617F VAF of ≥20%.

We calculated hazard ratios and 95% confidence intervals (HR (95%CI)) using the Cox proportional hazard regressionmodel. We performed a multivariable analysis adjusted for age, sex, smoking, and hypertension. Statistical significances were considered as p-values &lt; 0.05. All analyses were performed using the statistical software R.

Result: The cohort included 50 IFN-treated non-statin users, 30 IFN-treated statin users, 23 HU-treated non-statin users, and 23 HU-treated statin users. The patients treated with HU were older and included more women than the patients treated with IFN. The statin users had a higher prevalence of hypertension, type 2 diabetes, and thromboembolic events prior to diagnosis and a lower total cholesterol and LDL-C compared with non-statin users. The mean follow-up time was 4.1 years (range 1.2-12.1)

Statin use was significantly associated with achieving a CHR among the IFN-treated patients with a HR (95%CI) of 2.2 (1.2-3.8), p=0.007. Contrarily, statin use was not associated with CHR among the HU-treated patients with a HR (95%CI) of 1.5 (0.8-3.3), p=0.2.

Statin use was significantly associated with achieving a PMR in the JAK2V617F-subgroup by a HR (95%CI) of 3.3 (1.1-10.0), p=0.036.

IFN-treated patients received the same initial dose of treatment. Throughout the follow-up period, statin users had a significantly lower mean dose of treatment (36 µg/week) compared with non-statin users (51 µg/week) (p=0.001).

Conclusion: In conclusion, statin use may enhance the efficacy of IFN, resulting in higher rates of CHR and PMR with a lower dose of IFN.