Prime time for the use of statins in MPNs: from comorbidity drugs to disease-modifying partners.

For over 2 decades, the mevalonate pathway has been in focus as an interesting therapeutic target in Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). Initially explored for its potential in cytoreductive and antithrombotic therapy, the role of statins in MPNs is now experiencing a compelling renaissance. This renewed interest is fueled by the recognition of MPNs as "a human inflammation model," driven by chronic inflammation that fuels clonal expansion, premature atherosclerosis, fibrogenesis, and an increased risk of second cancers and comorbidities. Statins possess a wide spectrum of pleiotropic effects beyond lipid lowering, including anti-inflammatory, antiproliferative, proapoptotic, antiangiogenic, and antifibrotic properties. They dampen the activation of leukocytes, platelets, and endothelial cells. Recent epidemiological studies from Denmark demonstrate that statins protect against the development of MPNs in the general population. Furthermore, emerging clinical data suggest that statins enhance the efficacy of interferon alpha (IFN-α), the only known therapy capable of directly targeting the malignant stem cell and inducing minimal residual disease in a subset of patients. This review traces the 20-year journey of the statin-in-MPN concept, from its mechanistic rationale to the present, in which a confluence of evidence from comorbid disease prevention and oncoimmunology is supportive of their upfront use. I posit that we are at a watershed moment, at which statins should be integrated into the upfront treatment of MPNs and in combination therapy strategies, particularly with IFN-α, and potentially with ruxolitinib and metformin, to extinguish the chronic inflammatory drive and fundamentally alter the natural history of these neoplasms.