Hans Hasselbalch, MD Inflammation in the MPNs

Hasselbalch - Lecture on Inflammation in MPNs. International Patient Symposium
In recent years, new insights into the Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) have emerged, including the important role of chronic inflammation as the driving force for clonal evolution and disease progression and the impact of chronic inflammation upon symptom burden as well .1-7 In the biological continuum from early cancer stages (essential thrombocythemia , polycythemia vera ) towards the advanced myelofibrosis stage chronic inflammation may also have a major role in triggering thrombosis and development of accelerated (premature ) atherosclerosis 2,3,8 which are hallmarks of several chronic inflammatory diseases. Thrombotic, vascular, and bleeding complications are the most common causes of morbidity and mortality in MPNs in which circulating red cells, leukocytes, and platelets, as well as vascular endothelial cells are abnormally activated due to e.g. the inflammatory and thrombogenic JAK2V617F mutation. Their interactions with each other create a highly proadhesive and prothrombotic milieu in the circulation that predisposes patients with MPN to venous, arterial, and microvascular thrombosis.8-10 The inflammatory state amplifies the clinical thrombotic tendency and, at the same time, preferentially promote further MPN stem cell clonal expansion, thereby generating a vicious cycle that favors a prothrombotic state. Next generation sequencing may add novel information in predicting thrombosis risk due to additive atherosclerosis and atherothrombosis promoting mutations (DNMT3A/TET2/ASXL1)11,12 which together with the JAK2V617F mutation are prevalent in the aging population as CHIP ( Clonal Hematopoiesis of Indeterminate Potential ) 13 and at this precursor-stage of MPN development associates significantly with cardiovascular diseases and thrombosis.13-19 In both CHIP and MPNs biomarkers of inflammation ( C-reactive protein (CRP) and Neutrophil-Lymphocyte Ratio (NLR) associate with thrombosis.20-22 The role of interferon-alfa2 (IFN) in the initial treatment of MPNs has been increasingly recognized.7 Thus, the “wait and watch strategy” in low-risk patients is currently being challenged, since early treatment with IFN may induce minimal residual disease (MRD) with low-burden JAK2V617F and normal bone marrow after about five years of IFN-treatment.23-27 Most recent studies have unraveled MPNs to be far more prevalent than previously recognized, underscoring the unmet need of much earlier diagnosis of MPNs by molecular screening of patients at risk of having undiagnosed MPNs, thereby hopefully prohibiting life-invalidating and life-threatening thrombosis due to delayed MPN-diagnosis and treatment.23-27 This might also imply an earlier diagnosis of comorbidities , such as cardiovascular diseases and second cancers which MPN-patients are prone to develop, likely as a consequence of chronic inflammation, immunoderegulation and associated defective tumor immune surveillance.28-32 Second cancers also add to the thrombosis risk in MPNs and not only venous but also arterial thrombosis may be a warning of second cancer.33 In addition to lowering of cholesterol levels statins have several other beneficial effects , including being potently anti-inflammatory agents. Highly intriguing, use of statins protects against development of MPNs 34 and enhance the efficacy of pegylated interferon-alpha2 with a much faster decline in the JAK2V617F allele burden.35 Several of the above issues will be highlighted , including mathematical modelling studies, substantiating the proof of concept for chronic inflammation as a trigger and driver of MPN development, and underscoring the rationales and importance of initiating IFN-treatment as early as possible.26,36 A new bright future for patients with MPNs is foreseen, in whom early intervention with stem cell targeted therapy (IFN) or IFN in combination with agents targeting the chronic inflammatory state (e.g., ruxolitinib and statins)37-39 may open the avenue for many more patients to follow the path towards MRD23,24,40 , and even cure being obtained by vaccination strategies.30 In this paradigm shift with much earlier diagnosis and treatment of MPNs with pegylated interferon-alpha2 the CHIP-clinic, being driven by an interdisciplinary collaboration between among others hematologists, oncologists, cardiologists, neurologists and molecular biologists, is envisaged to be the catalyst of preventive medicine by early interruption of the vicious cycle of chronic inflammation, vascular diseases and cancer development , herein MPNs.41