Hematology.dk



SummaryThe chronic philadelphia-negative myeloproliferative neoplasms (MPN) are a group of chronic blood cancers arising from clonal expansion of stem cells in the bone marrow, and the diseases are characterized by elevated blood cell counts. MPN can be subdivided into essential thrombocythemia, polycythemia vera, and primary myelofibrosis. Over time, the diseases can develop into the fibrotic end stage with blood cell deficiency causing severe symptoms such as fatigue, infections, and bleeding; or the diseases can transform into uncontrolled cell proliferation causing acute leukemia. The life expectancy for patients with MPN ranges from a few years until near-to-normal depending on subtypes and risk profile. The primary complications are thrombotic/bleeding events, and MPN patients do also suffer from a higher comorbidity burden than the background population. MPN pathogenesis, progression, complications, and comorbidities may all be linked to a state of chronic inflammation. Accordingly, a new treatment strategy with immunomodulating drugs, such as interferon, has evolved as an alternative to the classical chemotherapeutics. Within the past 15 years, a handful of somatic so-called MPN driver mutations have been detected of which the JAK2 V617F and the calreticulin mutations (CALR) are the most frequent. JAK2 V617F was described in 2005 confirming MPN diagnosis; however, the mutation has also been detected within other disease entities and in healthy individuals in low frequencies. The quantity of mutation (allele burden) has been found to be associated to several MPN variables such as blood cell counts and treatment response. CALR was not described until 2013; consequently, current knowledge of the implications of this mutation was very limited when this PhD project was launched. Based on this, three studies within the PhD were performed:We assessed whether the CALR allele burden is associated to MPN variables as is the case for JAK2 V617F. By retrospective review of medical records for 21 interferon-treated MPN patients from the Department of Hematology, Roskilde, we confirmed a significant association between allele burden and blood cell count dynamics. In 19% of the patients, a treatment response with reduction of the allele burden was detected with a potentially long-lasting effect also after treatment discontinuation.We assessed whether CALR is present in the general population, also relative to the JAK2 V617F prevalence, via the General Suburban Population Study in Region Zealand with 20,000 citizens included. If present, we aimed to characterize mutation-positive individuals compared to the non-mutated. By use of a highly sensitive method (digital droplet PCR), we were the first to report a CALR population prevalence of 0.16%. Unexpectedly, we found a JAK2 V617F prevalence of 3.1% which was 3-30 times higher than previous reports. Only 2.5% of the mutation-positive individuals carried a MPN diagnosis according to their medical records. Even so, also the “healthy” mutation positives presented a blood cell profile that differed significantly from the non-mutated background population. We found this indicative of presence of chronic inflammation among mutation positives as well as indicative of a considerable underdiagnosis of MPN in the Danish population.We assessed whether follow-up investigation, including bone marrow examination, of “healthy” mutation-positive individuals from the population study would indeed reveal undiagnosed MPN and whether we were able to detect MPN in early disease stages – the rationale being that early upfront immunomodulating treatment might diminish disease progression and reduce the risk of complications. Among 41 mutation-positive individuals undergoing bone marrow examination, 17% fulfilled the diagnostic criteria for MPN, whereas 29% presented early/possible MPN changes in their bone marrow, and 46% had no MPN bone marrow changes. Mean allele burden was significantly highest among those with overt MPN changes in their bone marrow followed by those with early/possible MPN bone marrow changes and lowest among those with no MPN bone marrow changes. These findings confirm a MPN underdiagnosis in the general population and support our ambition of detecting early MPN. Also in this study, we found the blood test profile indicative of presence of chronic inflammation. ................
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