LAUSR

The chronic Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) are characterized by elevated blood cell counts and distinct histological bone marrow changes. We [1] and others [2] have raised concerns about a considerable underdiagnosis of MPN in the general population. As the risk of thrombohemorrhagic complications [3, 4] and associated morbidities [4–7] are present years before time of MPN diagnosis, we find a rationale for diagnosing MPN in earlier disease stages to prevent development of these complications and disorders. Another perspective is the possibility of diminishing MPN disease progression by early upfront treatment with immune modulating treatments such as interferon [8, 9]. From the Danish General Suburban Population Study in Region Zealand (GESUS) from 2010 to 2013 [10], we established two screening strategies: (1) a baseline mutation screening strategy only based on presence of either JAK2V617F or calreticulin type 1/2 mutations (CALR) and (2) an elevated blood count screening strategy with detection of JAK2V617F or CALR in citizens with long-term elevation of blood cell counts. Study protocols were approved by the Regional Committee on Health Research Ethics (SJ-452, SJ-114) and the Danish Data Protection Agency (REG-50-2015) and complied with the Declaration of Helsinki and General Data Protection Rules. Written consent from all participants was obtained. Digital droplet PCR was used to detect and quantify the JAK2V617F and CALR mutant allele burden. Long-term elevation of blood cell counts was defined as hemoglobin >15.3 g/dL (female)/ >16.9 g/dL (male); hematocrit >0.46 (female)/>0.50 (male); leukocytes >8.8 × 10/L; or platelets >390 × 10/L in GESUS (baseline) and in a follow-up blood test in 2016–2017 (Supplementary Fig. S1). Participants were offered medical investigation including bone marrow examination to detect possible/early or overt MPN. Of 29 invited, 25 mutation-positive citizens consented to participate from the baseline mutation screening strategy of which five declined bone marrow examination. The only measures taken into account in the selection of the 29 individuals were mutation type and allele burden to ensure that both JAK2V617F and CALR positives were represented as well as allele burdens both below and above 1%. Among 373 randomly selected citizens with long-term elevation of blood cell counts, we detected 32 to be mutation positive (Supplementary Fig. S1). Twenty-four consented to participate of which three declined bone marrow examination. Thus, in total, 41 (20 and 21 in each screening group, respectively) participants underwent bone marrow examination. Bone marrow examinations (biopsy, aspiration, and peripheral blood smear) were independently reviewed by two hematopathologists in a blinded setup where only data regarding patient age and gender were accessible. The findings were classified as either no MPN, early/possible MPN, or overt MPN based on Madelung et al. [11] and WHO classification 2016 [12]. For details, see Supplementary Information. These authors contributed equally: H.C. Hasselbalch, C. Ellervik