Clonal megakaryocyte dysplasia with normal blood values (CMD-NBV): an unique form of early myeloproliferative neoplasm

We report an in-depth retrospective analysis of an updated series of 30 subjects with clonal megakaryocyte dysplasia with normal blood values (CMD-NBV). Sixteen were men, median age was 47.5 years (IQR, 39–53 years). A thrombosis-driven situational diagnosis (69% of subjects), high incidence of thrombotic events (6.5 events x 100 subject-years), and indolent disease progression (one case only progressed towards an active disease) were the hallmarks of CMD-NBV. Nineteen subjects (63%) had a high body mass index (BMI) at diagnosis (median value, 26.2 m ² /kg) and 14 (48%) had ≥ 1 Charlson co-morbidities. In 21 individuals (70%) the driver variant was JAK2 ^V617F with a median variant allele frequency ( VAF) at diagnosis of 8.9% (IQR, 5.4–18.4%). Twenty-four subjects had undergone next generation sequencing (NGS) for myeloid neoplasm-related genes. Six (25%) had ≥ 1 pathogenic somatic variant in ASXL1 , TET2, DNMT3A , and SRSF2 . Twelve putative germline, non-pathogenic, missense variants in ASXL1 , TET2 , DNMT3A, RUNX1 , CUX1 , ABL1 , NF1 , KIT and CSFR or 5’ UTR in NF1 and 3’ UTR in ASXL1 were detected in 10 subjects (42%). Based on these data we hypothesize rare, low penetrance germline variants underly a predisposition to the early CMD-NBV myeloproliferative neoplasm.