Abstract
Lack of demonstrable mutations affecting JAK2, CALR, or MPL driver genes within the spectrum of BCR-ABL1-negative myeloproliferative neoplasms (MPNs) is currently referred to as a triple-negative genotype, which is found in about 10% of patients with essential thrombocythemia (ET) and 5–10% of those with primary myelofibrosis (PMF). Very few papers are presently available on triple-negative ET, which is basically described as an indolent disease, differently from triple-negative PMF, which is an aggressive myeloid neoplasm, with a significantly higher risk of leukemic evolution. The aim of the present study was to evaluate the bone marrow morphology and the clinical-laboratory parameters of triple-negative ET patients, as well as to determine their molecular profile using next-generation sequencing (NGS) to identify any potential clonal biomarkers. We evaluated a single-center series of 40 triple-negative ET patients, diagnosed according to the 2017 WHO classification criteria and regularly followed up at the Hematology Unit of our Institution, between January 1983 and January 2019. In all patients, NGS was performed using the Illumina Ampliseq Myeloid Panel; morphological and immunohistochemical features of the bone marrow trephine biopsies were also thoroughly reviewed. Nucleotide variants were detected in 35 out of 40 patients. In detail, 29 subjects harbored one or two variants and six cases showed three or more concomitant nucleotide changes. The most frequent sequence variants involved the TET2 gene (55.0%), followed by KIT (27.5%). Histologically, most of the cases displayed a classical ET morphology. Interestingly, prevalent megakaryocytes morphology was more frequently polymorphic with a mixture of giant megakaryocytes with hyperlobulated nuclei, normal and small sized maturing elements, and naked nuclei. Finally, in five cases a mild degree of reticulin fibrosis (MF-1) was evident together with an increase in the micro-vessel density. By means of NGS we were able to identify nucleotide variants in most cases, thus we suggest that a sizeable proportion of triple-negative ET patients do have a clonal disease. In analogy with driver genes-mutated MPNs, these observations may prevent issues arising concerning triple-negative ET treatment, especially when a cytoreductive therapy may be warranted.
Highlights
Essential thrombocythemia (ET), together with polycythemia vera (PV) and primary myelofibrosis (PMF), belongs to the so-called “classic” BCR-ABL1-negative myeloproliferative neoplasms (MPN) category
This mutation seems to be associated with peculiar phenotypes in the different BCR-ABL1negative MPNs: in ET its presence is consistently associated with older age at diagnosis, higher hemoglobin levels, higher white blood cells counts, and lower platelet counts; it clusters with a lower risk of fibrotic evolution and a higher risk of thrombosis [10,11,12,13,14]
In five cases (5/40, 12.5%) a mild degree of reticulin fibrosis (MF-1) was evident together with an increase of the micro-vessel density (6/40, 16%). In this real-life, single-center cohort study, we investigated the mutational profiles and reviewed the clinical data and bone marrow (BM) biopsies of 40 consecutive triple-negative ET patients with a median follow-up of 7 years
Summary
Essential thrombocythemia (ET), together with polycythemia vera (PV) and primary myelofibrosis (PMF), belongs to the so-called “classic” BCR-ABL1-negative myeloproliferative neoplasms (MPN) category It is mainly characterized by an increased platelet production and sustained thrombocytosis which leads to an increased risk of thrombo-hemorrhagic complications [1, 2]. In 2005 the JAK2V617F mutation has been reported to play a crucial role in the pathogenesis of these disorders, being identifiable in about 50– 60% of ET patients [6,7,8,9] This mutation seems to be associated with peculiar phenotypes in the different BCR-ABL1negative MPNs: in ET its presence is consistently associated with older age at diagnosis, higher hemoglobin levels, higher white blood cells counts, and lower platelet counts; it clusters with a lower risk of fibrotic evolution and a higher risk of thrombosis [10,11,12,13,14]
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