Myeloproliferative neoplasms (MPNs) are clonal haematopoietic stem cell diseases characterized by the abnormal proliferation of one or more myeloid lineages, including BCR-ABL-positive chronic myeloid leukaemia, BAR-ABL-negative polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF).(1) A new entity, namely, prefibrotic primary myelofibrosis (pre-PMF), was recognized in the 2016 revised classification of MPN as a subgroup of PMF, characterized by histopathologic features of bone marrow (BM) together with clinical parameters (leukocytes, anaemia, increased LDH, splenomegaly) (1, 2). Owing to the marked thrombocytosis and minimal reticulin fibrosis of pre-PMF patients, it is not easy to distinguish pre-PMF from ET in clinical practice (3). In ET, megakaryocytes are large, appear mature, and form loose clusters, whereas those in prefibrotic PMF display abnormal maturation with hyperchromatic and irregularly folded nuclei and form tight clusters (4). Overt PMF, another subtype of PMF, presents megakaryocyte proliferation and atypia in BM that is consistent with pre-PMF, but the superior fibrosis grade (grade 0–1 indicates pre-PMF and grade 2–3 overt PMF) along with peripheral blood leukoerythroblastosis is indicative of overt PMF (1). However, the usefulness and reproducibility of BM histopathologic features make it difficult to judge objectively (5). In published studies, pre-PMF patients had a significantly shorter overall survival (OS) than ET patients (6–9) but better OS than overt PMF patients (10–12); therefore, an accurate diagnosis is prognostically relevant.
Many studies have compared the clinical, haematologic, and molecular characteristics of patients with pre-MF to those with either ET or overt MF. Compared to patients with ET, those with pre-PMF had lower haemoglobin levels, higher platelet counts, higher leukocyte counts, higher LDH values, a higher number of circulating CD34-positive cells, and more frequent splenomegaly (3; 7; 8; 13; 14). Patients with pre-PMF presented with higher haemoglobin levels, higher platelet counts, higher leukocyte counts, lower LDH values, lower frequencies of splenomegaly, lower incidences of constitutional symptoms, lower circulating blast percentages, and lower IPSS risk categories than those with overt PMF (10–12). In terms of genetic mutations, several studies have implied that patients with pre-PMF have a higher incidence of driver molecular mutations (JAK2, CALR, or MPL), high-molecular-risk (HMR) mutations (ASXL1, EZH2, SRSF2, or IDH1/2), and a higher JAK2V617F allele burden than patients with ET (3, 8, 13, 14). On the other hand, compared with overt PMF, a previous study revealed that HMR mutations were less represented in pre-PMF (10); however, another study asserted that there was no significant difference in the distribution of HMR mutations (11).
Although the aforementioned studies elaborated the distinction between ET, pre-PMF, and overt PMF, in terms of clinical, haematologic, molecular profiles, and outcome, these studies only analysed a few genes, including driver and HMR mutations; therefore, a study focused on more gene mutations is needed for the distinction of the three entities. In this study, we aimed to assess the differences among ET, pre-PMF, and overt PMF patients in terms of clinical and haematologic presentation, molecular profiles, and patient outcomes.