WHO 2016 classification in 80 children and adolescents with chronic myeloproliferative neoplasms

Background The first classification of chronic myeloproliferative neoplasms (MPNs) was proposed in 1951 by Dameshek and since then it has been modified several times. The last classification of BCR-ABL1-negative MPNs, defined in 2016 by the World Health Organization (WHO), considers morphologic bone marrow (BM) features and driver mutations (JAK2V617F, JAK2 exon 12, CALR and MPL) as major criteria. Thus, the WHO 2016 criteria better define MPNs as polycythemia vera (PV), essential thrombocythemia (ET), prefibrotic/early primary myelofibrosis (PMF) (pre-PMF) and overt PMF, making the identification of masked PV (mPV) and “true” JAK2-mutated ET easier. Our experience has suggested that MPNs in children and adolescents are characterized by subtypes that differ from those found in adults and require specific diagnostic criteria. Aims The present study was carried out in order to (a) retrospectively review the diagnosis of MPNs in patients aged <20 years based on the WHO 2016 classification and adapted in accordance with our experience in this category of patients, and (b) analyze their clinical and biologic features according to both the initial diagnosis criteria and the adapted WHO 2016 criteria. Methods Out of 93 patients aged <20 years with a diagnosis of MPNs carried out from 1980 to 2015, 80 (median age: 14.6 years) with bone marrow (BM) evaluation and available molecular analysis (JAK2V617F, JAK2 exon 12, CALR, MPL, EPO-R and HIF) were considered. These patients were divided into different subgroups according to the criteria of their initial diagnosis (PVSG 1975, 1986, 1996, WHO 2001 and 2008): ET, PV, PMF. The subgroups were then retrospectively revised according to the WHO 2016 criteria into: ET, mPV, PV, pre-PMF, overt PMF. Patients with HIF mutations and/or criteria of familial erythrocytosis were defined as FE. Patients with MPLS505A mutation were diagnosed as hereditary thrombocytosis (HT). Results As shown in Fig. 1, of the 56 patients with an initial diagnosis of ET, 16 (28.5%) had HT due to a MPLS505A mutation, 3 (5.4%) were classified, according to the WHO 2016 classification, as mPV and 2 (3.6%) as PMF. Two out of 8 patients, with an initial diagnosis of PV, had FE due to a HIF2α mutation. Considering the adapted WHO 2016 classification, JAK2V617F mutation was found in 28.5% and 44% of ET and PV patients, respectively. CALR mutations and MPLW515_P518>KT were found in 26% and 2.7% of ET patients. Of 23 HT patients, 87% showed MPLS505A and 13% MPLV501A. Considering both the classification at initial diagnosis and the adapted WHO 2016 criteria, hemoglobin and hematocrit values were significantly higher in FE and slightly lower in PV patients (p<0.0001) and platelet counts were higher in ET and slightly lower in HT patients (p <0.0001) compared to other subgroups. Regarding the other features at diagnosis, leukocyte counts were significantly higher in PMF and ET patients (p= 0.0032), and the presence of medullary fibrosis (> 2 WHO grading) became significant in PMF patients (p= 0.0052), only according to the adapted WHO classification. Conclusion The WHO 2016 criteria are able to identify mPV, pre-PMF and overt PMF in children and adolescents with MPNs also. On the whole, 43%, 56% and 75% of ET, PV and PMF, respectively, did not show gene driver mutations. Hereditary forms can be observed in a significant proportion (41%) of young patients with MPNs. Taken together, our observations suggest that molecular analysis to identify inherited molecular defects must be performed in children and adolescents with MPNs.