Difficulty distinguishing essential thrombocythaemia from polycythaemia vera in children with JAK 2 V617F‐positive myeloproliferative neoplasms
Year: 2018
Type: article
Abstract: Classical Myeloproliferative Neoplasms (MPNs) include Essential Thrombocythaemia (ET) and Polycythaemia Vera (PV) (Arber et al, 2016). These diseases are frequently due to a mutation in the pseudokinase domain of the Janus Kinase 2 (JAK2) gene, JAK2 V617F (Baxter et al, 2005; Levine et al, 2005). The World Health Organization (WHO) recently revised its diagnostic criteria for MPNs (Arber et al, 2016; Swerdlow et al, 2017), including laboratory values, clonal driver mutations and bone marrow morphology to define specific MPN types (Table 1). The WHO criteria utilized adult reference ranges and experience with adult disease, therefore a number of these criteria are not generally applicable to children. The normal ranges of haemoglobin for children vary by age and are generally lower than adult values (Cembrowski et al, 2005). Applying the WHO haemoglobin cut-offs for PV would miss identifying children with haemoglobin levels clearly above their age-specific range. Increased red cell mass is included in the criteria but is virtually never tested in paediatrics. Normal bone marrow cellularity is higher in children (Hartsock et al,1965), making determination of “hypercellularity” difficult. Erythropoietin levels are infrequently performed in children with thrombocytosis. Given these issues, we reviewed a cohort of eight children diagnosed with JAK2 V617F-postive MPN to explore diagnostic considerations to help differentiate between ET and PV. The eight children in this cohort had white blood cell (WBC) counts, red blood cell (RBC) counts, haemoglobin level and platelet counts assessed. Bone marrows were re-evaluated for cellularity, fibrosis and megakaryocyte morphology. Pre-treatment erythropoietin and von Willebrand levels, and peak JAK2 allele burden were reviewed. The Weill Cornell Medical College Institutional Review Board (IRB) approved this study. Consents and assents were obtained from 7 of 8 families; consent could not be obtained from one family. Since the data was pooled and fully de-identified, approval to include this 8th subject was given by the IRB. Ages ranged from 3 to 17 years old, with a median age of 10 years; five out of eight were female. Five experienced extreme thrombocytosis; three had peak counts over 2000 × 109/l. Seven had peak WBC counts over 11 × 109/l and RBC counts above the 97·5th percentile for age; none had thalassemia trait. Three had peak haemoglobin levels above the 97·5th percentile for age. Serum erythropoietin levels were subnormal in five of six children (median 3 iu/l). Peak JAK2 V617F allele burden ranged from 19% to 54%, with a median of 39%. Three of four children had acquired von Willebrand disease, of which two had extreme thrombocytosis. No severe bleeding was reported. Headache was observed in all subjects. Six children presented with splenomegaly, three children of whom had Budd-Chiari syndrome. Bone marrow cellularity pre-treatment was normal in two children; six had hypercellular marrows. Megakaryocyte morphology revealed more pleiomorphism than typically reported with ET (Fig 1). Reticulin fibrosis, MF-1, was noted in three children. The presence of a JAK2 V617F mutation in the setting of thrombocytosis may imply ET, but PV cannot be excluded. The WHO criteria for ET (Table 1) requires that the subject not meet other MPN criteria, which can be complicated. Low serum erythropoietin and pleiomorphic megakaryocytes in some children favour PV. Using age-specific normal levels, five children had polycythaemia, defined by elevated haemoglobin level or RBC count. However, these children did not meet WHO PV criteria, creating uncertainty between two diagnoses. Proposed modifications of paediatric MPN diagnostic criteria are shown in Table 1. Given different normal ranges, children may not demonstrate polycythaemia according to the WHO PV criteria, but may still have PV; comparison of haemoglobin and/or RBC counts to age-specific norms is more appropriate (in the absence of thalassemia trait). Given how common reactive thrombocytosis is in children, our proposed criteria suggest a minimum duration of thrombocytosis. As many children with MPN are negative for known mutations, we gave absence of a reactive cause equal weight to mutation status. Erythropoietin is often not tested in children with thrombocytosis and should be part of their work-up. Furthermore, marrow pathology should be carefully assessed by haematopathologists experienced in reviewing paediatric specimens to optimally distinguish among MPNs. A recent study compared adults with JAK2 V617F-mutant ET and PV (Rumi et al, 2014). Patients with PV had higher WBC counts than those with ET. While some ET patients showed subnormal erythropoietin levels, the median erythropoietin level was significantly lower in PV (2·7 iu/l), close to that found in our group (3 iu/l). Similarly, some PV patients exhibited thrombocytosis with counts over 1000 × 109/l. The median JAK2 mutant allele burden was 18% in ET compared to 42% in PV, in line with the 39% seen in our cohort. JAK2-mutated MPNs exist on a continuum and can progress from ET to PV (Campbell et al, 2005; Rumi et al, 2014). Given the spectrum of JAK2-mutated MPN described in adults and varying laboratory findings in our cohort, it seems likely that some children may actually have PV. When diagnosing an MPN in a paediatric patient, assigning the diagnosis of MPN unclassified may currently be best. It is likely that knowing the MPN type will affect management and prognosis in children, as in adults. The development of paediatric-specific diagnostic criteria should allow more accurate identification of specific MPN type; our proposed alternative criteria for children take into account key differences between children and adults. Long-term follow-up and large patient numbers are required to validate these proposed criteria. Given the rarity of these diseases, this would require international, multi-centre, collaborative discussion and study. This work was supported by a grant from the NIH/NCATS (USA), Grant # KL2TR000458 (to NK) and from the National Heart, Lung, And Blood Institute of the National Institutes of Health (USA), under award #K23HL127223 (to NK). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank the families and colleagues who made this study possible. Study designed by NK, JB, AO. Research performed by NK, MA, DH, AO. Data analysed by NK, MA, DH, AO. Paper written by NK, MA, DH, JB, AO. Paper edited by NK, JB, AO. All authors reviewed the manuscript and agreed with its submission. The authors declare no conflicts of interest.
Source: British Journal of Haematology
DOI: 10.1111/bjh.15386
Institution: Weill Cornell Medicine
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2803186409