Mutations and long-term outcome of 217 young patients with essential thrombocythemia or early primary myelofibrosis

Abstract

We investigated the influence of molecular status on disease characteristics and clinical outcome in young patients (⩽ 40 years) with World Health Organization (WHO)-defined essential thrombocythemia (ET) or early/prefibrotic primary myelofibrosis (early-PMF). Overall, 217 patients with ET (number 197) and early-PMF (number 20) were included in the analysis. Median follow-up time was 10.2 years. The cumulative incidence of thrombosis, hemorrhages and disease evolution into myelofibrosis/acute leukemia were 16.6%, 8.6% and 3% at 15 years, respectively. No differences were detectable between ET and early-PMF patients, although the latter cohort showed a trend for worse combined-event free survival (EFS). Mutation frequency were 61% for JAK2V617F, 25% for CALR and 1% for MPLW515K, and were comparable across WHO diagnosis; however, JAK2V617F allele burden was higher in the early-PMF group. Compared with JAK2V617F-positive patients, CALR-mutated patients displayed higher platelet count and lower hemoglobin level. CALR mutations significantly correlated with lower thrombotic risk (9.1% versus 21.7%, P = 0.04), longer survival (100% versus 96%, P = 0.05) and better combined-EFS (86% versus 71%, P = 0.02). However, non-type 1/type 2 CALR mutations ('minor' mutations) and abnormal karyotype were found to correlate with increased risk of disease evolution. At last contact, six patients had died; in five cases, the causes of death were related to the hematological disease and occurred at a median age of 64 years (range: 53-68 years). Twenty-eight patients (13%) were unmutated for JAK2, CALR and MPL: no event was registered in these 'triple-negative' patients.

Antiplatelet therapy versus observation in low-risk essential thrombocythemia with a CALR mutation

“…6,7 Recent studies have suggested that CALR-positive ET can be considered a distinct clinical entity from JAK2 V617F -positive ET because of higher platelet counts and a lower incidence of thrombosis in the former. [8][9][10][11][12] This observation is especially relevant with regard to the use of antiplatelet therapy in CALR-mutated low-risk ET patients, in whom the increased risk of bleeding associated with higher platelet counts might offset the benefits of reducing the relatively low risk of thrombosis.…”

Spleen enlargement is a risk factor for thrombosis in essential thrombocythemia: Evaluation on 1,297 patients

“…Qualitative assessment of JAK2V617F mutation was performed as described elsewhere [19]; JAK2V617F allele burden was assessed in granulocyte DNA by quantitative polymerase chain reaction-based allelic discrimination assay (Ipsogen JAK2 MutaQuant Kit) on 7900 HT Fast Real Time PCR System (Applied Biosystem).…”

The relevance of a low JAK2V617F allele burden in clinical practice: a monocentric study

“…CALR mutations identified by NGS were confirmed by Sanger sequencing. MPL mutations were investigated by ipsogen MPLW515K/L MutaScreen Kit and by Sanger sequencing (for MPLS505N and other secondary exon 10 mutations), as previously described [55]. Additional masking mutations in JAK2 exon 14 were investigated by Sanger sequencing [39].…”

“…Additional masking mutations in JAK2 exon 14 were investigated by Sanger sequencing [39]. In case of clinical suspicion of PV, JAK2 exon 12 mutations were also tested by Denaturing High Pressure Liquid Chromatography (DHPLC) and confirmed by Sanger sequencing [55–58]. Diagnoses of all hematological diseases were made according to the WHO2008 criteria [1].…”