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Mutations and long-term outcome of 217 young patients with essential thrombocythemia or early primary myelofibrosis
F Palandri1, R Latagliata2, N Polverelli1
1Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology 'L. and A. Seràgnoli', University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy.
Insights
Molecular status impacts outcomes in young patients with essential thrombocythemia (ET) and early primary myelofibrosis (early-PMF). CALR mutations are linked to better survival and lower thrombosis risk, while minor CALR mutations and abnormal karyotypes increase disease evolution risk.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Essential thrombocythemia (ET) and early primary myelofibrosis (early-PMF) are myeloproliferative neoplasms affecting younger individuals.
- Understanding the molecular drivers of disease characteristics and clinical outcomes in this demographic is crucial for personalized treatment strategies.
Purpose of the Study:
- To investigate the influence of molecular mutations (JAK2, CALR, MPL) on disease phenotype and clinical outcomes in young patients (≤40 years) with ET or early-PMF.
- To compare outcomes between ET and early-PMF cohorts and identify specific molecular markers associated with thrombosis, hemorrhage, and disease progression.
Main Methods:
- Analysis of 217 patients (197 ET, 20 early-PMF) with comprehensive molecular profiling (JAK2V617F, CALR, MPLW515K).
- Median follow-up of 10.2 years to assess cumulative incidence of thrombosis, hemorrhage, and disease evolution.
- Comparison of clinical outcomes based on mutation status, including JAK2V617F allele burden and CALR mutation types.
Main Results:
- No significant differences in overall events between ET and early-PMF, though early-PMF showed a trend for worse event-free survival.
- CALR-mutated patients exhibited lower thrombotic risk, longer survival, and better event-free survival compared to JAK2V617F-positive patients.
- Minor CALR mutations and abnormal karyotypes were associated with an increased risk of disease evolution; 'triple-negative' patients showed no registered events.
Conclusions:
- Molecular status significantly influences clinical outcomes in young ET and early-PMF patients.
- CALR mutations represent a favorable prognostic marker, while specific CALR subtypes and karyotype abnormalities warrant closer monitoring for disease progression.
- Further research into 'triple-negative' myeloproliferative neoplasms is warranted to elucidate underlying mechanisms and guide management.
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.
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