Molecular profiling and risk classification of patients with myeloproliferative neoplasms and splanchnic vein thromboses

Abstract

Myeloproliferative neoplasms (MPNs) are the most frequent underlying causes of splanchnic vein thromboses (SVTs). MPN patients with SVTs (MPN-SVT) often have a unique presentation including younger age, female predominance, and low Janus kinase 2 (JAK2) mutation allele burden. This study aimed at identifying risk factors for adverse hematologic outcomes in MPN-SVT patients. We performed a retrospective study of a fully characterized cohort of MPN-SVT patients. The primary outcome was the incidence of evolution to myelofibrosis, acute leukemia, or death. Eighty patients were included in the testing cohort. Median follow-up was 11 years. Most of the patients were women with a mean age of 42 years and a diagnosis of polycythemia vera. The primary outcome was met in 13% of the patients and was associated with a JAK2V617F allele burden ≥50% (odds ratio [OR], 14.7) and presence of additional mutations in genes affecting chromatin/spliceosome (OR, 9). We identified high-risk patients (29% of the cohort) as those harboring at least 1 molecular risk factor: JAK2-mutant allele burden ≥50%, presence of chromatin/spliceosome/TP53 mutation. High-risk patients had worse event-free survival (81% vs 100%; P = .001) and overall survival at 10 years (89% vs 100%; P = .01) than low-risk patients. These results were confirmed in an independent validation cohort of 30 MPN-SVT patients. In conclusion, molecular profiling identified MPN-SVT patients with dismal outcome. In this high-risk population, a disease-modifying therapy should be taken into consideration to minimize the probability of transformation.

Clonal Megakaryocyte Dysplasia with Normal Blood Values Is a Distinct Myeloproliferative Neoplasm

“…This feature distinguishes them from prefibrotic myelofibrosis cases where disease progression and blast transformation are common. We hypothesize the low JAK2V617F allele frequency of persons with atypical myeloproliferative disorder might be responsible for the lack of clonal evolution during our prolonged observation interval [23].…”

JAK2V617F variant allele frequency >50% identifies patients with polycythemia vera at high risk for venous thrombosis

“…Moreover, it is still unclear why splanchnic vein thrombosis (SVT), including hepatic veins, portal veins, splenic veins, or mesenteric veins are a privileged site of thrombosis during MPN, particularly in PV patients, and it raises the hypothesis of a specific physiopathology. SVT are more common in young female patients and in those with a low JAK2 V617F allele burden [ 15 – 17 ], whereas in a recent paper a JAK2 -mutant allele burden ≥50% and the presence of chromatin/spliceosome/ TP53 mutations identified high-risk SVT-MPN patients with a worse event-free (including both AML and MF progression) and overall survival at 10 years [ 18 ].…”

The Classification of Myeloproliferative Neoplasms: Rationale, Historical Background and Future Perspectives with Focus on Unclassifiable Cases

“…Besides the diagnostic issues, it should be stressed that thrombotic events pose the highest threat for patients with early phase MPN. Despite the risk factors for vascular events are only partially defined, major determinants include JAK2 status, age, neutrophil count, and a positive history of thrombosis [43][44][45].…”

“…The quantitative assessment of VAF can also provide clinically relevant information on the disease burden and on the risk of adverse events. Indeed, the VAF of driver genes increases alongside myelofibrotic evolution, and high JAK2 V617F burdens correlate with the risk of thrombosis [45,48,59,60]. Together with mutational analyses, karyotyping proves informative to assess the risk of progression, particularly in the myelofibrotic setting [61].…”