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.

Graphical abstract

Figure 1.

Study profile. Of 284 patients with SVT and suspicion of MPNs, 195 patients had a confirmed MPN diagnosis. We excluded 8 patients without driver mutation and 107 patients without available NGS data. Eighty patients had an NGS analysis and were included in the testing cohort. Among them, 43 patients exhibited at least 1 additional mutation.

Figure 2.

Molecular profiling. Mutations found using a 36-gene NGS panel in the testing cohort, represented according to the presence or absence of clinical events of the primary outcome. Each column represents 1 sequenced patient. Eighty percent of patients with events had additional mutations vs 41% of patients without events. MF, myelofibrosis; ND, not determined.

Figure 3.

Survival of patients. Survival curves are represented in yellow for high-risk patients and in blue for patients with low-risk score. (A) EFS in the testing cohort. (B) OS in the testing cohort. (C) EFS in the validation cohort. (D) OS in the validation cohort.