Non-Driver Genomic Alterations and Venous Thromboembolism in Myeloproliferative Neoplasms

Introduction: The most common cause of morbidity and mortality in the myeloproliferative neoplasms (MPNs) is thrombosis. Current risk scoring systems for essential thrombocythemia (ET) and polycythemia vera (PV) predict the risk of thrombosis. The influence of non-driver co-mutations such as those affecting epigenetic regulation in thrombosis is not established. This study seeks to further characterize the genomic landscape and genomic predictors of venous thromboembolism (VTE) in a comprehensive cohort of MPNs that may have implications for the use of cytoreductive therapy and antithrombotic therapy.

Methods: We assessed clinical and molecular risk factors of VTE in a cohort of patients from Memorial Sloan Kettering Cancer Center from 2017 to 2023 with annotated myeloid molecular data. VTE were identified through the use of the CEDARS+PINES natural language processing platform (Mantha et al, 2024) and instances were manually reviewed. Univariate and multivariate (stratified by MPN subtype) was conducted using cause specific Cox regression analysis to identify factors associated with VTE while adjusting for competing event of death. Cumulative incidences of thrombosis were estimated from date of genomic testing with death considered as a competing risk as well.

Results: The cohort included 656 patients with MPNs: 103 (16%) with essential thrombocythemia (ET), 117 (18%) with myelofibrosis (MF), 100 (15%) with polycythemia vera (PV), and 336 (51%) with an unclassified MPN. JAK2, CALR, and MPL mutations were present in 68%, 18% and 6% of patients, respectively. The most common non-driver somatic mutations identified were ASXL1 (14%), DNMT3A (11%), and TET2 (18%). The overall cumulative incidence of VTE at 3 years was 5.7% (95% confidence interval [CI] 3.7-8.4%). In a univariate analysis the factors associated with increased risk of VTE were older age (>72 vs <55 years; hazard ratio [HR] 6.12, 95% CI 1.38-27.13), MF (HR 3.84, 95% CI 1.02-14.37), prior history of VTE (HR 7.12, 95% CI 2.47-20.54), and presence of mutations in ASXL1 (HR 3.2, 95% CI 1.44-7.08), NRAS (HR 4.15, 95% CI 1.25-13.78), and TP53 (HR 5.43, 95% CI 1.27-23.22). In a multivariable model stratified by type of MPN, the HR for VTE associated with non-driver mutations was 5.39 for TP53 (p=0.029), 3.51 for NRAS (p=0.056), and 1.98 for ASXL1 (p=0.13). The risk was not further influenced by the presence of JAK2 mutations. Associations were similar when excluding patients with a history of VTE prior to genomic assessment.

Conclusions: Non-driver mutations appear to influence the risk of VTE in patients with MPN. Future studies are needed to evaluate how inclusion of non-driver mutations can improve the accuracy of thrombosis risk prediction models in MPNs and identification of patients most likely to benefit from antithrombotic prophylaxis.