Distinct Clinico-Molecular Arterial and Venous Thrombotic Scoring Systems for MPN Patients Risk Stratification

Arterial and venous thrombotic events are the major complications of myeloproliferative neoplasms (MPN), responsible for a high rate of morbidity and mortality. Risk stratification and prediction of these events remain challenging clinical questions in MPN.

We investigated clinical and molecular risk factors of arterial or venous thrombotic events within a cohort of 1055 patients with MPN followed in our MPN reference center from 2011 to 2021. Using a univariate and multivariate Cox regression model, we first defined independent factors associated to arterial or venous thrombotic events, and then developed predictive risk scores for arterial thrombosis on one hand and venous thrombosis on the other hand. The discrimination power of each score was compared to the currently recommended European Leukemia Net (ELN) and IPSET scores.

Our cohort included 494 (46.82%) patients with essential thrombocythemia (ET), 362 (34.31%) with polycythemia vera (PV), 161 (15.26%) with myelofibrosis (MF), 9 (0.85%) with MDS/MPN and 29 (2.75%) with unclassified MPN. 115 patients (10.90%) and 146 patients (13.84%) presented arterial or venous thrombotic events respectively, prior to and/or at the time of MPN diagnosis. After a median follow-up of 9.45 years, 72 patients and 79 patients developed 75 arterial thrombotic events (0.75% patients-year) and 97 venous thrombotic events (0.97 % patients-year), respectively. The incidence rate for arterial and venous thrombotic events during follow up were 0.69% and 0.95% patients-year respectively in patients with PV, 0.75% and 0.78% for ET patients and 0.43% and 1.59% for MF patient. Acute myocardial infarction (32%), stroke (26.67%) and transient ischemic attack (24%), splanchnic thrombosis (37.11%) and deep vein thrombosis (27.83%) were the main arterial and venous thrombotic events during follow-up, respectively.

Prior arterial thrombotic events (HR 2.03, _95%CI[1.09;3.58], p=0.024), age >60 years at diagnosis (HR 2.29, _95%CI[1.34;3.91], p =0.002), cardiovascular risk factors (HR 1.86, _95%CI[1.09;3.46], p=0.023) and presence of TET2 or DNMT3A additional mutations (HR 1.74, _95%CI[1.08;2.80], p=0.022) were independently associated with arterial thrombotic events in multivariate analysis. An arterial thrombosis risk score, based on these four factors, defined low and high-risk patients (p=0.0001) (Figure 1). The performance of our arterial risk score was superior to ELN-risk score (ROC curves AUC: 0.68 versus 0.58; p=0.0008), across all MPN subtypes. Interestingly, cytoreductive treatment with interferon alpha (HR 0.45, _95%CI[0.24;0.83], p=0.011) or ruxolitinib (HR 0.049, _95%CI[0.006;0.35], p=0.003) was associated with decreased arterial thrombotic events, while hydroxyurea treatment was not (HR 1.27, _95%CI[0.73;2.20], p=0.381).

Prior venous thrombotic events (HR 2.48, _95%CI[1.42;4.34], p=0.001) and presence of a JAK2^V617Fdriver mutation (HR 2.66, _95%CI[1.47;4.86], p=0.001) were independently associated with venous thrombotic events in multivariate analysis. A venous thrombosis risk score, based on these two factors, defined low and high risk patients (p=0.035) (Figure 2). The discrimination potential of our venous risk score was similar to ELN-risk score (ROC curves AUC: 0.52 versus 0.50, p=0.67). As opposed to arterial events, all cytoreductive treatments; hydroxyurea (HR 0.43, _{95% CI}[0.28;0.68], p=0.001), interferon alpha (HR 0.15, _{95% IC} [0.07;0.31], p=0.0001) or ruxolitinib (HR 0.48, _{95% CI}[0.23;0.99], p=0.049) were associated with decreased venous thrombotic events.

Acute myeloid leukemia/myelodysplastic syndrome transformation free survival was shorter in patients who developed arterial thrombotic events than in those who harbored venous thrombosis (p=0.034). No difference was observed for secondary myelofibrosis transformation free survival or overall survival.

Our study offers a comprehensive landscape of MPN associated thrombosis across a large clinically and molecularly annotated long-term follow-up MPN patients' cohort. Our results pinpoint arterial and venous thrombosis clinico-molecular differences and define specific risk scores for each unique entity, hence improving patients' stratification. If further validated on external cohorts, our findings warrant consideration of arterial and venous thrombosis separately for future scoring systems and preventive treatment recommendations.

Soret:Novartis: Consultancy. Vainchenker:Incyte: Research Funding. Kiladjian:BMS: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees. Benajiba:Gilead: Research Funding; Pfizer: Research Funding.