Decreased serum total cholesterol is associated with worse outcomes among patients with myeloproliferative neoplasms

Abstract

Abstract Introduction: Myeloproliferative neoplasms (MPNs), which include essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), are a diverse group of hematopoietic stem cell disorders associated with an increased risk of cardiovascular disease (CVD), including arterial thrombosis and heart failure (HF). Elevated total cholesterol and low-density lipoprotein (LDL) levels are traditional CVD risk factors. However, evidence suggests that cholesterol levels are reduced in patients with certain malignancies, including MPNs, potentially reflecting an underlying hypermetabolic state. The impact of serum total cholesterol on clinical outcomes in patients with MPNs has not yet been evaluated. Methods: Analysis of a multicenter retrospective registry of MPN patients with ≥ 1 transthoracic echocardiogram (TTE) after diagnosis of MPN at Massachusetts General Hospital, New York University Langone Health, and University of Chicago from 2010 to 2024 was performed. Patients who were not on statin therapy and had lipid panel at the time of the first TTE were included. Patients with total cholesterol levels below the median were compared to those with levels above the median. Hematologic and CV outcomes were assessed. Hematologic progression was defined as disease progression to secondary MF or leukemia. CV outcomes were arterial thrombosis, HF hospitalization, and all-cause death. Multivariable competing-risk regression and Cox proportional hazards modeling was performed to estimate subhazard ratio (SHR) and hazard ratio (HR). Hematologic outcome models were adjusted for age, sex, race, MPN type, canonical driver mutation (JAK2, MPL, CALR), non-phenotypic driver mutation and white blood count (WBC). CV outcomes were adjusted for the same variables in addition to prior atherosclerotic CVD (ASCVD), prior HF, atrial fibrillation, aspirin use, anticoagulation use, MPN treatment and chronic kidney disease. Results: A total of 305 patients (118 PV, 100 ET, 87 MF) were included in the study of whom 131 (43.0%) had total cholesterol below median (147 mg/dL), 163 (53.4%) were female, 252 (82.6%) were White race. The median time of follow-up was 50.8 months (IQR 28.0, 81.4). Patients with total cholesterol levels below median were on average older (71 bs 68 years, p = 0.007), less likely to be female (38.2% vs. 64.9%, p < 0.001), and more likely to have MF (43.5% vs. 17.2%, p < 0.001) and non-phenotypic driver mutations (43.5% vs. 28.7%, p = 0.008) compared to those with levels at or above median. There was no difference in prior ASCVD and HF between groups. Patients with total cholesterol levels below median were less likely to be on aspirin (51.1% vs. 70.1%, p < 0.001) but more likely to be on anticoagulation (29.0% vs. 16.1%, p = 0.007). After multivariable competing-risk regression, lower than median total cholesterol was associated with higher risk of hematologic progression (19.8% vs. 9.2%; adjusted SHR 2.45, 95% CI 1.29 – 4.63), HF hospitalization (25.2% vs. 10.3%; adjusted SHR 2.81, 95% CI 1.52 – 5.18), and all-cause death (45.8% vs. 45.8%; adjusted HR 1.91, 95% CI 1.20 – 3.04) but not arterial thrombosis (19.8% vs. 15.5%; adjusted SHR 1.01, 95% CI 0.51 – 2.04). Conclusions: Among patients with MPNs who were not receiving statin therapy, a total cholesterol level below the median (147 mg/dL) was associated with a significantly increased risk of hematologic progression, heart failure hospitalization, and all-cause mortality. These findings suggest that low cholesterol levels in MPN may reflect an underlying hyperproliferative and hypermetabolic state and are linked to adverse clinical outcomes. As such, conventional cholesterol targets used for cardiovascular disease prevention may not be appropriate for this patient population. Our results underscore the need for further research to refine lipid management strategies in individuals with MPN.