Cardiovascular safety of bexarotene in mycosis fungoides: a propensity-matched analysis of 2,598 patients

Background Mycosis fungoides (MF) is a rare and indolent cutaneous T-cell lymphoma that requires systemic therapy in advanced stages. Bexarotene, a synthetic retinoid, is a key treatment option in such cases. While it has demonstrated significant efficacy in advanced MF, it has also been associated with notable metabolic side effects, specifically hypothyroidism and hypertriglyceridemia. Despite that, whether these translate into increased macrovascular risk remains largely unknown due to the rare nature of the disease and limited real-world cohorts. Purpose The study aimed to evaluate the real-world incidence of cardiovascular events and metabolic complications in patients with MF treated with bexarotene compared to those not receiving the drug. Methods A retrospective observational cohort study was conducted using the TriNetX global health research network. Adult patients with MF (ICD-10 C84.0) were stratified by bexarotene exposure. To minimize selection bias, 1:1 propensity score matching (PSM) was performed based on demographics, lifestyle factors, cardiovascular comorbidities, baseline medications, and key laboratory markers. The primary macrovascular outcomes included acute myocardial infarction (AMI), stroke, cardiac arrest, and heart failure (HF). Metabolic outcomes included hypertriglyceridemia, hypothyroidism, and hyperlipidemia. Results After PSM, two balanced cohorts of 2,598 patients each were analyzed (mean age ~61 years). The median follow-up was ~3.5 years. No significant differences were observed between the bexarotene and control groups for AMI (HR=1.01, 95% CI: 0.67-1.53), stroke (HR=0.84, 95% CI: 0.56-1.25), cardiac arrest (HR= 1.26, 95% CI: 0.67-2.38), or HF (HR=0.91, 95%CI: 0.72-1.15). The composite 3P-MACE (AMI, stroke, or cardiac arrest) risk was nearly identical between cohorts (3.90% vs. 3.91%; HR= 0.97, 95% CI: 0.73-1.29). Patients treated with bexarotene faced a significantly higher risk of metabolic complications. Specifically, bexarotene use was associated with an 8-fold increase in the risk of severe hypertriglyceridemia (HR=8.0, 95%CI: 5.47-11.71) and an 8-fold increase in hypothyroidism (HR=7.98, 95%CI: 6.52-9.76). Additionally, a 6-fold increased risk of hyperlipidemia (HR=6.44, 95%CI: 5.06-8.19) and hypercholesterolemia (HR=6.09, 95% CI: 4.09-9.08) were significantly elevated (p<0.001 for all). Conclusion In the largest real-world MF cohort treated with bexarotene to date, no association with increased risk of cardiovascular events over a 5-year period was noted. However, a significant increase in metabolic laboratory abnormalities was observed, including severe hypertriglyceridemia, hypercholesterolemia, hyperlipidemia and hypothyroidism. These findings suggest that while bexarotene necessitates intensive metabolic monitoring and management, its use does not appear to adversely affect short-to-medium-term cardiovascular safety in MF patients.