Risk of cardiovascular disease in Hodgkin lymphoma patients
Authors: Godtfredsen S J , Yonis H , Baech J , Al-Hussainy N R , Riddersholm S J , Haaber Christensen J , Hutchings M , Dahl-Sorensen R B , Kamper P , Dietrich C E , Andersen M P , Torp-Pedersen C , Sogaard P , El-Galaly T C , Kragholm K H 
Published: October 2024

Abstract

Background
Cardiovascular diseases are recognized as some of the most common and problematic late complications to the treatment of Hodgkin lymphoma (HL). However, the anticipated risk is predominantly based on studies of patients treated several decades ago with treatment regimens considered outdated by todays standard.

Purpose
To describe the risk of cardiovascular disease in HL patients undergoing contemporary treatment regimens and comparing this risk to matched comparators.

Methods
A register-based cohort study including all Danish HL patients ≥18 years at diagnosis, treated with anthracycline-containing chemotherapy between 2000 and 2022. Index date was defined as date of HL diagnosis. Matching with comparators from the background population was performed in a 1:5 ratio on age, sex, and comorbidities. Patients and comparators with malignancy and/or heart disease prior to the index date were excluded. The primary outcome was a composite endpoint of cardiovascular diseases: heart failure, ischemic heart disease, diseases of the aortic-, mitral-, and tricuspid valve, constrictive pericarditis, cardiomyopathies, atrial and ventricular arrythmias, or any invasive procedures related to these diagnoses. Follow-up began at index date and ended upon event, relapse, death, emigration, or end of follow-up (December 31, 2022), whichever occurred first. The cause-specific cumulative incidence of the primary outcome was computed with all-cause death and lymphoma relapse as competing events using the Aalen-Johansen estimator. Exploratory multivariable Cox regression analyses were performed to identify risk factors for cardiovascular disease among patients with HL. Risk factors were adjusted for sex, age, and comorbidities.

Results
A total of 1,917 HL patients and 9,585 matched comparators were included. Median age at diagnosis was 39 years (interquartile range [IQR]: 27-56), 57% were male, and median follow-up time was 10.2 years (IQR: 5.3-15.5). The majority of patients were treated with ABVD (83%) and the estimated median cumulative anthracycline dose was 250 mg/m2 (IQR: 200-300). During the study period, 50% of patients received radiotherapy. The cause-specific cumulative incidence of the primary outcome was higher among HL patients compared with comparators across follow-up: 3.7% (95% confidence interval: 2.8-4.6) vs. 2.0% (95% CI: 1.7-2.3) at 5 years, 7.2% (95% CI: 5.7-8.7) vs. 4.6% (95% CI: 4.1-5.1) at 10 years, and 14.2% (95% CI 11.6-16.9) vs 6.7% (95% CI: 6.0-7.5) at 15 years (Figure 1). Risk factors associated with development of heart disease in HL patients were history of hypertension (HR=1.81, 95% CI 1.15-2.84) and male sex (HR=2.01, 95% CI 1.39-2.91) (Figure 2).

Conclusions
The long-term risk of cardiovascular disease is still high in patients with HL after contemporary treatment suggesting that the use of modern radiotherapy has not eliminated the excess risk of cardiovascular disease.