Myocardial dysfunction in survivors of diffuse large B-cell lymphoma and a sibling control group
Few studies have addressed the risk of treatment-related (sub)clinical cardiovascular disease (CVD) in long-term survivors of diffuse large B-cell lymphoma (DLBCL). Yet, life expectancy of DLBCL survivors has increased substantially, since the addition of rituximab to CHOP (cyclophosphamide, doxorubicin, vincristine, prednison) in the early 2000s. Receipt of (R-)CHOP has been associated with decline in left ventricular function. Aim: to assess the prevalence of (biomarkers for) left ventricular dysfunction related to doxorubicin dose and receipt of mediastinal radiotherapy in ≥5-year DLBCL survivors and sibling controls.
During 2020-2022, we conducted a cross-sectional multicenter study and enrolled 142 5- to 20-year survivors of DLBCL or primary mediastinal B-cell lymphoma, treated in the period 2002-2015 with (R-)CHOP, aged 15-60 years at diagnosis and aged ≤75 years at study enrolment. Survivors were asked to invite a sibling (closest in date of birth to theirs) to participate in the study; 75 siblings participated. Prior CVD was not an exclusion criterion. Data on treatment were collected from medical charts and data on risk factors were derived from questionnaires at study visit. All participants underwent assessment of cardiac biomarkers (i.e. N-terminal pro-Brain Natriuretic Peptide (NT-proBNP), left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS). Associations of DLBCL treatment with NTproBNP, LVEF and GLS were evaluated using multivariable regression models, adjusted for sex and age.
Median age at DLBCL treatment was 44.2 years, 88.7% received ≥6 cycles of (R-)CHOP and 26.8% additionally received mediastinal radiotherapy. Median age at study visit was 55.5 years for survivors and 53.0 years for siblings; 60% of survivors were male compared with 51% of siblings. The prevalence of CVD risk factors did not differ between survivors and siblings. NT-proBNP was increased in 42% of survivors, compared with 10.7% in siblings. The incidence rate ratio (IRR) was 4.3 (95% Confidence Interval (CI) 2.1-8.4). The IRR for NT-proBNP ≥125 pg/mL increased 1.5-fold (95%CI 1.2-1.7) per 100 mg/m2 increase in doxorubicin dose. Thirty-one survivors (21.8%) and seven siblings (9.3%) had an LVEF<50%. The IRR was 2.3 (95%CI 1.0-5.0). Risk of LVEF<50% increased 1.3-fold (95%CI 1.0-1.7) per 100 mg/m2 increase of doxorubicin dose. Presence of CVD risk factors or receipt of mediastinal RT did not modify the association between doxorubicin and LVEF<50%. Mediastinal RT was not associated with LVEF<50%.
Long-term DLBCL survivors, treated with doxorubicin, have a high prevalence of (asymptomatic) left ventricular dysfunction compared with sibling controls. The association of doxorubicin with decreased LVEF was not affected by CVD risk factors or mediastinal radiotherapy. Our findings underscore the potential yield of cardiac monitoring, but longitudinal assessments are needed to understand subsequent risk of heart failure.