Survivors of non-Hodgkin lymphoma and a control group will be screened for (sub)clinical cardiovascular disease, to assess the influence of contemporary treatments on risk and burden of (sub)clinical cardiovascular disease and their influence on survival.

Rationale: Few studies have thus far addressed the burden from treatment-related cardiovascular disease in long-term survivors of non-Hodgkin's lymphoma (NHL). The life expectancy of patients with aggressive B-cell NHL has significantly increased since treatment regimens have improved. Although the addition of rituximab to CHOP chemotherapy does not appear to increase cardiotoxicity during treatment, little is known about the long-term cardiac safety of R-CHOP. Nonetheless, cardiotoxicity due to doxorubicin exposure appears to be a key problem in clinical practice, while radiation exposure of the heart may add to cardiac disease risk.

Objective: The main objective is to assess in detail risk factors for cardiovascular disease and cardiotoxicity and to compare heart function parameters, vascular parameters and biomarkers associated with cardiovascular function among five- tot fifteen-year survivors, treated for aggressive B-cell NHL, and sibling controls and to assess the effects of cumulative doses of individual immuno- and chemotherapeutic agents and radiation of the heart on cardiovascular function parameters. Secondary objectives are to assess the prevalence of other late effects (metabolic syndrome, quality of life and the predictive value of newly developed markers for cardiovascular disease).

Study design: These parameters will be assessed in a cross-sectional study, nested in a well characterized cohort of aggressive B-cell NHL survivors, with a control population consisting of siblings of these survivors.

Study population: 350 survivors will be invited who are between five and fifteen years after treatment with (R-)CHOP with/without mediastinal radiotherapy, and compare them with 175 sibling controls. Eligible participants will be approached and invited to the BETER clinic by their (former) treating physician.

Main study parameters/endpoints: The main study parameters will be echocardiographic systolic and diastolic heart parameters and global longitudinal strain measurement, arterial stiffness (by pulse wave velocity measurements), endothelial function (by peripheral arterial tonometry), electrocardiography, advanced glycation end products (by skin autofluorescence, AGE-reader), presence of (sub)clinical cardiovascular disease and biomarkers. Adverse cardiovascular events, risk factors and quality of life will be assessed through questionnaires and physical measurements. Exposure to (R-)CHOP and radiotherapy will be extracted from the medical history. Multivariable logistic and linear regression analyses will be used for analyses.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: With the results of our study, guidelines for follow up and prevention will be developed which will benefit the participants during their own follow up in the future. The burden of participating is expected to be low since the study is mainly observational and assessments required in the context of research as much as possible combined with the provided standard of care for survivors during one or two hospital visits.

Inclusion Criteria (survivors):

• 5-15 year survivors from the patient cohort with (mediastinal) large B-cell non-Hodgkin lymphoma (ICD-code 9679) or diffuse large B-cell non-Hodgkin lymphoma (ICD-code 9684), treated with R-CHOP:

  • 200 survivors treated between five to ten years ago (2007-2012)
  • 150 survivors treated between ten to fifteen years ago (2002-2007)

• Treated in one of the following centers: AVL, Amsterdam UMC (location VUmc or AMC), LUMC, EMC, UMCU, UMCG, UMC Radboud.

• Age at diagnosis 15 up to 60 years.

• Age at the time of inclusion: younger than 75 years old.

Exclusion criteria (survivors):

• Use of immunosuppressant and/or prednisolone
• HIV-infected individuals
• Pregnant women
• Mental disability or psychological condition potentially hampering compliance with the study protocol
• Insufficient understanding of the Dutch language

Inclusion criteria (siblings):

175 siblings of the above mentioned patients (maximum of 1 sibling per patient) with their date of birth closest to the birthdate of the survivor.

Exclusion Criteria (siblings):

• Use of immunosuppressant and/or prednisolone
• HIV-infected individuals
• Pregnant women
• Mental disability or psychological condition potentially hampering compliance with the study protocol
• Insufficient understanding of the Dutch language

• Survivors: Over the past years, a Dutch multicentre hospital-based patient cohort of 5-year non-Hodgkin lymphoma survivors has been established. Survivors will be invited for the current study by their treating physician through the BETER survivorship clinics, or when patients have been dismissed from clinical follow-up, by their former treating physician (or head of the medical department, if the treating physician is retired) within each BETER clinic.
• Siblings: As there are no patients who are unexposed to potential cardiotoxic treatment in the BETER cohort we will request every participating NHL survivor to approach one of their siblings, more specifically the sibling who is closest in birthdate to the birthdate of the survivor, for participation in the study.