Cardiomyopathy and heart failure risk after treatment for Hodgkin lymphoma or aggressive B cell non-Hodgkin lymphoma

Over the past decades, the 5- and 10-year survival of especially patients with
aggressive B-cell non-Hodgkin lymphoma (NHL) and to a lesser extent of patients
with Hodgkin lymphoma (HL) has improved. There is increasing evidence that late
cardiovascular complications of cancer treatment cause substantial excess
morbidity and mortality in long-term lymphoma survivors. In HL survivors, it
has been found that treatment with anthracyclines and exposure of the heart to
radiation are important risk factors for the development of heart failure.
However, variation in anthracycline dose in previous studies among HL survivors
was limited and the majority of included patients had received mediastinal
radiotherapy as part of the lymphoma treatment, therefore researchers were
unable to reliably assess the dose-response relationship of anthracyclines with
heart failure and had limited ability to study the presence of effect
modification between anthracycline exposure and exposure of the heart to
radiation. In order to better quantify the individual effects of (mediastinal)
radiation and anthracycline exposure, we will therefore conduct a case-control
study in a combined multicentre cohort of HL and aggressive B-cell NHL
survivors. Combining these two lymphoma cohorts will provide a much broader
range in both anthracycline-dose and radiation exposure. Also, little is known
about the possible interaction between treatment (radiotherapy and/or
chemotherapy) and conventional cardiovascular risk factors or genetic risk
factors and the risk of cardiomyopathy and/or heart failure. It is important to
know which lymphoma survivors have an increased risk of treatment-related late
effects in order to provide more targeted screening advice, medical
interventions and ultimately prevention.

To assess risk factors for cardiomyopathy and heart failure among lymphoma (HL
and aggressive B-cell NHL) survivors, focusing on the independent and joint
effects of doses of anthracycline-containing chemotherapy (doxorubicin) and
rituximab as well as radiation dose to the heart. We will also assess whether
conventional risk factors for cardiovascular diseases (CVDs), lifestyle and
genetic risk factors modify treatment-related cardiomyopathy and heart failure
risk.

We will conduct a case-control study that includes survivors who are already
included in a cohort of Hodgkin lymphoma survivors (P11CHT study), treated
between 1965 and 2000. In addition, survivors from a multicenter cohort of
aggressive B-cell NHL survivors (CRYSTAL cohort study), treated between 1989
and 2012, will be included. Cases are defined as lymphoma survivors who have
developed cardiomyopathy and/or heart failure after lymphoma treatment. Cases
are matched to lymphoma survivors (1:3) who have not developed cardiomyopathy
or heart failure, myocardial infarction or heart valve disease (controls).
Cases will be identified based on data from medical records or information from
general practitioners collected in the context of the P11CHT study or the
CRYSTAL control study.

We will perform linkage with the *Basis Registratie Personen (BRP)* to
determine if a survivor is still alive at the start of the study and to obtain
contact information. All 5-year survivors eligible as case or control who are
still alive at the start of the study will be approached in writing for study
participation by the survivors* former attending medical specialist, his/her
successor or the head of the department where the survivor was treated.
Eligible survivors will receive an invitation to participate in the study
together with a reply and informed consent form and an information file. The
General Data Protection Regulation (GDPR) and the Data Protection Act no longer
apply to identifiable data that relates to a person once they have died,
therefore, in case a HL or aggressive B cell NHL survivors eligible for
inclusion has died before study start, we will assume the survivor consents to
study participation. For cases and controls that are no longer alive at the
time of the study, only coded data from medical files will be used in this
study. For all cases and controls, detailed treatment information, including
radiation charts and simulation films and cumulative doses of all cytotoxic
drugs, information about risk factors for cardiovascular disease, family
history and demographic data will be abstracted from medical records. In order
to provide detailed radiation dose descriptions for exposure to the heart, we
will also collect scanned copies of original radiotherapy prescription sheets,
simulation films and radiation charts if available. For the current study,
radiation dosimetry will be carried out at the Clinical Trial Service Unit &
Epidemiological Studies Unit (CTSU) of the University of Oxford, United Kingdom
(Dr. D. Cutter and Prof. S. Darby) in close collaboration with the NKI-AVL
radiotherapy department (Dr. B.M.P. Aleman).

To obtain more complete information on cardiovascular disease risk factors,
survivors who are currently alive will receive a risk factor questionnaire that
will elicit information on family history of cardiovascular diseases, history
of smoking, alcohol use, lifetime weight changes, lifetime physical activity,
premature menopause in women and medication use. The risk factor questionnaire
will be sent after the participant has given consent for study participation.
If the participant has given consent to donating a blood sample for examination
of susceptibility genes (Genome screen array [GSA]) for chemotherapy and/or
radiotherapy-induced CVDs, we will send a blood sampling package to donate a 10
ml blood sample. After gene-analysis and when the participant has consented to
biobanking, the collected blood samples will be stored for future research in
the biobank.

The risk and burden of the measurements for the CRYSTAL case-control study are
estimated to be very low: we ask participants to complete one questionnaire and
ask for one blood sample (10 ml, minimally invasive).