Cumulative burden of cardiovascular morbidity in paediatric, adolescent, and young adult survivors of Hodgkin's lymphoma: an analysis from the St Jude Lifetime Cohort Study

Abstract

Background: The magnitude of cardiovascular morbidity in paediatric, adolescent, and young adult survivors of Hodgkin's lymphoma is not known. Using medically ascertained data, we applied the cumulative burden metric to compare chronic cardiovascular health conditions in survivors of Hodgkin's lymphoma and general population controls.

Methods: For this study, participant data were obtained from two ongoing cohort studies at St Jude Children's Research Hospital: the St Jude Lifetime Cohort Study (SJLIFE) and the St Jude Long-term Follow-up Study (SJLTFU). SJLIFE is a cohort study initiated on April 27, 2007, to enable longitudinal clinical evaluation of health outcomes of survivors of childhood cancer treated or followed at St Jude Children's Research Hospital, and SJLTFU is an administrative system-based study initiated in 2000 to collect outcome and late toxicity data for all patients treated at the hospital for childhood cancer. The patient cohort for our study was defined as patients treated at St Jude Children's Research Hospital who reached 18 years of age and were at least 10 years post-diagnosis of pathologically confirmed primary Hodgkin's lymphoma. Outcomes in the Hodgkin's lymphoma survivors were compared with a sample of SJLIFE community control participants, aged 18 years or older at the time of assessment, frequency-matched based on strata defined by 5-year age blocks within each sex, who were selected irrespective of previous medical history. All SJLIFE participants underwent assessment for 22 chronic cardiovascular health conditions. Direct assessments, combined with retrospective clinical reviews, were used to assign severity to conditions using a modified Common Terminology Criteria of Adverse Events (CTCAE) version 4.03 grading schema. Occurrences and CTCAE grades of the conditions for eligible non-SJLIFE participants were accounted for by multiple imputation. The mean cumulative count (treating death as a competing risk) was used to estimate cumulative burden.

Findings: Of 670 survivors treated at St Jude Children's Research Hospital, who survived 10 years or longer and reached age 18 years, 348 were clinically assessed in the St Jude Lifetime Cohort Study (SJLIFE); 322 eligible participants did not participate in SJLIFE. Age and sex frequency-matched SJLIFE community controls (n=272) were used for comparison. At age 50 years, the cumulative incidence of survivors experiencing at least one grade 3-5 cardiovascular condition was 45·5% (95% CI 36·6-54·3), compared with 15·7% (7·0-24·4) in community controls. The survivor cohort at age 50 experienced a cumulative burden of 430·6 (95% CI 380·7-480·6) grade 1-5 and 100·8 (77·3-124·3) grade 3-5 cardiovascular conditions per 100 survivors; these numbers were appreciably higher than those in the control cohort (227·4 [192·7-267·5] grade 1-5 conditions and 17·0 [8·4-27·5] grade 3-5 conditions per 100 individuals). Myocardial infarction and structural heart defects were the major contributors to the excess grade 3-5 cumulative burden in survivors. High cardiac radiation dose (≥35 Gy) was associated with an increased proportion of grade 3-5 cardiovascular burden, whereas increased anthracyline dose was not.

Interpretation: The true effect of cardiovascular morbidity in paediatric, adolescent, and young adult survivors of Hodgkin's lymphoma is reflected in the cumulative burden. Survivors aged 50 years will experience more than two times the number of chronic cardiovascular health conditions and nearly five times the number of more severe (grade 3-5) cardiovascular conditions compared with community controls and, on average, have one severe, life-threatening, or fatal cardiovascular condition. The cumulative burden metric provides a more comprehensive approach for assessing overall morbidity compared with currently used cumulative incidence based analytic methodologies, and will assist clinical researchers when designing future trials and refining general practice screening guidelines.

Funding: US National Cancer Institute, St Baldrick's Foundation, and American Lebanese Syrian Associated Charities.

Figure 1

Hodgkin Lymphoma Survivors Treated or Followed at St. Jude Children’s Research Hospital

Figure 2. Cumulative Incidence and Cumulative Burden of Chronic Cardiovascular Health Conditions among Hodgkin Lymphoma Survivors and Community-Controls

Technical note: The atypical pattern of the 95% confidence limits of survivors' curves is due to application of left-truncation and multiple imputation in the estimation of cumulative incidence and cumulative burden. Furthermore, the atypical pattern of the numbers at risk for cumulative incidence and cumulative burden is due to the following reasons: Cumulative incidence: For controls, everyone started the at-risk period at birth (age 0). At this beginning of the start of the at-risk period, the number of our community controls at risk is 272 (the total number of our community controls). Until the first censoring, death, or the first occurrence of cardiovascular conditions of interest, the number at risk remains at 272. For survivors, the start of the at-risk period is 10 years post Hodgkin lymphoma diagnosis or age of 18 years whichever comes later, i.e., the SJLIFE cohort entry. Thus, age at the start of the at-risk period differs across survivors, which led to the number of survivors at risk increasing over age up to about 30 years old and then decreasing. There are a total of 670 survivors and the latest age at the cohort entry was 35 years old. Because some people were censored before age 35, there is no time point at which the number at risk was 670. Cumulative burden: For cumulative burden, people stay at risk during their length of follow-up. Unlike cumulative incidence which stops the at-risk period at the occurrence of the event of interest, cumulative burden keeps subjects who have events of interest at risk: the two methods are equal in their handling of censoring at the end of follow-up and deaths.

Figure 3

Average Annual Increase in Cardiovascular Cumulative Burden

Figure 4

Contributions to Cumulative Burden by Cardiovascular Disease Group

Figure 5

Multivariable Analysis of Cardiovascular Burden by Grade for Anthracycline and Heart Radiation Exposure. Multivariable models included adjustment for gender, race, treatment era, time-dependent attained age and age at diagnosis.