Introduction: The documented treatment-induced excess mortality in Hodgkin lymphoma (HL) has led to significant changes in treatment regimens aimed at maintaining efficacy while reducing toxicity. These modifications include the replacement of alkylator-based regimens with anthracycline-based combinations and the adoption of highly conformal radiotherapy. Danish and Nordic radiation oncologists were pioneers in implementing these changes nationwide 10-15 years earlier than most other nations. These early adaptations make Danish HL data uniquely valuable for assessing long-term mortality in a cohort where modern treatment regimens have been implemented nationwide throughout the entire study period. The impact of these treatment modifications on mortality risk in HL survivors remains unclear, therefore, this study aims to assess cause-specific mortality among HL patients treated with contemporary strategies.

Methods: This nationwide, unselected study included all HL patients in Denmark aged 15-40 years at diagnosis and treated between 1995 and 2015. Patients were followed from diagnosis until emigration, death, or the study end. HL cases were identified through meticulous individual record reviews of medical records, national registries, and pathology data. Disease-specific death due to HL was the primary outcome, with other cause-specific mortality as a competing risk. Cox proportional hazard models assessed factors influencing overall survival and cause-specific survival. A landmark analysis was conducted to compare the risk of death between the study population and the national background population.

Results: Among 1,348 included HL patients, 66.5% had Ann Arbor stage I-II at the time of diagnosis. During 18,731 person-years of follow-up, 139 deaths occurred, resulting in a 5-year overall survival rate of 94.6% (95% CI 93.4-95.8). Factors associated with higher overall mortality risk included older age, advanced disease stage at diagnosis, earlier treatment periods, and exposure to intensive treatment regimens. Causes of death included: HL (71 cases), cardiovascular disease (9 cases), second malignancies (19 cases including 3 hematologic malignancies), bone-marrow transplant-related complications (9 cases), acute treatment-related toxicity (<5 cases), pulmonary diseases (<5 cases), other diseases not related to HL (11 cases), and deaths related to accidents, poisoning or suicide (7 cases). The cumulative risk of mortality due to HL steeply increased over the first 10 years, reaching a plateau at 5.3% at the 10-year mark. Cumulative risk of death due to cardiovascular or pulmonary disease and second cancers had a gradual increase around 10 years after HL diagnosis, but only reached 1.2% and 2.0%, respectively, at the 20-year mark. The cumulative risk of death due to other causes had a slower rise, reaching 2.5% 15 years after diagnosis. Stratifying the cumulative cause-specific risk of death into HL and other causes, we found an initial sharp increase in cumulative risk of death due to HL in the first year after diagnosis, which was surpassed by the risk of death from other causes by 17.8 years of follow-up, with a cumulative risk of death of 5.72%. HL cases had a 7.5-fold higher hazard of mortality compared to the background population.

Conclusion: Despite the implementation of contemporary treatment regimes, HL patients still face higher mortality compared to the general population. In the initial years after diagnosis, most deaths are disease-specific, while the risk of mortality due to possible treatment-related late effects gradually increases after 10 years. However, our findings demonstrate a markedly lower overall risk of mortality and cause-specific mortality among HL patients exposed to contemporary treatment, compared to the risk reported in earlier studies among patients from earlier treatment eras (Aleman, B. et al. Long-term cause-specific mortality of patients treated for Hodgkin's disease. J Clin Oncol21 2003, 3431-3439). Furthermore, we observe a remarkably low overall and cause-specific risk of death due to possible treatment-related late effects. The treatment of HL remains a balance between efficacy and toxicity in the individual patient, but our results suggest that recent changes in treatment strategies have led to a distinct reduction in the risk of fatal long-term toxicity and have improved HL-specific survival.