Long-Term Hodgkin Lymphoma Survivors Show Nearly 2-Fold Mortality Increase

Adults who survived at least 5 years after a diagnosis of Hodgkin lymphoma had a standardized mortality ratio (SMR) of 1.96 (95% CI, 1.89-2.03) compared with the general US population, according to a population-based cohort study published in JAMA Network Open.

What did the population-based study show for lymphoma survivors?

Among 20,057 Hodgkin lymphoma survivors identified across 16 Surveillance, Epidemiology, and End Results (SEER) registries, there were 2899 observed deaths vs 1480.8 expected deaths, corresponding to an excess absolute risk (EAR) of 81.9 (95% CI, 75.8-88.0) per 10,000 patient-years. Relative mortality risk was elevated across all major causes of death, driven primarily by malignant conditions, but the largest absolute number of excess deaths was attributable to noncancer and cardiovascular causes rather than lymphoma recurrence itself.

With a median follow-up of 173 months (IQR, 120-226) after the 5-year survivorship index date, the cumulative all-cause mortality rate reached 8.0% (95% CI, 7.6%-8.4%) at 10 years and 15.0% (95% CI, 15.0%-16.0%) at 15 years. At 10 years, mortality from noncancer causes was highest at 2.5% (95% CI, 2.3%-2.8%), followed by other neoplasms at 2.1% (95% CI, 1.9%-2.3%), cardiovascular conditions at 1.6% (95% CI, 1.5%-1.8%), and Hodgkin lymphoma itself at 1.6% (95% CI, 1.5%-1.8%). Hodgkin lymphoma-related deaths plateaued over time, while mortality from other causes continued to rise.

Excess mortality varied substantially across patient and disease subgroups. Standardized mortality ratios exceeded 2.50 among Hispanic patients (SMR, 2.62; 95% CI, 2.37-2.89), non-Hispanic American Indian or Alaska Native patients (SMR, 3.31; 95% CI, 2.16-5.08), non-Hispanic Asian or Pacific Islander patients (SMR, 3.54; 95% CI, 2.91-4.29; P <.001), and patients diagnosed at ages 20 to 39 years (SMR, 2.52; 95% CI, 2.34-2.72; P <.001).

However, the highest EARs were observed among adults aged 60 to 89 years (EAR, 346.1; 95% CI, 299.7-392.5), non-Hispanic American Indian or Alaska Native patients (EAR, 210.4; 95% CI, 81.5-339.2), and those with mixed cellularity Hodgkin lymphoma (EAR, 150; 95% CI, 126.3-173.7). Both SMR and EAR were lower among patients diagnosed in 2008 to 2017 than in 2000 to 2007 (SMR, 1.92 [95% CI, 1.79-2.06] vs 2.59 [95% CI, 2.4-2.79]; both P <.001), and mortality risk was higher among patients with stage III or IV disease than stage I or II disease (SMR, 2.27 [2.15-2.39] vs 1.72 [1.63-1.81]; P <.001).

Radiotherapy was associated with lower SMR and EAR overall (SMR, 1.66 [95% CI, 1.55-1.77] vs 2.12 [95% CI, 2.03-2.22] without radiotherapy; P <.001), but this association held only among patients with stage I or II disease (SMR, 1.52 [95% CI, 1.40-1.64] vs 1.94 [95% CI, 1.80-2.08]; P <.001). Among patients with stage III or IV disease, radiotherapy was not associated with a significant difference in SMR (2.26 [95% CI, 1.95-2.59] vs 2.27 [95% CI, 2.14-2.40]; P = 0.95).

By specific cause of death, Hodgkin lymphoma carried by far the highest relative risk (SMR, 638.65; 95% CI, 579.3-701.93) but contributed an EAR of 24.0 (95% CI, 21.7-26.3) per 10,000 patient-years, while cardiovascular disease (SMR, 1.63; 95% CI, 1.51-1.76; EAR, 15.0) and other noncancer causes (SMR, 1.42; 95% CI, 1.34-1.51; EAR, 17.9) contributed comparable or larger absolute excess risk despite substantially lower relative risk.

“The long-term predominance of noncancer and cardiovascular mortality supports integrated survivorship care beyond lymphoma recurrence surveillance. Our estimates quantify population-based disparities and excess mortality among adults diagnosed in the era of risk-adapted therapy, suggesting the need for continued improvement in survivorship care,” Luis Malpica Castillo, MD, assistant professor in the Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center, wrote in the publication with study coauthors.

How was the population-based study designed?

This was a retrospective, population-based cohort study using SEER data linked to US population mortality rates. Eligible patients were 20 years or older at diagnosis with a first primary Hodgkin lymphoma diagnosed between 2000 and 2017, received chemotherapy with or without radiotherapy, and survived at least 5 years after diagnosis, with follow-up available through December 2023. The median age at diagnosis was 36 years (IQR, 27-50); 53.7% of patients were male, 15.0% were Hispanic, 10.3% were non-Hispanic Black, and 69.2% were non-Hispanic White. A total of 63.4% had nodular sclerosis subtype.

SMRs and EARs were estimated using expected deaths matched by age, sex, race and ethnicity, and calendar period, assuming a Poisson distribution; cumulative incidence of mortality was estimated using competing-risks methods.

The study’s authors noted that prior reports in childhood Hodgkin lymphoma survivors have described higher SMRs, in the range of 4 to 8, which may reflect differences in age at diagnosis, treatment era, background comorbidity burden, and methodological differences in conditioning on 5-year survival. They acknowledged that SEER registries lack detailed clinical and socioeconomic data, limiting adjustment for potential confounders, and that associations with radiotherapy should not be interpreted as causal. Follow-up may also be insufficient to capture late radiation-associated outcomes, including second primary malignancies and cardiovascular disease, which often emerge decades after treatment.

Reference

Valcarcel B, Retamales J, Hildebrandt MA, et al. Mortality outcomes among long-term Hodgkin lymphoma survivors. JAMA Netw Open. 2026;9(8):e2629775. doi:10.1001/jamanetworkopen.2026.29775