Cause of non-cancer related death among patients diagnosed with lymphoid neoplasm: A SEER-based study

Abstract Introduction In the United States in 2024, around 89,190 adults were newly diagnosed with lymphoma and approximately 21,050 died of the disease.1 While lymphoma remains the primary driver of mortality, multiple retrospective studies—including SEER-based analyses—highlight a substantial non-cancer mortality burden. These deaths include infections, external causes (such as homicide or legal intervention), cardiovascular events, and suicide.2,3,4 Notably, non-Hodgkin lymphoma (NHL) patients typically exhibit higher rates of infectious mortality than Hodgkin lymphoma (HL) patients, and advanced disease stage correlates with increased SMRs; in contrast, radiation therapy appears associated with reduced SMRs and infection-related mortality.5 Moreover, HL survivors face elevated non-cancer mortality risk even decades after diagnosis.6 Methods We conducted a retrospective cohort study using SEER data (2000–2022) on 636,926 adult patients diagnosed with lymphoid neoplasms. Standardized Mortality Ratios (SMRs) with 95% confidence intervals (CIs) were calculated for non-cancer causes by comparing observed deaths to expected deaths in an age, sex, race, ethnicity, and calendar-year matched U.S. population. Patients were stratified by age (<50, 50–70, >70 years), gender (male, female), race (White/Caucasian, Black/African American, American Indian/Alaska Native [AI/AN], Asian/Pacific Islander), ethnicity (non-Spanish-Hispanic Latino [NSHL] vs Spanish-Hispanic Latino [SHL]), and lymphoma subtype (HL, NHL). Results Of 636,926 patients, 55.9% were male; 82.3% were White; and 87.8% were NSHL. Subtype distributions: 85.5% B-cell, 6.5% HL, 5.6% T-cell, and 2.3% precursor. Across the cohort, the highest SMR was for homicide/legal intervention at (SMR:26.08 , 95% CI: 20.86–32.21), followed by infectious and parasitic diseases including HIV (20.91 , 20.38–21.46), chronic liver disease/cirrhosis at (11.71, 11.07–12.39), suicide/self-inflicted injury (10.41, 9.65–11.20), and medical/surgical complications (10.31, 9.09–11.64). In the first five years post-diagnosis, homicide/legal intervention remained leading cause of death (19.55, 13.46–27.46), followed by treatment-related complications (15.74 ,12.09–20.13). Younger adults had markedly elevated mortality due to infectious and parasitic disease (54.13, 51.75–56.58), compared to older patients (2.67, 2.49–2.85). AI/AN individuals had the highest septicemia mortality (4.96, 2.56–8.67) compared with Black individuals (3.02, 2.74–3.32) and Asian/Pacific Islanders (2.77, 2.25–3.36). SHL ethnicity was associated with higher tuberculosis mortality (5.43, 1.99–11.82) vs NSHL (1.98; 1.35–2.81), and higher overall infectious/parasitic (19.19, 18.07–20.35 vs 7.85, 7.62–8.07, respectively). In both NHL and HL subsets, infectious/parasitic disease remained the leading non-cancer cause of mortality (SMR ~8.49 in NHL; 14.64 in HL). Younger NHL patients had higher mortality rates with pneumonia/influenza (SMR 5.97 vs 1.49), septicemia (5.94 vs 1.57), nephritis/nephrotic syndrome (5.51 vs 1.52), and vascular disease (4.24 vs 0.92) as compared to older adults. These age and subgroup patterns were consistent across other analyses. Discussion This large, population-based SEER analysis confirms that lymphoid neoplasm patients face substantially elevated non-cancer mortality, driven by homicide/legal intervention, infection, and self-harm. Risk is highest during the early post-diagnosis period, aligns with prior findings indicating elevated non-cancer mortality in cancer survivors and is shaped by demographic variables: younger age correlates with extreme infection-related risk, while AI/AN and SHL populations exhibit vulnerability to specific infectious causes. Clinical implications include the urgent need for holistic survivorship care that extends beyond oncologic follow-up: proactive infection control, psychosocial/mental health support, external injury prevention strategies, and addressing social determinants and safety risks—particularly in younger, AI/AN, and SHL subgroups—during the high-risk early years post-diagnosis.