Elevated risk of non-neoplastic mortality among adolescent and young adult patients with low-grade B-cell lymphoma

Abstract Background Adolescent and young adult (AYA) patients with low-grade B-cell lymphoma/leukemia (LoGL) typically have favorable cancer-specific survival, however, the risk of mortality from non-neoplastic causes (NNC) in this population remains poorly characterized. Methods We utilized data from the National Cancer Institute's SEER 17 registries to identify AYA patients (aged 15–39 years) diagnosed with LoGL between 2000 and 2022. Histologic subtypes were defined using ICD-O-3 codes and included lymphoplasmacytic lymphoma (9671/3), mantle cell lymphoma (9673/3), marginal zone lymphoma (splenic: 9689/3, and extranodal mucosa-associated lymphoid tissue: 9699/3), follicular lymphoma grades 1 and 2 (9695/3, 9691/3), hairy cell leukemia (9940/3), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; 9823/3). Data was extracted using SEER*Stat v9.0.41.4. Patients with missing age or race data were excluded. SEER defines non-neoplastic causes of death based on ICD-10 codes into 27 categories, such as diseases of heart, suicide and self-inflicted injury (SSI), septicemia etc. Standardized mortality ratios (SMRs) were used for risk estimation and calculated by comparing observed NNC deaths among AYA patients with LoGL to expected deaths in the age-, sex-, and race-matched general U.S. population. 95% confidence intervals (CIs) were computed assuming a Poisson distribution. Statistical significance was defined as p < 0.05. Results We analyzed 4,445 AYA patients with LoGL, comprising 55.8% males (n= 2481) and 60.5% white population (n=2687). Total 415 deaths (9.3%) were recorded during median follow up of 122 (95%CI: 118-127) months. Of these deaths, 34.4% (143/415) were due to NNC, while remaining 65.6% (272/415) were attributed to malignancy. The majority of NNC deaths occurred in males 4.1% (102/2481) compared to 2.1% (41/1964) in females. The LoGL subtypes among those who died of NNC were follicular lymphoma grade 1 or 2 (n= 50/143, 34.9%), marginal zone lymphoma (36/143, 25.2%), CLL/SLL (34/143, 23.8%), hairy cell leukemia (11/143, 7.7%), lymphoplasmacytic lymphoma (9/143, 6.3%), and mantle cell lymphoma (3/143, 2.1%). The common NNCs of death included cardiovascular diseases (CVD, n=30/143, 20.9%), infections (27/143, 18.9%), and SSI (11/143, 7.7%). The median (IQR) age at diagnosis was 36 (32–38) years, while at death it was 42 (38–47) years for patients who died due to NNC. Compared to the general U.S. population, AYA patients with LoGL had a 50% increased risk of non-neoplastic mortality (SMR: 1.5, 95% CI: 1.3–1.8, p<0.05), corresponding to an excess risk of 11.2 deaths per 10,000 individuals. Males exhibited double the excess mortality risk compared to females (14.4 vs. 7.2 per 10,000). Stratified analyses by race/ethnicity showed significantly elevated NNC mortality risks among non-Hispanic (NH) White (SMR: 1.3), NH Black (SMR: 2.25), and NH Other races (SMR: 3.3) (p < 0.05 each), whereas the increased risk among Hispanic individuals (SMR: 1.4) was not statistically significant (p > 0.05). Among specific NNCs, the risk of death was significantly higher due to septicemia (SMR: 3.9, 95% CI: 1.3–9.3) and pneumonia/influenza (SMR: 6.4, 95% CI: 2.8–12.7) in AYA with LoGL compared to the general population. The risk of mortality from CVD or SSI did not differ significantly compared to general population (p>0.05). Conclusion AYA patients with LoGL have a 50% higher risk of death from non-neoplastic causes compared to the general population. This risk is particularly higher among males and non-Hispanic ethnicities. A significantly higher mortality risk from infections was noted, suggesting long term immune dysfunction in this population. These findings underscore the importance of preventive strategies to mitigate infection-related mortality in AYA patients with LoGL.