Time-stratified risk of second primary solid malignancies among follicular lymphoma survivors in the United States

Abstract Introduction: Survivors of follicular lymphoma (FL) face an elevated risk of developing second primary malignancies (SPMs). The risk of SPMs varies over time and this time varying risk of SPMs is informative for SPM mitigation, surveillance, and early intervention. This study aimed to estimate the time-stratified standardized incidence ratios of SPMs among FL survivors in the United States. Methods: We used data from the Surveillance, Epidemiology and End Results Program (SEER)-12 registry to identify individuals diagnosed with FL between 2000 and 2021. Solid-tumor SPMs diagnosed at least six months after the initial FL diagnosis were included and categorized typographically using ICD-O codes. SPMs diagnosed <6 months from index date were excluded to reduce surveillance bias associated with the medical assessments at time of cancer diagnosis. Using patient's age, sex, and race/ethnicity, we calculated standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for each SPM across four-time intervals: 6–11 months, 12–59 months, 60–119 months, and ≥120 months post-diagnosis. We conducted separate models estimating overall solid tumor SIRs by sex, race, and age, controlling for the other factors and restricting the race analyses to categories with more than 1,000 FL survivors to minimize the risk of unstable estimates. Results: Among 37,830 FL survivors (median age 64 years; 49% female; 75% White; 12% Hispanic, 7.27% Asian; 3.89% Black), 4,707 (12%) developed an SPM over a median follow-up of 81 months. The overall standardized incidence ratio (SIR) for solid SPMs was elevated at 1.04 [95% CI: 1.01–1.08], with a decreasing trend over time from FL diagnosis: 1.23 (1.07–1.41) [6-11 months]; 1.07 (1.01–1.13) [12-59 months]. Elevated SIRs were observed for endocrine (1.71 [1.39–2.08]), respiratory (1.34 [1.24–1.44]), oral cavity/pharynx (1.22 [1.00–1.46]), melanoma (1.17 [1.02–1.33]), and urinary system (1.11 [1.00–1.23]). Respiratory cancer showed consistently elevated SIRs across all time intervals (range: 1.21–1.54). Endocrine cancers had a markedly high SIR in the 6–11 month window (10.31 [6.90–14.80]) and remained elevated at 60-119 months (1.58 [1.04-2.30]). Melanoma was elevated at 12-59 months (1.33 [1.06-1.66]), while urinary and oral cavity/pharyngeal cancers showed elevated SIRs only at 6-11 months (1.64 [1.07-2.41] and 120+ months (1.40 [1.02-1.88], respectively. Elevated SIRs for solid SPMs were observed among males (1.05 [1.00-1.10]), non-Hispanic White (1.08 [1.04-1.12]), and FL survivors <65 years (1.15 [1.08-1.23]); no significant elevations were found among females, other racial groups, or those ≥65 years. Conclusions: FL survivors are well-known to be at an increased risk for both hematologic and solid SPMs. In our study focusing on solid SPMs, we found that the SIRs for SPMs varied over time, across cancers, and by patient demographics. Brief elevations in SIRs may represent surveillance bias but could also be time period-specific risks related to the immunocompromised state of FL and/or cancer treatment. Recognition of time-stratified SPM incidence can inform surveillance strategies and opportunities for SPM risk mitigation. Further research is needed on how the interaction between FL therapy and patient's risk factors influence the risk of SPMs and how SPM surveillance practices influence the morbidity and mortality of FL survivors.