Background: Due to the historically less favorable prognosis of diffuse large B cell lymphoma (DLBCL), the burden of second malignant neoplasms (SMNs) has been rarely studied in DLBCL survivors. However, radiotherapy and chemotherapy may increase SMN risk among DLBCL patients. Anthracyclines may increase the risk of hematological malignancies, but it is not clear whether they also increase solid cancer risk. Methods: We established a multicenter cohort of 2,384 5-year DLBCL survivors treated at ages 15-60 years with radiotherapy and/or immuno-chemotherapy between 1989 and 2012. Observed numbers of SMNs were compared with expected cancer incidence in the general population to compute standardized incidence ratios (SIRs), absolute excess risks (AERs, per 10.000 person-years) and cumulative incidence. Treatment specific incidence was compared with general population rates and assessed within the cohort using Cox regression. Results: Most DLBCL patients received alkylating agents (95%), anthracycline-containing chemotherapy (95%) or radiotherapy (61%); 46% received rituximab. Median follow-up was 13.3 years; 17% of patients was followed ≥20 years. In total, 308 5-year survivors developed an invasive SMN (SIR 1.6; 95% confidence interval (CI), 1.4 to 1.8), translating into 56.2 excess cancers per 10.000 person-years (see Table for specific sites). In 20-year survivors of DLBCL, the SIR was 1.8 (95% CI 1.3-2.6). The 20-year cumulative incidence of any SMN was 18.7% (95% CI 16.5-21.0%). The SIR for any SMN was higher in patients <40 years at first treatment (SIR ≤40 years: 2.8, SIR >40 years: 1.4; p<0.001). Treatment specific results will be presented at ASCO21. Conclusions: DLBCL survivors experience higher risk of SMNs than the general population. Identification of patients at increased risk could improve follow-up care.

*Only first invasive cancers. ^†Excludes Kaposi sarcoma. ^‡Includes myelodysplastic syndrome. AER, absolute excess risk; CI, confidence interval; SIR, standardized incidence ratio.