Secondary primary lymphoma (SPL) following immune checkpoint inhibitor (ICI) therapy: FDA Adverse Event Reporting System (FAERS) review.

436 Background: ICIs targeting CTLA-4, PD-1, PD-L1, and LAG-3 are a mainstay in the treatment of solid tumors. While lymphomagenesis is rare, emerging reports suggest potential development of SPLs following ICI therapy. As clinical use expands, monitoring for emerging safety signals remains essential. Methods: We searched the FAERS database for reports submitted through March 31, 2025, involving nivolumab, pembrolizumab, ipilimumab, atezolizumab, durvalumab, cemiplimab, avelumab, dostarlimab, and relatlimab/nivolumab. We included cases of SPL following ICI therapy for non-lymphoid malignancies. Duplicated reports, disease progression, unknown indications, benign lymphoproliferative processes, and genetic findings without confirmed lymphoma were excluded. Results: A total of 181 SPL cases were reported in 181 patients. Median age was 66 years; 114 male and 50 female (unspecified 17). The ICIs involved were nivolumab (n=68), pembrolizumab (n=51), ipilimumab (n=35), atezolizumab (n=13), cemiplimab (n=3), and avelumab (n=1). There were 61, 10, 9 cases reported as lymphoma, B-cell lymphoma, T-cell lymphoma, respectively. Among the cases with subtypes of lymphoma reported, there were aggressive T-cell lymphomas including 8 Peripheral T-cell lymphoma, 7 Adult T-Cell Lymphoma/Leukemia, 3 Angioimmunoblastic T-cell Lymphoma, 3 Precursor T-Lymphoblastic Lymphoma, 3 Anaplastic Large Cell Lymphoma, 1 Hepatosplenic T-cell lymphoma as well as aggressive B-cell lymphomas including 21 Diffuse Large B-Cell Lymphoma, 5 Burkitt’s Lymphoma, 5 Central Nervous System Lymphoma, 4 Mantle Cell Lymphoma. There were indolent T-cell lymphoma (11 Cutaneous T-Cell Lymphoma) and B-cell lymphoma (6 B-cell Small Lymphocytic Lymphoma, 4 Follicular Lymphoma, 2 Lymphoplasmacytoid Lymphoma, 2 Extranodal Marginal Zone Lymphoma, 1 Splenic Marginal Zone Lymphoma). Other lymphomas reported include 6 Non-Hodgkin Lymphoma, 11 Metastatic Lymphoma, 3 Angiocentric Lymphoma, 1 Lymphoma Transformation. Death was reported in 32 cases. Conclusions: This analysis identified SPL cases following ICI therapy including aggressive T-cell and B-cell lymphomas warranting further pharmacovigilance study as well as investigation of immune-mediated mechanisms of lymphomagenesis following ICI exposure.