Second primary malignancies (SPM) risk after CAR T-cell therapy: A real-world analysis.

e23445 Background: Chimeric antigen receptor (CAR) T-cell therapy is an engineered T-cell therapy that offers curative potential for patients with relapsed, refractory hematological malignancies. Due to utilization of viral vector-based transduction, genetic modification, and durable remissions in CAR-T responders, ongoing surveillance for second primary malignancies (SPMs) is imperative. This study aims to quantify the burden and characterize SPM subtypes using a large-scale, real-world database of patients treated with FDA-approved CAR T-cell products. Methods: We conducted a retrospective cohort study using de-identified data from the TriNetX Global Collaborative Network, and using ICD-10 codes identified patients with hematologic malignancies between January 1, 2018 and January 25, 2026. Exposure was defined by the administration of CAR T-cell therapy (identified via RxNorm codes), with the index event marked as the first infusion. To ensure the accuracy of SPM status, patients with a documented malignancy prior to the index window were excluded. The primary outcome was the incidence of SPMs, stratified into hematologic versus solid tumor categories. Incidence proportions were calculated within the cohort to assess relative risk. Results: The study cohort included 3,886 patients that were 38.55% female, 61.54% male and had a mean age of 60 ± 12 years. We identified 800 SPMs among the cohort; with a median follow-up of 380 days, the overall cumulative SPM risk was 20.6% (95% confidence interval [CI], 19.3–21.9%). In the distribution of SPM subtypes, hematologic malignancies accounted for the largest proportion (12.25%), followed by solid tumors (8.34%). Among hematologic SPMs, the most frequently observed were MDS/AML (7.6%), non-Hodgkin lymphoma (7.1%), plasma cell disorders (1.5%), and myeloproliferative neoplasms (0.3%). Among solid tumor SPMs, non-melanoma skin cancers (2.8%) were most common, followed by genitourinary (1.4%), gastrointestinal (1.1%), lung (0.9%), sarcoma/GIST (0.7%), and melanoma (0.5%), with breast, brain, thyroid, and gynecological malignancies collectively accounting for less than 1.5% of cases. Conclusions: This large-scale analysis demonstrates that the development of SPMs is a clinically relevant long-term complication of CAR T-cell therapy. The cumulative incidence rates particularly for myeloid neoplasms and skin cancers underscore the necessity for rigorous, lifelong oncological surveillance in this patient population. Demographic characteristics of cohort. Ethnicity Not Hispanic/Latino 3,208 (82.6%) Hispanic/Latino 221 (5.7%) Unknown 457 (11.7%) Race White 3,096 (79.7%) Black/African American 369 (9.5%) Asian 113 (2.9%) Other* 308 (7.9%) Region South 1,360 (35.0%) West/Northwest 1,866 (48.0%) Northeast 622 (16.0%) *Other races include American Indian/Alaska Native, Native Hawaiian or Other Pacific Islander, and unknown race categories.