Background

CD20×CD3 bispecific antibodies: mosunetuzumab, epcoritamab, and glofitamab are approved for relapsed/

refractory B-cell lymphoma. Long-term safety regarding secondary primary malignancies (SPM) is incompletely

defined in a population already exposed to cytotoxic therapy, T-cell dysfunction, and cumulative immunosuppression.

No published study has systematically evaluated SPM risk across this class.

Methods

FDA Adverse Event Reporting System (FAERS) reports of mosunetuzumab, epcoritamab, and glofitamab in lymphoma

patients (Q4 2022–Q4 2025) were screened for SPM via MedDRA preferred terms, clinically adjudicated,

and deduplicated. Reporting odds ratios (RORs; 95% CIs; signal: lower limit of 95% CI >1.0) were calculated

overall and against CAR-T comparators.

Results

Among 4237 lymphoma reports (epcoritamab, 2368; glofitamab, 1138; mosunetuzumab, 731), 29 unique SPM

cases were adjudicated (12 certain/probable; 17 uncertain), pooled SPM rate 0.68%. Per-drug rates were: glofitamab,

1.23%; epcoritamab, 0.51%; and mosunetuzumab, 0.41% (all uncertain). Median age of SPM patients was

70 years (range, 29–90). The underlying lymphoma was DLBCL (53.6%) and follicular lymphoma (17.9%). Hematological

SPMs comprised 42.9% (12/28): AML/MDS (n=7), leukemia NOS (n=3), ALL (n=1), multiple myeloma

(n=1). Solid tumors accounted for 39.3% (skin, 14.3%; GI, 14.3%; breast, 10.7%). Nearly three-quarters (73.7%)

of SPM patients were aged ≥65 years, and one-third (31.6%) were ≥75 years; a population with elevated baseline

malignancy risk, supporting age-stratified post-marketing surveillance. Median time to onset (n=9 with available

dates) was 515 days (range, 1–1096). Case fatality was 21.4% (6/28); highest with glofitamab (28.6%) and lowest

with mosunetuzumab (0%).

Conclusion

In this comprehensive FAERS analysis spanning 13 quarters and over 4200 bispecific antibody + lymphoma

reports, SPM events associated with CD20×CD3 bispecific antibodies were rare (pooled rate, 0.68%) with no

disproportionality signal detected at the class or individual drug level. Hematologic malignancies (predominantly

AML/MDS) comprised the largest SPM subtype, consistent with known therapy-related myeloid neoplasm risk in

a heavily pretreated lymphoma cohort. The case fatality rate of 21.4% underscores the clinical significance of

SPMs when they do occur. Importantly, the bispecific class showed a significantly lower SPM reporting frequency

compared to CAR-T therapy. These findings provide reassuring real-world safety data for the CD20×CD3

bispecific class, though ongoing surveillance with longer follow-up is warranted as post-marketing exposure

accumulates.

ALL: acute lymphoblastic leukemia, AML: acute myeloid leukemia, CAR: chimeric antigen receptor, CD: cluster of

differentiation, DLBCL: diffuse large B-cell lymphoma, FDA: Food and Drug Administration, GI: gastrointestinal,

MDS: myelodysplastic syndrome, MedDRA: medical dictionary for regulatory activities, NOS: not otherwise

specified

Keywords

ABCL, aggressive B-cell lymphoma, secondary primary malignancies, bispecific antibodies, NHL, FAERS, pharmacovigilance,

reporting odds ratio