Background: Cytokine-release syndrome (CRS) and immune‐effector-cell–associated neurotoxicity syndrome (ICANS) remain the principal safety concerns with the CD20×CD3 bispecific antibodies (BsAbs) epcoritamab (Epco) and glofitamab (Glofi). Pivotal trials enrolled highly selected patients; whether baseline clinical or laboratory variables translate into differential CRS/ICANS risk in real-world practice—especially in older, trial-ineligible, or inpatient populations—has not been well described.

Methods: A single-center cohort of 81 consecutive adults with histologically confirmed B-cell non-Hodgkin lymphoma received ≥1 dose of Epco (n = 37) or Glofi (n = 44) between 06/2023–05/2025. CRS and ICANS were graded per ASTCT criteria; grades 3 and 4 were pooled owing to low counts. Baseline variables included inflammatory markers (CRP, ferritin), hematologic and renal parameters, ECOG status, prior CAR-T, CNS involvement, age ≥ 80 y, and trial-eligibility surrogates. Associations with maximum CRS and ICANS were explored with univariate ordinal logistic regression (OLR) and Spearman correlation.

Results: In total, 81 patients were evaluated. The median age was 70 years (range: 22–92), with 16% aged ≥80. The cohort was predominantly male (60%) and White (85%). At treatment initiation, 97% had Ann Arbor stage III–IV disease, 38% had ECOG ≥2, and CNS involvement was observed in 17%. Frequent comorbidities included coronary artery disease and arrhythmia (30%), diabetes (22%), and heart failure (13%). Only 16% of patients met pivotal trial inclusion criteria; primary reasons for trial exclusion were cytopenia (61%), ECOG ≥2 (38%), CNS involvement (17%), inpatient status (11%), heart failure (13%), and abnormal renal function (9%).

CRS occurred in 35.8% of patients: grade 1 (24.7%), grade 2 (4.9%), and grades 3–4 (6.2%). ICANS occurred in 16.0%: grade 1 (6.2%), grade 2 (6.2%), and grades 3–4 (3.7%). CNS involvement at baseline was associated with significantly higher odds of ICANS (OR 5.16, 95% CI 1.31–19.50, p=0.015) but not CRS (OR 2.12, p=0.19), although small subgroup sizes limit precision. Neither age ≥80, cardiac comorbidities, renal impairment, nor trial eligibility status was significantly associated with CRS or ICANS risk.

CRP levels correlated positively with CRS severity (OR 1.07, 95% CI 1.01–1.13, p=0.023). Higher ferritin levels trended towards increased CRS severity (Spearman ρ=0.20; p=0.07) but were not statistically significant in logistic regression (p=0.20). ANC, platelet count, and creatinine did not significantly predict CRS severity.

Lower hemoglobin significantly predicted higher ICANS severity (OR: 0.698 per unit increase, 95% CI: 0.464–0.964, p=0.049), potentially reflecting baseline vulnerability such as poor performance status or limited marrow reserve. CRP, ferritin, ANC, platelet count, and creatinine levels were not significantly associated with ICANS severity.

Thirty-one patients (38%) developed hypogammaglobulinemia (IgG <500 mg/dL) following BsAb therapy; two had pre-existing hypogammaglobulinemia. Median time to hypogammaglobulinemia was 52 days (range: 0–262 days), and 26 patients required IVIG prophylaxis. Severe neutropenia (ANC <500 cells/µL) occurred in 27 patients (33%), with two cases pre-existing, at a median onset of 32 days (range: 0–291 days). All received antibacterial and antiviral prophylaxis during neutropenia. Thirty-six patients (44%) required unexpected hospitalization during BsAb therapy, most commonly due to CRS and infections.

Conclusion: In this real-world cohort, rates of CRS were comparable, whereas ICANS incidence was slightly higher compared to pivotal trials, possibly due to broader patient eligibility, including older individuals and those with comorbidities or CNS involvement. Elevated baseline CRP predicted higher CRS severity, underscoring systemic inflammation as a driver of CRS. ICANS appeared slightly more common and were significantly associated with preexisting CNS involvement and baseline anemia, indicating vulnerability related to neurologic reserve or marrow function. However, the sample size is limited, warranting further validation. The high rates of hypogammaglobulinemia and neutropenia, accompanied by substantial hospitalization rates due to infections and CRS, underscore the necessity for vigilant supportive care, including prophylactic IVIG and antimicrobials, in broader patient populations receiving BsAb therapy.

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2025
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