Infections in patients with aggressive B-cell lymphomas treated with CD3xCD20 bispecific antibodies

Abstract

Abstract Introduction CD3xCD20 bispecific antibodies (BsAbs) can provide durable responses for patients with aggressive B-cell lymphomas. However, they can cause toxicity, including cytokine release syndrome, neurotoxicity, cytopenias, and infections. Although infections have been studied with BsAbs for multiple myeloma, data are more limited with CD3xCD20 BsAbs. Here, we aim to describe severe (grade 3-5, G3-5) infections in patients with aggressive B-cell non-Hodgkin lymphomas (B-NHLs) treated with BsAbs and define risk factors for severe infection. Methods A 14-site consortium identified patients with aggressive B-NHLs who received BsAb. Infections were microbiologically defined (attributed to specific pathogens) or clinically defined (based on clinical judgment in the absence of identified pathogens) by investigators. Since infection timing was documented in intervals after starting BsAb (0-30 days, 1-6 months, or >6 months), we estimated rates of first G3-5 infection using piecewise exponential models with interval as a covariate and a log(patient-time) offset. Likelihood ratio tests and inspection of variance components supported using random intercepts to account for repeated measures within patients. Patients were removed from the risk set after the interval in which their first G3-5 infection, death, or loss to follow-up occurred. G3-5 infection rates are presented as marginal means, whereas hazard ratios are presented as conditional means. Cumulative incidence and survival functions were estimated using the Aalen-Johansen and Kaplan-Meier estimators, respectively. Results 263 patients initiated BsAb 9/20/2018-4/15/2025. Baseline characteristics included median age 67 (range 24-101); 22% ECOG 2-4; 41% female; 14% African American, 3% Asian, 76% Caucasian, 7% other race; 10% Hispanic; 60% DLBCL, 16% double/triple-hit lymphoma, 15% transformed indolent lymphoma, 10% other aggressive B-NHL; and median prior lines 3 (range 0-12). BsAbs were 44% glofitamab, 30% mosunetuzumab, 23% epcoritamab, and 3% other BsAb. BsAbs were used 64% as monotherapy, 14% with polatuzumab vedotin, 9% with chemotherapy, and 14% with other combination partners. Median follow-up for overall survival (OS) was 1.4 years (range 0.0-5.4). Of 76 G3-5 infections, about 75.5% were microbiologically defined (40 microbiologically defined, 13 clinically defined, 23 missing). Microbiologically defined G3-5 infections were 55.0% bacterial, 45.0% viral (44.4% COVID-19), and 10.0% fungal (infections attributed to >1 type of pathogen are listed in multiple categories). Without accounting for follow-up, 11.8% and 13.9% of patients had a G3-5 infection by day 30 and any time. Taking follow-up into account, rates of first G3-5 infection were overall 4.5/100 patient-months (95% CI 1.2-7.8), day 0-30 8.9/100 patient-months (95% CI 2.4-15.4), 1-6 months 3.5/100 patient-months (95% CI 1.5-5.5), and >6 months 1.5/100 patient-months (95% CI 0.6-2.4). Baseline characteristics associated with rate of first G3-5 infection were: ECOG 2-4 (vs. ECOG 0-1, HR 2.43, 95% CI 1.06-5.55, p=0.035); double/triple-hit lymphoma (vs. DLBCL, HR 2.17, 95% CI 1.17-4.04, p=0.014) and other aggressive B-NHL (vs. DLBCL, HR 2.67, 95% CI 1.20-5.92, p=0.016); elevated LDH (HR 2.92, 95% CI 1.61-5.30, p<0.001); number of prior lines of therapy (HR 1.20, 95% CI 1.08-1.34, p=0.001); prior bendamustine (HR 2.80, 95% CI 1.57-4.99, p<0.001); prior CAR-T (HR 1.95, 95% CI 1.17-3.24, p=0.010); use of mosunetuzumab (vs. glofitamab, HR 0.27, 95% CI 0.13-0.55, p <0.001); and receipt of BsAb on a clinical trial (HR 0.47, 95% CI 0.26-0.84, p=0.010). Sex, age, baseline absolute neutrophil and lymphocyte counts, response status, prior autologous stem cell transplant, and agents used in combination with BsAb (vs. single-agent BsAb) were not significantly associated with rate of first G3-5 infection. Cumulative incidence of death from infection at 30 days was 1.9% (95% CI 0.7-4.2), at 6 months was 6.7% (95% CI 4.0-10.3), and at 1 year was 13.1% (95% CI 8.9-18.1). OS at 30 days was 92.7% (95% CI 89.5-95.9), at 6 months was 65.8% (95% CI 60.0-72.2), and at 1 year was 50.9% (95% CI 44.5-58.2). Conclusions Severe infections are common in patients with aggressive B-NHLs treated with CD3xCD20 BsAbs, with highest risk in the first 30 days of treatment. Baseline poor performance status, double/triple-hit lymphoma, elevated LDH, increasing exposure to therapy, and prior bendamustine and CAR-T are all associated with increased risk.