Infections in Lymphoma Patients Treated with Bispecific Therapies: A Systematic Review and Meta-Analysis
Authors: Reynolds Gemma K , Maclean Marsali , Teh Benjamin , Thursky Karin A , Slavin Monica A , Anderson Mary Ann , Hawkes Eliza A 
Published: December 2023

CONCLUSION
BACKGROUND
Bispecific antibodies (BsAb) demonstrate efficacy in newly diagnosed and relapsed/refractory lymphomas. BsAb act by forming immune synapses between an effector cell (T cell or NK cell) surface markers and target cell surface markers, typically CD19 and CD20 in B-cell lymphoma; and CD30 in T-cell lymphomas. Improved understanding of the infection risks associated with BsAbs is required to improve patient outcome.
METHODS
MEDLINE, EMBASE, Cochrane and Google Scholar were searched to identify relevant studies up to June 15, 2023. Phase I-III clinical trials and observational studies of BsAb monotherapy and combination therapy in adult patients were included. Study identification, data-extraction and bias-assessment were performed by two authors (Figure 1). The primary outcome was the number of bispecific-treated lymphoma patients who experienced ≥ 1 infection of any grade. Secondary outcomes included severe infections (grade ≥ 3), fatal infections and the incidence of microbiologically confirmed bacterial, viral and fungal infections. Sub-analysis by malignant target (CD19 vs CD20), and monotherapy versus combination therapy was performed. Meta-analysis of proportions estimated the pooled infection incidence using random effects model (Mantel-Haenszel). Cochran's Q test examined heterogeneity. PROSPERO registration (CRD42023433207).
RESULTS
Of 1796 studies, 23 studies (1423 pts) were included, with a median age of 64 years (IQR 60 - 66). Nineteen studies (1124 pts) reported the primary outcome of all-grade infections, which occurred in 37% of patients (95%CI: 30 - 45%) (Figure 2). 13% of patients experienced a grade ≥ 3 infection (12 studies, 843 pts, 95%CI: 9 - 17) and 2% (N = 35) experienced a fatal infection (18 studies, 1318 pts, 95%CI: 1 - 2%).
35 fatal infections were reported (1124 pts), with aetiology reported in 97% (N = 34). 68% of fatal infections (23/34) were microbiologically identified. Fatal infections were predominately viral (70%, 16 infections, 15 deaths from COVID-19, 1 death from EBV), followed by fungal (17%, 4 infections, 3 deaths from pneumocystis jirovecii, 1 death from candida species), bacterial (9%, 2 infections, E. coli and Klebsiella sepsis) and 1 parasitic infection (toxoplasmosis). 11 clinically defined fatal infections occurred; 3 fatal pneumonias, and 8 cases of fatal ‘septic shock’ without a causative pathogen listed.
302 patients (8 studies) with aggressive B-cell lymphoma were compared to 129 indolent lymphoma patients (2 studies). All-grade infections were significantly higher in the aggressive B-cell lymphoma subgroup (41%, 95%CI: 33 - 49%) compared to the indolent subgroup (27%, 95%CI: 10 - 44%, z = 2.77, p = 0.005). The weighted median of prior therapies in the aggressive lymphoma group was comparable to the indolent group (3 vs. 2.5 prior therapies). Grade ≥ 3 infections (14% vs 11%) and fatal infections (3% vs 0%) did not differ significantly between aggressive and indolent subtypes (p &gt; 0.05).
Patients receiving CD20/CD3 BsAb monotherapy experienced a significantly higher rate of all-grade infections (42% vs 29%, z = -3.14, p &lt; 0.01) and grade ≥ 3 infections (17% vs 7%, z = -3.23, p &lt; 0.01) than patients receiving CD19/CD3 monotherapy. Fatal infections were comparable between CD20/3 and CD19/3 products. Microbiological aetiology and clinical sites of infections were not commonly reported.
In subanalysis of CD20/CD3 products, pooled all-grade infections did not differ significantly between monotherapy epcoritimab (34% 95%CI: 21 - 47%) and glofitamab (39% 95%CI: 21 - 56%). Analysis of all-grade and grade ≥ 3 infections related to monotherapy mosunetuzumab and odronextumab was not possible due to inconsistent reporting of these outcomes across studies. When used in combination, all-grade infections for epcoritimab were comparable to epcoritimab monotherapy (34% 95%CI: 21 - 47% vs 42% 95%CI: 31 - 52%, z = 1.13, p = 0.258). Mosunetuzumab was given with R-CHOP in a single study, but all-grade and severe infection rates were not reported.
This systematic review reports a modest rate of serious infections in lymphoma patients receiving BsAb. The higher rate of fatal viral and fungal infections highlights a potential need for increased clinical vigilance for infections classically associated with T-cell depletion. Although further data is needed, CD20-targeted BsAb may confer higher infection risk than CD19-directed products.