Infections after bispecific antibodies in B-cell lymphomas.

Introduction

Recent progress in cancer immunotherapy, including the development of bispecific antibodies (BsAbs), has revolutionized the treatment of lymphoid malignancies. For relapsed/refractory B-cell lymphomas, mosunetuzumab started the race with US Food and Drug Administration approval in 2022 for the treatment of follicular lymphoma, followed by epcoritamab in 2023 and glofitamab in 2024 for the treatment of diffuse large B-cell lymphoma. 1 , 2 , 3 , 4 Although these new agents undoubtedly showed excellent efficacy, they have also led to a growing population of patients with B-cell lymphoma to face the short- and long-term side effects of treatments. 5 The cumulative immunosuppressive state caused by both the disease itself and the given BsAb treatment also place these patients at an increased risk of severe infections. 6 , 7

A recent systemic review revealed that 44% of the patients with lymphoma receiving BsAbs have infections, 20% of which are grade ≥3. However, this study was not able to capture the exact etiologies of the infections. Although consensus recommendations on the management of toxicity associated with CD20×CD3 BsAb therapy were published, 8 there are no specific guideline regarding the monitoring, prophylaxis, and treatment of infections in patients with lymphoma undergoing BsAb therapy. The situation is a bit different for multiple myeloma, another disease area in which BsAbs are being actively used and for which specific consensus recommendations regarding infection were established as early as 2023. 9 , 10

Recognizing such a knowledge gap, we conducted this study to delineate the epidemiology, characteristics, clinical course, and risk factors of infections associated with BsAb use in patients with B-cell lymphoma. The objectives were to enhance clinical awareness and to support the establishment of evidence-based monitoring protocols and prophylactic strategies that will ultimately lead to patient safety and maximum therapeutic efficacy.

Methods

Study population

All patients with B-cell lymphoma who underwent CD20×CD3 BsAb therapy (epcoritamab, glofitamab, mosunetuzumab, and odronextamab) between January 2016 and December 2024 at Seoul National University Hospital were included. Patients receiving BsAb therapy through a range of clinical trials were included, whereas those who received BsAbs for <28 days were excluded from the study. Initially, 136 patients were identified; however, after excluding 27 for short duration of BsAb exposure, 109 patients were included in the final analysis ( supplemental Figure 1 ).

This study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines. The study protocol was approved by the institutional review board of Seoul National University Hospital (number H-2502-076-1613). The requirement for informed consent was waived by the institutional review board due to the retrospective nature of the study.

Definition of infection

Each infectious episode was classified as a microbiologically defined infection (MDI), a clinically defined infection (CDI), or fever of unknown focus (FUF), 11 with severity graded according to the National Cancer Institute Common Terminology Criteria for Adverse Event version 5.0. 12 MDI was defined as an infection with a laboratory-confirmed pathogen corresponding to a compatible clinical syndrome, whereas CDI referred to infections in which the site of infection was identified, but no pathogen was isolated. FUF was defined as a febrile episode without an identifiable pathogen or focal symptoms. Fungal infections were defined according to the criteria of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group. 13 , 14 Systemic infection included bacteremia, viremia, fungemia, and infections affecting multiple organs.

Cytomegalovirus (CMV) reactivation was defined as the presence of CMV replication in blood or other sites among patients who were seropositive for CMV. 15 Clinically significant CMV infection (CS-CMVi) was defined as either CMV disease or CMV viremia requiring preemptive treatment. 16 CMV disease was defined by the presence of clinical symptoms and/or signs attributable to CMV, with the confirmation of CMV in the affected organ by histopathology, virus isolation, rapid culture, immunohistochemistry, or DNA hybridization, in accordance with established consensus criteria. 17

Data collection and outcomes

Demographic and clinical data, including patient and disease characteristics, laboratory findings, treatment, and any adverse events, were retrospectively obtained from electronic medical records. Comorbidity score was calculated using the Charlson comorbidity index, excluding age and diagnosis of primary disease. 18 The diagnosis and classification of non-Hodgkin lymphoma was established according to the fifth 2022 World Health Organization classification. 19 The definition of liver disease encompasses chronic hepatitis B or C virus infections, liver cirrhosis, or hepatocellular carcinoma. The corticosteroid dose administered beyond the requirements for BsAb step-up dosing or premedication within the first 30 days of BsAb initiation was calculated and expressed as a prednisolone-equivalent dose. High corticosteroid exposure was defined as the administration of dexamethasone at a dose of ≥10 mg/d for >3 days within a 7-day period. 20

Grading and management of cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) were conducted according to the American Society for Transplantation and Cellular Therapy criteria. 21 Response to BsAb therapy was evaluated according to the Lugano criteria. 22 Progression-free survival and overall survival were defined as the time from commencement of BsAb therapy to disease progression or death from any cause for progression-free survival and to death from any cause for overall survival.

In our institution, antimicrobial prophylaxis was routinely used. Valaciclovir (500 mg once daily) is used for herpes simplex virus and varicella-zoster virus prophylaxis, and trimethoprim/sulfamethoxazole (400/80 mg once daily) is given as Pneumocystis jirovecii pneumonia prophylaxis. 23 Both prophylactic agents were continued until 6 months after the completion of BsAb therapy. A comprehensive clinical and microbiological evaluation was conducted whenever the patient exhibited any symptoms or signs of infection during the BsAb treatment period. Infection episodes were retrospectively recorded from the first day of BsAb treatment until the earliest of the following conditions: 1 year after the last dose, 2 years after the first dose, initiation of subsequent treatment, or death. Follow-up continued until March 2025, with a median follow-up of 28.4 months (95% confidence interval [CI], 20.6-39.3).

Statistical analysis

Descriptive statistics are presented as median values with ranges or numbers with percentiles. Differences between the groups were analyzed using the Student t test or Wilcoxon rank-sum test for continuous variables and the Fisher exact test or Pearson χ 2 test for categorical variables, as appropriate. Median follow-up duration was calculated by the reverse Kaplan-Meier method. Survival outcomes were estimated using the Kaplan-Meier method. The cumulative incidence of infections was analyzed using subsequent treatment and death as competing events. Univariate analyses using Gray test were performed to identify potential predictors of infectious events. Variables with a P value of <.1 in the univariate analysis were included in a multivariate Fine and Gray model, and hazard ratios (HRs) with 95% CIs were calculated. The statistical software R version 4.4.1 ( www.r-project.org ) was used for all statistical analyses. P values of <0.05 were considered statistically significant.

Results

Patient characteristics

The baseline characteristics of the 109 patients are presented in Table 1 . The median age at BsAb therapy initiation was 67 years (range, 29-87). Thirteen patients (11.9%) were classified as underweight, and 5 patients (4.6%) had a Charlson comorbidity index score of >2. Diabetes mellitus and liver disease were present in 24 (22.0%) and 7 (6.4%) patients, respectively. Large B-cell lymphoma represented the most prevalent histologic subtype. The median absolute neutrophil count (ANC) was 3.05 × 10 9 /L (range, 0.06 × 10 9 /L to 18.12 × 10 9 /L), and 11 patients (10.1%) had an immunoglobulin G (IgG) level <400 mg/dL. The median number of prior lines of therapy was 2 (range, 0-6); 18 patients (16.5%) were treatment naïve, 14 (12.8%) had received 1 prior line, and 77 (70.6%) had received ≥2. Overall, 39 patients (35.8%) received BsAb therapy as part of a combination regimen. Median BsAb treatment duration was 5.4 months (range, 1.0-29.5). During the first 30 days of BsAb initiation, 31 patients (28.4%) received corticosteroids beyond premedication use. Among these patients, the median cumulative prednisolone-equivalent corticosteroid dose was 1000 mg (range, 10.0-1866.7).

Adverse events associated with BsAb therapy

CRS occurred in 41 patients (37.6%), including 6 cases (5.5%) of grade 3 severity; no grade 4 events were observed ( Table 2 ). ICANS occurred in 1 patient (0.9%), but no grade ≥3 events. Tocilizumab and dexamethasone were administered in 11 patients (10.1%) and 5 patients (4.6%), respectively, for the management of CRS and/or ICANS. Neutropenia occurred in 58 patients (53.2%) during the treatment period, with grade 3 and 4 neutropenia observed in 17 (15.6%) and 24 (22.0%) patients, respectively. Of the entire cohort, 19 patients (17.4%) received granulocyte colony-stimulating factor as primary prophylaxis. Overall, neutropenic fever occurred in 9 patients (8.3%). All but one of these patients experienced a single episode, with the remaining patient having 3 episodes. Thirty patients (27.5%) died during the study follow-up. Infection was the leading cause of death (16/30 [53.3%]), followed by disease progression (10/30 [33.3%]).

Infection episodes: characteristics and incidence

A total of 134 infection episodes were identified, of which 61.2% were grade ≥3 ( Table 3 ). The most common sites of infection were lower respiratory tract (42.5%), followed by systemic infection (11.2%). The median time from BsAb initiation to the onset of all-grade infections was 6.6 months (range, 0.1-23.5), with bacterial infections having the shortest median time to onset (5.9 months), followed by fungal (7.0 months) and viral infections (8.3 months; Figure 1 ). The number of infection episodes was similar across the 0 to 3, 3 to 6, 6 to 12, and 12 to 24 months, with the lower respiratory tract being the most common site in all periods ( supplemental Table 1 ). Of 134 infections, 95 (70.9%) were MDI, 22 (16.4%) were CDI, and 17 (12.7%) were FUF.

Viral infections were most common, followed by bacterial and fungal infections. There were 58 episodes of viral MDIs in 46 patients. Severe acute respiratory syndrome coronavirus 2 infection was the most common cause (n = 31), followed by CS-CMVi (n = 19). Other viruses detected included hepatitis B virus (n = 4), varicella-zoster virus (n = 2), herpes simplex virus (n = 1), and respiratory syncytial virus (n = 1). There were 25 episodes of bacterial MDIs; 8 were due to gram-positive and 14 to gram-negative organisms. Escherichia coli was the most frequently isolated (n = 7), followed by Pseudomonas aeruginosa (n = 3). There were 12 fungal infections, including 6 episodes caused by P jirovecii , 4 by Aspergillus spp., and 2 by Candida spp.

Among the 109 patients, 68 (62.4%) experienced at least 1 infection episode, with 41 (37.6%) having grade ≥3 infections ( supplemental Table 2 ). A total of 35 patients (32.1%) had ≥2 infections, and 22 (20.2%) had multiple grade ≥3 infections. There was no difference in the proportion of patients who experienced infections between those treated with BsAb monotherapy and those receiving combination therapy. Similarly, the proportion of patients who experienced infections did not differ according to the line of therapy ( supplemental Table 3 ).

The cumulative incidence of all-grade any infection and all-grade viral infection steadily increased over 24 months, reaching 34.7% (95% CI, 25.7-43.8) and 16.0% (95% CI, 9.7-23.6) at 6 months and 76.4% (95% CI, 62.1-85.9) and 54.2% (95% CI, 41.0-65.7) at 24 months, respectively ( Figure 2 A). The 24-month cumulative incidence of all-grade any infection, excluding FUF, was 71.5% ( supplemental Figure 2 ). The cumulative incidence of grade 3 to 5 any and viral infections exhibited a steady increase over 12 months, with 12-month incidences of 33.0% (95% CI, 24.0-42.2) and 16.0% (95% CI, 9.6-23.9), respectively ( Figure 2 B). The cumulative incidence of grade 5 infection was 8.1% (95% CI, 3.7-14.6) at 12 months ( Figure 2 C). In the subgroup analysis of 77 patients with large B-cell lymphoma, the infection profile and cumulative incidence exhibited patterns similar to those of the overall cohort ( supplemental Table 4 ; supplemental Figure 3 ).

Among 107 patients who were CMV seropositive, CMV reactivation occurred in 36 patients (33.6%) at a median of 3.2 months (range, 0.5-19.2; supplemental Table 5 ), and the 12-month cumulative incidence of CMV reactivation was 32.6% (95% CI, 23.1-42.5). CS-CMVi occurred in 16 patients (14.7%). Overall, 8 patients (7.3%) developed CMV disease, with the gastrointestinal tract being the most commonly involved site. The cumulative incidence of CS-CMVi and CMV disease steadily increased over 12 months, reaching 15.1% (95% CI, 8.3-23.7) and 8.6% (95% CI, 3.7-16.1), respectively, at 12 months ( Figure 3 ).

Risk factors for infection

Various factors, including age, sex, nutritional status, comorbidities, histologic subtype, disease status, baseline immune parameters (such as neutropenia), treatment type, and corticosteroid use, were assessed for their association with infection risk. In the univariate analysis, hypogammaglobulinemia (IgG level of <400 mg/dL) was consistently associated with an increased risk of any infection ( supplemental Table 6 ) and viral infection ( supplemental Table 7 ). High corticosteroid exposure was not a statistically significant predictor of infections. In the multivariate analysis ( Table 4 ), neutropenia (ANC of <1000/μL) and hypogammaglobulinemia were associated with an increased risk (HR, 6.18 [95% CI, 1.76-21.68] and HR, 3.44 [95% CI, 1.93-6.14], respectively) of all-grade infection, whereas hypogammaglobulinemia was the sole independent risk factor for grade 3 to 5 infection (HR, 5.29; 95% CI, 2.69-10.38). Regarding viral infection, hypogammaglobulinemia (HR, 2.50; 95% CI, 1.12-5.59) was the sole independent risk factor.

Discussion

This study represents, to our knowledge, the largest single-center, infection-focused cohort to date reporting detailed infection rates, characteristics, and risk factors in patients treated with CD20×CD3 BsAb for B-cell lymphoid malignancies. Throughout the treatment course, the rate of all-grade infection was 62.4% and grade 3 to 5 infections was 37.6%. A concerning rise in cumulative infection incidence was observed, reaching 75% at 24 months. We identified neutropenia and hypogammaglobulinemia as risk factors for infection. All our findings (1) highlight the need to raise physician and patient vigilance, (2) support the development of targeted infection prophylaxis and management guidelines, and (3) suggest that treatment duration and dosing strategies for BsAb therapy may warrant further evaluation.

As mentioned earlier, the infection rates captured in our study (all grades, 62.4%; grades 3-5, 37.6%) were higher than those reported by Reynolds et al. (all grades, 44%; grades 3-5, 20%) in their recent meta-analysis. 24 The observed difference is attributable to the composition of the study population: the meta-analysis predominantly included patients with more favorable performance status and fewer comorbidities, whereas our cohort comprised individuals with a broader range of frailty and disease burden. In this sense, our results not only complement the results of the meta-analysis, but also offer insights that are more relevant to real-world clinical practice. With an adequate median follow-up duration of 28.4 months, we were able to provide details of the infection trajectory in our study. Bacterial infections are first to come with a median onset of 5.9 months, followed by fungal infections (7.0 months) and viral infections (8.3 months). This infection pattern is somewhat similar to what we observe in patients after allogeneic hematopoietic stem cell transplantation(HSCT), but the overall severity and cumulative incidence seem to be higher probably due to deeper and sustained immune modulation with continued BsAb use. 25 , 26 , 27

Continuing on the types of infections, we reported some interesting observations concerning viral infections. Severe acute respiratory syndrome coronavirus 2 infection was the most common viral infection in our cohort. This observation aligns with the study time frame, which encompassed the peak years of the COVID-19 pandemic. Given the constantly evolving epidemiological circumstances, transmission rates, and associated mortality of emerging infectious diseases, continued vigilance and monitoring of prevalent infections at a given time are warranted. 28 The second most common viral infection was CMV, and this is a previously underappreciated observation. Most of the current understanding of CMV risk, incidence, and management is derived from studies in the solid-organ transplantation and HSCT settings. Depending on the organ type and donor serostatus, the reported incidence of CS-CMVi is as high as 60%, whereas CMV disease occurs in up to 30% of solid-organ transplant recipients. 29 , 30 , 31 In allogeneic HSCT, the incidence of CS-CMVi reaches up to 51% in seropositive recipients, and CMV disease in up to 8% of recipients. 32 , 33 In comparison, the incidence of CS-CMVi and CMV disease in our cohort was 14.7% and 7.3%, respectively. Although these rates seem lower, it is more than what we have observed in the rituximab era, and the accumulating evidence regarding the association between BsAb treatment and CMV infection underscores the need for better awareness and routine monitoring in selected high-risk patients. 34 , 35 , 36 The high incidence of CS-CMVi and CMV disease in this study highlights the need for effective preventive measures against CMV infection. Currently, in the absence of BsAb-specific guidelines, management is largely limited to preemptive therapy. 9 Nonetheless, evidence is lacking on whether asymptomatic CMV viremia during BsAb treatment leads to CMV disease, and the benefit of prophylaxis in this context remains uncertain. Prospective studies are needed to assess prophylactic approaches, such as fixed-duration letermovir. 37 , 38

To mitigate the infection risk, we found that it is important to manage neutropenia and hypogammaglobulinemia. Specifically, grade ≥3 neutropenia (ANC of <1000/μL) is a risk factor for all-grade infections, whereas hypogammaglobulinemia (IgG level of <400 mg/dL) is a risk factor for both all-grade infections and viral infections. Considering that neutrophils are the innate immune system’s first line of defense against infection, the severity and duration of neutropenia are directly correlated with infections, particularly for opportunistic organisms. 39 Given that the reported incidence of grade ≥3 neutropenia is ∼30%, 1 , 2 , 3 , 40 secondary prophylaxis, if not primary prophylaxis, should be considered for all patients.

Hypogammaglobulinemia is also a well-known risk factor for infections with encapsulated extracellular bacteria and certain viruses. 41 , 42 With the expansion of immunotherapy in B-cell lymphomas, more emphasis is being placed on monitoring immunoglobulin levels as a critical component of supportive care. Specifically, CD20×CD3 BsAbs induce hypogammaglobulinemia through on-target, off-tumor depletion of normal B cells, delayed B-cell reconstitution even after treatment cessation, and impaired IgG synthesis caused by T-cell activation. 43 This phenomenon warrants IV immunoglobulin replacement because IV immunoglobulin use has consistently showed a reduction of serious infections in patients undergoing BsAb treatment. 44 , 45 , 46 Based on our findings, our institution has implemented a protocol of monitoring serum IgG levels every 4 weeks in patients receiving BsAb therapy, with IV immunoglobulin administered when IgG levels fall below 400 mg/dL. The optimal use of IV immunoglobulin, including prophylaxis vs reactive usage, as well as appropriate dosing, requires further investigation. Reassuringly, the use of corticosteroids during the first month of BsAb treatment was not associated with an increased risk. Therefore, the use of corticosteroids to control CRS or ICANS should not be avoided.

Collectively, our results underscore the importance of ongoing efforts to optimize BsAb treatment, particularly in balancing efficacy and long-term safety. Biomarker-driven, risk-adaptive scheduling for individualized therapy is necessary but unfortunately, we are not able to provide corroborative data on immune profiling from our cohort due to the retrospective nature of the study. Furthermore, given that this is a single-center study leveraging patients from various clinical trials, extrapolation to other settings or real-world practice may be limited. Therefore, a larger longitudinal real-world cohort study, supported by biobank resources such as CMV-specific T-cell immunity profiling, is warranted.

In conclusion, patients with B-cell lymphoma undergoing BsAb treatment represent an emerging at-risk population for a distinct spectrum of infections. Through our study, we have characterized the infectious disease landscape and identified key risk factors to guide clinicians and patients toward optimal BsAb treatment outcomes. The prospective validation of preemptive strategies, including the use of primary neutropenia prophylaxis, prophylactic IV immunoglobulin use, type and duration of antimicrobial prophylaxis, and the development of biomarkers for tailored therapy should be encouraged.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Acknowledgments

The authors thank all the medical staff at Seoul National University Hospital, especially Eunhee Park and Minjeong Seo, for their devotion and unwavering support.

Authorship

Contribution: D.H.K. wrote, edited, and reviewed the original draft and contributed to visualization, formal analysis, investigation, data curation, and conceptualization; N.L. reviewed and edited the manuscript and contributed to investigation and data curation; Y.K. reviewed and edited the manuscript and contributed to investigation, resources, and supervision; H.J.J., C.K.K., P.G.C., and W.B.P. reviewed and edited the manuscript and contributed to investigation and resources; C.M.L. and J.M.B. wrote, edited, and reviewed the original draft and contributed to formal analysis, investigation, resources, data curation, supervision, and conceptualization; and N.J.K. reviewed and edited the manuscript and contributed to investigation and resources.

Footnotes

The data sets generated during this study are available from the corresponding authors, Chan Mi Lee ( heaven229@snu.ac.kr ) and Ja Min Byun ( jaminbyun86@gmail.com ), upon reasonable request.

The full-text version of this article contains a data supplement.

Contributor Information

Chan Mi Lee, Email: heaven229@snu.ac.kr.

Ja Min Byun, Email: jaminbyun@snu.ac.kr.

Supplementary Material

Supplemental Figures and Tables

References

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