Bispecific Antibodies in Non-Hodgkin Lymphoma Show Manageable Safety Profile in Meta-Analysis
Key Takeaways
- Frequent but manageable toxicities: High rates of neutropenia and infections require coverage for monitoring, prophylaxis, and supportive interventions.
- Combination therapy increases overall toxicity: Elevated rates of all-grade adverse events (AEs) with combination regimens may impact total cost of care and should be considered in value assessments.
- Low rates of severe cytokine release syndrome (CRS) and neurotoxicity: Favorable severe toxicity profile compared with other immunotherapies may support expanded site-of-care options.
- Differences across bispecific antibodies (BsAb) products: Variability in safety outcomes may influence formulary placement, prior authorization, and clinical pathways.
- Need for long-term and real-world evidence: Limited follow-up and inconsistent reporting highlight the importance of ongoing data collection to inform durable coverage decisions.
A systematic review and meta-analysis of 32 clinical trials involving 2192 patients is shedding new light on the safety profile of BsAbs in non-Hodgkin lymphoma (NHL), offering important insights for clinicians, payers, and managed care stakeholders evaluating their growing role in treatment.
Study Findings
BsAbs, which function by linking CD3-positive T cells to CD20-expressing malignant B cells, have emerged as a key immunotherapy option in relapsed or refractory (R/R) NHL. With 3 agents already approved for use in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), their integration into clinical practice is accelerating. However, questions around safety—particularly in heavily pretreated populations—have remained a critical concern.
The pooled analysis found that hematologic toxicities and infections were the most frequently reported AEs. All-grade neutropenia occurred in 38% of patients, with 26% experiencing grade ≥3 neutropenia. Infection rates were similarly notable, affecting 38% of patients overall and 12% at grade ≥3 severity. Fatal infections were uncommon, reported in 2% of cases.
Immune-mediated toxicities, often associated with T-cell–engaging therapies, were also examined. CRS occurred in 48% of patients, although severe CRS (grade ≥3) was rare at 2%. Neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS), was infrequent, affecting 5% of patients overall and only 1% at higher severity grades.
The study also identified meaningful differences between treatment strategies. Combination regimens—pairing BsAbs with chemotherapy or immunomodulatory agents—were associated with higher rates of all-grade infections (46% vs 30%) and neutropenia compared with BsAbs monotherapy. However, rates of severe infections did not significantly differ, suggesting that while combination therapy increases overall toxicity burden, it may not proportionally increase life-threatening complications.
Safety profiles varied across individual cases of BsAbs. Mosunetuzumab was associated with lower rates of infections and CRS, whereas odronextamab demonstrated higher rates of severe infections, though conclusions are limited by smaller sample sizes. These differences may become increasingly relevant for formulary decision-making and pathway optimization.
Despite these risks, the authors conclude that toxicity is generally manageable with current mitigation strategies, such as step-up dosing and supportive care. The authors noted that “BsAbs demonstrated an overall manageable safety profile, suggesting their viability as a treatment option in the relapsed/refractory setting.”
Conclusion
For managed care stakeholders, the findings highlight both opportunity and complexity. Compared with other immunotherapies such as chimeric antigen receptor (CAR) T-cell therapy, BsAbs may offer a more favorable severe toxicity profile, potentially enabling broader use in outpatient settings and reducing resource intensity. However, the relatively high rates of infections and cytopenias underscore the need for proactive monitoring and supportive care infrastructure.
The analysis also points to ongoing evidence gaps. Variability in adverse AE reporting across trials and a relatively short median follow-up of 9.4 months limit a fuller depiction of long-term risks, particularly in infections related to sustained immune suppression. As BsAbs move into earlier lines of therapy, real-world data and standardized reporting will be essential to guide coverage policies and optimize patient outcomes.
Reference
Fonesca R, Liu AJ, Langlais BT, Almader-Douglas D, Vickram HR, Hilal T. Safety landscape of bispecific antibody therapy in non-Hodgkin lymphoma: a meta-analysis. Blood Neoplasia. 2025;2(1):100061. doi:10.1016/j.bneo.2024.100061
