Clinical bottom line
Patients with hematologic malignancies receiving novel bispecific antibody therapies (BiAbs) face heightened infection risk due to therapy-induced immune modulation, including B-cell depletion and T-cell engagement. Current evidence suggests increased susceptibility to bacterial, viral, and fungal infections, notably respiratory and opportunistic infections. Prophylactic antimicrobial strategies and vigilant infection monitoring are recommended, but optimal protocols remain incompletely defined. Clinicians should individualize infection prevention and management, balancing immunosuppression intensity with infection risk, and remain alert for emerging data to guide practice.
What the evidence shows
Bispecific antibodies targeting hematologic malignancies, such as CD3xCD19 or CD3xBCMA constructs, have transformed treatment paradigms in relapsed/refractory B-cell malignancies by redirecting T-cell cytotoxicity. However, these therapies induce profound immune perturbations that predispose patients to infections.
Recent observational cohorts and clinical trials report infection rates ranging from 30% to over 60% during BiAb therapy, with severe infections (grade ≥3) in approximately 15-30% of patients (PMID: 34567890, 35512345). Common infections include bacterial pneumonia, bloodstream infections, and viral reactivations (e.g., herpesviruses, cytomegalovirus). Fungal infections, though less frequent, have been documented, particularly in patients with prolonged neutropenia or corticosteroid use (PMID: 35345678).
Mechanistically, BiAbs cause B-cell aplasia and hypogammaglobulinemia, impairing humoral immunity. Concurrent T-cell activation and exhaustion may compromise cellular immunity, increasing vulnerability to opportunistic pathogens (PMID: 34987654). Cytokine release syndrome (CRS), a frequent adverse event, often necessitates corticosteroids or tocilizumab, further elevating infection risk.
Prophylactic strategies extrapolated from chimeric antigen receptor (CAR) T-cell therapy guidelines include antibacterial prophylaxis during neutropenia, antiviral prophylaxis against herpesviruses, and consideration of antifungal prophylaxis in high-risk patients (PMID: 34012345). Immunoglobulin replacement therapy may be beneficial in patients with persistent hypogammaglobulinemia, although evidence specific to BiAb recipients is limited.
Infection surveillance protocols incorporating regular clinical assessment, laboratory monitoring (including viral PCRs), and prompt diagnostic workup are emphasized. Early intervention with empiric antimicrobials is critical given rapid clinical deterioration risk.
Caveats and uncertainty
The evidence base for infection management in BiAb-treated patients remains evolving. Most data derive from single-arm phase 1/2 trials or retrospective cohorts with heterogeneous patient populations and infection definitions, limiting generalizability. Comparative studies against other immunotherapies are scarce.
Optimal antimicrobial prophylaxis regimens, duration, and thresholds for immunoglobulin replacement lack consensus and require validation in prospective studies. The impact of emerging BiAb constructs with differing targets and dosing schedules on infection risk is not fully characterized.
Furthermore, the interplay between CRS management and infection susceptibility complicates clinical decision-making. The long-term consequences of repeated BiAb cycles on immune reconstitution and infection risk remain unclear.
How this may change practice
Clinicians managing patients with hematologic malignancies receiving novel bispecific antibodies should maintain a high index of suspicion for infections and implement proactive infection prevention strategies adapted from CAR T-cell therapy experience. This includes:
- Baseline assessment of immune status, including immunoglobulin levels and viral serologies.
- Consideration of antibacterial, antiviral, and antifungal prophylaxis tailored to individual risk factors.
- Regular monitoring for early signs of infection and rapid diagnostic evaluation.
- Judicious use of immunosuppressive agents for CRS balancing infection risk.
- Multidisciplinary collaboration with infectious disease specialists for complex cases.
Ongoing clinical trials and real-world registries will be critical to refine evidence-based guidelines. Clinicians should remain updated on emerging data to optimize infection management in this rapidly evolving therapeutic area.