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Bispecifics in DLBCL
Our Thoughts on Recognizing and Managing Adverse Events Associated With Bispecific Antibodies in the Management of Patients With DLBCL

Released: May 07, 2026

Kathleen Dorritie
Kathleen Dorritie, MD
Tycel J. Phillips
Tycel J. Phillips, MD
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Key Takeaways
  • CRS with CD20/CD3 bispecifics is mainly low grade, most likely to occur during the first 1-2 cycles of bispecific antibody administration, rare beyond cycle 2, and can generally be managed as an outpatient.
  • Best practice is to vaccinate patients against flu, COVID-19, and other viruses before starting on bispecific antibodies.
  • In patients with neurologic symptoms of ICANS who receive bispecific antibody treatment, symptoms usually resolve quickly after corticosteroid treatment.

Modern treatment for relapsed diffuse large B-cell lymphoma (DLBCL) is shifting away from chemo-immunotherapy-based salvage (eg, RICE and R-GEMOX) toward approaches like CAR T-cell therapies (eg, axicabtagene ciloleucel, lisocabtagene maraleucel, and tisagenlecleucel), bispecific antibodies (eg, epcoritamab and glofitamab), and adding antibody–drug conjugates like polatuzumab vedotin or brentuximab vedotin. Although CAR T-cell therapy can achieve durable long-term remission in many patients with DLBCL, several obstacles still exist which limit the accessibility of this option in those requiring salvage therapy. Bispecific antibodies are an off-the-shelf treatment option that serve as a standalone treatment or even a bridge to CAR T-cell therapy. Unlike issues with clinical integration of autologous stem cell transplantation, there is no age cutoff for bispecific antibodies. Even patients with significant comorbidities can receive these therapies. Nevertheless, there are expected challenges with adverse events (AEs) when new agents are introduced into clinical practice. Below is a summary of our perspectives on challenges associated with the optimal clinical integration of bispecific antibodies into care for patients with DLBCL.

Overall Strategies for Recognizing, Addressing, and Managing AEs

Tycel J. Phillips, MD:
Optimizing the safety of bispecific antibody therapy requires a proactive, multidisciplinary approach that emphasizes early recognition, risk mitigation, and coordinated management of treatment-related AEs across care settings. This includes (1) developing safe methods for administering bispecific antibodies, (2) monitoring for toxicities, and (3) ensuring equal access. Healthcare professionals must be comfortable recognizing, addressing, and managing AEs associated with bispecific antibodies. Although grade ≥3 cytokine release syndrome (CRS) and immune effector cell–associated neurologic syndrome (ICANS) affect <2% of patients, serious AEs, particularly cytopenias and infections, remain an important safety concern and vary by agent, disease setting, and patient population. It is also important to implement a team-based approach where the pharmacist, nurse, navigator, and physician work together to ensure the best outcome for patients receiving bispecific antibodies. Ongoing partnerships between large centers and community offices are critical.

Kathleen Dorritie, MD:
Several broad strategies are currently used to mitigate the safety and tolerability of bispecific antibodies that are either approved or under investigation for DLBCL care (ie, epcoritamab, glofitamab, odronextamab, and mosunetuzumab). One such approach is through corticosteroids, which are commonly given as a prophylactic measure with bispecific antibodies, unlike with CAR T-cell therapy, where steroids are not routinely given since they have lympholytic and T-cell–suppressive effects. Other approaches include the use of a priming dose or step-up dosing schedule and hospitalization for CRS or toxicity monitoring. At many centers, step-up dosing is done inpatient, although this approach is starting to shift toward the community setting because hospitals often have limited bed availability and space. Having strategies in place before a toxicity such as CRS occurs is key, like confirming the availability of acetaminophen, intravenous fluids, steroids, and tocilizumab and having staff trained to monitor and recognize AEs.

Deciding whether a patient is a candidate for bispecific antibodies is also a strategy for mitigating AEs, especially those with a high tumor burden who are at higher risk. Other concerns include underlying cardiac disease, comorbidities, or a lack of caregivers and social support. It is important for both patients and caregivers to know what to do if patients experience fever at home. In addition, providing patients and caregivers with printed, detailed information about symptoms to report, contact numbers to call, including after-hours numbers, and how to respond while they seek medical intervention can help.

Monitoring for Bispecific Antibody–Related CRS

Kathleen Dorritie, MD:
The window for CRS monitoring is important to note for outpatients receiving a bispecific antibody. The greatest severity of CRS occurs during the first cycle. Some patients do develop grade 1 CRS in cycle 2, but in cycle 3 and beyond, it is rare. For this reason, a large or academic center may initiate treatment with step-up dosing and then transition patients to a community site when the risks are much lower. Patients are typically assessed by a healthcare professional at 24 and 48 hours after infusion and as needed. Then, if the assessment is negative for CRS, the patient can continue therapy. CRS often starts with a fever, although it is possible to develop a fever because of an infection within 12-48 hours after the first dose. In addition, an elevated heart rate is usually an early trigger accompanied with fever. In a community center, if a patient has any concerning symptoms 24-48 hours after treatment, a simple communication plan should be in place to advise patients to go to their local emergency department.

Tycel J. Phillips, MD:
When monitoring for AEs associated with bispecific antibodies, I focus on CRS because it is the most common event. However, fortunately, the risk of high-grade CRS is quite low, usually <5%. In fact, the phase III SUNMO trial of mosunetuzumab plus polatuzumab vedotin in transplant-ineligible patients with relapsed/refractory LBCL reported that <1% of patients developed grade ≥3 CRS. Several strategies integrated into bispecific antibody treatment have helped reduce the risk of CRS. Optimization strategies incorporating more priming doses and intermediate step-up doses have also aimed to lower the incidence or severity of CRS with success. In addition, subcutaneous formulations of bispecific antibodies may lower the risk of CRS, probably because of slower absorption than intravenous formulations. Additionally, combination with additional agents including chemotherapy based or antibody drug conjugates have helped to mitigate this risk.

Before administering bispecific antibodies, it is important to have access to the following medications: immunosuppressive agents, corticosteroids, and tocilizumab. If patients have CRS, tocilizumab can be administered, as it blocks the effects of IL-6, a key cytokine that drives the syndrome. However, there is no role for tocilizumab in a patient who does not have CRS. Other supportive care measures, such as hydration and supplemental oxygen, can be given to patients who have higher-grade CRS. Prophylactic medications like dexamethasone, acetaminophen, and/or an antihistamine are administered during SUD to reduce risk of infusion related events. With glofitamab, corticosteroids are given during Cycle 1 Days 8 and 15, as well as Cycles 2 and 3+ as needed to reduce the risk of CRS and infusion-related reactions, whereas with epcoritamab, patients receive a corticosteroid on the first day of each weekly cycle and for 3 consecutive days following each weekly administration in Cycle 1. It is recommended to send patients home with steroids so they can take these medications if they experience these AEs at home. At a minimum, having medication available can help stabilize patients until they reach the hospital for intensive care management.

Another concern related to bispecific antibody administration and AE monitoring is an abnormal health status. For example, low blood counts observed in patients may be related to previous treatment and not the bispecific antibody. Similarly, cardiotoxicity may be related to preexisting cardiac disease, not the bispecific antibody. Replacement w/ granulocyte colony stimulating factor can be utilized to resolve this event. Stress may also be triggered by a CRS-induced fever or another event related to infusion. As stress can trigger atrial fibrillation in older patients, once-weekly ECGs can be considered, blood pressure should be monitored at each visit, and electrolyte supplementation is recommended.

Vaccinations and Infection Management

Tycel J. Phillips, MD:
Even though most infections related to bispecific antibodies are viral, they are a concern. I have seen reactivations of cytomegalovirus, Epstein-Barr virus, herpes simplex virus (HSV), and other dormant viruses in patients treated with bispecific antibodies, likely because of T-cell redirection. It is best practice to vaccinate a patient against flu, COVID-19, and other viruses before starting on bispecific antibodies. Although this does not mean vaccines cannot be given to patients receiving a bispecific antibody, vaccine efficacy is a concern. For example, data suggest that the COVID-19 vaccine has lower efficacy in patients who are currently receiving a bispecific antibody. For a vaccine to be effective, it must stimulate B-cells which are depleted, due to an on-target but off-focus effect of the bispecific antibody, and utilize the helper and cytotoxic effects of T-cells, which in the presence of a bispecific antibody may be diverted toward the malignant or bystander B-cells. Therefore, when a patient needs vaccination, it may be best to wait at least 6 months after bispecific antibody administration. In cases of virus reactivation, it is critical to hold the bispecific antibody and control the symptoms, treat the infection until institutional preference is achieved, and monitor IgG levels. Ideally, more T-cells will be redirected to the virus for suppression, not to the tumor. If a patient is on active therapy, the bispecific antibody must be withheld to allow B-cell recovery, and with a continuous therapy such as epcoritamab, this is an important consideration. If a patient is receiving glofitamab or mosunetuzumab, the patient can be given the vaccine 6-9 months after bispecific antibody treatment is complete. In addition, patients should maintain HSV/varicella zoster virus prophylaxis (eg, acyclovir) throughout their treatment course, but the optimal prophylaxis duration has not yet been established. Pneumocystis jirovecii pneumonia prophylaxis is also recommended, especially those on long term corticosteroids.

Kathleen Dorritie, MD:
I agree that when a patient is having a significant infection, the bispecific antibody should be withheld. It is recommended to consider permanent discontinuation with grade 4 infections. Often, I ask my infectious diseases colleagues to help identify infectious organisms and tailor treatment. Inexperience with rare and infectious diseases amongst those of us who treat hematologic malignancies can complicate the identification of such organisms. In addition, intravenous immunoglobulin can reduce the risk of recurrent infections in patients by supplying antibodies to the weakened immune system. For bacterial infections, empiric antibacterial agents can be given based on the infection site, broad-spectrum agents such as third-generation or fourth-generation cephalosporin or carbapenems can be given in the setting of concomitant neutropenia, and vancomycin is reserved for specific indications.

Recognition and Treatment of ICANS

Kathleen Dorritie, MD:
Although step-up dosing and premedications can help minimize the occurrence of ICANS among patients receiving bispecific antibodies, it may still arise. ICANS usually occurs right after or concurrent with CRS, with signs like headache, tremors, and difficulty speaking. Fortunately, symptoms often resolve quickly after receiving steroids. I also prescribe my patients, including those at home, dexamethasone, so if they plan on getting evaluated at the earliest sign, they can first take a dose of dexamethasone. In addition, if more severe neurologic toxicity is a concern, I typically prescribe an antiepileptic medication like levetiracetam.

Tycel J. Phillips, MD:
Additional signs of neurologic complications include ataxia, confusion, convulsion, delirium, and seizures. While new data suggests that CD20/CD3 bispecific antibodies can cross the blood-brain barrier, neurological toxicities rates remain low and could possibly be triggered by fever, prophy medications, as well as suspected inflammation. Indeed, in practice, I have seen higher rates of neurologic complications with CD19-targeted agents than with CD20-targeted agents, although the etiology is unclear. Corticosteroids are critical for managing a patient with ICANS. Caution should be taken when recommending diphenhydramine, especially in older patients, and oral diphenhydramine is preferred to intravenous diphenhydramine. If antiseizure medication and a neurologic consultation are needed, agents like anakinra and immunosuppressive drugs can help mitigate neurologic toxicity.

Your Thoughts
How do you monitor and manage AEs like CRS, ICANS, and infections when treating patients with DLBCL in your center?

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Which AE are you most commonly dealing with in your patients with relapsed/refractory DLBCL being treated with bispecific antibodies?

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