Click to Enlarge: A BiTE linking a T cell to a tumor cell. Source: Wikipedia
SEATTLE — Bispecific antibodies (BsAbs) are expanding treatment options across hematologic malignancies and a growing number of solid cancers, but putting them into practice—especially in a large, geographically dispersed system like the VA—requires deliberate planning, training, and safety infrastructure.
At the 67th American Society of Hematology held in Orlando, FL, Dec. 6-9, Nicholas Burwick, MD, of the VA Puget Sound Health Care System in Seattle, discussed a program designed to increase access to bispecifics. Burwick and his researchers from the France Foundation described BsAbs as “a breakthrough therapy” for hematologic conditions such as relapsed/refractory multiple myeloma, while noting that adoption within systems such as the VA can be limited by “clinical familiarity, multidisciplinary coordination, and safety infrastructure.” Veterans also might face barriers arising from “comorbid disease, lack of caregiver support, or transportation burden.”1
The initiative sought to build institutional readiness and clinical capacity for BsAb use in VISN 20. To do that, they established the VA Puget Sound Health Care System (VAPSHCS) as a specialty hub, then paired a structured clinical team education program with standardized clinical protocols. Over the course of a year, the faculty-led Project ECHO series delivered eight sessions to VISN 20 providers.
The sessions covered the mechanism of action, safety, efficacy, and use of BsAbs, while also identifying VA-specific barriers and focusing on the need to develop solutions that centered on veterans’ unique circumstances. Along with that educational effort, VAPSHCS “convened a multidisciplinary expert panel to create and implement two clinical protocols: one for the management of cytokine release syndrome (CRS), an immune effector cell-associated neurotoxicity syndrome (ICANS), and a second aligning with the VA national formulary guidance for BsAb eligibility and dosing.”
CRS and ICANS are the two most concerning adverse effects associated with BsAbs therapy. CRS is a systemic immune over-response that triggers a flood of inflammatory cytokines. Common in CAR T therapy, CRS also occurs, though typically at a lower rate, with BsAbs and bispecific T-cell engaging therapies (BiTEs). CRS symptoms range from mild flu-like aches and fatigue to severe multiorgan failure.
While related to CRS, ICANS seldom occurs at the same time. It is a “neurologic toxicity caused by the inflammatory actions of cytokines released after BsAb therapy causing disruption of the blood-brain barrier and accumulation of inflammatory cytokines in the central nervous system,” according to the VA’s February 2024 Bispecific Antibody (BsAb) Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) Neurotoxicity Guidance. ICANS is principally a diagnosis of exclusion.
Participation data from Project ECHO illustrated the multidisciplinary footprint required to operationalize these therapies: The eight ECHO sessions attracted pharmacists (67%), physicians (25%), and allied health professionals (8%). Further, “100% of the multidisciplinary providers reported that engagement in the ECHO sessions would help them overcome barriers in practice and [commit] to making practice changes that would impact patient care.”
Burwick and his colleagues reported that the “newly developed VA protocols have been successfully implemented at VAPSHCS,” and the work “informed broader efforts to scale these protocols across VISN 20,” using a hub-and-spoke model to expand access to more veterans.
What Frontline Clinicians Need to Anticipate
In a talk about epcoritamab use and toxicity management at last year’s AVAHO meeting, Andrew Ip, MD, chief, outcomes and value care division, division of lymphoma at the John Theurer Cancer Center at Hackensack University Medical Center, emphasized that the operational challenge of BsAbs in community and local settings hinges on anticipating and responding to immune effector toxicities, particularly CRS and neurotoxicity, while recognizing how their frequency and severity compare with CAR T therapy.2
“You have to really watch out, especially if you know about CAR T,” Ip said. “We always worry about the severity of these toxicities and whether they become unstable. But thankfully, … the most common adverse reaction (CRS) occurs in about 50% of patients at any grade,” with only 2.5% experiencing Grade 3 or higher events that may require ICU admission for vasopressors or high-flow oxygen.
The VA’s Bispecific Antibody Neurotoxicity Guidance echoes Ip’s experience. The guidance notes that “CRS with BsAbs is less severe than CRS with CAR T therapy” and emphasizes that “early management of CRS may prevent escalation to a higher grade.”
Operationally, VA guidance recommends, “For ALL Grades, hold BsAb therapy until CRS resolves, then resume except for Grade 4,” and if outpatient, “admit to inpatient if Grade >1 (Grade 1 might be managed as an outpatient).” During initial step-up therapy, “patient may need to be admitted to inpatient service depending on the BsAb.”
Beyond immune effector toxicities, Ip noted that day-to-day tolerability issues are common and matter operationally, especially in older populations like those treated at the VA. “Fatigue is probably the most common thing we see in the clinic, especially when treating an older population,” he said. “That’s the most common thing I hear from my patients. They feel tired, but they’re usually still able to function and do all of their activities of daily living.”
Ip also highlighted practical considerations specific to injected BsAbs therapies. “Some adverse events are related to the fact that this is a subcutaneous injection, which is different from some of the other bispecifics that are intravenous,” Ip said. “You do see local site reactions, local abdominal pain—usually in the pannus of the abdomen—and rash as well. These are all very manageable. Importantly, they are not Grade 3 toxicities, so there are really no significant Grade 3 toxicities overall.”
Patients receiving bispecifics like tarlatamab and linvoseltamab intravenously may experience immediate infusion-related reactions such as fever or chills, headache, nausea, or blood pressure changes.
In describing serious adverse events, Ip underscored the importance of context in attributing severe adverse reactions in the era when pivotal studies for many recently approved BsAbs therapies were conducted. “There were some fatal adverse events,” he said. “This trial was running during the time of COVID, and that was actually the most common Grade 5 event, patients with lymphoma receiving the drug who developed COVID.” He added, “It was unclear how much was due to the drug versus the disease itself causing multiorgan dysfunction.”
CRS: Common, Usually Early, and Often Manageable—If Systems Are Ready
“Grade 1 is essentially a temperature over 100.4°F with no other symptoms,” Ip noted. He added a caution that affects triage and workflows: “CRS has to be attributable to the drug. If a patient has a URI, that’s not CRS,” Ip told U.S. Medicine.
The distinction between Grade 1 and Grade 2 shapes monitoring decisions and admission thresholds. “About 1 in 5 patients experienced Grade 2 CRS, which is a fever plus hypotension or mild hypoxia, usually requiring only low-flow oxygen,” he said.
Timing also matters operationally. “What’s important to note is that over 90% of CRS events occur in the first month, and the majority happen with the first full dose,” Ip said. The VA guidance on CRS and ICANS says that, for CRS, “the highest risk is in minutes to hours after step-up or induction infusions, but it might occur once the patient is discharged.”
“That first full dose is the third dose, given in week 3. The median time to onset is within 24 hours,” Ip said. He connected that timing to monitoring practices: “Per the drug label, it is recommended, though not mandated, that patients be hospitalized for this first full dose to monitor for signs of CRS or ICANS.”
ICANS and the ICE Score: Recognizing Subtle Change
Ip described neurotoxicity as patients “being a little bit off” and explained how the immune effector cell-associated encephalopathy (ICE) score operationalizes detection and grading for ICANS. “Grade 1 is when a patient cannot answer one of the 10 questions on the ICE score, which ranges from 0 to 10.”
He highlighted that more severe neurotoxicity is uncommon but requires readiness. “Grade 2, which occurred in about 1% of patients, is mild encephalopathy,” Ip said. “Grade 3 or 4 is when patients require significant stimulation, such as a sternal rub. Grade 5 is fatal.” He also emphasized trajectory and expected course: “The majority were Grade 1, and about 9 out of 10 of these cases resolved with supportive care alone. ICANS usually occurs around the time of the first full dose, if it occurs at all, and the duration is about four days.”
Preparing the Infrastructure and Patients
While BsAbs may be delivered outside specialized cellular therapy centers, both the VA’s Project ECHO and VA neurotoxicity guidance frame readiness as multidisciplinary and protocol driven.
The VA’s guidance details a “Communication Plan for Management of CRS and ICANS/Neurologic Toxicity” that begins prior to patient admission, including communication across nursing, pharmacy, and intensive care unit as well as with veterans and caregivers. It outlines specific operational steps across services, including oncology provider ordering processes, nurse education and checklists, ICU/step-down unit notification and participation in multidisciplinary discussions and pharmacy readiness, such as ensuring that “necessary drugs [are] in stock, including at least 2 doses of tocilizumab if available or can be obtained quickly.” Tocilizumab is the primary agent for treating severe CRS.
The guidance also reinforces why step-up dosing is central to operational planning: “Since CRS occurs most often in the first several days of BiTE therapy (but can occur at any time during therapy), the strategy of using stepwise increases during initial administration helps to decrease the risk of CRS.”
Ip’s discussion of epcoritamab dosing and timing aligns with that operational reality. “During the first cycle, the first two doses are step-up doses—very small doses—followed by the full dose starting in week 3.”
A Replicable Model for Access
Taken together, the VISN 20 initiative and VA guidance describe an implementation pathway that matches IP’s clinical experience. BsAbs can be delivered locally, but only when systems can rapidly recognize and respond to CRS and neurotoxicity. Burwick’s group characterized the education-and-protocol model as “a replicable approach that can be used by other VA facilities to safely and efficiently implement BsAb therapy within their existing infrastructure and foster hub and spoke care between specialized and under-resourced VA facilities.”
- Burwick N, Glasner M, Chalal J. Integrating bispecific antibodies into VA oncology care: A multidisciplinary protocol and education model from VISN 20. Poster 902. Blood. 3 Nov 2025;146(S1):6198. Doi:10.1182/blood-2025-6198.
- Ip A. Unveiling a Subcutaneous Therapy in 3L+ DLBCL and FL. AVAHO 2024. Atlanta, Ga. 20 Sept 2024.
- Bi-specific T-cell engager. Wikipedia, url: https://en.wikipedia.org/wiki/Bi-specific_T-cell_engager