Don’t get BiTEn by bispecific T-cell engagers

After more than a decade on the job, it feels like I should have this emergency medicine thing figured out, but that just doesn’t seem to be how things work. There are constantly new presentations; patients that provoke new questions. However, I find it incredibly disconcerting when something is time sensitive and life threatening – the central area of my expertise – and I have literally never heard of it. What exactly is a bispecific T-cell engager (BiTE), and why is it so important for emergency physicians to know about these novel drugs?

Bispecific T‑cell engagers are a novel class of oncology medications that link CD3 on T cells to a tumor antigen, driving T-cell activation and cytokine release. They are associated with 2 severe complications we need to know: cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). (They can also lead to infection, but I think we know how to manage that in oncology patients.)

The drug names you might see on the patient’s chart: blinatumomab, teclistamab, or tarlatamab. (Even when I type these words, they just look like a garbled mess of letters. There is no way I would know if there was a typo in there.) 

Cytokine release syndrome (CRS)

CRS is apparently quite common with these agents (about 70% of patients will have some toxicity). It usually occurs during step-ups in therapy, and will present in the first 1-3 days.

The primary symptoms are fever, hypotension, tachycardia, hypoxia, and fever. However, because the underlying cause is a massive release of cytokines, the symptoms can include basically anything that involves the immune system. I will steal this image from a local hospital’s guidance:

The syndrome is divided into 4 grades based on severity, which guides management:

If your hospital is using these agents, I expect that you will have a specific protocol for managing CRS, but general management steps include:

Grade 1: Consult oncology very early. Hold therapy, IV fluids and supportive care, acetaminophen, and potentially dexamethasone. Check the neutrophil level and treat for neuropenic fever as appropriate. Assess for ICANS and consider seizure prophylaxis. (Tocilizumab is used if symptoms don’t improve in 48 hours, but that will hopefully never be an emergency medicine decision.)

Grade 2: All of the above, but dexamethasone is definitely given, and tocilizumab is probably going to be given, so consult your oncology ASAP. If there is no response to initial IV fluids, ICU consult will be required.

Grade 3: All of the above, except consult ICU right away. Higher dose dexamethasone (20mg IV q6-12 hours). 

Grade 4: Essentially the same as above from an emergency perspective, but early repeat doses of tocilizumab and steroids will be suggested. In life-threatening situations, you may see very high doses of steroids (methylprednisolone 1000mg IV) suggested. 

There are alternative cytokine blockers (anakinra or siltuximab) that might be used if there is no response to tocilizumab, but by the time that decision is made, the patient really should be out of your department. 

Immune effector cell-associated neurotoxicity syndrome (ICANS)

As if cytokine release syndrome was not enough, BiTE therapy has another potential life threatening complication: immune effector cell associated neurotoxicity syndrome. The presentation may include headache, tremor, dysgraphia, aphasia, confusion, somnolence, seizures, and rarely cerebral edema. Like CRS, this is a surprisingly common adverse effect, occurring in 20-50% of patients receiving BiTE therapy.

There is a specific scoring system for Immune Effector Cell-Associated Encephalopathy (the ICE score) that will be referenced for grading these patients. You get 4 points for orientation (orientation to year, month, city, hospital). You get 3 points for naming common objects (eg, point to a clock, pen, button.) There is 1 point for following simple commands (e.g. “Show me 2 fingers” or “Close your eyes and stick out your tongue”). You get 1 point for writing a sentence. And you get 1 point for attention (the ability to count backwards from 100). I imagine a consultant might ask you for the ICE score, but my sense is that our job is really to recognize the possibility of this syndrome, and that a basic description of their neurologic status and whether or not they are having seizures is enough. (The AVPU description will probably suffice).

Call oncology as soon as the syndrome is recognized. All patients will get basic supportive care, including aspiration precautions, and some sort of neuroimaging. Seizure prophylaxis (levetiracetam) seems to be suggested for all patients. Seizures, if they occur, should be treated with your usual seizure algorithm. 

Dexamethasone is the first line if there is an altered level of consciousness. Otherwise, the therapy is similar to CRS, with ICU admission, tocilizumab, anakinra, and high dose steroids all options.

Of course, these are oncology patients at high risk for infection, so it is important to consider encephalitis and meningitis. Lumbar puncture should be considered, and empiric therapy, including coverage for herpes encephalitis, is very reasonable. 

Bottom line

For any patient on a “bispecific” or “BiTE” therapy who presents acutely unwell, call oncology for guidance immediately. Initial therapy in the ED is primarily supportive care and dexamethasone. If there are neurologic symptoms, prophylaxis with levetiracetam can be started. Don’t forget the differential diagnosis. On presentation, CRS is essentially indistinguishable from sepsis – and these patients are also at risk for neutropenia – so treat both. 

References

Géraud A, Hueso T, Laparra A, Bige N, Ouali K, Cauquil C, Stoclin A, Danlos FX, Hollebecque A, Ribrag V, Gazzah A, Goldschmidt V, Baldini C, Suzzoni S, Bahleda R, Besse B, Barlesi F, Lambotte O, Massard C, Marabelle A, Castilla-Llorente C, Champiat S, Michot JM. Reactions and adverse events induced by T-cell engagers as anti-cancer immunotherapies, a comprehensive review. Eur J Cancer. 2024 Jul;205:114075. doi: 10.1016/j.ejca.2024.114075. Epub 2024 May 4. PMID: 38733717

Wattana MK, Rowland J, Qdaisat A, Levavi H, Anagnostou T, Sanchez L, Friedlander P, Rohs N, Lipe DN, Richter J. Diagnosis and management of bispecific T cell-engaging antibody toxicity: A primer for emergency physicians. Cancer Treat Rev. 2025 Mar;134:102889. doi: 10.1016/j.ctrv.2025.102889. Epub 2025 Jan 24. PMID: 39913958