Introduction

Bispecific T-cell engagers (BiTEs) have become a mainstay option across multiple myeloma, B-cell acute lymphoblastic leukemia, and B-cell lymphomas, but their signature toxicities, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANs), require the same vigilance as CAR T-cell therapy. An example case illustrates how these toxicities can present and how they're managed in real time.

Case Presentation

JS is a 75-year-old male with a history of hypothyroidism, hypertension, hyperlipidemia, chronic kidney disease stage IIIa, and IgG kappa multiple myeloma, previously treated with daratumumab, bortezomib, lenalidomide, and dexamethasone followed by consolidative stem cell transplant; carfilzomib, pomalidomide, and dexamethasone; cilta-cel (CAR T-cell therapy, day +195 at relapse); and isatuximab, pomalidomide, and dexamethasone. Recent imaging showed new soft tissue masses and a rising M protein, concerning for relapsed disease.

Given prior exposure to a BCMA-directed CAR T-cell product, the best next option targets a different mechanism: talquetamab-tgvs (Talvey), a GPRC5D-directed bispecific antibody, rather than another BCMA-directed agent like teclistamab, which would offer diminishing returns after prior BCMA-directed therapy.

What Are BiTEs, and How Do They Differ in Practice?

Bispecific T-cell engagers work by simultaneously binding CD3 on T cells and a tumor-associated antigen, creating an immune synapse that activates the T cell to kill the tumor cell while also driving T-cell proliferation. Several agents are now in routine use, each with a different target and a meaningfully different toxicity timeline:

  • Blincyto (blinatumomab): targets CD19, approved for B-cell acute lymphoblastic leukemia, given as a continuous IV infusion (the line must never be flushed, even when changing bags). Median time to CRS onset is 2 days; to ICANs, 2 weeks. No REMS program. Inpatient monitoring covers the first 9 days of cycle 1 and first 2 days of cycle 2.

  • Tecvayli (teclistamab-cqyv): targets BCMA, approved for multiple myeloma after 4 prior lines, given subcutaneously. Median time to CRS onset is 2 days (range 1–6); to ICANs, 4 days (range 2–8). REMS program required. Inpatient monitoring for 48 hours following all step-up doses and the first full treatment dose.

  • Talvey (talquetamab-tgvs): targets GPRC5D, approved for multiple myeloma after 4 prior lines, given subcutaneously. Median time to CRS onset is 27 hours from the last dose; to ICANs, 2.5 days. REMS program required. Same 48-hour inpatient monitoring window as teclistamab.

  • Epkinly (epcoritamab-bysp): targets CD20, approved for diffuse large B-cell lymphoma or follicular lymphoma after 2 prior lines, given subcutaneously. Median time to CRS onset is 24 hours (range 0–10 days) across all doses; to ICANs, 16.5 days (range 8–141 days) from the start of treatment. No REMS program. Inpatient monitoring for 24 hours after day 15 (48 mg) of cycle 1.

  • Columvi (glofitamab-gxbm): targets CD20, approved for diffuse large B-cell lymphoma after 2 prior lines, given by IV infusion. Median time to CRS onset is 14 hours from the first step-up dose; ICANs of any grade occurred in 4.8% of patients, most often presenting as headache. No REMS program. Inpatient monitoring for 24 hours following day 8 of cycle 1.

Beyond CRS and ICANs, each agent carries its own additional toxicity profile: talquetamab-tgvs is notable for dermatologic toxicity (erythema, rash) and oral toxicity (dysgeusia, dry mouth, dysphagia, stomatitis); teclistamab-cqyv and epcoritamab-bysp for cytopenias; blinatumomab for pancreatitis, tumor lysis syndrome, and hepatotoxicity; and glofitamab-gxbm for tumor flare.

Case Continued: Recognizing and Grading CRS

Four days after admission for talquetamab-tgvs ramp-up, JS developed a temperature of 101°F and a drop in blood pressure to 68/48, unresponsive to IV fluids, requiring a step-up to the ICU to start norepinephrine. This is CRS grade 3, defined as fever with hypotension requiring a vasopressor (with or without vasopressin) and/or hypoxia requiring high-flow nasal cannula, non-rebreather mask, or Venturi mask.

Management of CRS follows an escalating, grade-based algorithm:

  • Grade 1 (fever ≥38°C/100.4°F): Hold treatment (exception: blinatumomab); consider dexamethasone 8–12 mg x1 dose; consider tocilizumab 8 mg/kg if CRS is prolonged and steroid-refractory beyond 24–48 hours.

  • Grade 2 (fever with hypoxia requiring nasal cannula, or hypotension without vasopressors): Hold treatment (exception: blinatumomab); consider tocilizumab 8 mg/kg; consider dexamethasone 8–12 mg every 12 hours.

  • Grade 3 (fever and hypotension requiring a vasopressor, and/or hypoxia requiring high-flow nasal cannula or non-rebreather/Venturi mask): Hold treatment; ICU care as needed; dexamethasone IV 10 mg every 6 hours; tocilizumab 8 mg/kg; if persistent despite tocilizumab and steroids, consider anakinra or siltuximab.

  • Grade 4 (fever and hypotension requiring multiple vasopressors and/or hypoxia requiring positive pressure ventilation): Permanently discontinue the agent; ICU care; IV methylprednisolone 1000 mg daily for 3 days; tocilizumab 8 mg/kg; consider anakinra or siltuximab if persistent.

For JS's grade 3 CRS, management was to hold talquetamab-tgvs and give tocilizumab and dexamethasone. Blinatumomab is a notable exception to the "hold treatment" rule at low grades, given its short half-life as a continuous infusion, meaning simply holding it reverses toxicity quickly without needing to administer dexamethasone and consider interruption in therapy until grade 3-4.

Case Continued: Recognizing and Grading ICANs

Five days after admission, JS's nurse found that he only awakened to tactile stimuli and was unable to perform an ICE (Immune Effector Cell Encephalopathy) score. His ICE score was 0.

ICANs symptoms include delirium, encephalopathy, lethargy, headache, seizures, agitation, aphasia, ataxia, and motor weakness. Grading incorporates the ICE score, level of consciousness, and evidence of seizure, motor findings, or elevated intracranial pressure:

  • Grade 1 (ICE score 7–9): Hold treatment (if binatumomab, glofitamab, mosunetuzumab, can continue); dexamethasone 10 mg IV; consider levetiracetam.

  • Grade 2 (ICE score 3–6): Hold treatment; dexamethasone 10 mg every 6 hours; consider levetiracetam 750 mg BID.

  • Grade 3 (ICE score 0–2): Hold treatment; consider ICU care; methylprednisolone 1000 mg IV (if persistent, 1000 mg BID x 3 days); levetiracetam 750 mg BID.

  • Grade 4 (ICE score 0, patient unarousable): Permanently discontinue the agent; ICU care; methylprednisolone 1000 mg daily x 3 days; levetiracetam 750 mg every 12 hours.

Because JS could not answer questions or perform commands, his ICE score was 0, but because he was still arousable to tactile stimuli rather than unarousable, his ICANs was graded 3, not 4. Management was to hold treatment, give methylprednisolone 1000 mg for one dose, and start levetiracetam 750 mg twice daily for seizure prophylaxis.

For Patients

For people receiving a bispecific T-cell engager (a type of immunotherapy that helps the body's own T cells attack cancer cells) for multiple myeloma, leukemia, or lymphoma, two side effects require close monitoring in the days after each dose: cytokine release syndrome, which causes fever and can affect blood pressure and breathing, and a neurologic side effect called ICANs, which can cause confusion or difficulty speaking. Both are graded on a scale and managed with specific medications, including steroids and a drug called tocilizumab, depending on severity. This is why your care team asks you to stay in the hospital for observation after certain doses, and why they check on things like alertness and memory frequently during that window.

Key Takeaways

  • Bispecific T-cell engagers differ meaningfully in their target, administration route, and toxicity timeline; talquetamab-tgvs's CRS and ICANs onset (27 hours and 2.5 days) is notably faster than blinatumomab's (2 days and 2 weeks).

  • CRS is graded 1–4 based on fever, hypotension, and hypoxia, with escalating management from holding treatment and considering steroids/tocilizumab at grade 1–2, to ICU care and mandatory tocilizumab at grade 3, to permanent discontinuation at grade 4.

  • ICANs is assessed by calculating an ICE score and evaluating level of consciousness, seizure activity, motor findings, and signs of elevated intracranial pressure, with management following a similar escalating pattern.

  • Beyond CRS and ICANs, each bispecific agent carries distinct additional toxicities worth anticipating: dermatologic and oral toxicity with talquetamab-tgvs, cytopenias with teclistamab-cqyv and epcoritamab-bysp, and tumor flare with glofitamab-gxbm.

References

  1. National Comprehensive Cancer Network. Management of CAR T-Cell and Lymphocyte Engager-Related Toxicities. Version 2.2026. Accessed June 2026.

  2. Amgen. Blinatumomab (Blincyto) [package insert]. U.S. Food and Drug Administration website. Revised March 2018.

  3. Janssen Biotech, Inc. Teclistamab-cqyv (Tecvayli) [package insert]. U.S. Food and Drug Administration website. Issued October 2022.

  4. Janssen Biotech, Inc. Talquetamab-tgvs (Talvey) [package insert]. U.S. Food and Drug Administration website. Issued August 2023.

  5. AbbVie, Inc. Epcoritamab-bysp (Epkinly) [package insert]. U.S. Food and Drug Administration website. Issued May 2023.

  6. Genentech, Inc. Glofitamab-gxbm (Columvi) [package insert]. U.S. Food and Drug Administration website. Issued June 2023.