Summary

Centers manage cytokine release syndrome (CRS) very differently, and patient safety depends on the system, not only the drug. Mayo Clinic uses a stepwise outpatient approach supported by remote monitoring and a 24-hour clinic, while other centers admit all CAR-T fevers or use prophylactic tocilizumab or anakinra. Early recognition, decisive action even without admission, and a clear escalation pathway matter most, along with caregiver, lodging, and financial support.

Key Takeaways

  • Referral to an immune effector cell center should come early, at refractory disease or first relapse, with attention to clinical, social, logistical, and institutional factors.

  • Mayo Clinic manages first and second fevers after CAR-T outpatient with acetaminophen, then tocilizumab and dexamethasone, admits a third fever or any ICANS, and relies on remote monitoring and a 24-hour APP-staffed clinic.

  • Other centers admit all CAR-T CRS, use hybrid models, or use prophylactic tocilizumab or anakinra, and practices on giving tocilizumab with or without dexamethasone differ.

  • Bispecific step-up dosing is increasingly outpatient, with vitals checks every six hours, pocket dexamethasone, and escalation when fever persists or grade rises.

  • Safety depends on the system: early recognition, decisive action even without admission, standard protocols, lodging and caregiver support, and funded staff.

Learning Objectives for Real-World Delivery

Four objectives frame safe delivery: to evaluate patient-specific clinical risks and institutional capabilities in deciding between inpatient and outpatient initiation and step-up dosing; to develop toxicity management plans with CRS and ICANS risk stratification and an escalation pathway; to assess the operational infrastructure for safe delivery, including caregiver support, proximity to care, after-hours triage, and standard toxicity protocols; and to individualize sequencing of bispecifics and CAR-T by integrating efficacy, durability, prior exposure, toxicities, and logistics.

Identifying Patients Earlier and Referring Appropriately

The main message is to identify patients early in their treatment process and refer them to a facility with immune effector cell capability if the home center lacks it. The treatment center can then help with sequencing decisions, which speeds and improves care. Patients who are refractory to frontline therapy or in first relapse should be referred, because immune effector cell therapy is often more tolerable and less toxic than alternatives and reaches patients who are not eligible for consolidative autotransplant. Referral to a clinical trial site in the frontline setting should be considered whenever it is logistically feasible, with open communication with the immune effector cell team early and often.

Several considerations shape candidacy. Clinical considerations include disease burden and trajectory, how aggressive or indolent the disease is, stability, and the patient's suitability for potential toxicities. Social considerations include access to a good caregiver and whether the patient is ready and willing. Logistical considerations include financial burden, insurance coverage, and geography, which is a particular challenge in rural Minnesota. Institutional considerations include staffing and reliable escalation pathways, including 24-hour access to bring in a patient with toxicity in the middle of the night.

The Case: Fever on Day Plus Six After Cilta-Cel

A 65-year-old man with relapsed, refractory IgG kappa myeloma received cilta-cel and, on day plus six, had a temperature of 38.2 degrees caught on remote patient monitoring at his hotel. He had grade 1 CRS with fever alone.

The Mayo Clinic Approach

For a first occurrence of grade 1 CRS, Mayo gives a single dose of acetaminophen in clinic and completes an infectious workup. Because the patient was not neutropenic, antibiotics were not started. After the fever resolved, he returned to the hotel. Later that day he returned with a temperature of 39.2, a second occurrence of grade 1 CRS. He received tocilizumab, dexamethasone, and acetaminophen, was monitored for a couple of hours until defervescence, and was again discharged to the hotel. The next day a third fever earned admission to the hospital cellular therapy service, where he received tocilizumab, dexamethasone, and acetaminophen in the clinic and then went upstairs. He stayed fever free for 48 hours and was discharged, and the rest of his course was uncomplicated. Any neurotoxicity or ICANS symptom is an automatic admission.

The Infrastructure That Makes It Work

Mayo's infrastructure is well ironed out. A hospital-based outpatient clinic sits on the lobby level of the hospital, staffed 24 hours a day by the same APPs who cover inpatient services. A patient who calls in the middle of the night is told to come in, is dropped at the door, and goes to the clinic, and if admission is needed, goes upstairs. The system allows constant discharge and admission, so patients avoid long hospital stays unless they have significant toxicity. With volumes high, including 30 CAR-T patients in one month over the summer, keeping every patient in the hospital for the entire duration is not feasible.

Remote Monitoring

Patients receive a blood pressure cuff, thermometer, and pulse oximeter connected to a tablet, and they check vitals every four hours while awake. Results go automatically to a nursing team that monitors all day, so a fever on the tablet triggers an immediate call.

How Other Centers Manage CRS

Each institution manages CRS differently, as a panel of APPs and pharmacists from several centers found quickly.

At Tennessee Oncology, patients call an after-hours number for abnormal vitals, fever, hypotension, or neurologic changes. Within the first three days, a fever is treated with acetaminophen, dexamethasone, and tocilizumab, and after 72 hours the patient is brought into the hospital. Most patients are neutropenic at that point, so an infectious workup and long-acting antibiotics are started. All CRS after CAR-T is admitted. Patients have no remote patch, so they check their own vital signs at set times and receive a nightly telemedicine visit with a real-time ICANS assessment. The center recently moved from a tiered algorithm (acetaminophen only for the first fever, tocilizumab for the second, tocilizumab plus dexamethasone for the third) to a combined approach.

At MD Anderson, an acute treatment area, the CAR-T acute patient program, runs from 7 p.m. to 11 p.m. The first fever is still admitted with broad-spectrum antibiotics, because a patient may be functionally febrile, but admission lasts only as long as needed, and patients are seen daily through day 10. For an early fever in the first three days, especially a cardiac concern, tocilizumab and dexamethasone are given together; for a later fever, tocilizumab is given first and dexamethasone added if needed. In myeloma specifically, dexamethasone is not always given with tocilizumab.

At Sarah Cannon, a skin patch measures temperature and can falsely detect a fever, so patients confirm with an oral temperature. Grade 1 CRS is admitted as an alternative to intravenous antibiotics. If a patient arrives at the emergency department afebrile, tocilizumab is generally not given, though the patient is admitted. One panelist noted that patients often sit in the hospital waiting for discharge, so an outpatient-friendly program is a great practice if the center is set up for it.

Tocilizumab With or Without Dexamethasone

A debate arose over whether tocilizumab should be given without dexamethasone. At Mayo, tocilizumab is never given without dexamethasone. The reasoning offered is that tocilizumab alone can increase later ICANS risk by displacing IL-6 from its receptor, so that IL-6 travels to the brain. Mayo once avoided dexamethasone in a patient with steroid-induced bipolar disorder, and the patient developed psychiatric symptoms again. A year ago Mayo also changed practice for the first fever. They had given acetaminophen or dexamethasone with every first fever and saw no better outcomes, and they had early concerns that tocilizumab and dexamethasone would impair CAR-T efficacy, so the first fever is now acetaminophen only.

Bispecific Antibodies: Outpatient Step-Up Dosing

For bispecifics, Vanderbilt prefers outpatient care unless a patient or attending chooses otherwise. Patients receive a blood pressure cuff, thermometer, and pulse oximeter and check vitals every six hours while awake. Grade 1 CRS stays out of the hospital, with the patient taking a pocket dose of dexamethasone. Grade 2 or higher comes in. Recurrent grade 1 CRS continues to be treated as grade 1 if nothing else is changing and it is not within the same 24-hour period, though prolonged grade 1 may bring a patient in to confirm nothing else is going on, as long as the patient is not hypotensive. At Tennessee Oncology, patients prescribed pocket dexamethasone call the after-hours number for fever, retake their temperature after the dose, and go to the emergency department if still febrile. If afebrile, they are seen in clinic the next day and step-up dosing continues as planned.

Prophylaxis: Who Gets Tocilizumab or Anakinra

Practice varies widely. One center has given prophylactic tocilizumab to every myeloma bispecific patient for the past year, inpatient or outpatient, before the first step-up dose, and does not use it routinely for CAR-T unless a review team decides. That center uses anakinra more often for CAR-T prophylaxis, at 100 mg intravenously every six hours for five to seven days, the same dosing used for treatment, after a study using 100 mg every 12 hours. An NCCN line now allows prophylaxis, and the center plans to review CRS severity before and after, given the cost. Since August of last year it has used a hybrid model, with the first dose inpatient and discharge afterward.

Others differ. At Mayo, outpatient coverage for anakinra has proved nearly impossible. At Vanderbilt, prophylactic tocilizumab is reserved for high-burden disease or patients unlikely to tolerate higher-grade CRS, because when it is given CRS is essentially never seen, but incidence and grade without it are already so low that, given its cost, it is not needed in everyone. At Tennessee Oncology, every myeloma bispecific patient receives prophylactic tocilizumab, though insurance has not always approved it. Clinicians who remember trial participants with high disease burden who were febrile nonstop note how far management has come in a short time.

Lodging, Caregivers, and Financial Support

An audience member asked who pays for the hotel. For myeloma products, patient support programs exist, and a social worker sees every CAR-T patient at the first consultation along with the physician, nurse, and pharmacist. At Mayo, arranging housing is an expectation at the start of the journey and a requirement to proceed. Hotels across the street have tunnels to the hospital in winter, some patients use short-term rentals, transplant houses offer rooms for about $25 per night for those who have had a stem cell transplant, and a Hope Lodge is also an option. The cost of a basic hotel, now more than $200 a night, is astronomical, so support from pharmaceutical companies is critical. Panelists stressed that allotting full-time staff to arrange lodging is important, and that supporting patients across all aspects of treatment toxicity is part of safe delivery.

For Patients

CAR-T and bispecific therapies can cause fevers and flu-like symptoms called cytokine release syndrome, usually in the first days or weeks. Centers differ on how they handle it. Some send patients to a nearby hotel and monitor them with a blood pressure cuff, thermometer, and pulse monitor that report to a nurse team, while others admit patients to the hospital at the first fever.

What matters most is that you know what to watch for and whom to call at any hour. Any confusion, difficulty speaking, or shakiness is treated as an emergency. You will need a caregiver, a place to stay near the center for about a month, and a plan for travel.

Ask your team how your center monitors fevers, where you would go at night, who helps with lodging costs, and whether you would receive a preventive medicine before your first dose.

References

  1. Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;25(4):625-638.

  2. Tocilizumab prophylaxis for patients with multiple myeloma treated with bispecific antibodies. Blood Adv. 2025;9(19):4979.

  3. Prophylactic tocilizumab reduces the incidence of cytokine release syndrome in relapsed/refractory myeloma patients treated with teclistamab: implications for outpatient step-up dosing. https://pmc.ncbi.nlm.nih.gov/articles/PMC11266829/

  4. Outpatient administration of teclistamab or talquetamab for multiple myeloma with prophylactic tocilizumab or dexamethasone (OPTec/OPTal). ClinicalTrials.gov identifier: NCT05972135.

  5. Society for Immunotherapy of Cancer and Association of Community Cancer Centers. Expanding access to cellular and bispecific therapies: workshop report. https://www.sitcancer.org/get-involved/policy/expanding-access-to-cellular-and-bispecific-therapies

  6. Integrating bispecific antibodies into community myeloma care: challenges, insights, and educational impact. Blood. 2025. doi:10.1182/blood-2025-8134