Identifying CRS in Patients Who Underwent CAR T-Cell Infusion

Presentation

A 16-year-old male with previously relapsed B-cell acute lymphoblastic leukemia presented to his hematologist with fatigue, bruising, and headache. It had been two years since remission. The patient underwent a bone marrow biopsy, which demonstrated 20% blasts and was referred for CAR T-cell therapy. He underwent lymphodepleting chemotherapy with 30 mg/m² intravenously daily for 4 days and 500 mg/m² IV once daily of cyclophosphamide for 2 days, beginning with the first dose of fludarabine, prior to receiving an anti-CD19 CAR-T cell infusion of tisagenlecleucel. On Day 3 post-infusion, the patient developed a fever (100.4°F). 

Workup, Diagnosis, and Treatment

Day 3:
Initial vital signs for the patient were as follows: blood pressure (BP), 110/85 mm hg; heart rate (HR), 87; respiratory rate (RR), 20; temperature, 100.4°F; oxygen saturation (SpO2), 99% on room air. A full infectious workup (chest x-ray and blood and urine cultures) was negative, and the patient was non-neutropenic. The patient was given 650 mg of acetaminophen orally and observed.

Day 4:
Vital signs were taken in the morning and were as follows: BP, 95/70 mm hg; HR, 100; RR, 20; temperature, 100.4°F; SpO2, 95% on room air. A low-flow nasal cannula was initiated, but no vasopressor was required. Symptoms were responsive to fluids (1L normal saline 0.9%). A cytokine panel determined that IL-6 levels were elevated, so the AP discussed the case with the attending bone marrow transplant physician. The patient was then administered one dose of tocilizumab (8mg/kg) for grade 2 cytokine release syndrome (CRS).

The patient’s fever abated by the end of the shift (12 hours), and oxygen and blood pressure normalized with oxygen supplementation and fluids.

Discussion

CRS results from a large rapid release of inflammatory cytokines into the blood from immune cells. Although it has been shown to develop in 54% to 91% of patients who received CAR-T infusion, diagnosis and treatment of CRS is dependent on symptom manifestation.¹

The American Society for Transplantation and Cellular Therapy developed guidelines for grading CRS (the Lee Grading Scale) in 2018,² with other subsequent groups publishing grading scales that provide more specific guidance regarding hypotension and hypoxia.³ Although markers and risk factors for CRS tend to vary across disease settings, elevated IL-6 levels and male sex, respectively, are fairly consistent in the data. The hallmark symptom across patients and disease settings is always the appearance of fever.¹

The humanized immunoglobin G1κ (IgG1κ) anti-human IL-6 receptor (anti-IL-6R) monoclonal antibody tocilizumab was approved by the U.S. Food and Drug Administration in 2017 for treatment of CAR-T–related CRS in patients 2 years and older. Up to four doses of tocilizumab may be administered, with at least 8 hours separating each dose, and glucocorticoid steroids may be administered in conjunction with tocilizumab for grades 3-5 CRS.⁴ Although tocilizumab has demonstrated success in resolving symptoms associated with CRS both in clinical trials and in standard practice, it has been shown unable to inhibit development of subsequent neurotoxicity, especially in those patients who received anti-CD19 CAR-T therapy. Optimal timing of administration of tocilizumab has yet to be determined. Siltuximab has been used in conjunction with or after failure of tocilizumab, but siltuximab has not been sufficiently studied as a treatment for CRS and its use remains investigational.³ Likewise, the IL-1 inhibitor, anakinra, also has been studied in combination with tocilizumab for patients with CRS after CAR-T infusion and, despite not being approved for this indication, is recommended in the United Kingdom as a second-line approach in this setting after tocilizumab failure. There are no studies comparing either siltuximab or anakinra with tocilizumab for CRS.⁵

References:

1. Yan Z, Zhang H, Cao J, et al. Characteristics and Risk Factors of Cytokine Release Syndrome in Chimeric Antigen Receptor T Cell Treatment. Front Immunol. 2021;12:611366. Published 2021 Feb 23. doi:10.3389/fimmu.2021.611366
2. 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. doi:10.1016/j.bbmt.2018.12.758
3. Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of cytokine release syndrome after chimeric antigen receptor T-cell therapy. Ther Clin Risk Manag. 2019;15:323-335. Published 2019 Feb 28. doi:10.2147/TCRM.S150524
4. Tocilizumab: Drug information. UpToDate. https://www.uptodate.com/contents/tocilizumab-drug-information/print. Accessed October 3, 2022.
5. National Health Service; Specialist Pharmacy Service.Evidence for use of siltuximab or anakinra as second line therapies (after failure of tocilizumab) for cytokine release syndrome following use of chimeric antigen receptor T-cell (CAR-T) therapy. Available at: https://www.sps.nhs.uk/articles/evidence-for-use-of-siltuximab-or-anakinra-as-second-line-therapies-after-failure-of-tocilizumab-for-cytokine-release-syndrome-following-use-of-chimeric-antigen-receptor-t-cell-car-t-therapy. Accessed October 7, 2022.