Case Study: Managing Toxicities in CAR T-Cell Therapy

A 58-year-old woman with relapsed refractory diffuse large B cell lymphoma is referred for chimeric antigen receptor (CAR) T-cell therapy. After conditioning with fludarabine and cyclophosphamide, she receives 2.5 × 10⁶ CAR T cells/kg. On day 2, the patient begins to have fever with cough and oxygen saturation of 89 percent, which improves with supplemental oxygen. Blood cultures and a respiratory viral panel were checked. She was started empirically on vancomycin and cefepime. Computed tomography of the chest without contrast demonstrated no obvious infiltrates.

On day 4, vital signs are as follows:

She receives 2 L of normal saline with minimal improvement in blood pressure. Infectious work-up remains negative. She is transferred to the intensive care unit and started on norepinephrine and dopamine infusions, which help maintain mean arterial pressures above 65 mmHg. Laboratory results demonstrate no evidence of liver or kidney injury. She remains fully alert and oriented, without any deficits on neurological examination. What should be the next step in her treatment be?

1. Etoposide alone
2. Etoposide with dexamethasone
3. Tocilizumab alone
4. Tocilizumab with dexamethasone
5. Infliximab

Answer: C

Current U.S. Food and Drug Administration (FDA) approvals and indications for chimeric antigen receptor T cell (CAR T) therapy include tisagenlecleucel for the treatment of patients with precursor B cell acute lymphoblastic leukemia (ALL) up to 25 years of age with that is refractory or in second or later relapse and axicabtagene ciloleucel for highly refractory aggressive B cell non-Hodgkin lymphoma (diffuse large B cell lymphoma, primary mediastinal B cell lymphoma, or transformed follicular lymphoma).¹,² Cytokine release syndrome (CRS) is a common toxicity in patients undergoing CAR T therapy.

CRS is a CAR T toxicity occurring due to high-level immune activation. CRS manifests when large numbers of lymphocytes and/or myeloid cells become activated and release inflammatory cytokines, including TNF, IFN-γ, IL-1b, IL-2, IL-6, IL-8, and IL-10. Symptom onset typically occurs days to occasionally weeks after the T-cell infusion, coinciding with maximal in vivo T-cell expansion. IL-6 is considered a central mediator of toxicity in CRS.³,⁴

CRS can resemble sepsis and septic shock, presenting with fevers, rigors, rash, nausea and/or vomiting, diarrhea, cardiovascular compromise, respiratory failure, and liver and renal injury. Laboratory abnormalities may include cytopenias, hypofibrinogenemia, and hyperferritinemia. It is especially important to assess for neurologic toxicities including severe headaches, mental status changes, confusion, delirium, difficulty finding words, or frank aphasia, hallucinations, tremor, dysmetria, altered gait, and seizures. Treatment is based on grading of CRS:

• Grade 1: Non–life-threatening and requires symptomatic treatment only. These include fever, nausea, fatigue, headache, myalgias, and malaise. Patients should be assessed and empirically treated for infections, along with aggressive supportive care.
• Grade 2: Symptoms require and respond to moderate supportive interventions. These include oxygen requirement lower than 40 percent PaO2 or hypotension responsive to fluids or low dose of one vasopressor or grade 2 organ toxicity.
• Grade 3: Symptoms require and respond to aggressive intervention. These include oxygen requirement higher than 40 percent PaO2 or hypotension requiring high dose or multiple vasopressors, or higher than grade 2 organ toxicity. Patients should receive tocilizumab (humanized, immunoglobulin G1 (IgG1) anti-human IL-6 receptor monoclonal antibody that prevents IL-6 binding to both cell-associated and soluble IL-6 receptors).
• Grade 4: Life-threatening symptoms, requirement for ventilator support, or grade 4 organ toxicity (excluding transaminitis). Patients should receive tocilizumab and dexamethasone.

In this case, the patient has grade 3 CRS, and treatment with tocilizumab alone is warranted. Addition of steroids to tocilizumab (answer choice E) would be appropriate in a patient with grade 4 CRS. Treatment with etoposide, with or without steroids (answer choices A and B), would be reasonable in a patient with hemophagocytic lymphohistiocytosis (HLH) — a distinct, but related, hyperinflammatory syndrome, which likely exists on a continuum with CRS and shares many of the same clinical and laboratory features. Dexamethasone alone (answer choice C) would not be optimal to control severe CRS. Finally, infliximab (answer choice E) is a TNF inhibitor and does not currently have a role in controlling CRS.

Case study submitted by Prashant Jani, MD, of the Allegheny Health Network Cancer Institute, Pittsburgh, PA.

Resources 

1. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377:2531-2544.
2. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378:439-448.
3. Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome.. Blood. 2014;124:188-195.
4. Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood. 2016;127:3321-3330.