A novel CRS grading system and management algorithm was developed based on the clinical experience of patients with CRS treated at the University of Pennsylvania and Children’s Hospital of Philadelphia (Table 1).28 Following CTL019 infusion, symptoms such as worsening respiratory distress, increased oxygen requirements, hemodynamic instability despite IV fluids, need for moderate-dose to high-dose vasopressor support, or rapid clinical deterioration require medical intervention.
Increased levels of IL-6 have been reported in patients with more severe CRS caused by CAR T-cell therapy; the anti–IL-6 receptor antibody tocilizumab was used in these cases.29 Tocilizumab effectively reversed CRS in patients, and should be readily available for expedited administration to patients treated with CAR T-cells.12,30 If no improvement is seen after administering tocilizumab, additional management might include steroids. This is one of the few times when steroids would be administered to patients receiving CTL019 therapy. Nine of 30 patients with r/r ALL received tocilizumab for severe treatment-related CRS, which resulted in improvement in fever and hypotension.12 In addition, 6 patients also required glucocorticoids.12 Overall, of 97 evaluable patients at our institution, 3 patients were considered to have refractory CRS and died as a result.31 All of them were adults with ALL, and all had significant disease burden and concurrent infections.31
Coordinated nursing care between departments is essential for managing the treatment of patients with CRS. Written instructions given at the time of CTL019 infusion include what symptoms to watch for and who to contact if CRS is suspected. Usually developing a fever is the first symptom, and patients are instructed to call if their fever rises above 100.5°F. Patients must know how to contact a physician outside of normal business hours. A tocilizumab information sheet, and the potential of developing CRS, is reviewed and discussed with the patient at the time of CTL019 infusion.
The most important aspect of caring for patients with CRS is education between all departments of the hospital, from the emergency department to the intensive care unit. All departments need to work together so patients are effectively treated throughout the hospitalization. Giving the patient a copy of the clinical trial documents so they are appropriately triaged at the emergency department should CRS occur is beneficial for both clinical staff and the patient. At our institution, the inpatient hospital pharmacy receives a weekly email regarding which patients will receive CTL019 therapy and which patients have recently received treatment to allow the pharmacy to have the necessary drugs, such as tocilizumab, in stock. CTL019 infusion may be administered on an outpatient basis, if deemed appropriate by the treating physician.
Macrophage activation syndrome/hemophagocytic lymphohistiocytosis (MAS/HLH) is another potential adverse event of CAR T-cell therapy. It may occur concurrently with or shortly after CRS. MAS and HLH are generally considered to be overlapping syndromes, can also occur outside of CTL019 therapy, and are characterized by excessive activation of well-differentiated macrophages.32 MAS/HLH associated with CAR T-cell therapy displays characteristic patterns of laboratory test results, including highly elevated ferritin, C-reactive protein, and D-dimer levels.14,17 In a small number of patients, profound hypofibrinogenemia was observed, which may require administering blood products.29 Patients may also develop elevated levels of transaminases and triglycerides; moderate marrow hemophagocytosis may subsequently occur. In severe cases, tocilizumab can effectively treat MAS/HLH, and is typically used for concurrent CRS in the context of CAR T-cell therapy.33
Tumor lysis syndrome (TLS), which occurs when tumor cells lyse and release large amounts of cellular contents into the bloodstream, has also been reported in patients undergoing CAR T-cell therapy, as well as other therapies that cause rapid killing of malignant B cells.9,34 Symptoms of TLS are caused by overwhelmed organ systems and include nausea, vomiting, shortness of breath, irregular heartbeat, cloudy urine, lethargy, and/or joint discomfort.35 TLS is best managed through monitoring and anticipating the syndrome. Monitoring includes testing calcium, potassium, phosphorus, creatinine, and uric acid levels at least 2 to 3 times per week, depending on laboratory test results. The management strategy generally includes fluid hydration, allopurinol, and/or rasburicase.
Encephalopathy Neurologic toxicity has been described in several studies using CAR T-cell therapy for patients with ALL and NHL.12,16,22,23,30 In Maude and colleagues’ analysis, 13 of 30 patients experienced neurologic adverse events.12 These events ranged from delirium experienced during a high CRS-associated fever to global encephalopathy, which could include aphasia, confusion, and hallucinations. In another study, seizure-like activity in patients with CRS-associated neurologic toxicity was confirmed using electroencephalograms.30 Of the patients in our study who experienced high fevers, many had some degree of delirium, and a few patients experienced delayed encephalopathy independent of high fevers, CRS severity, or prior tocilizumab.12 Symptoms typically lasted 2 to 3 days.
Although the pathophysiology of CTL019-associated encephalopathy is not well understood, it may be a result of the cytokine-mediated inflammatory state. However, neurologic toxicity did not appear to correlate with CRS severity, and was not prevented by tocilizumab. A noteworthy finding by Maude and colleagues is that CTL019-modified T-cells were detected in the CSF of 17 of 19 patients with evaluable samples, and only a fraction of these patients experienced encephalopathy.12 When neurologic symptoms manifest after a CTL019 infusion, the patient is examined and appropriate imaging studies are obtained. If clinically indicated, a lumbar puncture may be performed, and the CSF is evaluated for the presence of CTL019 cells, infection, or disease relapse.