By late 2018, 2 chimeric antigen receptor T (CAR T) cell products have been approved by US and European regulatory authorities. Tisagenlecleucel (Kymriah, Novartis) is indicated in the treatment of patients up to 25 years of age with B-cell acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse (ELIANA trial), or adult patients with large B-cell lymphoma relapsed or refractory (r/r) after 2 or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma (JULIET trial). Axicabtagene ciloleucel (Yescarta, Kite/Gilead) is indicated for the treatment of adult patients with large B-cell lymphoma relapsed or refractory after 2 or more lines of systemic therapy, including DLBCL not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma (ZUMA-1 trial). Additional approvals for products in the same indications as well as other malignant diseases such as myeloma are expected in the coming year.

A review, offering a practical guide for the recognition and management of the most important toxicities related to the use of the current commercial CAR T cells, and also highlighting potential strategies to diminish these side effects in the future, has been published on HemaSphere, the open access journal of the European Hematology Association.

In Europe, the product information of tisagenlecleucel and axicabtagene ciloleucel specify that physicians should consider hospitalization for the first 10 days post infusion or at the first signs or symptoms of CRS and/or neurologic events. Patients should be monitored daily for the first 10 days following infusion of tisagenlecleucel and axicabtagene ciloleucel for signs and symptoms of CAR T cell related toxicities. After the first 10 days following the infusion, the patient should be monitored at the physician’s discretion. For patients followed in an outpatient setting, temperature should be checked twice a day for at least the first 14 days after CAR T cell infusion,6 and preferably for 3 to 4 weeks. The patient and caregiver should be instructed to be alert to any symptom (back pain, skin rash, dizziness, chills, shortness of breath, chest pain, neurologic events . . . ) or sign (tachycardia, hypotension) of CRS, Central Nervous System (CNS) toxicity or tumor lysis syndrome (TLS) for possible hospitalization. In patients who remain hospitalized after the CAR T cell infusion, vital signs should be assessed every 4 hours or more frequently if the patient experiences fever, hemodynamic changes, dyspnea and/or hypoxia (oxygen saturation <92% on room air) or neurologic symptoms. Fluid balance should be closely monitored, as well as daily weight. Assessment and grading of CRS should be done at least twice a day and whenever there are changes in patients’ status. Neurological evaluation to assess the CNS toxicity should include evaluation of mental status, headache and abnormal movements and be performed every 8 hours, or more frequently in the presence of changes. A complete blood count and biochemistry profiling, which includes basic metabolic panel, magnesium, phosphorus, uric acid and lactate dehydrogenase, liver enzymes, albumin and total bilirubin as well as coagulation tests with prothrombin time, partial thromboplastic time, fibrinogen, and D-dimer, C reactive protein and ferritin levels should be monitored daily in patients who are followed inpatient and when the visit is performed in the outpatient setting.

The benefit of CAR T cells has been demonstrated in relapsed/ refractory B cell malignancies that express the CD19 antigen. A detailed understanding of the early and late toxicities associated with this therapy and their management is essential for the safe use of the recently FDA and EMA approved CAR T cells, tisagenlecleucel and axicabtagene ciloleucel. Moreover, strategies to diminish the toxicity based on prevention and prompt recognition of severe adverse events are currently available for clinical use. Furthermore, ongoing development of new generation CAR T cells provide the opportunity to increase the cure rate of CAR T cells, while decreasing their toxicity.