CAR-T cell therapy – toxicity and its management

Abstract

Chimeric antigen receptor T-cell (CAR-T) therapy is an effective new treatment for hematologic malignancies. Two anti-CD19 CAR-T products, namely axicabtagene ciloleucel and tisagenlecleucel, have been approved for the management of relapsed/refractory large B-cell lymphoma after two lines of systemic therapy. Additionally, tisagenlecleucel is indicated for refractory acute lymphoblastic leukemia in pediatric patients and young adults up to 25 years of age. CAR-T cells are undoubtedly a major breakthrough therapy in hematooncology resulting in up to 90% response rate with durable remissions in population with refractory high-risk disease. However, there are serious side effects resulting from CAR-T therapy, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Manifestations of CRS mostly include fever, hypotension, hypoxia, and end organ dysfunction. Neurologic toxicities are diverse and include encephalopathy, cognitive defects, dysphasia, seizures, and cerebral edema. Since the symptoms are potentially severe, practitioners need to familiarize themselves with the unique toxicities associated with these therapies. In this article, we present a practical guideline for diagnosis, grading and management of CRS and CAR-T neurotoxicity. In addition, infectious complications and late toxicities including prolonged cytopenias and hypogammaglobulinemia are discussed.

New Era of Immunotherapy in Pediatric Brain Tumors: Chimeric Antigen Receptor T-Cell Therapy

“…Those symptoms can happen on the first day of the infusion of CAR T cells or can be delayed up to 14 days after the initiation of the delivery of CAR T cells. Anti-IL-6 receptor antibody, tocilizumab, has been demonstrated to reverse CRS [ 89 ]. Prophylactic administration of tocilizumab during CAR T-cell therapy is also undergoing clinical trial (NCT02906371).…”

Gene Modified CAR-T Cellular Therapy for Hematologic Malignancies

“…In addition, conditioning chemotherapy containing fludarabine was associated with the development of severe CRS [ 113 ]. Recent American Society for transplantation and cellular therapy has consensus on grading CRS according to body temperature, hypotension requiring a vasopressor or not, and oxygen demand from grade 1 to 4 [ 114 , 115 ]. Management of toxicity was based on its clinical presentations, and tocilizumab, an anti-interleukin (IL)-6 receptor antibody, was suggested once toxicity reached grade 2 or higher [ 114 ].…”

“…The Pediatric Oncology Group at the NCI and colleagues developed their own grading system combining patients’ cognitive test and observer-reported checklist [ 122 ]. The recent ASTCT consensus grading system then highlights the immune effector cell-associated encephalopathy scores, seizures, motor weakness, and raised intracranial pressure or cerebral edema as a new index [ 114 ]. It is suggested to closely monitor neurological toxicity throughout the treatment and exclude other possible factors like infection or electrolyte imbalance, which leads to neurotoxicity.…”

“…It is suggested to closely monitor neurological toxicity throughout the treatment and exclude other possible factors like infection or electrolyte imbalance, which leads to neurotoxicity. Levetiracetam 500 mg twice daily for seizure prophylaxis is also recommended to use in patient with grade 1–2 neurotoxicity and steroid in grade 2–3 [ 114 ].…”

Where dreams come true: CAR-T cell therapy in Poland!

“…therapy [2,3,4]. So far, it is feasible only for B-cell lineage hematological malignancies, but the door has been opened for further research and progress.…”