Management of chimeric antigen receptor T (CAR-T) cell-associated toxicities

Abstract

The use of chimeric antigen receptor T (CAR-T) cells is a significant therapeutic improvement increasing the prognosis for patients with a variety of hematological malignancies. However, this therapy has also sometimes life-threatening, complications. Therefore, knowledge of the treatment and management of these complications, especially in treatment centers and intensive care units, respectively, is of outstanding importance. This review provides recommendations for the diagnosis, management, and treatment of CAR-T cell-associated complications such as cytokine release syndrome, immune effector cell associated neurotoxicity syndrome, hematotoxicity, hypogammaglobulinemia, and CAR-T cell-induced pseudo-progression amongst others for physicians treating patients with CAR-T cell-associated complications and intensivists.

Keywords: CAR-T; CAR-T complications; CRS; ICAHT; ICANS; Intensive Care.

Fig. 1

The process preceding CAR-T cell therapy. 1) First, a lymphapheresis is performed through a large-volume venous access. 2) This is followed by the transduction of a chimeric antigen receptor (CAR) to the collected T-cells and 3) in vitro expansion of CAR-T cells. It is important to note that various generations of CAR-T cell receptors are now available, differing depending on the CAR-T cell product with different approvals. 4) The infusion of the CAR-T cells occurs after a few weeks. It is important to consider that, especially in highly proliferative diseases, other bridging therapies are administered in the time between lymphapheresis and CAR-T cell infusion. Furthermore, the infusion of CAR-T cells only occurs after a lymphodepleting chemotherapy has been applied

Fig. 2

The various gradings and respective measures for the most common side effect of CAR-T cell therapy—cytokine release syndrome (CRS). For a CRS I°, a systemic infection should be ruled out, and treatment with antipyretics and IV cristalloids should be administered. A CRS II° is defined by a temperature above 38 °C, decreased blood pressure, and/or the need for oxygen therapy with ≤ 6L/min. For a CRS II°, additionally the administration of tocilizumab 8 mg/kg IV should be carried out. In CRS III°, the administration of a vasopressor is necessary and/or oxygen therapy with > 6L/min is required. Transfer to the intensive care unit is necessary and intravenous administration of dexamethasone is performed. For CRS IV°, the administration of > 1 vasopressor is required, and intubation or PAP is often necessary. In addition to the previously mentioned therapy, the administration of intravenous methylprednisolone must be performed

Fig. 3

Grading and therapy of CAR-T cell-associated neurotoxicity (ICANS). In ICANS I°, an ICE score of 7–9 out of a total of 10 points is mandatory. This is determined with a simple questionnaire. Grade 1 indicates a mild disturbance of consciousness, where the patient is spontaneously arousable. Close monitoring of the patient should be carried out, and the prophylactic application of antiepileptics can be considered. ICANS II° is characterized by a disturbance of consciousness where the patient is arousable by speech. The application of intravenous dexamethasone must be carried out. Additionally, aspiration prophylaxis should be considered, and medications should no longer be administered orally. Cerebral imaging should be performed, and a lumbar puncture should be discussed. In ICANS III°, the disturbance of consciousness is more severe, and the patient only responds to tactile stimulus. Epileptic seizures may occur but respond to intervention. A focal cerebral edema in imaging may also be present. Transfer to the intensive care unit should take place, and the application of methylprednisolone must be carried out. In ICANS IV°, severe disturbance of consciousness is observed, where the patient is not spontaneously arousable and only responds to repetitive tactile stimuli. Epileptic seizures are life-threatening. Higher degree motor deficits (hemi- or paraparesis) and diffuse cerebral edema in imaging may occur, accompanied by symptoms such as decorticate or decerebrate rigidity, abducens palsy, papilledema, or Cushing’s reflex (increased intracranial pressure, increased blood pressure, decreased heart rate). The placement of intracranial pressure monitoring should and plasmapheresis may be considered. Additionally, further immunosuppressive drug strategies with anakinra IV amongst others may be applied

Fig. 4

The development of handwriting malfunction during the rise and fall of immune effector cell-associated neurotoxicity syndrome (ICANS). The patient is asked to repeatedly write down the same standard sentence (e.g. here: “my favourite color is green”, in German: “Meine Lieblingsfarbe ist grün”)