CRS and ICANS are the most common nonhematologic toxicities associated with immune effector cell therapy. They were once considered in aggregate, but the neurotoxicity and symptoms of ICANS are now considered separately from CRS, in part because of their potentially distinct timing. The neurologic symptoms of ICANS may occur early on, along with CRS symptoms, but they also may occur after and independently from CRS.

While having severe CRS is one of several predictors of ICANS, the pathophysiology of ICANS is unclear and appears to be distinct from that of CRS. Most cases of ICANS are reversible; however, some reported cases have been associated with prolonged morbidity and even mortality. Thus, ICANS remains a significant concern among patients receiving CAR T-cell therapy.

Considerable progress has been made with respect to monitoring for ICANS and risk mitigation. All patients with multiple myeloma should be carefully monitored post CAR T-cell treatment. ICANS may manifest as aphasia, altered consciousness and cognitive skills, impaired motor weakness, seizure, and cerebral edema. Guidelines such as those from the Society for Immunotherapy of Cancer and the American Society of Clinical Oncology on the diagnosis, evaluation, and management of ICANS are excellent resources. ICANS is most prominent among patients with a high tumor burden, so a reduction of the tumor burden prior to the administration of CAR T cells is an important mitigation strategy.

Routine cognitive function monitoring tests can be conducted each day to assess whether a patient is demonstrating early signs of ICANS. These include detailed neurologic evaluations with comparisons to the baseline assessments. Such commonly used tests include an assessment of the patient's handwriting skills or asking the patient to count back from 100 by 7's.

Along with reducing tumor burden prior to CAR T-cell therapy and careful monitoring, prompt intervention is critical to mitigate CRS and ICANS. Grading systems are available for the assessment of both, and their use is recommended to determine the severity and to guide therapy. In addition to symptom-driven supportive care, corticosteroids are uniformly used for the treatment of ICANS. Many patients also receive tocilizumab for CRS that is occurring concurrently with ICANS.

In negotiating a return to normal activity post CAR T-cell therapy, very close monitoring during the first month is essential, assessing not only the patient’s antimyeloma response and hematopoietic recovery but also their cognitive function and physical performance status. It is recommended that patients refrain from driving during the first month after CAR T-cell treatment and that they live close to a treatment center that is familiar with the complications of CAR T cells so that they can be treated quickly, if necessary. Some patients can have prolonged low blood cell counts, lasting weeks to months, so supportive therapy with platelets and red blood cells may be required in such individuals.

The efficacy of CAR T cells at depleting BCMA-positive tumors is remarkable. CAR T-cell use is also associated with the depletion of BCMA-expressing normal plasma cells. Patients who experience this effect need to be protected against infection and counseled on therapy, whether that be with the use of acyclovir for herpetic infection, trimethoprim/sulfamethoxazole for pneumocystis infection, or intravenous immunoglobulin if their immunoglobulin levels warrant it.

With our current prevention and monitoring strategies, most patients receiving CAR T-cell therapy actually quite rapidly return to normal performance status. And it is so exciting to see patients who have had years of multiple myeloma–related treatment, for the first time, not require any treatment at all.