Predictors of CAR-T-Associated Neurotoxicity in B-Cell Acute Lymphoblastic Leukemia

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High levels of CAR-T cell expansion in vivo and high pretreatment disease burden appeared to increase the likelihood that a neurotoxic event may occur following CAR-T administration.
High levels of CAR-T cell expansion in vivo and high pretreatment disease burden appeared to increase the likelihood that a neurotoxic event may occur following CAR-T administration.

The arrival of chimeric antigen receptor T-cell (CAR-T) cancer treatments is ushering in renewed concerns about how physicians should plan for the management of toxicities associated with these innovative cell therapies and, specifically, how to identify neurotoxicity risk factors across heterogeneous groups of patients.

Currently, reports of cytokine release syndrome (CRS) and neurotoxicity are grouped together in an overall toxicity profile, and CRS is generally managed through administration of the monoclonal antibody tocilizumab. But there is little information guiding which protocols are most effective for preventing or reducing severe neurologic adverse events, such as the cerebral edema that has been observed in many trials testing CD19-specific CAR-T therapies.

Investigators from the Memorial Sloan Kettering Cancer Center conducted a phase 1 trial of 53 adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) seeking to identify correlates of neurotoxicity in patients receiving a CD19 CAR-T medication. Their findings were published in Cancer Discovery.1

The median time for the first appearance of any neurological symptom was 5 days, and the median time to the first onset of a severe event was 9 days. Of the study participants, 22 (41.5%) developed severe reactions of grade 3 or higher, 19 (35.8%) experienced grade 3 reactions, and 3 patients (5.7%) developed grade 4 neurologic effects. Of the patients who saw extreme reactions, 72% (16 of 22) developed seizures. The most common characteristic of severe reaction was expressive aphasia, which in many patients resembled symptoms of a stroke or a seizure. There were no grade 5 reactions observed in the trial.

There was a significant correlation (P < .001) between severity of CRS and neurotoxicity, as all 33 patients who experienced neurotoxicity had CRS of at least grade 1 — but the authors noted that neurotoxicity can also occur in the absence of CRS. They determined that tocilizumab administration did not effectively reduce the severity of neurotoxicity, though it has been shown to temper CRS.

The predictors of enhanced risk of a severely toxic reaction to CAR-T were determined to be a high level of disease burden prior to treatment (measured by bone marrow blasts of at least 5% or radiographically evident extramedullary disease) or a higher peak CAR-T cell expansion in the blood following infusion. In addition, patients with more severe reactions were also more likely to have earlier onset of fever 3 days following drug infusion, low platelet counts, and higher levels of C-reactive protein (CRP) compared with those who only had mild neurological effects.

Following treatment, CSF protein levels were significantly elevated (P = .036) in patients with neurotoxicity, and concentration levels appeared to be directly correlated with the severity of the toxicity. “These findings indicate that there is increased blood­­­­­–CSF barrier permeability during neurotoxicity that may occur by a distinct mechanism from CAR T or other cell accumulation in CSF,” the authors concluded.

The phenotype of the T cell used in the manufacture of the CAR-T product (ie, whether the T cell was a naive, effector memory, or effector cell) did not appear to influence risk of neurological harm from adoptive cell therapy administration. And, unlike findings from other trials on CAR-T, the researchers did not see a link between a higher infused dose of CAR-T and neurotoxicity — but they acknowledged that the dose of CAR-T for each patient was adjusted based on the subject's level of disease burden.

Reference

  1. Santomasso BD, Park JH, Salloum D, et al. Clinical and biological correlates of neurotoxicity associated with CAR T-cell therapy in patients with B-cell acute lymphoblastic leukemia [published online June 7, 2018]. Cancer Discov. doi: 10.1158/2159-8290.CD-17-1319

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