Neurotoxicity in B-Cell ALL Not from CAR-T Therapy

Results from a recent clinical trial have demonstrated significant associations between cellular mechanisms other than T-cells and symptoms of neurotoxicity in patients with acute lymphoblastic leukemia (ALL) receiving chimeric antigen receptor (CAR) T-cell therapy (Cancer Discov. 2018 Jun 7. Epub ahead of print).

Although CD19-directed CAR T-cell therapy is a highly effective treatment for patients with relapsed or refractory ALL, treatment-related neurotoxicity limits the use of this immunotherapy, and attempts by researchers to determine the exact pathobiology of CAR T-cell–associated neurotoxicity have thus far have been unsuccessful.

Neurotoxicity is currently grouped in an overall toxicity profile alongside cytokine release syndrome, and managed with tocilizumab. However, there is currently no consensus for which therapeutic interventions are most effective at inhibiting or reducing the severity of neurologic adverse events associated with the use of CD19-specific CAR T-cell therapies, explained Bianca D. Santomasso, MD, PhD, Department of Neurology, Memorial Sloan Kettering Cancer Center (MSKCC), New York, and colleagues.

 “Better understanding of the clinical features and biological correlates of CAR T-cell–associated neurotoxicity in patients is needed to identify pharmacologically targetable pathways to mitigate toxicity,” they said.

To address this unmet need, Dr Santomasso and colleagues conducted a phase 1 clinical trial to comprehensively analyze and identify correlates of neurotoxicity in 53 adults with relapsed or refractory B-cell ALL receiving CD19-directed CAR-T therapy at MSKCC. They used the MSKCC cytokine release syndrome grading system and the National Cancer Institute common terminology criteria for adverse events v4.03 to grade cytokine release syndrome and neurotoxicity, respectively. Cytokine release syndrome at grade ≥3 was defined as severe.

Within 4 weeks of receiving CAR T-cell infusions, 33 (62.3%) of the 53 participants had neurotoxicity of any grade, 11 (20.8%) had mild neurologic symptoms, 22 (41.5%) had severe (grade ≥3) neurotoxicity, 19 (35.8%) had grade 3 neurotoxicity, and 3 (5.7%) had grade 4 neurologic symptoms. There was median of 5 days (range, 2-11 days) between CAR T-cell infusion and onset of first neurologic symptom of any grade, and a median of 9 days to the first occurrence of severe neurotoxicity, Dr Santomasso and colleagues reported.

Of note, although neurotoxicity can occur without the presence of cytokine release syndrome, all 33 patients who experienced neurotoxicity had cytokine release syndrome grade ≥1, demonstrating a significant correlation between severity of cytokine release syndrome and neurotoxicity (P <.001). Severe neurological reactions were also associated with a lower baseline platelet count, a higher tendency for earlier onset of fever 3 days after CAR T-cell infusion, and higher levels of C-reactive protein (a marker of inflammation in the blood) than minor neurological effects. In addition, patients with neurotoxicity had significantly elevated cerebrospinal fluid (CSF) protein levels (P = .036).

Dr Santomasso and colleagues identified high pretreatment disease burden, early and high elevations of proinflammatory cytokines, and a higher-peak CAR T-cell expansion in the blood after transfusion as predictors of a greater risk for neurotoxicity in patients receiving CAR T-cell therapy. They also noted a correlation between the grade of neurotoxicity and blood­­–CSF barrier disruption that was irrespective of CSF white blood cell count or the quantity of CAR T-cells in the CSF.

Interventions that reduce early inflammation and blood–CSF barrier disruption may further improve the safety of using CD19-directed CAR T-cells in patients with B-cell ALL, according to Dr Santomasso and colleagues.

“Future work to understand the interplay between systemically and centrally produced cytokines and excitotoxic metabolites in the development of neurotoxicity will be invaluable to the design of studies to ensure safe delivery of CAR therapy,” they concluded.—Janelle Bradley