Dr. Carl June Discusses Management of Neurotoxicity From CAR T-Cell Therapy

Though clinical work is ongoing and early, researchers are already considering how to manage potentially fatal neurotoxicities in patients treated with chimeric antigen receptor (CAR) T-cell therapy.

Carl H. June, MD

Though clinical work is ongoing and early, researchers are already considering how to manage potentially fatal neurotoxicities in patients treated with chimeric antigen receptor (CAR) T-cell therapy.

Carl H. June, MD, professor of Medicine, Hospital of the University of Pennsylvania, addressed the treatment of two toxicities in particular—cytokine release syndrome (CRS) and encephalopathy—during an educational session at the 20th Annual Scientific Meeting and Education Day of the Society for Neuro-Oncology.

June focused on neurotoxicities he’s seen in his work on CTL019, an autologous T-cell therapy, engineered through lentiviral transduction to express a CD19-specific CAR. At the 2014 ASH Annual Meeting, researchers reported a 92% complete response rate among 39 patients with pediatric acute lymphoblastic leukemia (ALL) in a phase I study of CTL019.

The first toxicity June highlighted, CRS, is reversible and is related to macrophage activation syndrome (MAS). The hallmark signifier of MAS is elevated serum ferritin (>500,000 ng/mL). The cytokine signature of MAS is elevated levels of IFN-gamma and IL-6; therefore, June suggests physicians use tocilizumab (Actemra) to reverse the adverse event (AE).

A single injection of tocilizumab, which is approved for rheumatoid arthritis and juvenile idiopathic arthritis, can eliminate fever from CRS in 4 hours, according to June. Trials are ongoing to determine if the agent can be given prophylactically.

“What we try to do is treat patients—to keep them out of the [intensive care unit],” said June, Richard W. Vague Professor in Immunotherapy, Perelman School of Medicine at the University of Pennsylvania, during his presentation. “The primary symptoms really are fever, but the clinical toxicity is manifest by hypertension and respiratory failure.”

June said that the first two patients to experience CRS, (pediatric patients with ALL) had fevers that started approximately 4 days after infusion and were correlated with increased cytokines (mainly IFN-gamma and IL-6).

June also pointed out that patients in the phase I study experienced tachycardia and hypertension 4 to 5 days after infusion. These patients also experienced liver function abnormalities, but not jaundice, and increased levels of lactate dehydrogenase.

Resolving organ failure took longer in patients with grade 3/4 CRS, June said, but was still reversed in almost all cases—3 of 180 total patients treated with CTL019 have died due to CRS.

Differences also remain across age groups and disease type, June said, though the reason is unknown.

“In adults with CLL [chronic lymphocytic leukemia], [CRS] is more delayed than it is with ALL, for reasons that remain obscured.”

Two patients with multiple myeloma were treated with CTL019 in a pilot study and both experienced CRS. One patient’s CRS was severe and lasted 3 weeks, while the other had a milder event.

The connection between CRS and neurologic AEs is apparent, though not completely understood.

Overall, there are a number of neurologic AEs that have occurred with anti-CD19 CAR T-cell therapy, all of which have a simultaneous or delayed onset with CRS. These toxicities have been observed in ALL, CLL, diffuse large B-cell lymphoma and myeloma. Cases of neurologic AEs with these agents have also been seen in ovarian cancer and pancreatic cancer.

Common symptoms of encephalopathy included aphasia, confusion, delirium, and hallucinations, and occurred in 33% of patients with pediatric ALL. Two seizures were observed.

“In the case of this encephalopathy, it is not associated with response rates—unlike the CRS, which is associated with good responses,” June said.

June pointed out that encephalopathy may be related to CD19. Similar events have been reported with blinatumomab (Blincyto), the anti-CD19 immunotherapy that is FDA-approved for the treatment for Philadelphia chromosome-negative relapsed/refractory B-precursor ALL.

Though the cause of encephalopathy is not completely understood, the toxicity was generally short lived.

In the phase I pediatric ALL study, specifically, encephalopathy often presented after CRS and lasted a median of 7 days. All patients recovered by day 18 and prior tocilizumab did not prevent the onset of encephalopathy. Two patients had seizures.

Before an anti-CD19 CAR T-cell therapy is approved, researchers and physicians alike hope to have a fuller understanding of how the drugs work and the toxicities associated with them.