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MONTREAL – The investigational chimeric antigen receptor T cell (CAR-T) therapy CTL019 induced "potent and durable responses" in children with central nervous system (CNS) involvement in relapsing/refractory acute lymphoblastic leukemia (ALL), a researcher reported here.

In a secondary analysis of the phase I/IIa CHP 959 study, looking only at children with CNS involvement, 71% remain in complete remission a median of 11 months after the therapy, reported Mala Talekar, MD, from Children's Hospital of Philadelphia.

Presenting the findings at the annual meeting of the American Society of Pediatric Hematology/Oncology here, Talekar said the "remarkable milestone" underscores the potential for CTL019, a Novartis product that recently received "breakthrough" designation and is undergoing priority review by the FDA.

"Everybody knows that we do a great job treating newly diagnosed cases of ALL, standard risk, high risk, or any risk, but when it comes to first relapse the curve basically plummets down," said Talekar. "Our best survival rates at first relapse fall between a dismal 20%-60%, and once a child relapses a second time they fall down to the 10%-20% range."

The CHP 959 study included 60 children with relapse/refractory CD19-positive ALL who underwent CTL019 CAR-T-cell therapy and were evaluated every 3 months for relapse in bone marrow and cerebrospinal fluid (CSF).

At 12-months post-infusion, overall survival was 79%, "and even at 24 months overall survival is somewhere in the range of 65%, which is awesome if you consider the population that is receiving this therapy," said Talekar. "This population is children who have had two or more relapses or have been refractory to therapy, with the majority being refractory to multiple therapies."

Overall, the study showed a 93% complete remission rate at day 28, with 100% of patients achieving CNS remission. Cytokine release syndrome was seen in 88% of patients but was only severe in 27%, she reported.

The researchers then decided to focus on the subset of 17 patients whose indication for the therapy was CNS relapse.

"We defined CNS relapse as CNS3 by lumbar puncture or brain or ocular involvement on imaging."

The number of relapses in this subgroup ranged up to seven, with 10 patients having isolated CNS relapse and seven with combined bone marrow/CNS relapse.

"When we first started enrolling, our eligibility criteria strictly specified either CNS 1 disease or CNS 2. We were not enrolling CNS 3 patients because we were not sure whether it was going to be efficacious or what the toxicities were going to be. But as we saw the trial evolving and that the CTL019 cells were trafficking to the CSF we decided to enroll CNS3 patients as well," she explained. They enrolled three.

At day 28 of follow-up, 16 of the 17 patients were staged as CNS1 according to CSF. Among the 3 patients who were CNS3 before therapy, one was not evaluable due to rapid progression of bone marrow disease, one was in complete remission, and the other had initial "pseudo progression" but subsequently complete remission at three months.

Of the 12 patients who remain in complete remission at 2-3 months post-infusion, five had isolated relapses in marrow but all were CNS negative, said Talekar.

Neurotoxicity with this therapy "is a hot topic right now," she added. "One would think that patients who have CNS disease would be the ones who had the most toxicity but that did not seem to be the case."

Among the 17 CNS patients the rate of Grade 3 encephalopathy was 18% compared to a 28% rate in the non-CNS patients, and while one patient in each cohort had a grade 2 seizure, there was also two more patients with Grade 3 and 4 seizures in the non-CNS group versus none in the CNS group.

"We did see a wide variety of neurotoxicity symptoms ranging from agitation, ataxia, dizziness, confusion, trigeminal neuralgia, speech disturbance and vision disturbance ... but the important thing to note was all patients were back to their neurologic baseline by month 3," she concluded.

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