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Attendees at 2018 ASCO Annual Meeting
©ASCO/Zach Boyden-Holmes 2018

CHICAGO—A specific gene signature might be able to identify patients at risk of CD19 CAR T-cell associated neurotoxicity, according to results of an exploratory analysis presented at the 2018 ASCO Annual Meeting.

The analysis, based on bone marrow samples from patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) treated with JCAR015 in the ROCKET trial, helped identify a set of neurotoxicity-associated genes that separated patients based on molecular subtype.

“These findings suggest that patient risk stratification by molecular subtype of disease or gene expression signature may play a role in identifying patients at elevated risk of neurotoxicity,” said Jae Park, MD, of Memorial Sloan Kettering Cancer Center, New York, New York, in a presentation of the findings (abstract 7007).

The phase 2 ROCKET study included adult patients with relapsed or refractory morphological (>5% blasts in bone marrow) CD-19 positive disease in first salvage or greater, including post allogeneic hematopoietic stem cell transplantation (HSCT). Prior blinatumomab was allowed.

The tumor gene expression study presented at ASCO was based on sequenced RNA from pre-apheresis bone marrow samples available for 31 patients in the ROCKET study.

Investigators identified a set of 10 genes expressed more frequently in bone marrow samples from patients in ROCKET with low (grade 0-1) neurotoxicity, and 7 that were more frequent in those who had severe (grade 4-5) neurotoxicity.

Looking at B-cell ALL samples in public datasets by molecular subtype, they found genes highly expressed in the low neurotoxicity ROCKET patients were also highly expressed in Philadelphia chromosome-positive (Ph+) and Ph-like subtypes.

Conversely, the genes highly expressed in the severe neurotoxicity patients were also highly expressed in non-Ph-like samples.

A total of 16 ROCKET patients were classified as having Ph-like gene expression and 15 as having non-Ph-like expression.

There were no grade 4-5 neurotoxicity events in the Ph-like patients, while both grade 3+ and grade 4+ neurotoxicity were significantly more prevalent in the non-Ph-like patients, investigators reported.

One of the most differentially expressed genes in the set was CCL17, which was higher in the low-neurotoxicity tumor samples, and likewise highly expressed in Ph-like B-cell ALL, according to the report.

“[CCL17] may serve as an early biomarker for differentiating severe neurotoxicity,” Dr Park said.

These findings are now being validated in the previously mentioned data set, as well as other studies to see if the findings can be replicated, according to Dr Park.

Juno Therapeutics, a Celgene company, shut down the phase 2 ROCKET trial of JCAR015 in 2017 after 2 clinical holds in 2016 and 5 patient deaths. 

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