Experts Propose New Consensus Scale for CAR T-cell Therapy Toxicities

Experts Propose New Consensus Scale for CAR T-cell Therapy Toxicities

The American Society for Blood and Marrow Transplantation (ASBMT) proposed a new consensus scale for toxicities associated with CAR T-cell therapies to better categorize their severity in both the hospital setting and clinical trials.

The study, “ASBMT Consensus Grading for Cytokine Release Syndrome and Neurological Toxicity Associated with Immune Effector Cells,” appeared in the journal Biology of Blood and Marrow Transplantation.

Chimeric antigen receptor (CAR) T-cell therapy consists of collecting a patient’s own immune T-cells and modifying them for improved recognition and killing of cancer cells.

Yescarta (axicabtagene ciloleucel, by Kite Pharma) and Kymriah (tisagenlecleucel, by Novartis) are two CAR T-cell therapies currently available in the U.S. and Europe for patients with relapsed or refractory B-cell acute lymphoblastic leukemia and adults with large B-cell lymphoma, with other immunotherapies in development for lymphoma and other malignancies.

CAR T-cell therapy may have side effects, including cytokine release syndrome (CRS), a form of systemic inflammatory response causing flu-like symptoms; and neurological toxicity — now referred to as immune effector cell associated neurotoxicity syndrome (ICANS) — that manifests as difficulty concentrating, agitation, tremor, and seizures, among other symptoms.

The assessment and grading of these side effects have varied significantly, representing a challenge to compare safety and toxicity of different treatments and limiting the ability to develop optimal strategies to manage these toxicities.

“Without a unified grading system in CAR T-cell therapy, there have even been doctors at the same treatment center using different products in the same types of patients and reporting toxicities differently,” Stephan Grupp, MD, PhD, one of the study’s authors and chief of the Children’s Hospital of Philadelphia’s Cell Therapy and Transplant Section, said in a press release.

“Having entered the era of commercially available CAR T therapy products, it is crucial that data are reported in the same way,” Grupp said.

Aiming to address this, the ASBMT supported three meetings in 2018, where 49 experts worked to develop a single definition and grading system for CRS and neurotoxicity. The participants included stakeholders from major CAR T-cell therapy centers, industry representatives, the Center for International Blood and Marrow Transplant Research, the American Society of Hematology, and the National Cancer Institute.

Noting that CRS is not unique to CAR T-cell therapy and that its symptoms may have other causes, the experts defined CRS as “a supraphysiologic response following any immune therapy that results in the activation or engagement of endogenous or infused T cells and/or other immune effector cells.”

They also agreed that symptoms can be progressive and “must include fever at the onset, and may include hypotension, capillary leak (due to oxygen deficiency) and end organ dysfunction.”

Although encouraging laboratory measurement of cytokines — a type of of pro-inflammatory molecules — the team favored clinical observation for the definition and grading of CRS.

Five CRS grades were proposed, ranging from having fever not attributable to any other cause and without low blood pressure or oxygen deficiency (grade 1), to death by CRS (grade 5).

ICANS was defined as a central nervous system (brain and spinal cord) disorder “following any immune therapy that results in the activation or engagement of endogenous or infused T cells and/or other immune effector cells.”

In ICANS’ grading scheme, the experts proposed a slightly modified version of the CARTOX-10 tool, named Immune Effector Cell-Associated Encephalopathy (ICE) score.

As with CRS, five grades were proposed for adults, ranging from grade 1 — a score of 7-9, delayed response or disorientation, mild inattention, difficulty in counting numbers backward and impaired handwriting —  to grade 5, death by ICANS.

In children younger than 12, the experts recommended the Cornell Assessment of Pediatric Delirium to help grade ICANS.

“We believe that our proposed grading system is objective, easy to use, and more accurately categorizes the severity of these toxicities,” the scientists stated.

“The response has been overwhelmingly positive both from the academic medical community as well as the industry all over the world, including North America, Europe, and Asia,” said Sattva Neelapu, a study co-author and professor at the University of Texas MD Anderson Cancer Center. “Everyone is eager to implement this new grading system at their hospitals, as well as in prospective clinical trials.”

Grupp said, “With the release of this ASBMT report, I believe stakeholders will see the added value of implementing a consistent grading system.”

John DiPersio MD, PhD, and ASBMT’s president, said: “I am incredibly proud of the work ASBMT and the authors have done highlighting the importance of a unified grading system in CAR T-cell therapy. This work furthers our advancement of the field of cellular transplantation and, more importantly, helps us give better care to our patients.”

José is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.
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José is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.
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