The American Society of Blood and Marrow Transplantation (ASBMT) is in the process of developing a toxicity rating system for CAR-T therapies, a new type of cancer therapeutic approach, for indications like diffuse large B-cell lymphoma (DLBCL) to provide a universal guide in measuring side effects for clinicians, ASBMT President John DiPersio said. The hope is that it will be finalised in the next couple of months for submission to the journal Biology of Blood and Marrow Transplantation, added a source familiar to the development of the rating system.

The consensus manuscript, which would be peer-reviewed, proposes new definitions and grading for cytokine release syndrome (CRS), a systemic inflammatory response, and CAR-T cell related encephalopathy syndrome (CRES) that aim to be objective, easy to use and more accurate in categorising toxicity severity, DiPersio explained. CRES, typically characterised by a toxic encephalopathic state with symptoms of confusion and delirium, features a neurological assessment score, among others.

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The rating system’s initial goal is to address comparisons between already approved CAR-T agents, as their current clinical trial data may have used different toxicity grading systems, the source said. However, the rating system could also be used by pharmaceutical companies to measure toxicity in drug development, he added.

CAR-T therapies approved in DLBCL are Gilead Sciences’ Yescarta (axicabtagene ciloleucel) and Novartis’ Kymriah (tisagenlecleucel). Celgene’s JCAR017 is in a 100-patient Phase I/II trial (NCT03310619).

Pharmaceutical companies with approved CAR-T therapies are involved in the discussions to some capacity, the source said. An FDA spokesperson said it is aware of the planned rating system and was invited to participate. The agency believes it could be useful but declined to speculate further, she added.

DiPersio said a writing group led by Dr Stephan Grupp, director, Cancer Immunotherapy Program, Children’s Hospital of Philadelphia, Pennsylvania, and Dr Sattva Neelapu, professor, Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, is finalising the manuscript reporting the consensus of the group.

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Gilead, Novartis and Celgene did not respond to a request for comment.

Consensus would establish universal toxicity scale

Drafting of the toxicity rating system started during an ASBMT consensus conference in June, with the idea being it would be used across clinical trials and institutions to more accurately assess and manage CAR-T toxicities, the source and DiPersio said.

At present, there are various scales used to measure toxicity in DLBCL clinical trials, and thus a universal scale would be valuable for clinicians, said Dr Jonathon Cohen, assistant professor, Bone Marrow and Stem Cell Transplantation Research Center, Emory University, Atlanta, Georgia, and Dr Sarah Rutherford, assistant professor of medicine, Weill Cornell Medical College, Cornell University, New York. This differential makes it challenging to compare the toxicity profiles of different CAR-T therapies, the source said.

One is the SSPedi, a self-report symptom tool for children with cancer and haemetopoietic stem cell transplant recipients. Another is the CAR-T cell therapy associated toxicity (CARTOX) score, which provides recommendations for monitoring, grading and managing acute toxicities. The third is the Penn grading scale, which offers CRS grading.

Additionally, there are variations of these three most common toxicity scales that can also be used in clinical trials, the source added. Cohen noted that Gilead and Novartis have their own toxicity algorithms covering CRS and neurotoxicity side effects in the real world.

Another issue with these scales is that the grading system could be subjective, where a neurotoxicity Grade of 2 and 3 could vary between clinicians, the source said. The new rating system would feature a grading rationale and a consensus on toxicity reporting, he added.

CAR-T head-to-head trials unlikely, and universal management advice also needed

A universal rating system would be welcome because CAR-T therapies under investigation are unlikely to be in a head-to-head trial with already approved CAR-T therapies, said Dr Tanaya Shree, hematology and oncology fellow, Stanford University, California. There is little incentive for pharmaceutical companies to conduct such a trial, considering, in general, yet-to-be approved therapies are typically investigated versus standard of care, and CAR-T therapies are not considered as such, Shree said. Yescarta was approved in October 2017 and Kymriah in May 2018. The ongoing Phase I/II trial JCAR017 does not have an active comparator.

Apart from DLBCL, this rating system could be used in other blood malignancies like follicular lymphoma that have CAR-T therapies under investigation, as its side effects are specific to the therapeutic approach, Shree said.

Ideally, Cohen noted, the toxicity rating system could also include details on how varied toxicities could be managed. For example, Yescarta and Kymriah’s side effect of neurotoxicity can have different management advice according to the product labels; Yescarta’s label notes corticosteroids as an important way to ease symptoms, which is not mentioned on the Kymriah label, he said. This conflicting information makes it challenging for patient care, he noted.

Shree agreed, adding the rating system would only be used in the real world in the context of managing patients. Early toxicity recognition in the first 30 days after infusion is critical as it could be life-threatening, and so the rating system with management advice could help manage patients earlier, she said.

But the source noted toxicity grading and reporting is the focus rather than toxicity management.