CAR-T CELL TOXICITY

This therapy has very unique side effects that are unlike other regimens used for cancer treatment. Dr Sattva Neelapu

This is similar to what was initially experienced with stem cell transplantation, said lead author, Sattva Neelapu, MD, professor of lymphoma and multiple myeloma at MD Anderson. "That was a new type of therapy, and physicians had to learn how to care for these patients, and recognize and treat side effects."

For CAR T-cell therapy, it is a very steep learning curve not only for physicians but for all staff involved, Dr Neelapu told Medscape Medical News. "This therapy has very unique side effects that are unlike other regimens used for cancer treatment. The purpose of this paper was to offer a step-by-step guideline beginning with preparing the patient for the infusion of CAR T-cells to recognizing and managing side effects."

Dr Neelapu also noted that they updated several grading systems to account for the common toxicities observed with this therapy.

To develop these recommendations, Dr Neelapu and his team created a CAR T‑cell  therapy–associated TOXicity (CARTOX) working group, which comprised investigators from several institutions and medical disciplines who were experienced in treating patients with various CAR T‑cell agents.

The paper describes the multidisciplinary strategies for treating toxicities that were adopted at their individual institutions and proposes recommendations for monitoring, grading, and management.

Three-Step Approach

Overall, the authors recommend a basic three-step approach to assessing and managing acute toxicities.

The first step is to monitor both clinical and biological symptoms to determine the nature of the CAR T‑cell–related toxicity and to diagnose CRS, CRES, and HLH/MAS.

In the second step, the severity of CRS, CRES, and HLH/MAS should be graded by using the criteria provided in the recommendations and also according to the Common Terminology Criteria for Adverse Events (CTCAE).

The third step is to manage the toxicities by using the algorithms provided in the framework for CRS, CRES, and HLH/MAS.

The authors provide detailed recommendations for the management of each of these toxicities, with interventions depending on the stage and severity of the adverse event. For CRS, the interventions include treatment with the interleukin-6–blockers tocili­zumab or siltuximab and corticosteroids, and in severe cases mechanical ventilation may be needed. They authors note that CRES appears to develop in a biphasic pattern; the interileukin-6 inhibitors appear to be effective in the first phase but not in the second, when corticosteroids are the preferred treatment; in severe cases, patients should be monitored in an intensive care unit because mechanical ventilation may be necessary.   

New Test for Neurotoxicity

The authors also developed a new grading system for CRES and a 10‑point neurologic assessment (CARTOX‑10) tool.

Table. CRES Grading System

Chimeric antigen receptor (CAR) T-cell therapy has emerged as a breakthrough in the treatment of leukemia and lymphoma, but it has been associated with unique acute toxicities that are uncommon with other cancer therapies.

These toxicities can be fatal and require specialized monitoring and prompt treatment. For the first time, a set of guidelines to serve as a framework for systematically dealing with these toxicities has been developed, by clinicians at the University of Texas MD Anderson Cancer Center in Houston.  

"CAR T cells provide an entirely new level of improved disease response among patients with certain blood cancers and hold promise for more wide-ranging use," said Elizabeth Shpall, MD, deputy chair and professor of Stem Cell Transplantation and Cellular Therapy at MD Anderson, in a statement.

"The algorithms that we published are conservative, detailed, and will help us save lives as we move forward with these exciting but also more toxic therapies," Dr. Shpall said.

The guidelines were published September 19 in Nature Reviews Clinical Oncology.

Two specific toxicities unique to treatment with these agents are covered in the recommendations: cytokine-release syndrome (CRS) and CAR T-cell–related encephalopathy syndrome (CRES).

CRS, the most common adverse event observed after CAR T-cell therapy, is an escalated immune response and on rare occasions can evolve into fulminant hemophagocytic lymphohistiocytosis (HLH), also known as macrophage‑activation syndrome (MAS).

CRES is the second most common adverse event and can occur concurrently with or after CRS. It may sometimes lead to fatal cerebral edema.

Need for Guidance

This new framework comes right on the heels of the entry of the first CAR T-cell therapy into the marketplace: tisagenlecleucel-T (Kymriah, Novartis), approved in the United States in August.

Other products using this novel approach are in development, primarily for hematologic cancers. The next candidate most likely to receive approval is axicabtagene ciloleucel (KTE-C19, Kite Pharma), which has already received priority review status for use in refractory aggressive non-Hodgkin's lymphoma. 

While CAR T-cell therapy has generated a great deal of excitement, with studies showing dramatic results in patients with refractory/relapsed disease, problems related to toxicity have surfaced during clinical trials. In one extreme case, the plug was pulled this year on an investigational agent known as JCAR015 (Juno) after five patients died of treatment-related cerebral edema.

Because of the risk for severe adverse events, the FDA has restricted the use of tisagenlecleucel-T to specially certified centers. The certification would require that all personnel involved in the prescribing, dispensing, or administering of tisagenlecleucel-T be trained to recognize and manage CRS and neurologic events.

Sign or Symptom	Grade 1	Grade 2	Grade 3	Grade 4
CARTOX-10 score	7 - 9 (mild impairment	3 - 6 (moderate impairment)	0 - 2 (severe impairment)	In critical condition, and/or cannot perform assessment
Raised intracranial pressure	NA	NA	Stage 1 - 2 papilledema or CSF opening pressure <20 mmhg="" td="">	Stage 3 - 5 papilledema or CSF opening pressure ≥20 mmHg or cerebral edema
Seizures or motor weakness	NA	NA	Partial seizure, or nonconvulsive seizures on EEG that responds to benzodiazepines	Generalized seizures, or convulsive or nonconvulsive status epilepticus or new development of motor weakness
CSF = cerebrospinal fluid; EEG = electroencephalography; NA = not applicable.

The CARTOX‑10 was developed to simplify evaluation of the acute neurotoxic events that have been observed in patients treated with CAR T cells. Incorporating some of the key components from the 30‑point Mini‑Mental Status Examination, it emphasizes alterations in concentration, speech, and writing ability that are associated with CRES.

One point is assigned for answering each of the following correctly: orientation to year, month, city, hospital, and president/prime minister of the patient's home country or residence (total of 5 points); naming three nearby objects (maximum of 3 points); writing a standard sentence (1 point); and counting backwards from 100 in tens (1 point).

A patient with normal cognitive function would be able to achieve an overall score of 10.

"The scoring system is something that can be done very easily by clinical staff as well as family members for those who receive treatment as an outpatient," said Dr Neelapu. "In the hospital, nurses can easily and quickly do this when taking routine vital signs. With this scoring system, we can identify toxicity very early on."

Future Trends

While some of the underlying pathophysiology of these side effects is understood, much is still unknown, he pointed out. "There was some concern that interventions to manage side effects could affect the efficacy of the product, but they don't seem to impact patient outcomes."

That said, he emphasized that there are differences in the products. "That's something that needs to be tested and analyzed carefully in clinical trials before we draw those conclusions," he said.

Dr Neelapu also noted that they have started testing interventions to see whether these toxicities can be prevented, but those data are not yet available. "But I think we might be able to achieve that, and in the future, we may be able to use preventive strategies," he said.

The research was funded by MD Anderson's Cancer Center Support Grant from the National Cancer Institute of the National Institutes of Health and by philanthropic support for MD Anderson's Moon Shots Program. Dr Shpall is coleader of the Moon Shots Program Adoptive Cell Therapy Platform. Dr Neelapu has served as a consultant to Kite Pharma and Novartis. Several other coauthors report relationships with industry as noted in the paper.  

Nature Rev Clin Oncol. Published online September 19, 2017. Abstract