Training 'Front-line' Staff to Manage CAR T Toxicity Is Critical

Theodore Bosworth


April 26, 2018

For centers considering a chimeric antigen receptor (CAR) T-cell program, training nurses and support staff to manage the life-threatening toxicities that come with these new therapies can save lives, according to those experienced with administering CAR T-cell treatments.

With CAR T cells now approved for the treatment of several hematologic malignancies in the refractory or relapsed setting, the question has turned to how access will be rolled out to more centers and cancer patients.

The decisions made immediately after an emergency transfer to the intensive care unit (ICU) or by support staff during after-hours care are critical, said Daniel W. Lee, MD, director of pediatric stem cell transplant at the University of Virginia Health System in Charlottesville. At the 2017 annual meeting of the American Society of Hematology (ASH), Lee methodically reviewed the lessons he learned managing life-threatening events from CAR T-cell administration. Then he presented a list of key points.

"Probably the most important thing is providing an education to the ICU teams, nurses, fellows, residents—the people on the front line for this therapy—because you cannot be there 24 hours a day. You need to rely on your team," Lee said.

Common, Serious CAR T Toxicities

Cytokine release syndrome (CRS), a cause of numerous deaths during CAR T-cell development, is the most well-known life-threatening toxicity. It is not, however, the only serious risk. Neurotoxicity is also common and life-threatening.

In a summary of one center's experience presented at the 2017 ASH annual meeting, 40% of patients developed neurotoxicity, of which approximately half were grade 3 or higher.[1] Deaths due to neurotoxicity occurred in 3%.

On the basis of this series of patients, who were treated with a CD19 CAR T-cell construct, a detailed investigation was conducted into the underlying mechanisms. According to data presented by Cameron J. Turtle, MBBS, PhD, an attending physician in the bone marrow transplant program at the Fred Hutchinson Cancer Center in Seattle, neurotoxicity may be caused by increased blood-brain permeability. Cytokine-induced endothelial cell activation in the brain appeared to be involved.

A logistic probability analysis in this study associated lower peak CAR T-cell blood count with reduced risk for neurotoxicity, but lower doses of CAR T cells were also projected to reduce antitumor efficacy. In modeling to identify those destined for grade 4 or higher neurotoxicity, fever of 38.9˚ C higher, serum IL-6 levels of 16 pg/mL or higher, and MCP-1 [monocyte chemoattractant protein-1] of 1343.5 pg/mL or higher within 36 hours after CAR T-cell infusion were predictive, according to Turtle. These three factors provided a sensitivity of 100% and a specificity of 96%.

These data imply that high levels of cytokines drive neurotoxicity like they drive CRS, but Lee, providing his own experience in pediatric patients, said that there is not a perfect correlation between neurotoxicity and cytokine levels. He also cautioned that he and others have encountered two periods of risk. While the first occurs within the same timeframe as CRS, another occurs a week or two after CAR T-cell infusion when patients are hemodynamically stable. The two periods of risk may be driven by different mechanisms.

Of a list of potential mediators of neurotoxicity, Lee agreed that cytokine activity in the cerebrospinal fluid is a prominent suspect, but he said that other potential mechanisms are being explored. Moreover, tracing the causes of neurotoxicity "has been complicated by the fact that cerebral edema has been noted in a couple of clinical trials," Lee said. "It remains to be seen what causes cerebral edema and whether this is an end result on the same spectrum of the other neurotoxicities associated with CAR T cells or a completely unrelated event."

Counteracting CAR T Neurotoxicity

The symptoms of neurotoxicity are sufficiently diverse that they do not implicate pathology in any single area of the brain, according to Lee. They include tremor, agitation, hallucinations, aphasia, and life-threatening seizures. In data that he presented on a series of 52 pediatric patients treated with a CD19 CAR T-cell construct, only three patients developed a grade 3 or higher neurotoxicity and there were no deaths. While grade 1 or 2 events were common, all events, including grade 3 events, "were entirely reversible with supportive care plus or minus corticosteroids."

In the experience of several experts, including Lee, the risk for serious neurotoxicity and CRS can be reduced when early detection permits prompt intervention. It was for this reason that he advocated teaching every member of the clinical team how to recognize and treat these events. The same point was made in a recent review article from the University of Texas M.D. Anderson Cancer Center in Houston.[2] The authors, led by Sattva S. Neelapu, MD, director of laboratory and translational research at M.D. Anderson, called CAR T-cell therapy "potentially curative," but cautioned, "Intensive monitoring and prompt management of toxicities is essential" at centers embarking on a treatment program.

Grading systems can provide a systematic approach to this intensive monitoring, according to Neelapu. These systems are important because there are risks from intervening too early as well as too late. Immunosuppressive therapies, such as steroids and the IL-6 inhibitor tocilizumab, are effective for many of the complications of CAR T-cell therapy, but they may also attenuate the treatment effect. Clinicians need to know when to move quickly from supportive care to immunosuppressive agents, according to Neelapu.

First author of an often-cited grading system for CRS,[3] Lee made the same point. In the treatment algorithm based on this system, tocilizumab can be considered for grade 2 CRS in patients with comorbidities but is otherwise reserved for CRS grade 3 or higher. Key symptoms of serious CRS that warrant tocilizumab include hypotension unresponsive to a single low-dose vasopressor, hypoxia unresponsive to low-dose oxygen, or grade 3 or higher transaminitis. In those who meet the criteria, it is important to act quickly.

"If you have a patient who has been hypotensive for a couple of days [before intervening], you waited too long," Lee said. He cautioned that repeat dosing of intravenous fluids, although standard for hypotension associated with sepsis, can exacerbate the complications of CRS. This is an example of why ICU staff requires specific instruction to manage the complications of CAR T-cell-related CRS.

In experienced centers adept at identifying and quickly treating CRS, death due this complication is becoming an uncommon event, but there is still much to learn about potential sequelae from the effect of CAR T-cell therapy on immune function. In a small series of 30 patients with acute lymphoblastic leukemia treated with an anti-CD22 CAR T-cell therapy, a link was made even between low grades of CRS and subsequent development of disseminated intravascular coagulation (DIC) and macrophage activation syndrome (MAS).[4]

The link between CRS, DIC, and MAS has been described previously, but the authors of this study, led by Nirali N. Shah, MD, from the Center for Cancer Research at the National Cancer Institute in Bethesda, Maryland, proposed potential strategies for treatment. Of notable findings, the IL-1 receptor antagonist anakinra was identified as a potential targeted approach to MAS, avoiding steroids without compromising the response to CAR T-cell therapy. More data are needed to validate this approach, however.

Best Practices Still Evolving

In addition to ensuring that any clinical staff encountering patients treated with CAR T cells can recognize serious adverse events, the other key points Lee made include remaining vigilant for signs of neurotoxicity even after CRS resolves. He also emphasized that the best practices for managing CAR T-cell toxicities are still evolving.

"Each CAR T cell is slightly different, and each one is likely to have its own CRS and neurotoxicity profile in regard to both the timing of onset and its resolution," Lee said. These therapies may also differ for risk for DIC, MAS, and other immune-related adverse events that are now being described in greater detail.

Although CAR T-cell therapy has been shown to save lives in advanced disease, the risks associated with this novel therapy underscore that any center embarking on a CAR T-cell treatment program must be fully prepared to address life-threatening toxicities.


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