Neurotoxicity after CAR T-cell therapy has no effect on survival in lymphoma subset
Click Here to Manage Email Alerts
Development of immune effector cell-associated neurotoxicity syndrome did not negatively affect survival outcomes among patients treated with axicabtagene ciloleucel for relapsed or refractory large B-cell lymphoma, study results showed.
About half of patients in the single-center study, published in Neuro-Oncology, experienced immune effector cell-associated neurotoxicity syndrome (ICANS) after treatment with axicabtagene ciloleucel (Yescarta; Kite Pharma/Gilead), a CD19-targeted chimeric antigen receptor T-cell therapy also known as axi-cel. Nearly three-quarters of ICANS cases were grade 3 or grade 4.
The analysis also showed that baseline fibrinogen levels may serve as a predictive biomarker for ICANS.
“We wanted to see how our experience with neurotoxicity compared with others,” Saurabh Dahiya, MD, FACP, assistant professor of medicine and director of cellular therapy in leukemia/lymphoma at University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, told Healio.
What they found was at odds with a report published last year in Blood that showed neurotoxicity had an adverse effect on OS among patients who received CAR T-cell therapy for lymphoma.
“Our clinical experience had not shown there to be a difference in survival between those who had neurotoxicity and those who didn’t,” Dahiya said. “Having ICANS doesn’t portend poorer survival based on our data.”
Study findings
Dahiya and colleagues identified 45 adults (median age, 60 years; range, 26-75; 51% women) who received axi-cel for treatment of relapsed or refractory large B-cell lymphoma at Greenebaum Comprehensive Cancer Center between April 2018 and May 2019.
Laboratory values collected for biomarker analysis included C-reactive protein, ferritin, fibrinogen and lactate dehydrogenase levels.
Researchers routinely monitored patients for evidence of ICANS using the CARTOX Working Group’s CARTOX-10 scoring criteria and graded the severity of ICANS using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 criteria.
Results showed 25 patients (56%) experienced ICANS after CAR T-cell infusion. Eighteen (72%) of those who developed neurotoxicity had either grade 3 or grade 4 ICANS, with a median time to development of ICANS of 5 days (range, 3-11).
Most patients (92%) with ICANS required steroids to resolve their symptoms.
ICANS of any grade did not affect complete response to therapy, PFS or OS.
Biomarker analysis showed associations of ICANS with elevated preinfusion levels of fibrinogen (517 mg/dL vs. 403 mg/dL; ULN 438 mg/dL; P = .01) and lactate dehydrogenase (618 U/L vs. 506 U/L; ULN 618 U/L; P = .04).
The retrospective, single-center design of the study served as a limitation, according to the researchers. Because the results are also limited to patients who underwent CAR T-cell therapy for large B-cell lymphoma, they should not be applied to other indications, Dahiya said.
“Each disease has specific factors that influence response and survival rates,” he told Healio. “It’s not likely that this could be generalized to other CAR-Ts or indications. However, the finding that higher fibrinogen levels increase the chances of ICANS might be more generally applied to other CAR-Ts for other indications because it is reflective of an increased inflammatory state.”
Clinical significance
The laboratory measurements the researchers considered collecting were among those that are easily or routinely collected and available in clinical practice, Dahiya said. A coagulation panel would be routine at nearly all CAR T-cell therapy centers, and knowing it could influence the development of ICANS would be clinically useful when monitoring patients after therapy.
“For example, you may want to consider performing routine neurotoxicity assessments more often in patients who had high fibrinogen levels,” he said.
Dahiya said his group plans to study this relationship further via validation studies to confirm the association.
He described the response rates and survival outcomes as “very reassuring.”
“Oftentimes, our patients are highly educated on the latest developments with the therapy and results like ours help to further inform them — if they experienced these toxicities — of what it may mean for their overall outcomes,” he told Healio. “With these data, we can say to our patients that adverse effects like [cytokine release syndrome] and ICANS may not necessarily have a negative effect on their outcomes.”
Reference:
For more information:
Saurabh Dahiya, MD, FACP, can be reached at sdahiya@umm.edu.
Perspective
Back to Top
Jorg Dietrich, MD, PhD, FANA, FAAN
ICANS is an important and frequent complication of CAR T-cell therapies. Among the challenging questions in this context is whether the presence of ICANS and the use and duration of corticosteroids has an impact on outcomes such as PFS and OS.
The study by Holtzman and colleagues suggests that the presence of ICANS per se and the use of steroids may not influence patient outcomes. These findings appear to contradict prior observations from a study by Karschnia and colleagues — on which I was a co-author — who identified that both the presence of high-grade ICANS and prolonged steroid use beyond 10 days may negatively influence overall outcomes.
Differences in study design and patient populations between the studies may account for the discrepancy in the findings and conclusions. Karschnia and colleagues studied a heterogenous group of 25 patients treated with various CAR T-cell products for different underlying malignancies, whereas Holtzman and colleagues focused their analysis on patients treated with axi-cel, specifically for relapsed or refractory large B-cell lymphoma. Moreover, both studies were retrospective in design and included a relatively small number of patients, which further constitutes a limiting factor to the generalizability of both study findings.
The existing literature suggests that the frequency and severity of ICANS varies among CAR T-cell products and disease populations. In addition, disease burden is considered an important risk factor for worse outcomes and influences the onset of cytokine release syndrome, which on its own affects outcome and is strongly associated with ICANS.
The current body of literature does not provide sufficient data to conclusively answer the important questions of whether and how ICANS and corticosteroids influence patient outcomes and survival rates.
Future prospective and comprehensive studies are needed to address these clinically relevant questions and to identify robust biomarkers that will guide patient management in the rapidly growing field of immunotherapies and, specifically, CAR T-cell-based applications.
Harvard Medical School
Perspective
Back to TopNeeraj Saini, MD, and Muzaffar Qazilbash, MD
The use of adoptively transferred T cells modified with a CAR has heralded a new era in the treatment of large B-cell lymphoma. Treatment with axi-cel for relapsed or refractory large B-cell lymphoma showed unprecedented overall response (82%) and complete response (54%) rates, with durable responses among complete responders. This treatment, however, was marked by unique toxicities, including high-grade cytokine release syndrome in 10% to 15% of patients and ICANS in 30% to 40% of patients.
The retrospective study by Dahiya and colleagues is an important addition to the growing literature on ICANS and its predictive biomarkers among patients with large B-cell lymphoma treated with CAR T cells. Toxicity of CAR T cells varies, depending on the vector construct, manufacturing process, disease burden, patient characteristics and dosing schemes. Axi-cel has the highest ICANS rate among all FDA-approved CAR T-cell products, with nearly 65% of patients experiencing this toxicity in the pivotal ZUMA-1 clinical trial. The exact pathophysiological mechanism leading to ICANS remains elusive; however, it is believed to be related to endothelial activation and blood-brain barrier disruption.
The single-center study by Dahiya and colleagues corroborates the finding that axi-cel therapy is associated with high rates of ICANS of any grade (56%), with 40% patients developing grade 3 or greater events. This study offers two new insights: the elevated baseline serum fibrinogen level is a novel predictive biomarker for ICANS, and axi-cel-related ICANS was not associated with worse treatment outcomes.
The investigators’ discovery that baseline serum fibrinogen level is a predictive biomarker for ICANS has to be validated in prospective clinical trials. Similarly, the lack of association between the severity of ICANS — or its treatment with steroids — and survival outcomes is contrary to the existing data on axi-cel, and may be due to the relatively small number of patients and the retrospective design of the study. Other limitations of the study were the absence of data on CAR T-cell persistence and serum cytokine levels.
Overall, this study is an important contribution to the growing literature on the efficacy and toxicity of axi-cel.
Reference:
Collapse
Click Here to Manage Email Alerts