Infections cause ‘high’ rate of nonrelapse deaths among CAR-T recipients
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Key takeaways:
- Infection caused nearly half of all nonrelapse deaths among CAR-T recipients.
- None of the clinical trials leading to CAR-T approvals collected data on nonrelapse mortality.
SAN DIEGO — Infections are the main driver of mortality not related to disease relapse among individuals who received chimeric antigen receptor T cells, results of a meta-analysis presented at ASH Annual Meeting and Exhibition showed.
The analysis, which included clinical trials and real-world studies across several commercially available products and indications, also revealed a high incidence of secondary malignancies as the third-leading cause of nonrelapse mortality among CAR-T recipients.
“The number of patients who died of infections was high,” David Cordas dos Santos, MD, postdoctoral research fellow in the department of medical oncology at Dana-Farber Cancer Institute, told Healio.
“That nearly 50% died of infection was nonetheless surprising,” he added. “A lot of researchers in the field would have assumed that the CAR-T-specific side effects — such as cytokine release syndrome and neurotoxicity — would have had a larger impact on nonrelapse mortality.”
Background
Infection has proven to be a major risk after receipt of CAR T-cell therapy, according to Cordas dos Santos.
It has been the focus of prior studies conducted by co-investigator Kai Rejeski, MD, clinician-scientist at Ludwig Maximilian University Hospital in Munich, who helped develop a scoring system that predicts infection risk among CAR-T recipients.
“We wanted to know how treatment-related toxicities translate into mortality rates,” Cordas dos Santos said. “This is why we looked at nonrelapse mortality, which is typically a metric used on the allogeneic hematopoietic cell transplant field. We wanted to see what the actual causes of death were and whether it was driven by etiologies like infections or the CAR-T-specific toxicities with which we are familiar.”
Methods
Cordas dos Santos and colleagues conducted a meta-analysis of published clinical trials and real-world studies to determine the main causes of nonrelapse mortality among CAR-T recipients.
The researchers conducted a literature search that included all phase 1 through phase 3 studies related to FDA approval of six CAR-T products. Their review of real-world data included studies published through September on the use of commercial CAR-T products in clinical practice. Real-world studies in the analysis included a minimum 80 adults.
Of 2,018 publications considered, 16 clinical trials (n = 2,005) and 18 real-world studies (n = 5,241) met the investigators’ inclusion criteria.
Key findings
Investigators observed overall poor reporting of nonrelapse mortality in published studies. Approximately 33% of real-world studies did not report cumulative incidence rates of nonrelapse mortality, and none of the clinical trials included in the analysis reported such data.
This required researchers to use nonrelapse mortality point estimates based on fixed-effects models to fill in the data gaps left by clinical trial reporting.
Investigators calculated a nonrelapse mortality of 7.6% among CAR-T recipients at median follow-up of 13.2 months.
Infections accounted for nearly half (48.7%) of the 554 patient deaths observed in the meta-analysis, making infection by far the primary cause of nonrelapse mortality among CAR-T recipients.
Cardiovascular and respiratory complications served as the second-leading cause of nonrelapse mortality (7.8% of all deaths), followed by secondary malignancies (6.3%).
Clinical implications
The study findings are useful because determining the causes of nonrelapse mortality allows clinicians to focus efforts on mitigating those factors, Cordas dos Santos said.
“The question becomes can we develop clinical guidelines that can be used by centers to mitigate the risk for severe infections following CAR T-cell infusion,” he said.
“Since this is a meta-analysis, we can only report on what has already been presented, and there were clear deficiencies in the reporting of nonrelapse mortality, which was unfortunately underreported,” he added. “Our results need to be viewed within the backdrop of the COVID-19 pandemic and the fact that many CAR-T patients were heavily pretreated. Still, these results should get us thinking about how we can optimize our management for preventing infectious complications of CAR-T.”
Collapse
Cordas dos Santos DM, et al. Abstract 1064. Presented at: ASH Annual Meeting and Exhibition; Dec. 9-12, 2023; San Diego.
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