SAN DIEGO — Infections account for nearly half of all deaths not caused by disease relapse among patients with advanced blood cancers after treatment with chimeric antigen receptor (CAR) T-cell therapy, a new meta-analysis of clinical trials and real-world studies shows.
The study, which analyzed nonrelapse mortality among 7246 patients after treatment with any of the six currently approved CAR T-cell therapies, showed that infections accounted for 48.7% of all nonrelapse deaths, although the pathogen was specified in only one third of cases with infection listed as the cause of death, reported David Cordas dos Santos, MD, at the American Society of Hematology (ASH) annual meeting.
"Our findings highlight the importance of post-CAR-T infections, and the need for comprehensive guidelines to mitigate infection risks," said Cordas dos Santos, a research fellow at the Dana-Farber Cancer Institute in Boston.
Although CAR T-cell therapy has been "practice-changing" for treating B-cell cancers, these agents also come with a range of toxicities that can be "profound and long-lasting," Cordas dos Santosexplained.
However, how these adverse events contribute to mortality after treatment remains less clear.
In the current analysis, the researchers identified 34 studies with data from clinical trials or real-world clinical practice in which US Food and Drug Administration (FDA)–approved CAR T-cell products were used to treat adults with indolent lymphoma, large B-cell lymphoma, mantle cell lymphoma, or multiple myeloma.
The team found that the cumulative incidence rates of nonrelapse mortality were not reported in 16 of the clinical trials included in the analysis and were missing from 12 of the 18 real-world studies.
Among the six studies that did report nonrelapse mortality, the 1-year cumulative incidence of nonrelapse mortality was 7%.
To compensate for the missing data, Cordas dos Santos and colleagues calculated nonrelapse mortality point estimates by dividing all deaths by the size of each cohort. To test for significant deviations, the team compared the point estimates with the 1-year cumulative incidence of nonrelapse mortality reported in the six real-world studies.
The comparison showed that for most of the studies, the point estimates deviated from the actual reported incidences by less than 1%. The overall point estimate of nonrelapse mortality among all patients was 7.6% at a median follow-up of 13.2 months.
The point estimates were higher among patients with mantle cell lymphoma and multiple myeloma than among those with indolent lymphoma or large B-cell lymphoma.
In addition, the point estimates differed according to the CAR T-cell product, reaching 9.1% with axicabtagene ciloleucel in large B-cell and indolent lymphoma compared with 4.0% with lisocabtagene maraleucel or tisagenlecleucel
Among patients with multiple myeloma, point estimates indicated nearly twice the rate of non-relapse mortality with ciltacabtagene autoleucel compared with idecabtagene vicleucel: 14.1% vs 7.9%.
For patients with mantle cell lymphoma, the point estimate with brexucabtagene autoleucel, the only CAR T-cell therapy approved for this indication, was 9.4%.
Infections accounted for almost 50% of all nonrelapse deaths. When studies specified the pathogen linked to nonrelapse mortality, COVID-19 accounted for more than half of these deaths, fungal infections accounted for 18%, and bacterial pathogens accounted for 20.2%. The remaining deaths were attributed to unspecified viral causes or infection.
In 11.6% of cases, the cause of death was unknown or undocumented, followed by 7.8% of deaths attributed to cardiovascular or respiratory causes. Thromboembolic events, including strokes and ischemic brain injuries, accounted for one third of the deaths attributed to cardiovascular or respiratory causes. Respiratory failure was listed as the cause of death in 20.9% of cases and cardiac arrest in 18.6% of cases in this category.
A total of 35 deaths (6.3%) were attributed to secondary cancers. Myelodysplastic syndromes or acute myeloid leukemias were the most common secondary cancers leading to nonrelapse death followed by carcinomas and, in one case, a sarcoma of unspecified histology.
Although the FDA recently announced its investigation into reports of T-cell cancers, the researchers found no T-cell cancers reported in the studies, Cordas dos Santos noted.
The investigators also noted differences in the specified causes of nonrelapse mortality between clinical trials and clinical practice. In real-world studies, immune-related adverse events, including cytokine release syndrome, neurotoxicity, and hemophagocytic lymphohistiocytosis, were cited as the cause of death in 19.3% of cases compared with 7.3% of cases in clinical trials. In clinical trials, deaths from cardiovascular or respiratory causes (18.7%) were nearly three times more common than in real-world studies (6.3%).
Jay Spiegel, MD, who presented a study at ASH 2023 showing that CAR T-cell therapy is generally safe even in high-risk patients, told Medscape Medical News that "we have learned over the years that there is significant risk for opportunistic infection, typically early in the post-CAR process, but there is accumulating data that these risks can be prolonged as well."
In terms of treatment, "our main approaches for prophylaxis are acyclovir (an antiviral to prevent shingles) and Bactrim or a similar medicine to prevent opportunistic infection, particularly Pneumocystis jirovecii pneumonia," added Spiegel, from the Sylvester Cancer Center at the University of Miami.
Cordas dos Santos commented that although the COVID-19 pandemic may have contributed to infection-related nonrelapse deaths, it's important to note a possible bias in reporting of COVID-19-related deaths as an adverse event.
Still, patients who receive CAR T-cell therapy directed against CD19 are more likely to experience poor immune responses to vaccines against SARS-CoV-2 infections, putting them at increased risk for severe or fatal complications from COVID-19, explained Lee Greenberger, PhD, chief scientific officer for the Leukemia & Lymphoma Society, who was not involved in the research.
"We strongly recommend that these patients receive their vaccinations prior to the start of CAR T therapy, if possible," Greenberger said. "It's also important, when possible, that they do not receive anti-CD20 antibodies, such as rituximab, for 6-12 months before vaccination, as these treatments can also cause B-cell suppression that may last long after treatment is given."
The study was a collaboration between the Dana-Farber Cancer Institute, Ludwig Maximilians University Hospital in Munich, Germany, and Memorial Sloan Kettering Cancer Center in New York City. The authors did not report a study funding source. Cordas dos Santos reported no conflicts of interest. Greenberger reported no conflicts of interest. Spiegel reported no relevant conflicts of interest.
Neil Osterweil, an award-winning medical journalist, is a long-standing and frequent contributor to Medscape.
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