A meta-analysis of CAR-T cell therapy studies found that just over half of cancer patient deaths that are not because of relapse are due to infections.
“The main takeaway as clinicians is infections, infections, infections,” Memorial Sloan Kettering Cancer Center visiting investigator Kai Rejeski told Endpoints News. “We need to do a better job at reporting infections, managing and preventing infections.”
The vast majority of patient deaths following CAR-T cell therapy are due to the cancer coming back. But a group of researchers led by Rejeski looked into the causes of deaths not from relapse — many of which are tied to safety concerns related to the CAR-T cell therapies.
In their analysis published in Nature Medicine Monday morning, the researchers estimated that roughly 7% of patients died from causes other than their cancer progressing or coming back. The meta-analysis included data from over 7,500 patients across 18 clinical trials and 28 real-world studies — the largest study on non-relapse death following CAR-T cell therapy published to date, according to the study authors.
Over 5,800 patients in the study had large B cell lymphoma, where there are three approved cell therapies: Yescarta, Kymriah and Breyanzi. Also, nearly 1,200 patients had multiple myeloma, where there are two approved cell therapies: Abecma and Carvykti.
The researchers highlighted a lack of comprehensive reporting on these deaths, noting that they had to use statistical models to estimate non-relapse mortality. “There was a clear deficiency in reporting non-relapse mortality — none of the clinical trials did,” Rejeski said. “Some of them reported well on the underlying causes of death, but there were also many that did not.”
In 574 reported deaths not from relapse, 50.9% were attributed to infections, the study group found. “We expected to find infections to be the main driver of non-relapse deaths,” said David Cordas dos Santos, a postdoc at Dana-Farber Cancer Institute and the first author on the study. “But we didn’t expect that it’s like over half of the cases.”
An important caveat was that, among the infection-related deaths with a reported pathogen, just over half were due to Covid-19. But Cordas dos Santos noted that when the researchers looked at non-relapse deaths before and after Covid, they did not see a huge shift in mortality. However, he added another possibility was that clinicians could have gotten better at managing the side effects of cell therapies and that Covid hid those impacts.
In real-world studies alone, infections were an even more prominent cause of death — leading to 65% of non-relapse deaths — and it remained the leading cause of death even when excluding Covid-related deaths.
Meanwhile, CAR-T cell-specific side effects – including neurotoxicity and cytokine release syndrome — were responsible for low percentages of non-relapse deaths at 5.2% and 4.7%, respectively. The FDA recently relaxed reporting requirements for these side effects as researchers have gotten better at managing them.
Interestingly, the distant second-leading cause of non-relapse deaths was secondary cancers at 7.8%. Looking at all patients in the study, 0.59% of patients died of a secondary cancer, referring to a cancer that is different from the first cancer the patient was being treated for. Cancer patients are at higher risk for developing another cancer in part due to some of the therapies they receive (outside of CAR-T cell therapies).
The FDA last year launched an investigation into secondary cancers following CAR-T cell therapy, and earlier this year added black box warnings to approved cell therapies noting the risk. However, experts have said that the chance of CAR-T cell therapy causing a secondary cancer is very low.