Factors outside CAR T-cell therapy are associated with increased risk of secondary cancers after the treatment, meta-analysis shows
A meta-analysis of 25 studies—totaling over 5,000 participants—focused on a question that has been troubling patients, physicians, and regulators: Does treatment with CAR T-cell therapy contribute to the development of secondary cancers?
The study results, published Sept. 11 in Clinical Cancer Research, may help lay some of these concerns to rest.
Many risk factors associated with secondary cancers after CAR T-cell therapy have nothing to do with that particular treatment, the new systematic review and meta-analysis found.
The study identified follow-up time, the number of prior treatment lines, and treatment setting (clinical trial versus real-world study) as independent risk factors associated with second primary malignancies, or SPMs.
“This really validates the theory that CAR T may be unmasking—by virtue of getting people into remission for longer—some prior risk factors, either from their malignancy or from their prior treatment,” Rahul Banerjee, assistant professor in the Clinical Research Division at the Fred Hutchinson Cancer Center, said to The Cancer Letter.
“And the longer that patients are doing well, and the longer they’re in follow-up, the higher the odds of these SPMs,” said Banerjee, who was not involved in the study.
A subgroup analysis included in the study also found that the frequency of SPMs arising after CAR T-cell therapy was comparable to their frequency after other standard-of-care therapies.
“Oftentimes, you’re asking, ‘Is there an increased SPM incidence relative to another treatment line?’ We don’t see that in this study—we see similar SPM estimated,” Kai Rejeski, senior author of the new study and a visiting investigator and research fellow at the Adult Bone Marrow Transplantation Service at Memorial Sloan Kettering Cancer Center, said to The Cancer Letter.
“I think that’s an important message for the community, or it at least tempers a little bit of the considerable media attention that’s been garnered by the FDA black box warning,” he said.
Clarion call
In Nov. 2023, FDA announced that CAR T-cell therapy may put patients at risk for SPMs and that the agency was investigating the possibility. Two months later, the agency required updated boxed warnings on CAR T-cell products after finding that 22 of more than 34,000 patients treated with the class of drugs developed T-cell secondary malignancies (The Cancer Letter, Feb. 2, 2024).
“That was really a clarion call for us to take this seriously and to perform rigorous analyses that help to contextualize this for our patients,” Rejeski said.
There are currently six FDA-approved CAR T-cell therapies, all of which are indicated for blood cancers—leukemia, lymphoma, and multiple myeloma.
FDA’s boxed warning decision largely relied on data from the FDA Adverse Event Reporting System, and other studies have examined FAERS data to investigate the risk of secondary cancers from CAR T-cell therapy as well.
“The issue with these reports, or these studies, is essentially that they lack a true denominator, and they can suffer from considerable reporting bias,” Rejeski said.
Also, Rejeski and colleagues recently found that when excluding deaths from relapse or recurrence, SPMs were the second most common driver of death after going through CAR T-cell therapy. The top driver was infection (The Cancer Letter, July 12, 2024).
FDA, too, has considered early deaths of patients receiving two CAR T-cell products in clinical trials, although the FDA Oncologic Drugs Advisory Committee voted overwhelmingly in favor to expand the agents’ indications (The Cancer Letter, March 22, 2024).
Rigorous analyses
In the new study, Rejeski and colleagues identified 18 clinical trials and seven real-world studies that included adults with a form of lymphoma or myeloma, used FDA-approved CAR T-cell products, and involved comprehensive reporting of all SPM cases throughout the entire follow-up period. Leukemia was excluded to create a more homogeneous cohort, since patients with leukemia tend to be younger than those with lymphoma or myeloma, Rejeski said.
The researchers’ meta-analysis revealed 326 SPMs across a total of 5,517 participants at the study’s median follow-up time of 21.7 months, providing an overall SPM point estimate of 5.8% (95% CI 4.7%-7.2%). Point estimates did not differ significantly across the primary malignancies (indolent lymphoma, large B-cell lymphoma, multiple myeloma, mantle cell lymphoma) or the six CAR T products, indicating patient-specific factors and treatment history might drive the risk for SPMs.
Rejeski and colleagues turned to study-level risk factors, parsing them out using a multivariate meta-regression analysis. This identified CAR T treatment in clinical trials, longer follow-up time, and higher numbers of previous therapy lines as independent risk factors associated with increased SPM.
“The factors that we identified that were associated were actually not related to CAR T cells themselves,” Rejeski said.
These factors may have surfaced because CAR T-cell therapy might be so effective that patients are living long enough to develop new cancers, the study authors wrote. Further, clinical trials tend to include younger, healthier participants and have better follow-up and reporting mechanisms than real-world studies. And patients have often received pro-tumorigenic therapies, including alkylating agents, lenalidomide, and high-dose chemotherapy, prior to CAR T-cell therapy.
“Our findings suggest that the risk factors driving SPM development are multifaceted, highlighting the need for a nuanced discussion with patients about the myriad of potential contributing factors before attributing causation to the CAR T-cells themselves,” the study authors wrote.
As a field, we are now moving towards a new phase where we have a therapy that’s been in the mainstream for almost 10 years. We’re starting to talk less about the short-term side effects—we’re talking more about these themes of survivorship.
Kai Rejeski
A subgroup analysis of four randomized phase III trials—encompassing 1,253 patients—comparing CAR T-cell therapy to standard-of-care therapies showed similar SPM frequencies at 5.0% (95% CI 3.6%-6.9%) and 4.9% (95% CI 3.4%-6.9%), respectively.
And T-cell malignancies—the SPM class emphasized by FDA—accounted for only 1.5% of all SPMs. At five reported cases across the entire study population, the T-cell malignancy point estimate was 0.09% (95% CI 0.04%-0.2%). “That’s less than one in 1,000 patients—and that just highlights this is very rare,” Rejeski said.
Three of those five cases were tested for the CAR transgene’s presence in malignant T cells, and only one case turned up as positive. Researchers are still debating whether CAR vector insertion even contributes to the development of T-cell malignancies, Rejeski said.
“I haven’t seen a case yet where people could definitively show that the CAR T-cell integration has caused the new cancer,” Helen Heslop, director of the Center for Cell and Gene Therapy at Baylor College of Medicine, Texas Children’s Hospital, and Houston Methodist, said to The Cancer Letter.
“And even if we do, it looks like the incidence is going to be very low,” said Heslop, who was not involved in the new study. She is also a professor in the departments of medicine and pediatrics, section of Hematology-Oncology and Dan L Duncan Chair at Baylor College of Medicine, and the leader of cancer cell and gene therapy at Dan L Duncan Comprehensive Cancer Center.
Long-term vigilance
“I think this study helps to contextualize some of the discussions that have been in the media, but also questions, to a certain extent, the issuance of a black box label by the FDA,” Rejeski said.
Not only can such warnings worry patients; drug developers might be more hesitant to create new CAR T-cell platforms, too, which is far from ideal for patients, he said.
Additionally, the higher rate of SPMs in clinical trials and studies with longer follow-up times stress the importance of staying vigilant, Banerjee said. “In our experience at Fred Hutch, typically, when SPMs happen, they’re often caught by our Long-Term Follow-Up program and not by the primary CAR T expert at that center.”
“Academic centers need to do a better job at really diligently screening not just, ‘Are you alive or have you passed away?’ but ‘What other medical conditions have happened to you?’” Banerjee said. And some SPMs—even T-cell malignancies—that appear after CAR T-cell therapy might be easily treatable or not need treatment at all, he said.
Long-term reporting of side effects is key, agreed Rejeski. And a future step should be exploring patient-individual risk factors to predict who might be at greater risk for long-term adverse events, he said.
“As a field, we are now moving towards a new phase where we have a therapy that’s been in the mainstream for almost 10 years,” Rejeski said.
“We’re starting to talk less about the short-term side effects—we’re talking more about these themes of survivorship.”
