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CAR T-cell therapy carried a risk of second primary malignancy (SPM) that was no worse than that of other standard-of-care (SOC) cancer therapies, according to a systematic literature review and meta-analysis.

The analysis showed a 5.8% rate of SPM among 5,517 patients with a median follow-up of 21.7 months. The rate did not vary according to the type of disease treated or the CAR T-cell product used. The only factors associated with a higher rate of SPM were study setting (clinical trial vs real-world experience), longer duration of follow-up, and number of therapies prior to CAR-T treatment.

Additionally, an analysis limited to four clinical trials that compared CAR T-cell therapy and SOC treatments showed virtually identical rates of SPMs (5.0% vs 4.9%), reported Kai Rejeski, MD, of Memorial Sloan Kettering Cancer Center in New York City, and co-authors in .

"Currently, I would not say that there is strong evidence that, relative to other treatment modalities, there is an increased risk for developing SPMs with CAR T-cell therapy," Rejeski told MedPage Today. "I think what that really does is question, to some extent, the black-box warning label by the FDA."

The SPM issue came to light late last year when the FDA announced an investigation into multiple reports of secondary T-cell malignancies in recipients of CAR T-cell therapy. The reports came from clinical researchers and postmarketing adverse-event (AE) data. Subsequent reports of SPMs, based primarily on the FDA's AE reporting system, led the agency to require a black-box warning on labeling for all approved CAR T-cell products.

Some CAR T-cell therapy researchers have expressed concern about potential inherent biases in the AE data, including reporting bias. Proper assessment of SPM risk should include accounting for confounders such as patient age, follow-up duration, the type of CAR T therapy received, the patient's initial diagnosis, and other types of treatment the patient received before CAR T-cell therapy.

"We have to understand that there are many different reasons why a CAR T-cell patient can develop a secondary malignancy," Rejeski said.

"I think what we're able to show in this study, using meta-regression modeling in a large cohort of patients, is that factors not related to the CAR T-cell therapy were most associated with the development of SPM," he said. "Specifically, patients with longer follow-up, the amount of treatment prior to CAR T-cell therapy, and treatment in clinical trials, where patients are followed more closely."

The present study ultimately highlights the need for more long-term data to understand better the factors underlying SPM.

"Patients are reading this in the news and, appropriately, asking questions to providers," Rejeski said. "We need to understand the potential risks, but at the same time, we need to interpret the data cautiously and contextualize it for our patients."

To address some gaps in understanding, Rejeski and colleagues performed a systematic review of published literature and meta-analysis. Eligible studies involved adults with lymphoma or myeloma treated with one of the six currently approved CAR T-cell products.

The review identified 18 clinical trials and seven studies in real-world settings, involving a combined total of 5,517 patients. The most common indications for treatment with large B-cell lymphoma (3,614), multiple myeloma (1,362), indolent lymphoma (425), and mantle-cell lymphoma (116). Investigators identified a total of 326 SPMs, the most common being hematologic malignancies (37%), solid tumors (27%), and non-melanoma skin cancers. Notably, T-cell malignancies, of particular interest with CAR T-cell therapies, accounted for only 1.5% of the SPMs.

The 5.8% overall rate of SPM did not differ significantly by T-cell product or indication for treatment. The authors found a significant association between follow-up duration and SPM (P=0.009). The SPM rate was 8.5% among patients followed longer than the median of 21.7 months versus 4.2% for those with shorter follow-up (P<0.001).

"A patient has to be alive to develop a second malignancy," explained Rejeski. "To a certain extent, the efficacy of CAR T-cell therapy, the curative potential that we see, is sort of the friend and enemy of this treatment modality at the same time. On the one hand, we're providing patients additional life years, but these additional life years now mean that, as a field, we have to think more about themes of survivorship."

The authors reported that patients who received more than three prior lines of therapy had a numerically higher SPM rate (8.7% vs 5.7%, P=0.13). Given that SOC therapies carry a risk of second malignancy, the potential contribution of those prior therapies to the overall rate of SPM is a confounding factor, Rejeski acknowledged.

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