A systematic review and meta-analysis revealed that cancer survivors who undergo CAR T-cell therapy see a frequency of second primary malignancies (SPMs) that is statistically similar to those receiving other standard treatment options.
As of January 2024, the U.S. Food and Drug Administration (FDA) mandated that labeling for all available CAR T-cell therapies include a boxed warning. This warning is intended for both healthcare providers and patients, highlighting the potential risk of developing secondary cancers after receiving CAR T treatment. In particular, the boxed warnings inform patients about the risk of developing new T-cell cancers independent of the original B-cell lymphoma or multiple myeloma for which they were treated using CAR T.
This decision was largely influenced by insights from the FDA Adverse Event Reporting System. However, some researchers, including Rejeski, have raised concerns regarding possible biases in the data, particularly reporting bias. When evaluating the risk of SPMs, it is crucial to consider factors such as the patient’s age, how long they were followed up, the type of CAR T treatment administered, their initial diagnosis, and any prior treatments they may have received before CAR T, Rejeski pointed out.
“Patients are seeing this information in the news and rightly asking their providers questions,” said Rejeski. “While it’s essential to comprehend the possible risks, we must also analyze the data with care and provide context for our patients.”
Rejeski and his team conducted a systematic review and meta-analysis that included clinical studies involving adult patients with lymphoma or multiple myeloma treated with one of six approved CAR T-cell therapies: idecabtagene vicleucel (Abecma), lisocabtagene maraleucel (Breyanzi), ciltacabtagene autoleucel (Carvykti), tisagenlecleucel (Kymriah), brexucabtagene autoleucel (Tecartus), or axicabtagene ciloleucel (Yescarta). To be included in the analysis, studies had to present data on SPM occurrences throughout the entire follow-up period, which spanned from 6.6 months to 65.4 months. Ultimately, 18 clinical trials and seven real-world studies were selected, encompassing a total of 326 SPMs among 5,517 patients.
With a median follow-up of 21.7 months, SPMs were observed in 5.8% of patients. The researchers found no significant differences in SPM rates among patients with varying cancer types or those receiving different CAR T-cell therapies.
Studies involving patients who had undergone a median of over three treatment lines prior to CAR T indicated a notably higher risk of SPMs compared to those with fewer than three previous treatments. Moreover, the incidence of SPMs was found to be 4.2% in studies with follow-up periods shorter than the median and 8.5% in those exceeding the median follow-up duration.
Among the 326 identified SPMs, hematologic malignancies, including myelodysplastic syndrome and acute myeloid leukemia, comprised the largest fraction at 37%. Within this, five cases were classified as T-cell malignancies, representing a rate of 0.09% in the overall study population. In three of these instances, the malignant T cells were tested for the presence of the CAR transgene (indicating potential origins from CAR-edited cells), with one case returning a positive result.
Four of the clinical trials in the analysis directly compared patient outcomes from CAR T therapy against standard care treatment. In total, 1,253 patients participated in these studies, with SPM rates showing 5% for those receiving CAR T and 4.9% for those on standard care, a statistically insignificant difference.
“These findings do not imply a heightened risk of SPMs compared to other standard treatments,” Rejeski stated. “I am concerned that the warning labels could discourage patients from this therapy without just cause.”
Rejeski further noted that the study findings could help identify particular factors that heighten the risk of SPMs among patients undergoing CAR T therapy. For example, the higher incidence of SPMs observed in patients with multiple prior treatments might reflect cumulative damage from those therapies. He also suggested that the increased risk associated with longer follow-up periods could signify a survivorship bias, where more patients are at risk simply because they are living longer post-treatment.
“CAR T therapy is the first advancement in over two decades demonstrating a survival benefit over standard treatments for refractory large B-cell lymphoma,” Rejeski emphasized. “I would advise against withholding this therapy solely due to the negligible risk of T-cell malignancies.”
He also highlighted the need for ongoing investigation to better understand the specific contributions of CAR T-cell therapy to SPM development and to assess individual patient risks more accurately. Rejeski insisted that proper reporting of SPMs over extended follow-up periods, particularly in clinical trials, would significantly aid in this vital research.
“We must remain vigilant in our efforts to comprehend this adverse event, and that necessitates clear reporting standards,” Rejeski asserted.
However, the study did face limitations, including the variability among the data sets and the absence of patient-level information regarding comorbidities and prior treatments that could impact an individual’s SPM risk.
This research was funded by several organizations, including the School of Oncology of the German Cancer Consortium, the Walter Benjamin Fellowship from the German Research Foundation, Arnold Ventures, and others. Rejeski has indicated he has received research funding from Kite/Gilead, serves as a consultant for Kite/Gilead and Bristol Myers Squibb/Celgene, has received fees from the same companies, and has also been granted travel assistance from Kite/Gilead and Pierre Fabre.
