Part One: Drs. Dahiya, Spiegel Discuss CAR-T Secondary Malignancies Risk

In this episode of The HemOnc Pulse, Saurabh Dahiya, MD, FACP, of Stanford Medicine, and Jay Spiegel, MD, of the University of Miami, discuss the link between chimeric antigen receptor (CAR) T-cell therapies and secondary T-cell malignancies in light of the US Food and Drug Administration (FDA) statement on the potential risk of secondary malignancies after treatment with the six CAR-T therapies indicated to treat blood cancers.

The episode follows a November 2023 FDA statement on the potential risk that was released prior to the 65th American Society of Hematology (ASH) Annual Meeting & Exposition in December 2023.

Subsequently, on January 9, 2024, the FDA sent another notice to drug manufacturers to update the safety label information of the therapies.

Right before the December ASH meeting, the FDA had reported 19 cases, 12 of which were associated with a variety of the commercially approved therapies, Dr. Spiegel recalled.

“In the large cell lymphoma and B-cell space [those therapies] would be axi-cel, tisa-cel, and cilta-cel, ” Dr. Spiegel said. “In multiple myeloma, the two approved CARs [are] ide-cel and cilta-cel. All five had cases reported to the FDA, and then there were seven additional cases for a CAR product that is likely investigational, which we don’t have further information on.”

Dr. Spiegel provided some context as to why the report set off a “firestorm,” as he put it.

“The way that CAR-Ts are created is that there is genomic data inserted into the genome of the T cell,” Dr. Spiegel said. “Obviously, there is a risk for an insertion of mutagenesis where this genomic data is inserted into an area of the genome where it can turn on the T cell and … potentially turn it into a cancer itself. I think that is why everybody was concerned about the report.”

Drs. Dahiya and Spiegel were both part of the US Lymphoma CAR-T Consortium, which looked at the outcomes of patients with lymphoma after being treated with CAR-T therapy. The authors reported those results during the 65th ASH Annual Meeting & Exposition.

According to Dr. Spiegel, the US Lymphoma CAR-T Consortium reported that 9% of 275 patients experienced a secondary malignancy, and the majority (5%) of those cases were therapy-related myeloid malignancies, primarily myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).

Dr. Spiegel mentioned that although there’s a risk for insertional mutagenesis, in which genomic data inserted into an area of the genome can turn on the T cell and potentially turn it into a cancerous cell, the probability is low.

Dr. Dahiya agreed, emphasizing that some patients would not be alive without CAR-T. He mentioned that 19 cases of T-cell lymphoma were reported in thousands of patients treated with CAR-Ts, and that 842 of approximately 8,000 patients (7.6%) developed a second primary neoplasm.

“These are the patients who are heavily pretreated and have a median of four lines of therapy,” Dr. Dahiya said. “As such, they already have a risk of having myeloid genotoxic injury from all this prior exposure.”

Dr. Dahiya also added that insertional mutated genesis has been observed approximately three times in the literature. However, he said that it’s still something to council patients on.

Dr. Speigel acknowledged that 10% of patients on cilta-cel who developed MDS or AML is “a lot,” and he described his clinical experience with cilta-cel as “quite a wild ride” due to side effects such as inflammation. However, he still feels that the FDA report should be taken “with a grain of salt.”

“As a field, we feel relatively reassured that the risk of T-cell lymphoma, while real, appears to be quite low,” Dr. Speigel said. “Based on where we are now, the T-cell lymphoma story does not change how we approach the use of CAR-Ts across both diseases where they are approved.”