For those unable to link to Shellbell's postNicole...

For those unable to link to Shellbell's post

Nicole DeFeudis

Editor

A day after the FDA launched an investigation into rare cases of secondary blood cancer in patients who received CAR-T therapies, clinicians are calling it a small risk factor for an otherwise effective drug class.

Regulators are tracking 20 reports of T-cell malignancies since the first CAR-Ts were approved in 2017, including 15 from the FDA’s self-reporting adverse event system FAERS. In the context of the tens of thousands of patients who’ve received CAR-T therapies, that small number represents “an extreme minority,” UChicago faculty physician and Hematopoietic Stem Cell Transplantation Program director Michael Bishop told Endpoints News on Wednesday.

Michael Bishop

“When we consult patients and consent them to receive it, we always mention the risk of secondary cancers,” said Bishop, who has been involved with several CAR-T trials, including for Novartis’ Kymriah and J&J and Legend’s Carvykti, and has never seen a T-cell malignancy case among the hundreds of patients he’s treated. “At least from the current perspective, the benefit far outweighs this risk.”

Secondary cancers are a known but rare risk with many anti-cancer treatments, including chemotherapy. Patients taking CAR-Ts may be predisposed to secondary malignancies, including from prior treatments, Bishop said. But what makes these cases interesting is that T-cell cancers are “not a common secondary malignancy in any disease setting that I’m familiar with,” Bishop said.

The FDA said in a news release yesterday that “the overall benefits of these products continue to outweigh their potential risks for their approved uses,” though the agency is currently “evaluating the need for regulatory action.”

The agency has not responded to requests for comment on how many CAR-positive T-cell malignancies were detected and the severity of the cases. Bishop noted that CAR-positive cases do not necessarily mean the patient’s cancer was caused by CAR-T treatment, and more information will be necessary to determine whether patients were predisposed to T-cell lymphomas.

Mikkael Sekeres, chief of hematology at the University of Miami’s Sylvester Comprehensive Cancer Center and former chair of the FDA’s Oncologic Drugs Advisory Committee, told Endpoints that he isn’t surprised rare cancers are emerging now that thousands of patients have been treated with CAR-Ts.

“There is no way that these would have emerged on clinical trials of CAR-T cells or in a single institution’s experience,” he said. “That sounds like the sort of ratio that would emerge in post-marketing surveillance. And it also sounds like it’s not an accident. We can’t just dismiss this.”

He added that the potential risk “certainly has to enter the discussion of potential benefits and risks of the therapy,” though noted that “it’s not a high risk.”

Cynthia Dunbar, a hematologist at the NIH’s National Heart, Lung, and Blood Institute, said during a call with reporters Wednesday that it’s possible that the cases have “more to do with the underlying state of the patients.” She noted that “a lot of the drugs that you give to patients with lymphoma or any kind of malignancy are themselves mutagenic,” and that it will be important to sort this out quickly.”

“The immediate hypothesis is, did you manipulate the T cells in such a way that it made them prone to development of a T-cell lymphoma?” Bishop said. Important data to evaluate going forward will include how long it takes new cancers to develop, and how many cases are CAR-positive, he added.

Lei Lei Wu contributed reporting.

Editor’s Note: The FDA has updated the number of T-cell malignancy reports to 20, as of Nov. 28.