From MedPage Today, by Charles Bankhead, Senior Editor, MedPage Today November 28, 2023, Last Updated November 29, 2023. Posted FYI without comment:
FDA Investigating 'Serious Risk' of Malignancy After CAR-T Therapy - Applies to all approved therapies, but benefits still outweigh risks, agency says
The FDA has launched an investigation into what it called a "serious risk" of T-cell malignancies in patients treated with autologous chimeric antigen receptor (CAR) T-cell therapies targeting B-cell maturation antigen (BCMA) or CD19.
The agency has received multiple reports of T-cell malignancies, including CAR-positive lymphomas, from clinical trials and postmarketing adverse event data sources, according to a statement posted on the FDA website. Serious outcomes of these secondary malignancies have included hospitalization and death. The notice and investigation pertain to all currently approved BCMA- and CD19-targeted CAR T-cell products:
Axicabtagene ciloleucel (Yescarta)
Brexucabtagene autoleucel (Tecartus)
Ciltacabtagene autoleucel (Carvykti)
Lisocabtagene maraleucel (Breyanzi)
Tisagenlecleucel (Kymriah)
"Although the overall benefits of these products continue to outweigh their potential risks for their approved uses, FDA is investigating the identified risk of T-cell malignancy with serious outcomes, including hospitalizations and death, and is evaluating the need for regulatory action," agency officials said in the statement. "As with all gene therapy products with integrating vectors (lentiviral or retroviral vectors), the potential risk of developing secondary malignancies is labeled as a class warning in the U.S. prescribing information for approved BCMA-directed and CD19-directed genetically modified autologous T-cell immunotherapies."
According to an FDA spokesperson, the agency has received 19 reports of CAR-associated T-cell malignancies, five from clinical trials and 14 from the FDA's adverse event reporting system. The agency is investigating "the identified risk of T-cell malignancy with serious outcomes, including hospitalization and death," but no specific numbers were provided for those outcomes.
A principal investigator in trials of CAR T-cell therapies said he is unaware of any peer-reviewed reports of T-cell malignancies associated with the approved therapies.
"That said, it is not out of the realm of possibility that one or two out of 10,000 patients could develop T-cell lymphoma," Frederick Locke, MD, of the Moffitt Cancer Center in Tampa, Florida, told MedPage Today via email. "We know that the CAR gene, in at least one case, has mediated disruption of the TET2 gene, which enhanced clonal proliferation and effectiveness of CAR-T for leukemia."
"In addition, several patients previously developed CAR-positive T-cell lymphoma after receiving an investigational CAR that utilized transposon technology, which is not used with FDA-approved CAR T cells," he added. "Finally, we know that cancer immunotherapy such as checkpoint blockade for solid tumors, which does not rely on gene therapy, can very rarely result in T-cell lymphomas."
Locke said he looks forward to learning more about whether patients "have truly developed CAR-positive T-cell lymphoma" after treatment with the approved therapies, and if so, how many. He echoed the FDA position that the therapies' benefits outweigh the risks, as reflected in the clinical experience involving thousands of patients.
"I firmly believe that these therapies offer tremendous value to patients, curing those without other viable treatment options and improving survival in the case of lymphoma," he noted.
In response to the FDA safety notice, Bristol Myers Squibb (BMS) issued the following statement:
"Bristol Myers Squibb has treated more than 4,700 patients across clinical and commercial settings with Abecma and Breyanzi, which use only lentiviral vector. To date, BMS has not observed any CAR-positive T-cell malignancy cases and therefore, we have not found a causal relationship between our products and secondary malignancies."
"Patient safety is a top priority for BMS, and we remain confident in the safety profile and clinical value of our cell therapies," the company continued. "We are collaborating with the FDA in its ongoing investigation and are responding to FDA's requests for information."
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MedPage Today article is here:
FDA Investigating 'Serious Risk' of Malignancy After CAR-T Therapy - Applies to all approved therapies, but benefits still outweigh risks, agency says, by Charles Bankhead, Senior Editor, MedPage Today November 28, 2023, Last Updated November 29, 2023
FDA statement referenced in the Article can be found here:
FDA Investigating Serious Risk of T-cell Malignancy Following BCMA-Directed or CD19-Directed Autologous Chimeric Antigen Receptor (CAR) T cell Immunotherapies, November 28, 2023.
Thank you for posting this - that's an item off my posting list for today. The FDA is tightening up on drug safety, with the result that PI3K inhibitor drugs used in the treatment of CLL, are having their approval revoked (idelalisib) and newer PI3Ki versions are facing tighter scrutiny, for example;
FDA Alerts Healthcare Professionals About Clinical Trials with Zydelig (idelalisib) in Combination with other Cancer MedicinesThe U.S. Food and Drug Administration is alerting health care professionals about reports of an increased rate of adverse events, including deaths, in clinical trials with the cancer medicine Zydelig (idelalisib) in combination with other cancer medicines.
It makes you wonder whether the FDA would nowadays approve FCR, the gold standard treatment for CLL for about a decade, given the known increased risks for the subsequent development of AML and MDS.
As I pointed out in at the end of my post on thalidomide and the use of the derivative lenalidomide (Revlimid) in CLL treatments, healthunlocked.com/cllsuppo... the FDA is also strengthening the regulation of dietary supplements fda.gov/news-events/press-a...
JerrysGirl3 separately posted this link to this Drugs.com Newsletter
Neil - Glad to provide a minor assist to your always-exhaustive efforts to keep the community here updated on any and all development related to CLL. Thanks, as always. Best to you, Ciao - Cujoe
2 in 10K? Does that mean already 90K patients were treated with CAR-T? And that's just based on the number of reported cases. That does not sound correct. All in all seems like bad news 😔
Conclusion: Overall Benefits Do Outweigh the Risks
Despite these latest concerns with the CAR T-cell therapy, both the FDA and ASH leaders agree that the overall benefits of these therapies currently outweigh potential risks for approved uses in treating blood cancers. However, continuous and lifelong monitoring may be necessary, they said.
“I think that the path forward anyway, practically, is going to be using third-party cells that have been modified to not be rejected immediately and not to cause graft-versus-host disease,” said
ASH Secretary Cynthia Dunbar, MD. “That's one potential way forward.”
Additionally, she noted the mutagenic, or genetic-altering, effects of certain cancer drugs like CAR T, and emphasized the need to understand patients' health conditions before starting such treatments.
ASH President Robert Brodsky, MD, said that impacts may not be seen in certain therapies for some time. He added that with any treatment, including CAR T, there is a risk-benefit ratio to consider.
“In diseases that are immediately life-threatening, it's not a big consideration,” Dr. Brodsky said. “But if you're going to start using it in patients who are already in remission and at high risk of relapse ... it's going to take some monitoring to really see what's going on.”
FDA official says CAR-T ‘incredibly beneficial’ despite secondary malignancy risk
January 09, 2024, 2 min read
Benefits of chimeric antigen receptor T-cell therapy far outweigh the risks involved, including secondary T-cell malignancies, according to Peter Marks, MD, PhD, director of the FDA’s Center for Biologic Evaluation and Research.
The FDA issued a safety advisory for patients receiving CAR-T regarding T-cell malignancies at the end of November, but Marks said only 22 cases out of more than 27,000 individuals treated had been reported by the end of 2023.
“Make no mistake, the overall risk-benefit profile [for CAR-T] is still incredibly beneficial,” Marks said during the Alliance for Regenerative Medicine state of the industry briefing on cell and gene therapy on Monday. “For all of the approved uses, we don’t have any concerns with continued use of these products.”
CAR T-cell approaches are the stuff of science fiction: We filter a patient's blood to get a sample of their immune system, re-engineer it to have a monomaniacal focus on killing that patient's own cancer cells, and re-infuse the mixture as we watch the patient's cancer recede -- and it works most of the time! At least for a while. Is it any surprise though, as we monkey around with the immune system, that cancers of the immune system such as lymphoma might arise?
Probably not. Perhaps the real surprise should be that it happens so infrequently.
The FDA has identified at least 22 patients who developed secondary T-cell malignancies so far, out of tens of thousands of people treated with CAR T-cell approaches. That's a risk ratio of approximately 1 in 1,000 in patients who, by the way, had also received traditional chemotherapy prior to the CAR T-cells -- chemotherapy that itself can damage cells enough to cause secondary malignancies. I should know -- for years I have seen patients in my own clinic with secondary myelodysplastic syndromes or leukemias following similar chemotherapy. Compare that 1 in 1,000 risk to the high risk of the recalcitrant leukemia, or lymphoma, or multiple myeloma marching on (if active), or returning with a vengeance if a patient is in remission.
:
I don't think our patients should be concerned about CAR T-cells any more than they would be about other cancer therapies. When we offer treatments for cancer, unfortunately there are no free rides -- every effective cancer therapy has the potential to cause side effects, and we are willing to accept some pretty major side effects when we are treating life-threatening diseases. If I were told that I could receive a treatment for relapsed cancer that had an 80-90% chance of working, with a 1 in 1,000 risk of getting another cancer, I would definitely decide to take the therapy and accept that risk. That's what my patient decided, too.
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Alterations of the immune system caused by CLL B‐cells 
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