Porter Discusses FDA’s Call for Secondary Malignancies Boxed Warning on CAR T-Cell Therapies

David L. Porter, MD

In late January 2024, the FDA called to add a class-wide boxed warning for secondary malignancies to all approved CAR T-cell agents following a safety probe.¹ However, the benefits of these therapies still far outweigh the risks, as the patients with hematologic malignancies who receive them often have advanced disease with limited effective options outside of CAR T-cell therapy, according to David L. Porter, MD.

The announcement affected all 6 FDA-approved CAR T-cell therapies which are indicated by the agency for patients with hematologic malignancies, and include ciltacabtagene autoleucel (Carvykti), tisagenlecleucel (Kymriah), idecabtagene vicleucel (Abecma), lisocabtagene maraleucel (Breyanzi), axicabtagene ciloleucel (Yescarta), and brexucabtagene autoleucel (Tecartus). On January 19, 2024, the FDA sent 6 letters to the manufacturers of the approved CAR T-cell agents, noting that this class of drugs had been deemed to be associated with the risk of developing secondary malignancies. The manufacturers were given 30 days to submit proposed changes to their agents’ safety labels or file a rebuttal if they do not agree with the FDA.

In an interview with OncLive^®, Porter, the Jodi Fisher Horowitz Professor in Leukemia Care Excellence and the director of the Cell Therapy and Transplant Program at Penn Medicine in Philadelphia, Pennsylvania, discussed his thoughts on the boxed warning and gave perspective on the standing of CAR T-cell therapies in hematologic malignancies in light of the news.

OncLive: What was your initial reaction when heard the news from the FDA about the boxed warning on CAR T-cell therapies?

Porter: We already knew that [the FDA] had identified numerous cases [of secondary malignancies] and that they were going to provide more information. I wasn’t completely surprised that they came out with a boxed warning. It seems logical for now.

Still, there are very limited data on the majority of cases they’ve reported so far––I think they’re up to 22. So, I wasn’t surprised that they put a boxed warning [on the agents]. Sometimes you have to err on the side of caution until more information is available.

How great is the risk of secondary malignancies with CAR T-cell therapies and what steps can be taken to mitigate it?

The risk of CAR-induced malignancies, particularly T-cell lymphomas is very low. This group of patients who get CAR T cells for B-cell malignancies [already] have a real risk of secondary cancers––that’s been well described and reported. In most cases [of secondary malignancies], it’s not at all clear that they are related to the CAR T cells; these patients get secondary malignancies even without getting CAR T cells. The added risk that these are CAR-manufacturing induced is quite low.

It's not clear to me right now that there are active steps that can [be taken to] minimize the risk, other than paying very close attention and being aware that there is a risk. [It’s also important to] identify these cases, if or when they develop, and make sure that they’re reported appropriately, so that the whole field can better understand why they occur, how to identify them, and, ultimately, how to mitigate that risk. Right now, the biggest thing is to be aware that this is a risk, be able to identify these cases, and report them appropriately so that the entire field can learn from this.

Besides treatment with CAR T-cell agents, what other factors could be contributing to these secondary malignancies?

These patients tend to be heavily pretreated. They already have a malignancy, [whether it be] myeloma or lymphoma, with abnormal immune systems. The majority of patients have been exposed to multiple types of chemotherapy in the past, all of which we know lead to a risk of developing secondary cancers. Most of these patients are at risk even without the CAR T-cell therapies.

Do the benefits of CAR T-cell therapies still outweigh the potential risks?

Yes. Particularly if you look at the commercially approved products and their indicated usages, they are indicated for patients who are at a very high risk of dying of their disease without effective therapy. Most of them have already been through just about every conventional treatment and have limited treatment options. The risk of these [secondary] lymphomas appears to be very, very low––less than 1%. The potential benefit far exceeds that potential risk. That doesn’t mean we should ignore the risk and [believe] that it’s not real, that we shouldn’t be very aware of it and consider it. But for now, the potential benefits seem to significantly outweigh that very small risk.

What is your takeaway message for your colleagues considering this news?

The risk [of secondary malignancies with CAR T] is very low. For most patients, the benefits still exceed the risks significantly. This shouldn’t preclude patients who need CAR T cells from getting CAR T cells.

Another takeaway is that we have to be aware of this as a potential risk; patients, caregivers, and clinicians need to be aware of it. We need to continue to monitor patients for development of these complications and secondary malignancies. They need to be reported, because that is the only way the community understands what the risks are and what’s happening. The only way you can mitigate it is to understand what the risks are.

This also shows that the long-term follow up program is working. This is why patients are followed and why there is a reporting system because this [treatment] is relatively new. Hopefully the systems are working to make clinicians, patients, and caregivers aware of this. We will continue to monitor [these patients], [any events will] be recorded, and the whole community will benefit from understanding it better.

References

1. Manalac T. FDA calls for boxed warnings on CAR-T therapies regarding secondary cancer risks. BioSpace. January 23, 2024. Accessed March 4, 2024. https://www.biospace.com/article/fda-calls-for-boxed-warnings-on-car-t-therapy-labels-regarding-secondary-cancer-risks/?keywords=cancer
2. 2024 safety and availability communications: January 2024. FDA. Updated January 24, 2024. Accessed March 4, 2024. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/2024-safety-and-availability-communications