Hi, I'm doctor Michael Bishop. I am director of the David and Etta Jonas Center for Cellular Therapy at the University of Chicago. And I'm at the 2024 annual meeting of the American Society of Hematology here in San Diego.

I have the pleasure and honor of chairing a session on late complications. I think what's an underappreciated aspect is the long term care that is necessary for a patient with CAR-T cells. And again, one of my areas of interest is working with community oncology. I want to see this technology brought forward to as many people as possible. And the inclusion of the community oncology practice is imperative.

And that's just not the referring physicians, but also their APPs and their pharmacists and most importantly, their nurses because the majority of their care is going to be near their home. And so part of this is we worry about the acute toxicities of neurologic toxicities and cytokine release syndrome. But there can be late toxicities. And when I refer to late toxicities, this is more than three months after they received their CAR-T cells.

And so probably the biggest thing that I emphasize to my patients is that they have a compromised immune system because when they received lymphoma leading chemotherapy, which takes out both their B cells and their T cells. And so that leaves them extremely vulnerable to viral infections. And as a matter of fact, viral infections are the number one cause of death other than recurrent disease after CAR-T cell therapy. So that's very, very important.

And sometimes that immune reconstitution takes up to a year. And if you think about it with CAR-T cells, what do they do? What are they targeting? They're targeting proteins that are associated with B cells. And by association, because B cells become plasma cells that take up plasma cells. And when you take out plasma cells, plasma cells produce immunoglobulin. So those are what are protecting your body usually from viral infections.

And so hypogammaglobulinemia can be a significant problem. It's seen in excess of 40%. And about 20% of patients may actually need intravenous immunoglobulin replacement to help them boost their immune system to protect them from that. So that's one aspect of infection.

The other thing is late cytopenias. And when I talk about cytopenias, it can be low neutrophils, anemia, and thrombocytopenia. And we can actually see this in about 20% of patients. And it can be isolated, which is kind of unique. You could just have thrombocytopenia alone. You could have neutropenia alone. You could have anemia alone.

But the thing is, if you think about it, neutrophils are down, so you don't have B cells, you don't have T cells, you don't have neutrophils, you're going to have a higher risk of infection. And that's where the community oncologist and his or her team play such an important role. As well as the caregiver that is participating in the patient's care once they receive CAR-T cell therapy.

Another important aspect, which was really highlighted probably at last year's ASH, it made buzz, is secondary cancers. Now all of the CAR-T cells have a black box warning relative to the risk of T-cell leukemias and lymphomas. And this was found... it's not really been... it's primarily been seen with CD19 CARs. But there is this inherent risk because the CAR-T cell construct could insert in a bad place in the T cell. And so they were seeing both T-cell leukemia and lymphoma.

But the thing I really want to emphasize in regard to that is when they look very, very closely at all the commercial products that have been administered, and all of these are reported, the incidence of that is 0.1%. You know, so because a lot of patients come in, "I don't want to get T-cell leukemia and lymphoma."

So I don't make light of it. It's just, when the societies, which I belong to, the American Society of Hematology, American Society of Transplant and Cellular Therapy, called a position paper. Are they still? Yes. This is an inherent risk, tiny, but it doesn't... The benefits far outweigh that risk.

However, I want to emphasize that the incidence of secondary cancers overall is about 5%. So you got 0.1% versus 5%. So I think of again, relative to complications, we need to monitor because these patients go through lots of prior therapy, which makes them vulnerable to secondary malignancies, particularly myeloid malignancies like myelodysplastic syndrome and acute myeloid leukemia.

So they need to continue monitoring for that as well. So if you take those together—infection, late cytopenias, secondary cancers—these are the things that we need to continue to monitor in the community and report those outcomes so that we can inform patients better about not only the great benefits of CAR T-cell therapy, but also potential toxicities.