Hi, I'm Zach Avigan.
I'm a fellow at Mount Sinai in New York in the multiple myeloma group,
and I'm excited to present our work on hematologic toxicity after CAR-T for multiple myeloma.

So neutrophils are really important white blood cells that help to fight infection.
They're sort of like the infantry in the white blood cells that help to be our first line of defense against all kinds of infections, but especially bacterial infections.

After CAR-T, CAR T-cells against BCMA (B cell maturation antigen) are very effective in myeloma.
But one of the really important toxicities that some people have is this hematologic toxicity, where they have delayed blood count recovery, especially delayed neutrophil recovery after the CAR-T.
And actually, around 20% of patients still don't have neutrophil recovery even at three months after their CAR T-cell treatment.

This causes a lot of burden on patients because they need more visits to their doctor to get treatments or supportive care.
But it also means that they're at much higher risk of infection because of those low white blood cells.

And when you look in the long term, patients who have this delayed recovery of neutrophils and other blood cells, have shorter survival.
So worse long-term outcomes.
So it's really important for us to try to understand why these patients have this delayed neutrophil recovery and delayed blood count recovery.
What pathways lead to that and how to better understand how to prevent it to improve outcomes for patients.

We found, when we looked at this study and other groups have shown this before, that patients who have baseline inflammation, so higher levels of these nonspecific inflammatory signs in the blood, are more likely to have these delayed blood count recovery, and especially delayed neutrophil recovery after CAR-T.
But we're really interested in focusing on which specific inflammatory pathways might be involved in causing this delayed blood recovery, so we can better understand how to target those pathways in the future.

So we looked at all of our patients who had gotten CAR-T cells targeting BCMA for multiple myeloma at our center, Mount Sinai, since 2017—about 200 patients.
We looked at the total recovery time for those patients, and we did show that patients with delayed recovery had significantly worse survival.
We focused in on about 47 patients where we had serial measurements in the blood of some of these cytokines, which are different markers of inflammatory pathways.
So we started at baseline before the CAR-T and measured out till day 14.
We compared patients who had shorter or prolonged recovery of their neutrophils and other blood cells.

We saw that patients who had prolonged recovery, so they took a longer time until they had neutrophil recovery, had some elevated inflammatory markers that started at baseline but really peaked all the way at day 14.
Some of those pathways included things like TNF alpha, IL-18, IL-6 and IL-8, which are different inflammatory pathways that we think about targeting with different drugs to reduce inflammation in patients, as well as some of these T-cell checkpoint molecules like PD1, PD-L1, LAG-3, and Galectin-9, which are also some markers that happen with persistent inflammation that can start to tamp down the immune system's ability to fight myeloma or infection.

So those are some of the findings related to specific inflammatory pathways that might potentially be involved in driving some of these delayed neutrophil recovery.

When we looked at patients who had really prolonged recovery—delayed recovery all the way out towards 100 days—we found that interleukin-1 (IL-1) was a really important cytokine that was elevated at baseline and very high in that early period through day 14.
Now, we didn't have cytokine levels after day 14, but we looked at ferritin, which is an inflammatory marker that seemed to be driven by that interleukin-1.
We showed that higher levels of ferritin, potentially suggesting that IL-1-based inflammation, were high in all of these patients all the way up until day 100.
So at day 30, 60, and 100, suggesting that this IL-1-based inflammation or this specific inflammatory pathway might be really high in the early days and likely persists in these patients all the way through day 100.

This gives us a little bit more of an understanding of what specific inflammatory pathways we can maybe target to try to reduce this toxicity for patients and help improve the outcomes for myeloma patients thinking about CAR-T.

So right now for CAR-T, for patients who have delayed blood count recovery, the main treatments are just supportive care.
So things like filgrastim or CSF to help support the neutrophil counts, as well as transfusions for red blood cells or platelets.
Right now, it's supportive care and infection prophylaxis to help prevent those patients from having severe infections.

There are drugs that we could think about in the future that target some of these specific inflammatory pathways.
There's a drug called Anakinra that is sometimes used in the early phase to block IL-1, as well as other drugs that can block specific inflammatory pathways.
These are not in use right now specifically for patients who have delayed neutrophil recovery or other delayed blood count recoveries.
But we hope with this kind of work to, when we can better uncover these specific pathways, we can work in future trials, probably starting in blood cells and starting in mice, and then eventually working towards patients to block some specific inflammatory pathways like IL-1 or other interleukins to try to prevent this toxicity for patients.

We know from a lot of different studies looking at blood count recovery and other things that patients who have baseline inflammation—through a number of pathways like these different interleukin pathways—might also experience T-cell dysfunction.
T-cells are the cells that are really specific and try to help fight the myeloma cells.
Some of the cancer cells that this T-cell dysfunction can help reduce our ability to fight myeloma.

As we uncover some of these specific pathways, we learn more about how the inflammatory milieu or overall inflammatory state of the patient can affect how we're able to fight myeloma or other infections, but also helps us understand how some of these specific toxicities, like delayed blood count recovery, might be related to reduced blood count recovery and how that can affect the outcomes long term.

In some prior work that's been shown by our group and others, it's been shown that patients who have self-reported black race are potentially more likely to have delayed neutrophil recovery.
When we looked at that more closely, not in this abstract, but actually in an earlier paper, we showed that part of the reason for that is that a lot of these patients with self-reported black race are more likely to have what's called a Duffy null phenotype, which is a particular blood group that's very common in patients of African ancestry because it causes resistance to malaria.
Those patients, separate from myeloma, have slightly lower baseline neutrophil counts, which is actually not dangerous, and it's a normal variant for those patients that doesn't cause an increased risk of infection.

Some prior work showed that patients with self-reported black race might have delayed neutrophil recovery, but it turns out that when you correct for that Duffy null phenotype, that's actually the main cause of that neutrophil recovery.
So we found that there were actually no racial differences in neutrophil recovery.
It's really more about patients with baseline inflammation.

Also, patients who are more heavily pretreated with more triple class or penta-drug refractory disease, so more prior lines of therapy, older age, and high-risk cytogenetics, are those patients who are at higher risk for developing prolonged neutrophil recovery.

We don't always know the answer to that question.
There are some patients who, going into the CAR-T cell therapy, seem to have higher levels of these nonspecific inflammatory markers, suggesting that they just have a more active immune system and more inflammation in the blood.
It seems like some of that higher activity might lead to dysregulation and dysfunction in the immune system.

That makes it harder for them to fight infection, harder for them to fight the myeloma.
We still don't totally understand all the details of which patients and why.
Again, as we said, we know that patients with more prior lines of therapy and high-risk disease might fall into that category,
but this work, and work from other groups, is trying to better understand what specific inflammatory pathways are involved, and which ones to target.

But for now, what we know is that immune dysregulation in general, in some of these patients, is a harbinger of long-term poor outcomes in various diseases.

I think the main thing to say right now is that we know CAR-T cells are very, very effective, but that there can be toxicities—this is one of many possible toxicities of CAR-T cells.
Of course, talk to your doctor about when you're thinking about CAR-T.
I do think that hematologic toxicity is very common, but some of these prolonged hematologic toxicities—this prolonged neutropenia you're talking about—is still unusual.
And we still have really good treatments for it in terms of growth factors and other things.

So I don't think that this is something that should potentially prevent you from thinking about going through with the CAR-T,
but it's something to be aware of as a possible toxicity and a possible thing to be aware of after the CAR-T,
and something that might require more treatment, but we do have really good supportive care to help get people through that period.