Dr. Strati shares about trials happening at MD Anderson for DLBCL and follicular lymphoma. This includes the following:

 

Two completed follicular lymphoma trials: 

Phase I study of evorpacept and R2 in relapsed indolent B-NHL

Phase 2 study of acalabrutinib and R2 in previously untreated indolent B-NHL

 

One ongoing DLBCL trial:

Phase 2 study of loncastuximab as consolidation after CART in DLBCL

 

One upcoming DLBCL trial:

Phase 2 study of emapalaumab for the treatment of persistent severe cytopenia after CART in DLBCL

Kat: Welcome to today's episode of HealthTree Podcast for DLBCL and Follicular Lymphoma, a show that connects patients with lymphoma researchers. I'm your host, Kat Richardson. Thank you to our episode sponsors, Regeneron and Bristol Myers Squibb, for their support of this HealthTree Podcast show. Before we get started with today's show, I'd like to mention an upcoming event that we will be hosting. On May 22nd, we will have a live webinar with Dr. Miklos discussing CAR T cell therapy advances in B cell lymphoma. To register for this event and submit questions, visit www.healthtree.org/DLBCL/community/events. And with that, we'll begin today's topic. 

MD Anderson has the nation's largest cancer clinical trial program. Dr. Paolo Strati is a doctor and researcher in the Department of Lymphoma. He recently completed two trials for indolent B-cell non-Hodgkin's lymphoma and is working on two others for diffuse large B-cell lymphoma. We are so pleased to have you with us on the show today. 

Dr. Strati, before we begin our discussion, let me provide an introduction for you. Dr. Strati is an assistant professor in the Department of Lymphoma and Myeloma and in the Department of Translational Molecular Pathology at MD Anderson Cancer Center in Houston, Texas. He is also the Clinical Director for the Lymphoma Tissue Bank. Dr. Strati earned his medical degree cum laude from the San Rafael University in Milan, Italy in 2008 and completed an internal medicine residency at the same institution and subsequently at the Mayo Clinic in Rochester, Minnesota. He also completed a hematology on fellowship at MD Anderson Cancer Center, a leukemia and lymphoma fellowship at the same institution, and a malignant hematology fellowship at Bart's Cancer Institute in London. Dr. Strati is committed to gaining further insight into the biology of the lymphoma immune microenvironment and manipulating its components in order to develop novel, effective therapies and decrease the toxicity of treatment strategies already available for patients with B cell lymphoma. Thank you so much for being here with us today.

Paolo Strati: Well, thank you so much for having me today. I'm very excited to have the opportunity to share some updates with you. As you said, I've written about two clinical trials for patients with indolent B-cell lymphoma, including follicular lymphoma, and two upcoming trials for patients with aggressive B-cell lymphoma. I will start with the first two.

And I think it may be helpful first to provide some background about indolent lymphomas, and then I'll provide more details about these trials. Follicular lymphoma is the most common indolent lymphoma, and it typically affects patients who are elderly and, as such, may also have comorbid health conditions. As an example, the median age for follicular lymphoma is greater than 70. Despite this, unfortunately, chemotherapy remains today the standard first treatment for patients with indolent lymphoma. Either a regimen called BR, which stands for bendamustine rituximab, or a regimen called R-CHOP, which is a combination of multiple chemotherapy agents, are the most commonly utilized frontline regimens for indolent lymphoma, both in the US and Europe.
But as you heard, these patients are very frequently too frail for chemotherapy in general. More specifically, they may also have long-term side effects, including secondary cancers. So, there's been a lot of interest in trying to develop immunotherapy instead of chemotherapy as the first treatment for patients with indolent lymphoma.

This has been a pioneering effort at my site. I'm very grateful to have been able to work at MD Anderson years ago with the combination of two drugs. One is called lenalidomide, a pill that improves the immune system. The other is an infusion called rituximab, an antibody that can directly target lymphoma. So, this combination is typically referred to as R-squared.

So R-squared has been compared to chemotherapy also in a very large randomized phase three trial called the Relevance Trial. We were able to demonstrate that immunotherapy is not inferior to chemotherapy as a first treatment for follicular and marginal zone lymphoma. Unfortunately, though, the way the trial was designed, the expectation was that immunotherapy was going to be superior to chemo. Because of this, currently, formally, immunotherapy with R-squared is not approved by the FDA as a first treatment for indolent lymphoma. 

We've also demonstrated that if we can achieve deep remissions with immunotherapy, so complete remissions, there's a good chance that immunotherapy may, with time, become superior to chemotherapy. As such, myself and many others have performed multiple studies trying to understand what can be done to increase the activity of immunotherapy in follicular lymphoma and marginal zone lymphoma patients. 

So to this regard, years ago, we performed this study where we collected tissue biopsies before starting immunotherapy and a time of relapse or progression in patients with follicular lymphoma who were receiving R-squared. What we were able to observe was that at the time of progression, there was a significant increase in a very special type of immune cell called macrophages. They seem to nurture the lymphoma growth and be more pro-tumoral instead of being anti-tumoral. We realized that targeting these macrophages and their interaction with the follicular lymphoma cells may have potentially increased the efficacy of immunotherapy. 

So, as a next step we decided to start the first of two clinical trials that I'm going to share with you today. There was a phase two trial where we combined R-squared with a pill called acalabrutinib. Now acalabrutinib is what we call a BTK inhibitor, so a medication able to target the B-cell receptor, which is truly crucial for the interaction between follicular lymphoma cells and macrophages. This pill is currently approved by the FDA for several types of lymphoma including CLL, marginal zone lymphoma, and mantle cell lymphoma, but it's not approved for follicular lymphoma. 

So, in this case, really, the combination with R-squared was experimental. Years ago, we performed a phase one trial looking into the same combination for a patient with relapsed follicular lymphoma and demonstrated that it was safe. That was the phase one trial. 

So as the next step, we moved to phase two trial, trying to assess not only the safety, but also the efficacy. So overall, 24 patients have been enrolled in this clinical trial, and they all had follicular lymphoma. In this trial, during the first cycle, and we defined one cycle as 28 days of treatment, we gave acalabrutinib as a single agent and the standard dose, which is 100 milligrams twice a day.

We added R-squared for 12 cycles. So overall, patients received 13 cycles of treatment. I need to start by emphasizing that in this phase two trial, patients who were enrolled had heavily presenting features of high tumor burden. The size of their lymph nodes was quite high. The activity on the past scans was also quite high. So, this was not a low-risk population. Despite this, when we performed the first PET scan after only three cycles of treatment, 60% of patients were in complete response, and 92% after six cycles. After now longer than 30 months of follow-up, the vast majority of patients who were in complete remission remained in complete remission. Close to 70% of patients had no minimal residual tissue, which is unprecedented, particularly with immunotherapy in follicular lymphoma patients. So, in light of this very exciting data from this Phase II trial, we have reopened the study and we have enlarged the trial from 24 to 50 patients overall.

We have already treated an additional 26 patients. The last patient received treatment about two months ago, and we will observe them all for an additional two years before we share additional data. We have also included 10 patients with marginal zone lymphoma in this revised trial. Again, once the last patient receives treatment, they will be observed for two years, and then we will share more data with you. I would also like to say that the addition of acalabrutinib to R-squared did not result in any increased toxicity.

So we hope that once we have data from 60 patients, that will be enough to support a randomized phase three trial where this new chemotherapy, which seems to be quite promising, will eventually bring the approval of immunotherapy as a first treatment for follicular lymphoma and marginal zone lymphoma patients.

This is the first of the two follicular lymphoma trials that we recently presented. The second one is a phase one trial, but the background is the same. In this case, instead of utilizing acalabrutinib, we combined R-squared with a different drug called ALX148 or evorpacept. Data from this phase one trial was very recently presented at the AACR meeting.

Evorpacept, different from acalabrutinib, is what we call a CD47 antagonist or blocking antibody. CD47 is a protein that lymphoma cells are able to express and they give a do-not-eat-me signal to macrophages, the immune cells that I mentioned before. So evorpacept is able to interrupt the crosstalk between follicular lymphoma cells and protumoral macrophages.

The combination was given together from the first cycle for 12 cycles in the phase one trial. A phase one trial differs from a phase two trial in that it is aimed at identifying the right dose, assessing safety and toxicity, and eventually establishing the recommended phase two dose. So, overall, 20 patients were enrolled in this trial. The vast majority, 90%, had either follicular or marginal zone lymphoma. 

These patients were heavily pretreated. All of them had previously received rituximab. The vast majority were refractory or had experienced a progression of disease within 24 months after prior chemotherapy, which is a factor known to be associated with shorter overall survival. So again, a very high-risk population. 

The combination overall was safe, and we did not notice any increased toxicity. The only new finding that was partially expected was a slight increase in the frequency of very low-grade liver function test elevation. I'm saying that this is expected because macrophages are rich in the liver and when they're activated by this combination, they are expected to give some minor liver function test elevation that in this case did not result in any study delay, dose reduction, or treatment interruption, so it was really clinically not relevant. As a matter of fact, we were able to move from the first and lowest dose level to the highest, and only three patients were treated at the highest dose level, and no dose-limiting toxicity was met. 

In terms of efficacy, the combination was quite impressive. Just to set the stage, when we utilize R-squared alone in patients who have relapsed indolent and B-cell lymphoma, no more than 30% of patients are able to achieve complete remission. But in this trial, after only three cycles of treatment, more than 80% were in complete remission, and the vast majority now with a follow-up longer than two years remain in complete remission. So also in this case, results were very encouraging, and now that phase one is completed, we have already activated a phase two trial, where we're using the same combination for only six cycles in patients who have previously untreated high tumor burden and advanced stage follicular and marginal zone lymphoma. And these are the two follicular lymphoma and marginal zone lymphoma clinical trials that I wish to share with you today.

Kat: Thank you so much for that summary of both of those trials. I have a couple of questions regarding them. For our audience, can you explain what indolent means and also what cancers that includes?

Paolo Strati: Yeah, thank you. I think that's a great question, and I'm glad I can provide some clarifications here. So first of all, we call lymphoma typically a cancer of the lymph nodes, which are the glands that swell up when we have an infection. But it's truly a cancer of the lymphocytes, which are white cells that can be everywhere. Now, in the lymphoma world, we tend to divide B-cell non-Hodgkin lymphoma into two types: indolent or slow-growing and aggressive or fast-growing. 
So, indolent or slow-growing lymphoma is mainly caused by follicular and marginal zone lymphoma. Because they are indolent or slow-growing, about 40% of patients never need treatment and we actually utilize very specific criteria called GELF criteria to make a determination about who needs to be treated. But more than 50% of patients eventually meet those criteria and need to start treatment. For those patients, these two trials hopefully will provide a new start in the near future.

Kat: Thank you for that. So, another question for the phase one study: Does it need a phase two to be FDA approved? And when would that be? And the same question for the phase two study: Will it go on to phase three?

Paolo Strati: Yeah, that's a very relevant question for these two trials. In general, to have full approval from the FDA, we need to have what is called a randomized phase three trial, which is a clinical trial where you flip a coin and you give either the standard treatment in this case could be chemotherapy, for example, or the experimental treatment. That's what brings us to a definitive final FDA approval. However, in the United States, we have a mechanism in place called accelerated approval, where the FDA is willing to give some sort of preliminary approval so the patient can start to get treatment outside of a clinical trial based on a phase two trial. This is under the assumption that there's already an ongoing randomized phase three trial. So ultimately, all medications require a randomized phase three trial for FDA approval.

So in this specific case, the phase one, as mentioned earlier, has already moved to a phase two trial. Small phase two trials are usually too weak to grant accelerated approval. But a larger phase two trial may. For our ongoing phase two trial of acalabrutinib and R-squared, the sample size is quite big, 60 patients overall. So, that may help to provide accelerated approval. But for the smaller phase 2 trial, following the phase 1 that I just described, they will need to be either enlarged or turned into a randomized phase 3 trial.

Kat: Do you have a timeline for when these next steps would take place? Is it months or years?

Paolo Strati: Yeah, so this brings us to another important point to make. For the FDA to make decisions about approvals for follicular lymphoma, because it's a slow-growth lymphoma, they usually require longer follow-up than we do for more aggressive lymphoma. So for more aggressive lymphoma, usually, a response at the end of treatment may be enough for the FDA to make a decision, and that can be observed very quickly after a few months. But for indolent lymphoma, many times we wait for follow-up as long as 24 months for progression-free survival or 30 months for complete remission because those responses need to be durable. We'll need to wait at least two years from the last patient to run in each trial before the FDA may make any decision.

Kat: Perfect, thank you. And then the last question about these two trials—what would be the benefit if these trials were approved in the future, and how would this change the future of follicular lymphoma treatment? Is it just another option for patients, or are there fewer side effects with these drugs? What's the biggest benefit of these two trials?

Paolo Strati: I'm glad you're asking this question, because in my opinion, there are two layers of answers. The first thing that we need to keep in mind is that when we look into clinical trials that are currently published for follicular lymphoma or marginal lymphoma, they have brought two FDA approvals. Typically, patients in those trials are very young, their median age is not greater than 60. That does not reflect the real world.

In the real world, patients with follicular and marginal zone lymphoma are typically older than 70. As such, they are many times unable to receive a lot of the treatments currently approved by the FDA, including chemotherapy, bispecifics, or cellular therapy. So, to your point, immunotherapy, if approved by the FDA, has the advantage of being better tolerated than chemo. I think that it would allow older patients with other health conditions to be treated properly and non-suboptimally. 

The other thing is that these are still preliminary data. We do see, which is not typically described with chemotherapy, minimal residual disease eradication. Now, a word that a lot of providers are afraid to use when it comes to follicular lymphoma and marginal zone lymphoma is the word cure. I'm not ashamed to use it. Of course, the community is divided. But I think that as we develop newer regimens, including those that we are investigating in these trials, we will be able to demonstrate that these regimens can eradicate even minimal residual disease, which is a very small amount of disease that we're not able to see on a PET scan. Those may start generating cures. So I think that would also be a potential advantage of these potential approvals in the near future.

Kat: Thank you so much for that explanation. Now, we can move on to discussing your phase two study for consolidation after CAR T in DLBCL. If you'd like to explain that, that would be wonderful.

Paolo Strati: Yeah, so this brings us to a different topic, a different type of lymphoma in this case, as you said, DLBCL or diffuse large B-cell lymphoma. Going back to what I mentioned before, this is a fast-growing or aggressive lymphoma that cannot wait and needs to be treated, usually the first time with chemo. Currently, for patients who have either what we call primary chemo-refractory lymphoma, so patients who have DLBCL that get chemo and the lymphoma comes back very early, within one year from treatment. Or later, but then patients are ineligible for stem cell transplant. Or for patients who do get transplant as a second treatment and then the lymphoma comes back a second time, the standard treatment in the United States and Europe is currently represented by cellular therapy. The cellular therapy that we have currently in the US is first of all, autologous, so it's based on cells that we collect from the patient themself and targets a very specific protein called CD19. And it's called chimeric antigen receptor or CAR T-cell therapy. So what we do, we collect the patient's white cells and more specifically the patient's T-cells and then we engineer them in the lab. It takes a minimum of 17 days and sometimes longer than a month so that those cells are able to better recognize CD19. And when the cells are ready, we give our patients chemotherapy for three days just to prepare their body and make sure they don't reject the CAR T cells. Then we infuse the CAR T cells, typically through a port or a central line. Now, when we do this, usually about half of patients are able to achieve a durable complete remission in second line, and about 30% of the time in third line.

About 30% of patients either in their second or third line will have no more than a partial response. So some decrease in the activity of the lymphoma, but not a complete resolution. That's a problem in aggressive lymphoma. So with aggressive lymphoma, achievement of a partial remission after CAR T, almost inevitably in about 70% of patients will translate into a subsequent relapse. But despite this, for patients who have a partial response after CAR T, the current standard approach is observation. Based on the numbers that I mentioned, again, a 70% chance of relapse, you may argue, is evil; it's a Russian roulette. So there's a lot of interest in trying to consolidate those patients. The goal is to take those in partial remission and try to push them to complete remission. 

I mentioned earlier that the target of CAR-T is CD19. Now we also have a drug, an antibody, called loncastuximab which is also able to recognize CD19, go to the CD19 positive lymphoma cells, and release a small amount of chemo. 

So the overall overarching idea of this trial, a phase two trial, is that by using loncastuximab in those patients who are only in a partial response after CAR T, may push their response to a complete response by further targeting CD19.

So this trial is actually still ongoing, and I'm unable, unfortunately, today to share data, but we should be able to share more toxicity and safety data with everybody in the next few months. 

We've already enrolled eight patients. We should be able to enroll two more in the next few months.

Overall, patients are receiving loncastuximab at the standard dose, usually a higher dose for the first two cycles and then half the dose for the remaining four cycles. So overall, six cycles of treatment. And we do a PET scan after cycles three and six, and we expect that the number of patients who will convert from a partial response to a complete response will increase from 30% to 60% or higher. Hopefully, in the next few months data will be publicly available and we can have a follow-up podcast episode about this.

Kat: Thank you. I have a few questions, and some of them you've answered in your general explanation. But just to break down the study for our listeners, I might just ask them again. So the patient population for this study is DLBCL patients. But what other inclusions are there to participate?

Paolo Strati: This is actually very important to clarify. So these are patients with large B-cell lymphoma, those who are overall eligible for CAR T. There currently are really four types. Diffuse large B-cell lymphoma, high grade B-cell lymphoma, like double hit lymphoma, primary mediastinal B-cell lymphoma, and transformed follicular lymphoma. So these are pretty much four types of aggressive B-cell non-hodgkin lymphoma that are currently covered by the FDA label for CAR T. So all of those patients who are otherwise eligible for CAR T-cell, standard care CAR T-cell therapy and have no more than a partial response after CAR T cells are eligible for this trial.

Kat: Perfect, and you said that you're enrolling two more patients, is that the goal that you mentioned?

Paolo Strati: The overall study aims for 30 patients overall, but every clinical trial has built in some boundaries to make sure that the study is not futile. So typically in a 30-patient study, every 10 patients, we pause, we stop, we sit down altogether, we look back into side effects and efficacy, and only if we feel that the balance is in favor of efficacy, then we continue the study.

Kat: Okay, and is this just at MD Anderson right now because it's a phase two study?

Paolo Strati: Yeah, so at this time, it's a single center study just at MD Anderson.

Kat: And what are you hoping to prove during this phase of the study? What needs to be shown for it to move on to phase three?

Paolo Strati: So what we need to be able to demonstrate is meeting our primary endpoint. So the primary endpoint of this phase two trial is efficacy defined as rate of conversion from PR or partial response 30 days after CAR T to a complete response subsequently. The historical rate of spontaneous conversion, so patients without doing anything will go from a PR to a CR, is around 30%. Our goal is to see this going up to at least 60%.

We also need to make sure that there's no added toxicity. So there are some typical side effects associated with the use of loncastuximab, including skin rash, edema, and myeloid suppression. But we need to make sure that their amount and also the onset of other adverse events is not any higher than what we would expect utilizing loncastuximab in another setting. If so, those criteria of efficacy and safety will be met.

Then we will discuss whether either to make this phase two trial larger or looking to a randomized phase three trial where we will compare loncastuximab consolidation to the standard approach that again currently is represented by observation.

Kat: Okay. And what challenges have you had during this study? Or are you expecting to have to reach approval?

Paolo Strati: So I think the main challenge is accrual. And the reason, it's actually a good reason for patients. Again, the first one being that we don't have a lot of patients who are today in partial response after CAR T. Our center in the Anderson is one of the centers with the largest volume of CAR T patients, not the one. But despite that, as we use more and more CAR T in second line, and as we refine our bridging therapy, so the treatment that you do before taking patients to CAR T, we see more and more patients achieving complete remission even before receiving CAR T. So this is decreasing the number of patients who are with active disease going to CAR T and are in PR 30 days later. Again, that's a great problem for our patients. I think it's great because that translates into higher chances of cure.

But that's of course currently the main barrier to acrrual and this trial. But as I mentioned earlier, if once we'll make it to the futility analysis in the next few months, we'll see the using long car T as a consolidation does result into higher rates of conversion from PR to CR without increasing toxicity, then we will most likely open this trial at other sites. Many times for populations performing multi-center trials is the only venue to be able to achieve your accrual goal.

Kat: Thank you. And for our viewers who are obviously patients and maybe new to some of these words, can you briefly explain in a simple term what consolidation is in therapy and also kind of what the regimen looks like weeks wise or how it's done?

Paolo Strati: Yes, thank you. And I should have made this clear earlier. So there are two words that lymphoma patients hear frequently. One is consolidation, and one is maintenance. So in general, we use the term consolidation when at the end of a treatment, either chemotherapy or immunotherapy, biological therapy, CAR-T in this case, we don't have a complete remission. But we just have a partial response. And we want to do something to push the partial to a complete remission. So a treatment done to change a partial to a complete remission is typically called consolidation because you do have a response but it's not complete. So you want to make it better. Maintenance is something different. Maintenance is done for somebody who has already achieved a complete remission and you want to maintain it. You do an additional treatment to make sure that the complete remission is as durable as possible.

Now in terms of duration, it's very durable. It depends on what treatment strategy you are utilizing and that completely changes the schedule. In this specific trial, the consolidation, which is represented by loncastuximab, is given every three weeks for six times.

Kat: And with consolidation, is that always a different drug than they were on with the partial response in general?

Paolo Strati: Yeah, so currently there is no consolidation strategy approved by the FDA for lymphoma patients who receive CAR-T. So this is really novel. To your question, there's not really a standard consolidation strategy that I can share with you. The current approach is observation.

Kat: Wow, that is a big deal then. Very cool. Let's move on to your upcoming study, the phase two study for DLBCL patients. If you could just start with a general summary of that study and where that's going.

Paolo Strati: Yes, I'm very excited about this trial, which is really the first in kind for this patient population. I'll give you some background. I mentioned earlier that CAR-T, or cellular therapy, is currently approved by the FDA for a patient with aggressive B-cell lymphoma. It's not a simple treatment. It's associated with multiple adverse events. Some happen within the first month and they're due to the CAR T cells themselves trying to attack the lymphoma. One is called CRS or cytokine release syndrome, which is mainly fever, and the other one is called ICANS or immune cell associated neurotoxicity syndrome, or more simply neurotoxicity, which is usually difficulty finding words and confusion. Those typically happen within 30 days after CAR T cell infusion and virtually almost never happened beyond that. There are a lot of trials looking into those, trying to minimize and prevent those. So it's not really currently a hot topic of research. What remains hot because it's still an unmet need is cytopenia. About 30% of patients one month after CAR T have very low blood counts. They are severely anemic, severely thrombocytopenic, so low platelets, or severely neutropenic, and low white cells. That's a problem because if patients are in complete remission and they have such low counts, they can have infections that require hospitalization and sometimes can be life-threatening or they require frequent transfusions. Even if they're in complete remission and they're done, they keep coming back to the hospital to get transfusions. So their quality of life is affected. 

For those instead who, unfortunately, don't respond to CAR-T, and they require another treatment, if their counts are low, that can become a major barrier to receiving additional treatment or to be, for example, eligible for clinical trials. These patients can lose their life because they are unable to receive further treatment. So persistent severe cytopenia, or again, very low counts after CAR T, remains a major problem. And there's no currently any standard treatment for these patients. That's why I was mentioning before.

This is going to be a first-in-kind type of trial. Now, for many years, we have thought that the reason for these fatal counts was the chemotherapy that we used before CAR-T, a combination of two drugs called fludarabine and cyclophosphamide. However, over the last several years, with the help of one of my colleagues at MD Anderson, Dr. Michael Green, one of our physician scientists and basic researchers, we have prospectively collected bone marrow samples from these patients, but also from patients who did not develop persistent severe cytopenia after CAR T. And we have analyzed those samples by performing what is called single cell RNA sequencing. So like very deep genetic characterization. And we have been able to identify a very special cellular population in the bone marrow patients who develop persistent severe cytopenia, a population that is not usually present in normal individuals, and that produces a molecule called interferon gamma, which is able to keep counts very low for a very prolonged time. We have been the first to describe the biological mechanism of persistent severe cytopenia after CAR-T. Now, this mechanism is providing a potential target. This mechanism is telling us that by targeting interferon gamma, we may be able to resolve persistent severe cytopenia after CAR T. There is a drug called emapalumab, which is an antibody targeting interferon gamma. It is currently approved by the FDA for a different condition called primary HLH, which is an inflammatory condition. But it could be used also for this patient population, again, because it does target interferon gamma. So I've written this phase two trial where a patients with agressive lymphoma will receive CAR T and independently from whether they are in complete response or no response to CAR T at all, and have persistent severe cytopenia at least one month after CAR T cell infusion. So these patients will be eligible for this trial.
If one month later they're partially better, we can give a second cycle, usually no more than two. And we will also perform bone marrow samples to better characterize the response to this treatment. As I mentioned earlier, this trial is really addressing highly unmet clinical need in the field. We hope that we will be able to activate this trial in May.

This trial will be open to us at MD Anderson. And I do think that it will enroll very quickly. We already have actually several patients lined up for this trial. And I think that if the expectation based on translational data will hold true, we may be able to help a very large patient population.

Kat: Thank you for that explanation. It was very helpful. So different from the other studies you explained to us, this one, and correct me if I'm wrong, the study drug is for the side effects, not for cancer, but for the side effects of cancer treatment, CAR-T.

Paolo Strati: You nailed it. You're right. Which is unusual in the lymphoma space. Most of our clinical trials are focused on making drugs more effective, but you're completely right. This instead aimed at decreasing the toxicity of another treatment, in this case, CAR-T.

Kat: Perfect. And I think that's very relevant for patients. I've heard a lot of patients say that they can't tolerate certain treatments. So as much as the growth of cancer treatment is important, but this is just as important to minimize side effects.

Paolo Strati: Yeah, I completely agree. And again, it's for in both scenarios that we described, patients who, thanks to CAR-T, are in complete remission and potentially cured, but have severely low counts thanks to this drug will have a better quality of life. But also those who don't respond to CAR-T and need another treatment, and as of today, have been unable to receive additional treatment because of their low counts thanks to this trial, may actually even experience a prolongation of their life.

Kat: And is this a drug that can only be used after CAR T therapy or could it be used during as well?

Paolo Strati: So there's another trial that may be open in the next few months, led by Dr. Marcela Maus at MGH, where emapalumab may be utilized earlier during CAR T. Now there are some open biological questions around that. Interferon gamma is also needed for CAR T cells to work. So we need first to understand if it's safe to use emapalumab very early, like within the first 30 days after CAR T.

It's definitely safe afterwards because CAR T cells in lymphoma mainly work the first month. So beyond the first month, their persistence is not clinically relevant and utilizing emapalumab is going to be safe. But before day 30, that remains an open question.

Kat: Perfect. And for this study, the patient population, is it only DLBCL patients or there are other indications?

Paolo Strati: So currently it's only open to patients with aggressive B-cell lymphoma, including, as for the other trial, DLBCL, high-grade B-cell lymphoma, primary minastinal B-cell lymphoma, a transformed follicular lymphoma. But CAR T cells are now approved by the FDA also for other indications, including multiple myeloma and follicular lymphoma. If we see some positive data from this trial, we may expand the trial also to other indications in the future.

Kat: Okay, and the drug itself, did you say it's given orally or through an IV?

Paolo Strati: So it's an infusion at this time. It's an infusion that has been already extensively utilized in another condition, this primary HLH or hemophagocytic lymphoesocytosis, which is typically a pediatric condition. And then sometimes we use off-label, so outside of the FDA label, for secondary HLH in adults. But as of today, unfortunately, it's only available by vein.

Kat: And can you remind us the schedule for that, how often they would get those infusions?

Paolo Strati: Yeah, so despite being by vein, the schedule is quite easy because we give no more than two cycles, or we call one cycle 28 days, and it's only given the first day over the course of a couple of hours. So schedule-wise, it's gonna be very simple.

Kat: Okay, perfect. And then with the bone marrow biopsies that you mentioned, do you have a number of how many those patients who enroll would have to get?

Paolo Strati: So first of all, to make sure that patients are eligible for this trial, they all will need a bone marrow biopsy to be done at the beginning of the study. And that's because we need to make sure that the reason for the low counts is not something else. If we do the bone marrow biopsy and we see a lot of lymphoma in the marrow or leukemia or a bone marrow infection, of course you don't want to get in this trial because the reason for the low counts is something else. So everybody gets a bone marrow biopsy at the beginning of treatment, and then an additional bone marrow biopsy at the end of each cycle. 

So, for patients who receive only one cycle, there will be two bone marrow biopsies, and for those who receive two cycles, three bone marrow biopsies overall. That is actually a relatively small number. Patients who have leukemia or myelodysplastic syndrome will have several bone marrow biopsies. And patients who have this condition, persistent severe cytopenia after CAR T, look very similar to leukemia or MDS patients.

Kat: Okay, do you see bone marrow biopsies being a barrier for enrollment? Do you think some patients wouldn't want to enroll because they have to do those?

Paolo Strati: No, I don't think so. I think, again, patients who have persistent severe cytopenia know exactly what I'm talking about. Their life is miserable. They are here every other day for a blood transfusion, weekly for severe infections. Their life already, unfortunately, looks very similar to the life of patients with leukemia. I don't think that will be a better to enrollment.

Kat: I see, I see that makes sense. Are there any known side effects for this drug or any contraindications that you couldn't have somebody on the trial because of that?

Paolo Strati: Yeah, so in the pivotal trial, so the trial that has brought to the approval in primary HLH, because of the mechanism of action, which is targeting interferon gamma, the main concern was infections. So patients, to be able to get in this trial, they need not to have any active infection, particularly no tuberculosis, no fungal infections, which are infections that are very dependent on interferon gamma.

So if they do, they will not be eligible for this trial. But during the trial, to be safe, weekly, we will check for multiple types of infection, including bacterial, viral, and fungal. I have to say that as we use emapalumab more and more, even at higher doses in HLH, we don't see as many infectious complications as they were described in the original trial. But of course, safety is our priority.

And so as I mentioned, weekly infectious workup will be done for patients who are on this clinical trial.

Kat: And so I know you mentioned that it will be enrolling soon at MD Anderson, correct?

Paolo Strati: Yeah, we hope to activate in May.

Kat: Okay. And what is the timeline look for this phase and future phases? Is it years down the road till this is approved?

Paolo Strati: Yeah, so when it comes to medications for toxicity, the FDA, I have to say, is more sensitive because it's a space where there's not really a comparator. I mentioned at the beginning that there's not really treatment for this specific condition. 

So just to make an example, I mentioned before a side effect of CAR-T called CRS or cytokine release syndrome. This side effect can be life-threatening. And actually, when we started to do CAR-T, now longer than seven years ago, several patients died because of CRS. But we realized with time that the biological mechanism of CRS was driven by a specific molecule called IL-6 , and there's an antibody called tocilizumab that can target IL-6. Now, because this is a very severe condition, as is persistent severe cytopenia, the FDA was able to provide an approval based just on retrospective data. There was not even a clinical trial. So what I'm trying to say is that the bar for approval when it comes to life threatening toxicities from the FDA, fortunately is not as high as for agents that are just trying to improve efficacy. 

This is a phase two trial. Overall, we will enroll 20 to 30 patients. And based on the data that we see, if the overall resolution of cytopenia is going to be really high, I would not be surprised that data would be enough for the FDA for an approval.

Kat: I see. So when you don't have a comparison, because I know in clinical trials where I used to work, we were comparing to the current standard of care and we had to prove that was equal or better. So with this, it's not as difficult, which you're saying, because there is no, there is no competitor at the moment.

Paolo Strati: You're right, as a general concept in clinical research, you always need to run, as I mentioned before, for the efficacy trials, randomized phase 3 trials, where you compare the experimental treatment to the standard treatment. And in general, you will do that even if the standard treatment is no treatment, like observation. But that's if you have the luxury of time and lives. 

When it comes to life-threatening conditions where it's not ethical to just observe, many times the FDA will be okay not having a randomized phase three trial. They may require a larger sample size though. So I wouldn't be surprised if 30 patients is not gonna be enough of course for an approval. We may need to do a larger phase two, but it may be enough due to the nature of this complication for a full FDA approval without a randomized phase three trial.

Kat: I know you said that you're not expecting any difficulty in enrolling patients, which I know is usually the difficult part of trials. Is there any challenges that you see ahead of this that could be difficult when you're doing this phase of the study?

Paolo Strati: No, because again, cytopenia is frequent, 30% of patients and there's no standard option. And even utilizing CAR-T earlier in second line, the rate of cytopenia has not gone down differently from the rates of partial response for the prior trial. Patients are quite miserable. As mentioned earlier, actually, some of them are already lining up in the hope that this trial can activate as soon as possible to be treated. I don't think we'll have any difficulty in completing the trial timely, probably in a couple of years.

Kat: Thank you for sharing. OK, perfect. I think that these trials offer so much hope, even though it might not be tomorrow that they're approved. It's a huge deal for these patients, especially, like you mentioned, that they're miserable, and they're suffering while getting treatment. So we appreciate your work towards this. I know it's not easy.

Paolo Strati: No, I thank you. And actually, if I can make a comment on what you just said, you know, every time I hear what you said, I remember why I moved to this country in the first place, as you can easily guess from my name and accent, I'm from another country, from Italy. When I moved the first time in 2009 to the U.S. I was as an observer, at MD Anderson in the leukemia department. At that time, I used to take care of patients with chronic lymphocytic leukemia or CLL in my country. The treatment was chemotherapy, a combination called FCR. And at time of relapse was a biological therapy and antibody called Alemtuzumab. But unfortunately, it did not work well. It was very toxic and almost everybody would inevitably die. Then I came here at MD Anderson and I was in the clinic of a world renowned CLL expert, Dr. Keating. I would see patients on his clinical trial, patients with CLL were relapsing after chemo, taking a pill, and doing well and living for years and not having any significant side effects or very minor side effects. 

Fast forward years later, this pill is called Ibrutinib and is extensively used not only for CLL but also for other conditions. And it's even shown to be better than chemotherapy as a first treatment. That taught me that being in a country where you can access clinical trials can give you access ahead of time before FDA approval to medications that can completely change your life. I highly value clinical research and I made major life choices to pursue this goal.

Kat: Thank you for sharing that. I know that you probably have so many patients that are grateful for that sacrifice. I know moving away from home would be such a hard thing, but I think it's very admirable that you've done that. That's all the questions I have for you. Thank you so much for joining us. And we're grateful that you were so generous with your time. I know that you have so many patients to visit and that your schedule is very booked. Yeah.

Paolo Strati: Thanks.

Kat: We really appreciate you sharing this expertise and breaking down those trials because they're even hard for me to understand. And I know that the patients, it's comforting for them to understand it better. And we're so excited about what's to come for you this year and would love to have you on for more updates later.

Paolo Strati: Thank you so much for giving me the opportunity to share the results of my completed written trials and upcoming trials. It's truly an honor. And as you mentioned, I'm actually on call today, so I will go back and take care of my patients. Thank you for your time.

Kat: Of course, and thank you for all that you shared with us, and we wish you the best in your clinical practice. Thanks for listening to Health Tree for podcasts for DLBCL and follicular lymphoma. Join us next time to learn more about what's happening in lymphoma research and what it means for you. Once again, thank you to our sponsors, Regeneron and Bristol Myers Squibb, who made this event possible. Have a wonderful day.