Modified Drug Regimen May Reduce Risks in Allogeneic Hematopoietic Cell Transplant Patients

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research in clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic, overseeing our Taussig Phase I and Sarcoma Programs. Today, I'm happy to be joined by Dr. Betty Hamilton, Associate Director of the Blood and Marrow Transplant Program. Betty joined us last year to discuss CAR T-cell therapy, and that episode is still available. She's here today to talk to us about data she presented at the recent American Society of Hematology meeting on preventing graft-versus-host disease. Welcome, Betty.

Betty Hamilton, MD: Thank you. Thanks for having me again.

Dale Shepard, MD, PhD: Absolutely. So maybe you can remind us, what's your role here at Cleveland Clinic?

Betty Hamilton, MD: So I'm currently the Interim Director of the Blood and Marrow Transplant Program. So I help take care of patients undergoing allogeneic transplant for a variety of blood cancers.

Dale Shepard, MD, PhD: Very good. Well, today we're going to talk about graft-versus-host disease. And some data that you've presented. So wide range of people that'll be listening in. So we're going to talk about allogeneic transplants and graft-versus-hosts. So let's start really basic. Remind us, what is allogeneic transplant?

Betty Hamilton, MD: So what allogeneic transplant is, is basically a potentially curative therapy for again, a variety of blood cancers, so acute leukemias, myelodysplastic syndromes, chronic leukemias. And it's our ability to not only deliver chemotherapy to patients, but basically replace their bone marrow. And by using a donor and a donor's new stem cells, which then become a new immune system, we're basically using that immune system to help then fight against the blood cancer. So it's a therapeutic approach to potentially cure some high-risk blood cancers.

Dale Shepard, MD, PhD: Very good. Graft-versus-host, we're going to talk about graft-versus-host disease. What exactly is that?

Betty Hamilton, MD: Yeah, so that is one of the most common complications of an allogeneic transplant. It's when the donor's immune system can potentially recognize the host or the patient's organs and body as different and foreign. So unlike, for example, a solid organ transplant, like a kidney transplant, it's basically the opposite of rejection. It's when the immune system basically matures and becomes the patient's new blood, but can also recognize organs such as the skin, the gut, eyes, mouth, liver, all as different and foreign. So it almost becomes an inflammatory, almost like an autoimmune disorder.

Dale Shepard, MD, PhD: And we'll talk about your study and how toxicity's involved and things like that. Been a while since I did my rotation doing bone marrow transplants. So remind me, what's the current thinking about whether graft-versus-host, although it has morbidity, is actually a good thing?

Betty Hamilton, MD: Yeah, exactly. So I often tell my patients when they come see me for initial consult for a bone marrow transplant that a little bit of graft-versus-host disease is thought to not necessarily be a bad thing, because it also indicates that the new blood system, or new immune system, is strong and active and also fighting against leukemia. So that graft-versus-leukemia effect is very closely tied to the graft-versus-host disease. Sort of the side effect of that graft-versus-leukemia effect is attacking other organs as well.

Now, when we identify a donor, we try to obviously match that donor as best as possible, but it's never a perfect match. Nor do we ever want a perfect or identical match, because again, we want that immune system to recognize bad leukemia cells as different and foreign as well. So a little bit of graft-versus-host disease is not necessarily a bad thing. But severe forms or a lot of graft-versus-host disease can lead to a lot of complications and be associated with a lot of morbidity and mortality.

Dale Shepard, MD, PhD: Let's jump in. Tell me a little bit about the study you reported on.

Betty Hamilton, MD: Sure. So we do use a lot of different methods to help prevent graft-versus-host disease. And for actually decades and decades, even when you were on your bone marrow transplant rotations in training, the standard has always been the combination of methotrexate and a calcineurin inhibitor, which is basically an anti-rejection or immunosuppressive medicine. Most commonly tacrolimus. Occasionally, we also use cyclosporine. But most commonly it's this combination of tacrolimus and methotrexate. And so it's been used over the past several decades. It is associated with several toxicities. So primarily that includes severe mucositis, or mouth sores and throat sores. It can also affect the kidneys and the liver and can be difficult to tolerate.

However, the reason why we continue to use it, and it's still considered the standard, is that despite many trials trying to test different combination of medications, there hasn't necessarily been anything that has shown to be better than tacrolimus methotrexate. Many things have sort of shown similar findings, but every medicine also has their side effects and toxicity. So nothing has been necessarily been shown to be better. So for this trial, our goal was to try to find, and in general, in the transplant field, we're trying to find ways to have the best effect with the lowest toxicity and trying to make our treatments always better tolerated.

So the goal of this study was to evaluate a new regimen, still using these drugs that we know are effective. So using tacrolimus. Still using methotrexate, but a lower dose of methotrexate. And a third drug called mycophenolate, which is another anti-rejection, or immunosuppressive, medicine that is also commonly used in transplant. So basically, then comparing that combination that we know is a little bit better tolerated with the standard doses of methotrexate and tacrolimus.

Dale Shepard, MD, PhD: And so you compare regular methotrexate based regimen, what was referred to as a mini methotrexate regimen, and what happened?

Betty Hamilton, MD: So we took about a hundred patients. We randomized them. So nobody got a choice. A computer told us which group they would be in. And we found that the patients who got the mini-dose regimen, the three-drug regimen, had very similar incidences of graft-versus-host disease. No big, significant differences. But they had a much better toxicity profile. So they had lower rates of mucositis and severe mucositis, of mouth sores, which led to decrease in use of pain medications, decrease in the length of time that their blood counts were low, so faster engraftment. It also led to shorter hospitalization days. And there were some trends. Although they didn't necessarily reach statistical significance, there were trends towards lower non-relapse mortality or mortality related to complications of the transplant. We also found that there was lower kidney toxicity, liver toxicities, lower ICU stays as well.

Dale Shepard, MD, PhD: You mentioned about efficacy and this anti-leukemic affecting things. So since the incidence of graft-versus-host itself was similar, then you wouldn't expect any difference in mortality or effectiveness. Is that safe to say?

Betty Hamilton, MD: Whenever we do any sort of trial and transplant and, in particular, a trial to look at prevention of graft-versus-host disease, all of the things you mentioned are really important endpoints to look at. So we don't just look at graft-versus-host disease. It is incidents of disease coming back or relapse. So it is incidents of survival, transplant-related mortality, and other things like that. So we did look at incidents of relapse and there was no significant difference. The rates were very similar. We also look at more specific things like the severity of graft-versus-host disease. There are actually, we didn't go into this, but two types of graft-versus-host disease, an acute type, which typically happens early on and a chronic type that typically happens later in the course.

And although we, again, didn't show any major statistical significant differences in severe acute GvHD, there might have been a little bit of a trend of increase of severe acute GvHD with the mini-dose regimen. But that did not actually seem to translate into transplant-related complications or non-relapse mortality. It definitely didn't translate into change in relapse. It also didn't change any differences in survival as well.

Dale Shepard, MD, PhD: And certainly, I guess, on a positive side, if you get faster engraftment and less ICU stays, then, I'm guessing, things like length of stay probably improved.

Betty Hamilton, MD: Yes, exactly. So I think it was by a couple days that patients were out of the hospital quicker.

Dale Shepard, MD, PhD: Now, of course, you mentioned that patients go into a trial like this and it's kind of the electronic flip of the coin. Is there a hesitancy on the part of patients? Realizing that graft-versus-host is one of those things that they're probably worried about going into a trial, was there concern on the patient's part about participating, thinking that maybe they would be at increased risk?

Betty Hamilton, MD: I think patients were reassured by the fact that all of these drugs have been used very safely and commonly in transplant, perhaps not necessarily all in combination or in this specific setting, but these drugs are very common in the transplant field. So they were comfortable knowing that. And also knowing the fact that we can certainly do better. When we talk to them about the toxicities of full-dose, methotrexate, the mucositis that we expect, and the other toxicities, they're very willing to sort of try something that might improve things.

Dale Shepard, MD, PhD: Based on this, have you adopted this as sort of the standard moving forward for most patients?

Betty Hamilton, MD: Yeah, that's a great question. So we're in the process of actually evaluating that a little bit more, because there have been a lot of advancements in not only treating graft-versus-host disease, but prevention as well. Just recently, there was an FDA approval of a drug called abatacept in prevention of graft-versus-host disease. And so we're evaluating sort of our practices and sort of the data and literature in all these different settings, but we are moving forward with likely changing our practice to this mini-dose regimen.

Dale Shepard, MD, PhD: Is there a thought that there might be certain groups of patients who would benefit more or less from a high or low dose methotrexate?

Betty Hamilton, MD: Yeah, that's a great point, too. So of note, this trial was only done in patients in myeloablative transplants, meaning that it's high intensity chemotherapy. And that chemotherapy basically completely wipes out the bone marrow. So this type of preparative regimen, or myelo ablative transplant, is typically reserved for younger patients and patients without other medical problems or comorbidities. So certainly, methotrexate is primarily only used in that setting. And so that is the group that we're focusing on. There are different chemotherapy and radiation type of preparative regimens as well. And we know that in particular, for example, in patients with acute lymphoblastic leukemia, we use a preparative regimen that includes radiation. And in particular, those patients have very severe mucositis, the combination of methotrexate and radiation. So that's another sort of subgroup that we definitely are looking for a better regimen and more tolerated regimen.

Dale Shepard, MD, PhD: So the point of this was to try to minimize risk for developing graft-versus-host disease. And you mentioned here a moment ago about maybe better ways to treat it. Remembering back on my rotation days, it seemed like room to room guessing how much steroid to give people. That was kind of the daily event, was how much steroid. What are the newer things that are being developed?

Betty Hamilton, MD: Yeah, amazingly, still, steroids are still the first line treatment for graft-versus-host disease, both acute and chronic. That being said, as a field, we are moving away toward non-steroid approaches, just because we know how much steroids can lead to other toxicities as well and other bad side effects, especially long-term steroids. So in the chronic graft-versus-host disease setting, we now have three FDA approved drugs to treat chronic graft-versus-host disease. That's ruxolitinib, a drug called belumosudil and a drug called ibrutinib. In the acute graft-versus-host disease setting we have one FDA approved therapy, which is ruxolitinib. This is huge for the GvHD world.

So as you remember, we really didn't have any therapies that were FDA approved, ever. And we've been doing transplants for decades now. And it was still very much, how much steroids? Just throw a huge dose of steroids at people and picking and choosing just based on preference and whatnot and not necessarily on data and what the next draw drug to try was. So these are great advancements in the field of graft-versus-host disease, to at least have these therapies that are more accessible to patients and that have good clinical trial data behind them as well.

Dale Shepard, MD, PhD: And so what are the biggest gaps that remain on the prevention side? You said there's a new drug that's approved. Anything else that looks particularly promising in that area?

Betty Hamilton, MD: Yeah. There is another approach that has gained a lot of increasing use. And we also use it. It's called posttransplant cyclophosphamide or posttransplant cy. Now, cyclophosphamide is a chemotherapy drug that's also been around forever. But it was initially used several years ago and has been shown to really be able to prevent graft-versus-host disease pretty effectively, even in mismatched transplants. So it has allowed the field to do what we call haploidentical transplants, or half-matched transplants. And it's sort of overcome our ability to cross that HLA barrier, the barrier when we match donors. That's become an increasingly effective strategy. We use it also now in fully-matched transplants. And again, this is in particular in the setting of reduced intensity transplants. So that is a less intense chemotherapy, typically reserved for older patients or patients with comorbidities.

It hasn't been used as much in the myeloablative setting. So determining really what is the best GvHD prevention approach is one thing. There's currently a bone marrow transplant clinical trials network trial that is close to accrual, but is still undergoing follow up that is comparing posttransplant cytoxin with tacrolimus methotrexate in that reduced intensity setting. So that is potentially going to create a new standard of care. Trying to balance the graft-versus-host and graft-versus-leukemia effect is sort of the holy grail of transplant. So always trying to improve on preventing graft-versus-host disease without affecting graft-versus-leukemia effect and something that's well tolerated.

And then also, being able to choose best treatments. Even though we have new therapies that are FDA approved, having a straightforward algorithm or knowing what drug is going to work in what patient and understanding when to sort of start that treatment, they're all sort of unanswered questions or questions that we're trying to still do trials around.

Dale Shepard, MD, PhD: Yeah. So, I guess, to that last point, that was what I was going to ask next is, certainly, you want as a good a match as possible. But are there any other patient factors, or treatment factors, or disease factors, or anything else that is particularly predictive right now of who's most at risk?

Betty Hamilton, MD: Yeah, absolutely. So, as you mentioned, the probably biggest factor is degree of match. That is now being mitigated by strategies like this posttransplant cytoxin. We also know that the graft source, whether it's straight from the bone marrow from the donor or mobilized with peripheral blood cells, called peripheral blood stem cells, we know that peripheral blood stem cells are a risk factor for increased chronic graft-versus-host disease. It is somewhat of an easier stem cell source or an also increasingly used stem cell source. And in particular, because of COVID that their use has also greatly increased, because when you'd use peripheral blood stem cells, you're able to cryopreserve, or freeze, those cells for use, just to ensure that we have a donor stem cell source.

So there are many reasons why we continue to use peripheral blood stem cells, despite the fact that we know it leads to increased chronic graft-versus-host disease. So there are some risk factors that we know of.

Dale Shepard, MD, PhD: Very good. Any other particular areas of excitement in this area? What are you looking forward to?

Betty Hamilton, MD: Yeah, I think the biggest thing is really continuing to understand the biology of both acute and chronic graft-versus-host disease. Back in the day, it sort of was a pick-and-choose in trying to determine what the best treatments and best prevention strategies are. It wasn't always based on sort of understanding how graft-versus-host disease develops. And I think as a field, we're continuing to try to base our clinical trials on the biologic development of graft-versus-host disease. And we have now more standard guidelines of grading graft-versus-host disease, criteria for response. And so this also allows for more robust and more standard clinical trial design to allow for the development of new drugs and testing on them.

Dale Shepard, MD, PhD: That's great. Well, it looks like there have been some big advances since my rotation days. So you've provided some great insights. And thanks for being with us.

Betty Hamilton, MD: Thanks. Thanks for having me.

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