Latest FDA Approvals for Patients With Steroid-Refractory Graft-Versus-Host Disease

Yi-Bin Chen, MD, Massachusetts General Hospital, Boston, Massachusetts, provides insight into the latest FDA approvals for the treatment of patients with acute and chronic graft-versus-host disease (GVHD), including ruxolitinib, and ibrutinib and belumosudil.

Transcript:

Hi, my name is Dr. Yi-Bin Chen. I direct the Hematopoietic Cell Transplant and Cell Therapy Program at Massachusetts General Hospital in Boston. I've been on staff for 15 years. I am a clinical researcher and I spend a good deal of my time taking care of patients undergoing both autologous and allogeneic transplantation. My research has been in conducting clinical trials to try and improve the outcomes of patients both undergoing autologous and allogeneic transplant. The areas that I've conducted trials in have spanned out of defining conditioning regimens for autologous transplant, looking at reduced intensity regimens for allogeneic transplant, and most recently incorporation of maintenance therapies after allogeneic transplant to prevent disease relapse and of course looking into novel agents for the prevention and treatment of graft-versus-host disease. In today's session, we'll be discussing a recent manuscript in The Oncologist, published by myself and my co-authors, first author Dylan Martini and last author is Zachariah DeFilipp, also at Mass General working with me on the recent FDA approvals in both acute and chronic graft-versus-host disease.

OLN: What is graft-versus-host disease (GVHD)?

Allogeneic transplantation is undertaken for a variety of malignant and non-malignant causes. However, the most common indication is for a hematological malignancy. In any allogeneic transplant, there is chemotherapy and/or radiation given prior to the transplant and that does have a disease modifying effect. However, most of us in the field believe that the predominant mechanism of action is an immunological graft-versus-malignancy effect. Meaning the donor cells eventually can attack or eradicate any residual malignancy that is left behind in the recipient. And this immunological graft-versus-malignancy effect is a predominant mechanism for why we think allogeneic transplantation works. It's the purest and the oldest form of immunotherapy, if you can think about it in that way. The problem with that mechanism is that there is a risk of what we call graft-versus-host disease, meaning that the donor cells not only attack the patient's malignancy, but also can potentially attack the patient's healthy body.

The attack of a patient's healthy body by the donor cell or the donor's immune system is graft-versus-host disease. Graft-versus-host disease can come in two flavors. There's acute graft-versus-host disease, which tends to happen earlier and chronic graft-versus-host disease, which is a bit more indolent and happens later. We tend to not distinguish them so much by timeframes these days, but by clinical manifestations. Acute graft-versus-host disease generally involves the skin, the intestinal tract, or the liver with the skin and the GI tract being the most common. Chronic graft-versus-host disease is a bit more heterogeneous and can involve almost any organ in the body. Most commonly the eyes and the mouth in a dry sickle syndrome type of presentation. The skin rash is a bit different than acute graft-versus-host disease and it's much more scaly, resembling psoriasis or eczema. And the other common organs involved, the joints with the most serious manifestations, being the fascia presenting as scleroderma, or the lungs in a syndrome called bronchiolitis obliterans.

What is the current treatment landscape for graft-versus-host disease?

Every patient receives some form of prophylaxis or prevention against graft-versus-host disease. Yet, even receiving that prevention, there is a certain percentage of patients who will still develop acute or chronic graft-versus-host disease that requires systemic therapy. If you look at modern series, certainly the incidences are quite variable, but in general, probably about 30% to 35% of patients will develop acute GVHD that requires therapy and probably 40% to 45% of survivors will develop chronic that requires some form of systemic therapy.

Unfortunately, the standard treatment for both acute and chronic graft-versus-host disease for the last few decades has been systemic steroids, meaning in the oral form, prednisone or in the IV form, usually methylprednisolone, if you're an inpatient and a bit sicker. Steroids were developed because traditionally we viewed graft-versus-host disease as what it was: an immunological attack by the donor on the recipient. The initial therapy being steroids was developed to suppress that effect and knock down the donor's immune system to hopefully treat the graft-versus-host disease. Over the last couple of decades, there have been a variety of agents that have been proposed and tried to improve upon that therapy, be it either to help or replace steroids as frontline or to treat patients who have what we call steroid refractory acute or chronic graft-versus-host disease respectively. And it hasn't been until recently that we've been able to say that we've made progress with approvals in both of those settings.

What are the recent FDA approvals for GVHD?

In steroid-refractory acute graft-versus-host disease, we have now 1 approved agent, which is the JAK1/2 inhibitor ruxolitinib. Ruxolitinib, we in the hematological malignancy world have known for years, given it has been approved for the treatment of myeloproliferative diseases, or myeloproliferative neoplasms. Years ago we realized that the primary effect of ruxolitinib in myeloproliferative neoplasms was actually its broad anti-inflammatory effect, as many mediators of inflammation signal through the JAK stat pathway. So ruxolitinib, which blocks JAK1 and JAK2 signaling, was a very powerful anti-inflammatory agent. Early studies in mice suggested that inhibition of JAK1 and JAK2 could have a very powerful effect in graft-versus-host disease. And because the drug was available commercially, many colleagues attempted to use it for patients who had no other options. And the first case series that came out showed impressive response rates to ruxolitinib for both steroid refractory acute and chronic graft-versus-host disease.

The makers of ruxolitinib, Incyte, sponsored a large clinical trial mostly conducted in the United States called the REACH-1 trial, which enrolled about 70 patients with steroid refractory acute graft-versus-host disease and studied the use of ruxolitinib in this setting. The response rates were very impressive. Over 50% overall response rate in this setting and did not show any significant safety signals. Many of these patients were quite sick and complications do occur to these patients during this treatment time. Based on the results of the REACH-1 trial, ruxolitinib was FDA approved for the treatment of steroid-refractory acute GVHD. Incyte then undertook the REACH-2 trial, which was an international study, which was a randomized study for patients with steroid refractory acute GVHD comparing the treatment of ruxolitinib to a control, which was called BAT or Best Available Therapy. They couldn't pick just 1 control because there was no 1 accepted standard for the treatment of steroid refractory acute GVHD. It was more a dealer's choice, and they gave several options that were accepted as the standard treatments.

That randomized clinical trial, which is quite rare for graft-versus-host disease, confirmed the results of REACH-1, showing the superiority of ruxolitinib to best available therapy. Because of the results of these 2 trials and our experience of ruxolitinib thus far, I would say that ruxolitinib has become a standard, if not the standard, for the treatment of steroid refractory acute graft-versus-host disease. That's not to say there isn't room for improvement. If you look at the REACH trials, certainly there are patients with significant lower GI disease at the time of starting ruxolitinib. Still, it's only a minority of patients who have a durable remission from their disease, and novel agents are sorely needed to help those patients. I think a lot of people look at the use of ruxolitinib and how safe and effective it is thus far, and also are interested in moving ruxolitinib to earlier in the course, either using it with the initial therapy for acute graft-versus-host disease or even in prevention and we look forward to those efforts.

What is significant about the FDA approvals for chronic GVHD?

The initial therapy for chronic graft-versus-host disease has also remained systemic corticosteroids for the last couple of decades. The dose is admittedly less than in acute. In acute, we usually think of the standard dose as 2 mg/kg of prednisone per day. And in chronic it's much less being about 1/2 to 1 mg/kg per day of prednisone, or its equivalent. Adding steroids for chronic graft-versus-host disease has a lot of morbidity. Many of these patients had had prior acute and had long course of steroids already. Many of these patients are frail and have experienced the toxicity of complications prior. And steroids do a number on not just the immune system, but on bones, on inducing diabetes, on hypertension, mood symptoms, body dysmorphia, and so forth and so it's really been a big push for us to find alternatives to steroids thus far. It's not until recently that we've succeeded.

Now, very excitingly, we have 3 agents that are approved for the treatment of steroid-refractory chronic graft-versus-host disease. Back several years ago, ibrutinib, the oral BTK inhibitor, which is approved for a variety of B-cell lymphomas, was the first agent approved in this setting. This was approved on the strength of a single-arm 42 patient trial showing impressive overall response rates as well as even some complete response rates to using ibrutinib. On the strength of that trial, ibrutinib was approved by the FDA for the treatment of steroid refractory chronic graft-versus-host disease. A recent trial in pediatrics has extended that approval to not just adults, but also pediatric patients as well. I think in the real-world setting, we've been less impressed with the activity of ibrutinib, partly because those 42 patients had a highly selected study eligibility, and ibrutinib is also a bit more toxic in terms of side effects as well as effects on the immune system than our other alternatives. Yet it still remains an option.

The B-cell pathway is clearly activated in a certain subset of patients with chronic graft-versus-host disease. The 2 more recent approvals involve one is belumosudil and the other is ruxolitinib. I'll talk about belumosudil first. Belumosudil is an oral ROCK2 inhibitor. It was approved last year for the treatment of steroid-refractory chronic graft-versus-host disease in patients 12 years and older. It is officially approved for patients who have failed 2 lines of therapy, though many of us are eager to move it up to either second-line or even first-line therapy. The ROCK2 cascade is thought to be fairly important in the process of fibrosis, which is the pathological hallmark of chronic graft-versus-host disease. Specifically, the 2 most serious manifestations are scleroderma and bronchiolitis obliterans, which are both very fibrotic diseases.

Belumosudil was approved on the heels of the pivotal ROCKstar Study, which was a large study that was studying 2 different doses of belumosudil. Overall results from that entire cohort of patients showed an overall response rate of greater than 70%, with the vast majority of those responses being partial responses as one would expect in chronic graft-versus-host disease, though a vast majority of patients who responded also had significant improvements in their quality of life. It's a very well-tolerated drug. There is a signal of liver function test elevations in a small subset of patients, but otherwise it is very well-tolerated. I think most of us feel that once starting it, we should give it at least 3 to 6 months to try and see if it is working. It's tough to know the actual kinetics, and we look forward to the real-world experience of this agent as we use it more.

The most recent approval in steroid refractory chronic graft-versus-host disease was ruxolitinib. Ruxolitinib, as we discussed, was first approved for the treatment of steroid refractory acute graft-versus-host disease based on that REACH1 and REACH2 studies. REACH3 was a large study, which randomized patients with steroid refractory chronic graft-versus-host disease to either ruxolitinib, or again, a control of best available therapy as there's no agreed upon control for steroid-refractory chronic graft-versus-host disease. REACH3, again, showed a significant benefit for ruxolitinib over best available therapy. Primary response rate was assessed at 24 weeks after therapy showing about a doubling in the response to ruxolitinib compared to best available therapy.

There's also a very significant advantage in failure-free survival, this composite endpoint, which has become fairly important in trials for chronic graft-versus-host disease. It's very exciting to have these 3 agents now, whereas 5 years ago we had 0 agents approved for steroid refractory chronic graft-versus-host disease. In general, as you can see, the field has moved towards less global immune suppression for the treatment of graft-versus-host disease as clearly that wasn't helping our patients, and was probably harming them from toxicities and opportunistic infections and more towards agents which have specific pathway suppression.

Hopefully this progress certainly will help improve the outcomes for our patients. I think we're all seeing that in the clinic already. I think many of us are excited to now take these agents, and again, move them up earlier in therapy either in frontline therapy with steroids or possibly even to replace steroids for certain subsets of patients, or even to use them in either the prophylactic or the preemptive setting to prevent the development of acute or chronic graft-versus-host disease to begin with.

Will there be an immediate impact of the recent FDA approval of ruxolitinib in real-world practice?

The approval of ruxolitinib in steroid refractory chronic graft-versus-host disease—I don't think it changed practice all that much for a lot of us. Many of us had already known that ruxolitinib was effective in chronic graft-versus-host disease and had access to the agent because it was commercially available, and also approved for steroid-refractory acute graft-versus-host disease. I think what it changed was that it widened the access for many patients whose payors now would actually cover ruxolitinib for that diagnosis.

I think it didn't change what we all wanted to do practically, but it allowed us to do what we wanted to do. Ruxolitinib has been our standard for steroid-refractory chronic graft-versus-host disease for a few years now based on the publications we knew of as well as our own experience. Access to the other agents is certainly very helpful, and belumosudil and ibrutinib are used, but we generally use those after ruxolitinib has not succeeded.

What do you see in the future for graft-versus-host disease?

Looking forward, I think there is still a lot of room for improvement in acute graft-versus-host disease. The progress we made, I think we definitely have developed regimens that are better at preventing acute graft-versus-host disease and we're better at caring for patients. Not just with improved therapy, but supportive care in general, so patients are surviving more after that complication. Still, I think there is room for improvement to develop more agents in patients who develop, especially lower GI graft-versus-host disease. I think the general movement towards focusing on organ resiliency is really exciting. Many of us are eager to see the results of those efforts.

In steroid-refractory, chronic graft-versus-host disease or chronic graft-versus-host disease in general, we now have multiple agents. We don't know how to sequence them. We don't know how to use them in combination. We don't know how to taper or stop them if they're not working and all this needs to be flushed out in real-world experiences. I think the priority should be a few things. First is to develop biomarkers or a system to better predict which patient will respond to which therapy. That's number 1. Number 2 is to develop a system to risk-stratify patients that's beyond clinical manifestations, and to start to conduct risk-stratified chronic graft-versus-host disease trials as we've done in acute. And 3 is to move towards trials that can replace steroids. So, defining a phenotype that we would be comfortable using novel agents, either alone or in combination, to replace steroids entirely so we can avoid the morbidity from such.

It's a really exciting time for GVHD and I think all of us are buoyed by these approvals, and are really excited to continue conducting these clinical trials.

Source:

Martini DJ, Chen YB, DeFilipp Z. Recent FDA approvals in the treated of graft-versus-host disease. The Oncologist. 2022;27(8):685-693. doi:10.1093/oncolo/oyac076