Non-Steroid Treatments Lead Progress in GVHD Management

The emergence of non-steroid treatment options is among one of the greatest developments made in graft-versus host disease (GVHD) in recent years, according to Jeanne M. Palmer, MD, and ongoing biomarker research efforts continue to push the envelope.

“With treating [patients with] GVHD, one of the most exciting developments is the use of non-steroid treatments for patients low-risk acute disease, so adding sirolimus (Rapamune) as opposed to adding steroids,” said Palmer. “For those with steroid-refractory GVHD, we had our first drug approved, which was ruxolitinib (Jakafi); this has had some very promising activity in patients, although it does come with certain toxicities. Regardless, it's definitely worth accepting those toxicities in light of the benefit achieved with this agent. For chronic GVHD, we have our first FDA-approved drug, ibrutinib (Imbruvica), which works with B-cell inhibition. This has a great role in reducing the need for steroids and creating responses in patients.”

Biomarkers might possess the potential to further understand which patients are at increased risk for treatment-related mortality, as well as which patients might be appropriate candidates for steroid-free options, according to Palmer. Although these efforts appear to show promise, more research is needed before these markers can be utilized in clinical practice.

In an interview with OncLive^® during the Institutional Perspectives in Cancer webinar on Leukemia/Lymphoma, Palmer, a hematologist and oncologist in the Bone Marrow Transplant Program at Mayo Clinic, discussed advances made with non-steroid treatments in GVHD and how biomarkers such as ST2 and REG-3 alpha might help to inform future treatment decisions.

OncLive: Could you discuss the incidence rate of GVHD in patients with cancer following transplant and the mechanisms behind why some develop it?

Palmer: When we look at acute GVHD, depending on factors such as the conditioning regimen, the patient's age, GVHD prophylaxis, approximately 40%-50% of patients who undergo transplant will have some form of the disease. Different [factors] can predict GVHD, such as the donor and the degree human leukocyte antigen matching. However, the most challenging aspect is even if you take a perfectly matched donor undergoing a transplant, half of patients will get it and half won't. [Beyond that], there isn't a lot else that we can do to predict [who will get this condition]. Investigators have tried to examine numerous markers to determine how we can predict who will have GVHD and who will have the best donor. From the pre-transplant setting, however, there is not too much that can be done to predict for it other than looking at the [aforementioned factors], most of which are not controllable.

In chronic GVHD, the occurrence is a little less understood; 30% to 70% [of patients will experience chronic GVHD]. This is also something that can vary quite a bit in terms of conditioning regimen; different manipulations can be made at the time of transplant that may help to reduce the risk of chronic GVHD. Although, this remains somewhat controversial

because some feel that by doing these manipulations up front, even though you reduce the risk of chronic GVHD down the road, you may also reduce the effect of this new immune system or the graft to actually work against the disease. Not much else [can be done beyond this] to predict or prevent chronic GVHD.

What biomarkers are currently being investigated in GVHD?

The use of biomarkers in GVHD disease has been in the works for over a decade. This research started with investigators doing proteomics. A couple of transplant programs had the forethought to say, ‘Let's save samples [from] patients getting transplanted at day 7, 14, and 28, and so on’ They then asked, ‘What can we use at certain time points right after a patient gets transplanted to help predict their outcome?’ That's what started this research and a couple of different biomarkers came to light as a result. The first one was ST2, which is a suppressor of tumor genesis and a soluble receptor for interleukin-33. This marker was found when looking early post-transplant and it predicts long-term, non-relapsed mortality. From the standpoint of our day-to-day practice, we're not ready to use that in a routine fashion.

The Mount Sinai Acute GVHD International Consortium, is a group led by James L. Ferrara, MD, DSc, who has done an amazing amount of work in this field. This has looked at different biomarkers at GVHD diagnosis and at different time points after starting therapy for the disease. Several different timepoints can be looked at in that setting. The first one would be at initiation of GVHD. What these biomarkers aim to do is add to the clinical risk that is assessed and make it more granular in saying who is at risk of having more or less treatment-related mortality. This leads to the idea of avoiding steroids and using other medications because if you can appropriately assess risk, you might be able to determine which patients this might be appropriate for. Using biomarkers at that time to determine how the treatment should go is not quite at primetime, but it’s a really interesting concept and one that I’m looking forward to seeing the development of.

Some ongoing studies would suggest that if someone has high-risk GVHD based on these biomarkers, maybe we need to start with 2 agents up front rather than just 1. When it comes down to what we know, biomarkers, especially those like ST2 and REG-3 alpha, are very helpful in predicting how patients will do with GVHD. [These markers might also influence] whether one should change treatment, either downgrading the treatment to make it less aggressive versus upgrading it and making it more aggressive. However, we still have a little bit more to learn about this. More information is always better to be able to help assess risk and determine treatment for these patients.

If a patient does present with GVHD what treatments are available? Do these options vary between acute versus chronic disease?

The first-line treatment is almost universally steroids. A couple of situations exists for which that may not be the case. Recently, really interesting data have come out indicating that in you may be able to spare using steroids and use another immunosuppressant in patients who have

lower-risk acute GVHD, which is actually kind of exciting. The mainstay up-front treatment is steroids, which can be either methylprednisolone (Solu-Medrol), which can be given intravenously, or prednisone (Rayos) given as a pill. Generally, we start it anywhere between .5 mg/kg to 2 mg/kg dosing, and that dose is gradually tapered off over time as long as the patient shows a response. If after 3-5 days you do not see an adequate response, then they have steroid-refractory GVHD; this is a more challenging group of patients to treat.

For acute GVHD, when patients are considered steroid refractory, there are many different second-line treatments, but none have really been shown to be superior. Recently, however, we actually saw an FDA approval for a drug for acute GVHD, which is really exciting because there has never been approved drugs for this disease. Investigators have used ruxolitinibin acute GVHD, which has an interesting history because it was initially used for JAK2-positive myeloproliferative diseases. As such, investigators created this JAK inhibitor, hoping that they would be able to eradicate this disease, similar to what we do with the TKIs in chronic myeloid leukemia. However, they found that the agent doesn't actually take away the full disease, but the pathway that it blocks is very involved in inflammation. By blocking inflammation, it mediates some of its effects for the myeloproliferative diseases. This blocking of the inflammation is actually very critical in treating GVHD, so when we look at second-line treatment, this is probably one of the first times that a multicenter, randomized study showed a benefit with a second-line therapy, which is pretty exciting.

For chronic GVHD, that's a little bit different in terms of the tempo. You want to start [out] treating with steroids, but you really don't want to have someone on long-term steroids. Even if you get patients to respond beautifully to treatment with whatever front-line [regimen you use], whether that’s steroids or steroids plus another agent, the majority of patients you won’t be able to get off the drug without having to add something new. Steroids have many different toxicities such as weight gain, increased risk of infection, and metabolic disturbances, such as diabetes, which causes osteoporosis. Because of these complications, the goal really is to get patients off steroids at some point and use a second-line agent.

For that, so many different agents have been used. However, this is another setting where have had another FDA-approved drug in the past 2 years: ibrutinib. This agent is currently approved for use in the frontline setting for chronic lymphocytic leukemia (CLL) and it works by blocking certain pathways and B-cell activation, which is a component of the immune system. Clearly, other effects occur because we know it takes many other cells besides B cells to create chronic GVHD, but that is one of the settings where ibrutinib can have benefit, hence leading to the FDA approval.

What are some of the biggest challenges faced in GVHD management that future research efforts should be focused on?

When a patient has acute GVHD of the skin, we generally can see fairly good recovery. The gut, however, is a very challenging organ to treat. When patients have really bad GI GVHD, they get all the inflammation, sometimes they'll get denuding of the intestines, and then it takes a very

long time to heal. When this happens, patients experience continuous diarrhea, which is how we monitor GVHD. As we're treating someone, sometimes we don't know whether they have ongoing GVHD or if this is a failure of the gut to recover the lining. Understanding that process, being able to define whether there's ongoing inflammation versus a problem with regard to healing of the gut is an important thing. To this end, investigators are examining different strategies to enhance healing of the gut.

One such thing is beta human chorionic gonadotropin; even though it is used for fertility and pregnancy, there is actually a lot of EGF in there. There is some thought that by providing that to patients, you may enhance healing of the intestines. I know investigators have also examined the use of lithium to achieve this goal; I don't think that is anywhere near ready for primetime, but is certainly a really interesting approach because the healing process of the gut is so critical. What ends up happening a lot is you don't know whether their gut is still having diarrhea because they're not healing or because of ongoing inflammation.

With chronic GVHD, the big challenge is that by the time someone starts presenting with symptoms, scar tissues often develop. If we consider some of the hallmark symptoms of chronic GVHD—dry eyes, mouth ulcers, skin and joint tightness, and sclerosis of the joints—the problem is that once a patient develops scar tissue, it's very hard to reverse it. As such, patients often end up with long-term disability. In trying to understand and differentiate who has active problems warranting immunosuppression versus who has ongoing scar tissue that probably won't be impacted by what you do, is a really critical piece to try and differentiate.

What is your advice for your colleagues treating patients with GVHD?

Biomarkers [can be used to] identify who is going to be at higher risk of non-relapse mortality versus who's not. We're not at the point where we can say, ‘We can use these markers to predict how we're going to treat someone,’ but I do believe that these markers can help us decide as we're choosing second line therapy how quickly we want to activate it. These markers are definitely something we're going to see more of. Although there's a lot more to understand, there are already some really compelling data that show that biomarkers can be helpful.