
Yi-Bin Chen, MD, director, BMT Program, Cara J. Rogers Endowed Scholar, Massachusetts General Hospital, associate professor of medicine, Harvard Medical School, discusses risk factors for developing chronic graft-vs-host disease (cGVHD) in patients who receive an allogeneic transplant.

Certain factors, such as older age, male patients who receive a graft from a female donor, and the transplant platform, increase a patient’s risk of developing cGVHD, Chen explains. Utilizing myeloablative conditioning therapy, particularly with high-dose total body irradiation, instead of reduced-intensity or nonmyeloablative therapy also increases the risk of a patient developing cGVHD.

Additionally, the type of donor and the graft source influences a patient’s risk of developing cGVHD, Chen says. Data from randomized studies have shown that grafts with peripheral blood stem cells are associated with a higher incidence of cGVHD vs bone marrow or cord blood. However, with the latter options, early complications can arise that require management, Chen adds. Notably, the development of acute GVHD is the biggest risk factor for developing cGVHD.

Ultimately, prevention of cGVHD is critical. Including polyclonal anti–T-cell globulins, such as ATG products, and ex vivo manipulations, such as T-cell depletion, reduces the incidence of cGVHD, Chen says. A post-transplant, high-dose, cyclophosphamide-based GVHD prevention strategy is an additional, novel approach to mitigate cGVHD risk.

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Yi-Bin Chen, MD, discusses risk factors for developing chronic graft-vs-host disease in patients who receive an allogeneic transplant.  



Dr. Chen on Risk Factors for Developing cGVHD 

Joyce L. Neumann, PhD, APRN, AOCN, BMTCN, FAAN, program director, Stem Cell Transplantation and Cellular Therapy, adjuvant ethicist, Section of Integrated Ethics, The University of Texas MD Anderson Cancer Center, discusses tapering steroids for patients with chronic graft-vs-host disease (cGVHD).

Depending on a patient’s disease presentation, a newer agent, such as ruxolitinib (Jakafi), may be introduced to the treatment plan to control symptoms while the patient is receiving steroids as bridging therapy, Neumann explains. In those situations, the steroids may be tapered more quickly than if steroids were being given as a primary treatment. However, as the patient begins the novel agent, the steroids may be slowly tapered to avoid abruptly stopping a treatment, Neumann adds. 

Ultimately, tapering patients off steroids is a main goal of treatment for cGVHD, but patients who abruptly stop steroids may have a cGVHD flare, Neumann explains. Sometimes, cGVHD can be controlled with minimal interventions, but during a flare, the patient can develop symptoms quickly.

Utilizing low-dose immunosuppressant agents is necessary in cGVHD as infections are associated with a high risk of morbidity and mortality in this patient population, Neumann concludes.

Joyce L. Neumann, PhD, APRN, AOCN, BMTCN, FAAN, discusses tapering steroids for patients with chronic graft-vs-host disease.



Dr. Neumann on Tapering Steroids in cGVHD 

The variability in symptomatic indicators of chronic graft-vs-host disease (cGVHD) emphasizes the need to closely monitor patients posttransplant for signs of cGVHD development, said Joyce L. Neumann, PhD, APRN, AOCN, BMTCN, FAAN, adding that the field is continuing to learn how to optimize frontline corticosteroids amid novel, FDA-approved second- and third-line options.

“cGVHD has been sometimes described as an ember where sometimes it flares up and quickly causes a lot of symptoms. Other times, it is this small ember that is there for a period, sometimes years, but we can control it with minimal intervention,” said Neumann, program director of Stem Cell Transplantation and Cellular Therapy at The University of Texas MD Anderson Cancer Center.

“Immunosuppression is always the main stumbling block in terms of controlling GVHD because infections can also be a high-risk factor for morbidity and mortality. We try to minimize [the risk] and manage [the disease] with low-dose immunosuppressant drugs,” Neumann added.

, Neumann discussed the variability in cGVHD presentation, key symptoms of the disease in patients with cancer, and how the field is navigating between available therapies.

: What are some symptomatic indicators that a patient may have developed cGVHD?

: The changes related to cGVHD that we see are much different than [those seen with] acute GVHD [aGVHD]. Although the skin, liver, and gastrointestinal [GI] tract can be involved [in aGVHD], they tend to be much more subtle at onset [than in cGVHD]. It’s important for clinicians and providers to realize what some of those early signs might be.

Related to skin, instead of the typical erythematous maculopapular rash that we see with aGVHD, [cGVHD can have] changes related to the texture, thickness, or sense of the skin in terms of scleroderma-type changes. It can also be changes to the surface of the skin, such as drop-out of pigment or hyperpigmentation.


Several different changes can occur in the GI tract. [cGVHD can also be characterized by] malabsorption syndrome or, typically for aGVHD, diarrhea or another GI malady.

Almost every organ system can be involved in cGVHD. Sicca syndrome is where there is dryness of the eyes and mouth. Vaginally, there can be dryness as well, in addition to the dryness that some women experience posttransplant with the decrease in estrogen. The lungs can also be affected, so almost every organ in the body can be [affected] by this type of change in the immune system.

Is there a diagnostic tool that can confirm cGVHD or is diagnosis based on clinical symptoms?

There are some diagnostic [tests] that we can do. For example, we may do a skin biopsy or a GI biopsy. Sometimes it is a clinical implication, so that examination is a key. However, we also have pulmonary function tests that are essential for diagnosis of lung GVHD. We also have scanning and imaging that can be helpful in making the diagnosis.

What resources are available to patients to ensure they understand potential symptoms of cGVHD?

It is just the recognition of those changes that can occur, and they can occur over time. It takes knowledge of what to examine for. Patients need to be educated on what some of those signs and symptoms are, and we try to do that before they even leave our transplant center. We also provide them with documents and education for their providers in the community if they don’t live in our area so that their providers can contact and consult our GVHD experts and stem cell transplant physicians.

Is there anything that can be done to minimize the risk of a patient acquiring cGVHD after transplant?

This is where the science has changed over the years, and [we have seen] some important changes. We recognize now that the type of donor we have can affect [the likelihood of a patient developing cGVHD], just like aGVHD and its incidence. All factors related to donor selection, whether it is a haploidentical, cord blood, or matched unrelated with the registry, can minimize [the risk of cGVHD]. Certainly, the prophylactic treatment for GVHD [is a factor]. When do we take patients off [prophylactic treatment]? Unlike a solid or organ transplant patient, our patients [who undergo stem cell transplant] can eventually come off most immunosuppression, which sometimes keeps the GVHD in check.

Recognizing that tapering has to occur rather than abrupt changes [is important]. The recognition of what may appear to be GVHD after those immunosuppressive agents are tapered off [is also critical].

Some of the things that can minimize [the risk of cGVHD] is patient education about healthy living, avoiding sun exposure, and other things that could perhaps set off a GVHD sequelae.

Similar to aGVHD, donor selection is probably the key, as well as what we are using for prophylactic immunosuppression to prevent GVHD.

How have initial therapeutic options changed in cGVHD?

We’ve been very fortunate over the past several years. The gold standard has always been steroids, perhaps on top of immunosuppressive drugs like tacrolimus or sirolimus. However, we all know that steroids produce a lot of different toxicities and problems. We’re fortunate in that there are new agents are now on the market that have come out over the past few years. They have been FDA approved. [The new agents] affect the immune system in a different way to our typical immunosuppressants.

Ibrutinib [Imbruvica] was the first on the market for cGVHD, followed by ruxolitinib [Jakafi]. The newest agent is belumosudil [Rezurock], which is approved for cGVHD. We are looking at those agents in terms of their safety profiles. We participated in some of the initial studies of those drugs, so it is exciting to see other options.

Extracorporeal photopheresis [ECP] has been an option for the treatment of [patients with] cGVHD; however, between a central line placement and [the need to be] close to a center that does ECP, that treatment has been burdensome and expensive for our patients. We are excited by the new agents that are now available.

You highlighted that steroids are associated with their own unique toxicities and burdens. If a patient is experiencing steroid-related toxicities, do you taper the steroids or jump immediately to one of the newer agents, such as ruxolitinib?

Depending upon presentation, we may start to get a quick start on controlling the signs and symptoms of cGVHD by starting the newer agent while using steroids as a bridging agent. Then we taper [the steroids] more quickly than we might have done in the past. As we add the newer agent, we might slowly taper the steroids. Getting patients off steroids is one of the first things that we try to do when we are managing cGVHD, but we don’t usually do anything abruptly because we know patients can flare.

With agents like ibrutinib, ruxolitinib, and belumosudil approved, is there any utility for off-label use of agents like rituximab (Rituxan), for example?

We had been using rituximab in the past with some success. It’s a weekly infusion, usually given 4 times. It is not our first go-to drug because, again, if patients are from out of town, it can be difficult to coordinate intravenous treatment over that 4-week period. However, we have used rituximab.

With ibrutinib and ruxolitinib approved for the same indication, how is the field selecting between the agents?

That’s a good question and it’s been more about the safety profiles. If the patient has low blood counts and the graft is somewhat difficult to control to keep those counts in a normal range, we might go with 1 drug vs the other. Although some of them have the same toxicity profile, we [ask questions like]: How are patients tolerating the drug? Does it cause toxicities like diarrhea or pancytopenia in addition to dropping counts?

[Treatment selection is made on] an individual basis, but as a rule, we are looking to set some standards or guidelines for our patients.

What was observed from the phase 3 REACH2 trial (NCT02913261) regarding the differences in responses by grade with ruxolitinib? What questions remain with ruxolitinib that need to be answered?

The difference has to do with the safety profiles and how the dosing affected some of those adverse effects. Ruxolitinib has been a major benefit for patients, but we are [parsing out] dosing and assistance programs if the patient does not have good coverage for medications. What can we do to help patients manage the expense and financial toxicity of therapies?

What are some ongoing research efforts for cGVHD management?

Newer agents are coming on the market. We are looking at some of those right now with some of the other agents that tend to have a better safety profile. We are always researching this topic and we will continue to look at what our colleagues around the world are finding as it relates to newer therapies.

Articles

Joyce L. Neumann, PhD, APRN, AOCN, BMTCN, FAAN, discusses the variability in cGVHD presentation, key symptoms of the disease in patients with cancer, and how the field is navigating between available therapies.  

Variable Chronic GVHD Presentations Stress the Need for Close Symptom Monitoring 

Although steroids remain the frontline standard of care in chronic graft-vs-host disease (cGVHD), research into ways to augment their use and potentially replace them with more effective agents has become a significant area of interest, explained Corey S. Cutler, MD, MPH, FRCPC. He added that doing so could spare patients unwanted adverse effects, including metabolic disturbances, osteoporosis, and neuro-psychological effects.

“In the cGVHD space, we’re excited about the ongoing randomized trial of axatilimab. There’s so much activity,” said Cutler. “We’re excited that our pharmaceutical colleagues are pushing the envelope here. We are looking forward to doing head-to-head trials in the acute and cGVHD space, as well as trials that will pit our novel agents against steroids rather than in addition to steroids in multiple lines of therapy. That is the future of our next generation of clinical trials.”

, Cutler, medical director, Adult Stem Cell Transplantation Program, director of Clinical Research, Stem Cell Transplantation, director, Stem Cell Transplantation Survivorship Program, institute physician, Dana-Farber Cancer Institute, and associate professor of medicine, Harvard Medical School, discussed the diagnostic and treatment landscape of cGVHD.

: Can tissue biopsies be used to provide a definitive diagnosis of cGVHD?

: cGVHD is always diagnosed clinically. There currently are no required diagnostic tests, although we certainly use supporting laboratory-based values to help us make the diagnosis and sometimes use tissue biopsy. This includes biopsy of the skin, and sometimes the liver, the gastrointestinal tract, etc., but none of these are required. There are not pathognomonic findings on tissue biopsy that always make the diagnosis of cGVHD, so largely, this remains a clinical diagnosis.

Are there agents that are used to supplement steroids in the frontline setting?

Currently in the frontline setting, corticosteroids, unfortunately, remain the standard of care although we often use additional agents such as calcineurin inhibitors or mTOR inhibitors. We will use these other agents in an attempt to try to reduce the amount of steroids or the length of time that steroids are required, but they don’t actually increase the overall response rate. Some of the factors that we will consider when initially treating cGVHD is the likelihood of steroid toxicity in patients who are about to start corticosteroids and how they have tolerated other agents such as the calcium and inhibitors in the past.

What are some of the concerns of long-term steroid use?

Steroids are truly toxic agents even though they’re very effective, at least in the initial stages of treatment of cGVHD. They are very immunosuppressive and anti-inflammatory, and that’s where their benefit is derived from.

On the other hand, long-term use of corticosteroids leads to things like glucose intolerance, chronic hypertension, and other metabolic disturbances such as hyperlipidemia. There is osteoporosis or osteopenia and sometimes avascular necrosis of large joints, such as the hips. There are also the neuro-psychological effects of being on chronic corticosteroids, so things like depression are associated with it, sleeplessness, anxiety, etc.

Overall, they are not tolerated extraordinarily well in the long term, and that’s why we are trying to find agents that might be additive to steroids, or that could eventually replace steroids in the frontline setting for the management of cGVHD.

What is available to patients who progress on steroids?

We have been very fortunate in cGVHD because there’s been so much clinical interest in novel drug development in the space. We now have 3 drugs that are FDA approved in second-line therapy and beyond: ibrutinib [Imbruvica], belumosudil [Rezurock], and ruxolitinib [Jakafi] in the order they were approved. Selection of these agents in the second-line setting and beyond really relates to patient factors, such as what drugs they will tolerate and what other toxicities they might have, which might guide us in terms of which drug would be beneficial for the patient in the second- and third-line settings.

Then, of course, there are clinical trials. When available, we always try to push our patients towards participating in trials of novel agents. There are several that are being evaluated right now, some of which are very promising, but it’s a little too early to speak about the approval process for these agents.

Did the REACH2 trial (NCT02913261) provide any insight into which patient populations may derive the most benefit fromruxolitinib?

The REACH2 study [enrolled] patients with steroid-refractory moderate or severe cGVHD for the most part. I will note that in that trial patients had to be refractory to steroids, but it could have been as little as 1 weeks’ worth of steroids. About 35 to 40% of patients were enrolled on that basis. We don’t know a ton about organ-specific responses in that trial. Unfortunately, there didn’t appear to be a high response rate among patients with pulmonary involvement. We currently do not have a great way of predicting which patients will respond to which agent. That is the focus of several large research efforts in the field to try to match the appropriate drug to the appropriate patient, either based on a biologic mechanism or a cGVHD phenotype. We don’t have that quite yet. At this point, selection of drugs is based on experience with the agent and anticipated toxicities.

Corey S. Cutler, MD, MPH, FRCPC, discusses the diagnostic and treatment landscape of chronic graft-vs-host disease.

Long-Term Toxicity With Frontline Steroids Remains a Key Consideration of Chronic GVHD Management  

As the armamentarium continues expanding for the treatment of patients with chronic graft-vs-host disease (cGVHD), research is ongoing to determine whether earlier integration of novel therapies, such as ruxolitinib (Jakafi), could yield better response rates for patients, said hematologist/oncologist Haris Ali, MD. He added that, ultimately, preventive strategies for cGVHD will be the next frontier.

“Early treatment rather than waiting too long [to intervene] is the key to success [with ruxolitinib] to get better responses,” said Ali, an associate professor in the Division of Leukemia of the Department of Hematology and Hematopoietic Cell Transplantation at City of Hope. “[However], it’s a dynamic field and things are changing. Down the road, we will probably be looking less at treating GVHD and more at prevention.”

®, Ali discussed the importance of assessing patients post-transplant for signs of cGVHD, frontline treatment considerations based on disease severity and organ involvement, and the next steps the field should take with ruxolitinib in the management of this disease.

: How do you follow patients to assess for signs of cGVHD?

: Usually in the post-transplant follow-up, we evaluate patients proactively for any cGVHD. We ask them questions directed toward the symptoms of cGVHD and do a thorough physical examination. It’s very simple. We ask questions about whether they have dry mouth, dry eyes, or joint stiffness. The [physical evaluation consists of] a skin examination, mouth and eye [examinations], and [testing] range of motion. The diagnosis is basically [made from] proactively checking on patients so we can catch them earlier rather than later.

Are there certain types of patients who are at an increased risk of developing cGVHD?

It used to be that patients who [underwent] myeloablative conditioning and [had] an unrelated donor for transplant would be at a higher risk for developing GVHD. Other factors [include] patients getting a transplant from female donors who had undergone multiple pregnancies and patients with aplastic anemia. There are multiple risk factors.

[We’ve seen] a slight change in cGVHD because of more use of post-transplant cyclophosphamide. We tend to see [cGVHD] a bit less than before based on comparative studies.

How do frontline treatment considerations for cGVHD change based on severity and organ involvement?

When a person presents with cGVHD, [frontline treatment] typically depends on the extent of involvement. If someone presents with oral GVHD with dry mouth, we will typically use topical steroids to stimulate saliva production. If someone presents with dry eyes and GVHD that is limited to the eyes, we will use more artificial tears. If those patients progress, we refer them to our cGVHD-specific ophthalmologists who can screen patients for trials using agents such as cyclosporine [Restasis] or, in very advanced cases, scleral lenses for treatment.

For patients with more extensive GVHD, such as someone with multiple organ involvement, the initial treatment is systemic steroids.

What second-line options are available to patients?

Most patients who [need] steroids will have an incomplete or suboptimal response and require some sort of additional therapy to help their current GVHD. Currently, we have 2 approved medications [in the second-line setting]: ibrutinib [Imbruvica] and ruxolitinib. Another treatment that is often used is extracorporeal photopheresis [ECP].

Ruxolitinib was approved [in September 2021], but in the transplant community, it was used quite frequently [before that] because of the data that were available from a German paper. Generally, [second-line] treatment could be ibrutinib or ruxolitinib, but more data are available with ruxolitinib, and we have a randomized trial supporting its use. [Ruxolitinib is] usually the go-to treatment at this point. If someone mainly has GVHD with skin involvement, we can use ECP, which is a very good option for patients who are more at risk for immunosuppression and potential infections. ECP doesn’t make patients immunocompromised.

What did the data from the phase 3 REACH2 trial (NCT02913261) show in terms of responses with ruxolitinib by grade? How are you interpreting these data?

Patients who had [low-grade GVHD], such as grade 2 disease, had higher responses compared with patients with grade 3 and 4 disease. Patients who had only skin involvement also had higher responses [compared with patients with additional organ involvement].

These data suggest that we should use [ruxolitinib] early rather than late because late-stage disease responded less [than early-stage disease].

What were some of the key conclusions that can be drawn from the results of the phase 3 REACH3 trial (NCT03112603)?

The key takeaway was that more patients had complete or partial responses [with ruxolitinib vs best available therapy], so the overall response rate was much higher.

We don’t get a 100% response rate though; responses [occur] in about one-third of patients. In the transplant community, [we would like to see] development of combination trials [with ruxolitinib] or [trials evaluating] a higher dose of ruxolitinib in patients who can tolerate it to see if these responses can be improved upon. Ruxolitinib is approved at 10 mg twice daily, but we have good science behind using a potentially higher dose that may give us better and more responses.

Where is belumosudil (Rezurock) currently being used in the management of cGVHD?

The trial [of belumosudil] was open at our site and we enrolled several patients to it. We saw a good number of responses in patients who got belumosudil. It is definitely [an option] for patients who have progressed on ruxolitinib and ibrutinib. These patients have much more advanced and refractory disease, so being able to give an option to them to improve their cGVHD is good.

What advances do you foresee regarding the management of cGVHD in the coming years?

Preventive strategies for cGVHD are evolving. We know that the use of anti-thymocyte globulin is decreasing in cGVHD. We are seeing more frequent use of post-transplant cyclophosphamide, which seems to be decreasing the incidence of cGVHD.

So, in addition to looking more toward treating cGVHD, we are moving ahead to look at preventing cGVHD. Data are available showing that peri-transplant use of various medications that are currently being used for the treatment [of patients with cGVHD], such as JAK inhibitors, can help with downstream acute and cGVHD.

As the armamentarium continues expanding for the treatment of patients with chronic graft-vs-host disease, research is ongoing to determine whether earlier integration of novel therapies, such as ruxolitinib, could yield better response rates for patients.

Preventive and Early Intervention Strategies Among Next Steps in cGVHD Management 

The approvals of ruxolitinib (Jakafi) and belumosudil (Rezurock) have shaken up the second- and third-line treatment of patients with chronic graft-vs-host disease (cGVHD), said Yi-Bin Chen, MD, who added that real-world data with these agents could further inform their utility in clinical practice and whether there is a place for frontline use in combination or in place of systemic steroids.

“Enough time has passed where we will see more real-world data for ruxolitinib in cGVHD to get a better handle on what is actually happening,” said Chen, director of the BMT Program and the Cara J. Rogers Endowed Scholar at Massachusetts General Hospital, and an associate professor of medicine at Harvard Medical School. “We all trust randomized trials, such as REACH3 [NCT03112603], but we do appreciate real-world experiences as we apply it because the majority of our patients don’t fit the eligibility [criteria] for how these trials are designed.”

“It’s too early to get any data on the real-world experience of belumosudil, but in the next couple of years that should be coming,” Chen added.

, Chen discussed the nuances of diagnosing patients with cGVHD, the need for biomarkers to inform who is likely to develop the disease, the introduction of ruxolitinib and belumosudil to the paradigm, and future directions with novel strategies in the space.

: How is cGVHD diagnosed? Is there a telltale feature of the disease?

: The diagnosis of GVHD, be it acute or chronic, is still a clinical diagnosis that requires the [patient’s] entire history, their symptoms, exam findings, and laboratory diagnostics. Although we can biopsy affected tissue—and those histological findings can help support a diagnosis of GVHD or rule out other things—the diagnosis remains the entire clinical picture.

There are times when it’s a bit difficult to know what is causing something for a patient. Of anything that happens to our patients in at least the first 2 years after transplant, cGVHD is always in the differential; we have to think about it. The disease is unbelievably heterogenous from patient to patient, so we can’t read a textbook to understand what we are going to see.

The manifestations are protean; it can affect almost any organ in the body. It’s interesting because cGVHD is not only a disease of the immune system and direct attack of that immune system on the patient, but it reflects a state of immunological disarray and probably causes that as well. [Patients] lose their normal regulatory mechanisms.

Therefore, we see some manifestations that are classical cGVHD where the donor immune system attacks recipients, but there are other manifestations that are just a reflection of immunological disarray. Those manifestations aren’t necessarily GVHD in the classical sense but are things such as immune-mediated thrombocytopenia or nephrotic syndrome. Those aren’t thought of as classical manifestations of the donor attacking the host, but they are evidence that the immune system has gone awry.

Are there particular patient populations that are at an increased risk of developing cGVHD?

We pay attention to everyone who gets an allogeneic transplant. However, we must think about certain patients who are more at risk than others. That’s based on certain clinical risk factors that are inherent to the patient, the disease, the transplant platform used, GVHD prevention, and the events that happen afterward.

To take that in order, we know that certain characteristics of a patient make them more at risk for cGVHD. Specifically, the older in age someone is, if they are male and receive a graft from a female donor, and the actual transplant platform [are all risks]. If we use myeloablative conditioning vs reduced-intensity or nonmyeloablative therapy, which is certainly much more borne out for acute GVHD [aGVHD], it is a signal for cGVHD, especially [regarding] the use of high-dose total body irradiation.

Certainly, the type of donor matters in terms of donor and host [human leukocyte antigen] matching. That by far predicts for the most GVHD relationship. The graft source [also matters]. We know from randomized studies that peripheral blood stem cells have a much higher incidence of cGVHD vs bone marrow or cord blood if we can get [patients] past the early complications.

GVHD prevention [is critical]. We know that the inclusion of polyclonal anti–T-cell globulins, such as ATG products reduce the incidence of cGVHD. Ex vivo manipulations, such as T-cell depletion, do that as well. If we use the newly emergent, posttransplant, high-dose cyclophosphamide-based GVHD prevention [strategy], that appears to reduce the incidence of cGVHD as well.

By far, if we play all this out, the biggest risk factor along the way would be the development of aGVHD. That’s just a biological reflection of allogeneic reactivity. That is how we think of patients and what we have done. For a patient with a benign disease, such as aplastic anemia, I would design a transplant platform that would maximize GVHD prevention. I would know that patient is at a much lower risk [of developing GVHD] compared with someone with a high-grade hematologic malignancy who has a higher rate of relapse.

[In that situation], I would at least tolerate some GVHD to bring about better graft-vs-leukemia. That is how we think about patients as we go forward. We make conscious decisions about how we manage their immunosuppression in terms of rapidity of taper [of steroids] and things like that.

Going forward, it behooves us to invest in studies to try to define better ways to [make those decisions], not just with the diagnosis, but in real time along the way. That would [mean identifying] cGVHD biomarkers. That could help risk-stratify patients in real time to high or low risk for developing cGVHD. That would be a huge step forward and ongoing research is already trying to figure this out. It’s much more along for aGVHD vs cGVHD for a lot of reasons, but [ultimately] the key is to have biomarkers that can predict for certain manifestations. We could then either design preemptive approaches to prevent [cGVHD] or predict for differential responses to therapies. That way we could tailor our therapies based on those biomarkers.

What initial therapeutic considerations are needed for patients with cGVHD? What options are available for frontline management?

In patients who present with localized cGVHD, which is very common, we tend to try to maximize local therapy. That includes eye drops to the eyes, topical mouth rinses for mouth involvement, and topical skin cream for limited skin involvement. At some point, if the manifestation becomes so severe or there is clear multi-organ involvement, [treatment] becomes much more of a systemic process than initially appreciated. There comes a time when we must decide to initiate systemic therapy.

Unfortunately, systemic therapy at this point remains the reinitiation of systemic steroids, such as prednisone. Most of these patients are outpatients [and receive] prednisone in oral tablets. We tend to give [prednisone] in a dose somewhere between 0.5 mg/kg and 1 mg/kg of the recipient’s body weight per day. That has been the same for the past couple of decades.

It is heartbreaking to add steroids back to a patient’s treatment because many patients have already been through a lot of complications like aGVHD or infections. Certainly, we need to treat the cGVHD, but we also know the patient is accruing some morbidity and risk [with additional steroids].

I worry about infections, causing or worsening diabetes, bone health and osteoporosis, worsening hypertension, and mood effects from long-term prednisone. [We also worry about] the effects on body habitus in terms of fat distribution and cushingoid appearance. All of those [risks] make steroids not an ideal choice.

We don’t have any data to say whether we should use a different agent for first-line therapy or combine steroids with something else; however, those trials are ongoing, and we are awaiting the results. More than half of patients will have an unsatisfying response to steroids, be it no response or a plateaued response that is not good enough for their quality of life. In more than half of patients, we need to add something [to steroids].

It’s sobering that recent data from the cGVHD Consortium would suggest that in anybody who we start on systemic steroids for cGVHD, only about a third of them ever get off steroids for a durable time. That is a reality that makes us think about how to frame [treatment] for patients in terms of long-term expectations.

For patients who progress beyond steroids, what therapies are available for second-line treatment?

In terms of second-line therapy, we view GVHD in general as an immunological disease, which it is. The historical therapies were immunosuppressive to treat the GVHD. Although that works to a certain extent, it comes with a high cost––that being certain opportunistic infections.

However, just as in aGVHD, the evolution in cGVHD [treatment] is toward more pathway-specific inhibitors that we think are especially active. Those [agents] also have less off-target toxicities, thus they yield less risk and morbidity to our patients who are a bit fragile.

We have some more options, excitingly. A few years back the BTK inhibitor ibrutinib [Imbruvica] was approved in steroid-refractory cGVHD. That [approval] was built on the foundation that there is some B-cell activity in cGVHD. For a subset of patients, that is why ibrutinib does work to a certain extent.

Other agents, such as rituximab [Rituxan], have had some efficacy. However, the real-world experience with ibrutinib has not mirrored what we saw in the clinical trial that led to its approval. That trial was somewhat restrictive in its eligibility criteria, so [the lack of consistency with the real-world experience] makes sense. That real-world experience has been a bit difficult not only in efficacy but just in the inherent toxicities [associated with ibrutinib].

More recently, ruxolitinib was approved for second-line therapy. This was based on the findings from the REACH3 study, which was one of the only large, randomized phase 3 studies in steroid-refractory cGVHD. [The results] showed a significant benefit with ruxolitinib vs best available therapy. The primary end points were overall response rate at 24 weeks and failure-free survival. Ruxolitinib had a significant benefit [in those end points] compared with best available therapy.

We’ve been using [ruxolitinib] at Massachusetts General Hospital as our standard second-line therapy for the past 4 years for cGVHD. This was partly because of the anecdotes that had been published, partly from our own experience, and partly because we have a lot of experience using ruxolitinib in aGVHD and other indications in which it is approved for. We had found it to be a very satisfying drug, although it is not a “home run.” We don’t have a home run if we look at all the trials to date for cGVHD. Of responses reported, complete remissions are the extreme minority. That’s how we know we don’t have a home run.

There is more work to be done in diagnosing cGVHD earlier and designing better therapies. Anecdotally, we have found that ruxolitinib benefits at least three-quarters of patients started on it. It is a well-tolerated agent, but we must watch for cytopenias. If a patient develops [adverse effects (AEs)], they can be managed with dose adjustments or dose interruptions. I hope one day to be able to see how [ruxolitinib] functions as first-line therapy or even in prevention [of cGVHD].

How has the experience with belumosudil as a treatment for patients with cGVHD been thus far?

[In July 2021], belumosudil, an oral ROCK-2 inhibitor, was approved for third-line therapy of cGVHD. That [approval] was based on the momentum of the ROCKstar study [NCT03640481], which showed a response rate of over 70% with 2 different dosing strategies. Belumosudil is interesting in terms of its mechanism of action, in that it targets the fibrosis cascade. It certainly appears to help most patients without a significant amount of concern over toxicity. I want to see more data on the real-world experience with belumosudil in patients.

What are some next research steps regarding the treatment of patients with cGVHD?

A couple of agents are being studied. We shouldn’t forget about extracorporeal photopheresis [ECP]. That is a modality that has been around for a long time and certainly has efficacy in cGVHD without much in the way of immunosuppression. The reason why it is not as attractive as the other agents is the logistics it takes for patients to receive the therapy in terms of proximity, time spent at the center, and [the need to insert] an indwelling catheter. Learning how to sequence ECP with [systemic] therapies is a must going forward.

A monoclonal antibody against CSF1R is being developed by a company called Syndax. That agent is being [tested] as an every-other-week infusion and targets activating macrophages that are thought to be very active in the fibrotic process, which is the histological hallmark of GVHD. Large expansion trials are ongoing right now [with that agent, called axatilimab]. We are all eagerly awaiting the results.

Outside of that, other agents are very early in development and are not yet ready for prime time. We saw an interesting abstract from Europe using a form of arsenic as frontline therapy that showed a very high response rate when combined with steroids. That goes along with what the next step is in cGVHD, which is to move approved therapies up to study them with systemic steroids in the frontline setting. This could not only improve response rates but allow more rapid steroid tapers to spare patients [from AEs] during response.

We also want to think about designing trials where we can parse out a subset of patients that don’t need steroids because they are low risk or [we] don’t think that that phenotype or biological sign of patients will respond to steroids. [In these populations], we can try these newer agents as frontline therapy without steroids. A goal is to replace steroids in the frontline setting, so these are trial designs being talked about in the community going forward. Now, one big step is already out of the way because these novel agents are approved in later-line settings.

What data are you most intrigued to hear about in the coming years?

I’m always interested in the newer agents being studied. These are small trials out of single centers, but those start the whole process. I am keeping my eye out for those types of studies.

As we move forward, it will be less about designing more therapies for third-, fourth-, or fifth-line treatment and more about how we can better prevent cGVHD either by doing so preemptively or by adding to the prevention backbone without sacrificing other factors. That has been much of the discussion in the community to try to glean whether there are any data we are going to see that will inform us to design those steps going forward.

Beyond potentially looking at it as frontline therapy, what is next for ruxolitinib in the treatment of patients with GVHD?

Now that ruxolitinib is approved and a lot of us are using it as our standard second-line agent, we are going to see a lot of different formulations of ruxolitinib or other JAK inhibitors. In the community, we have been asking for about 3 years for some form of JAK inhibitor eye drops, skin creams, and mouth rinses. Right now, we use steroids for those topical formulations. Not only do we think that some sort of localized ruxolitinib application would be more effective, but certainly less toxic [vs steroids]. We will be watching out for that as adjunct treatment for the populations that have limited disease and don’t need systemic therapy.

Yi-Bin Chen, MD, discusses the nuances of diagnosing patients with cGVHD, the need for biomarkers to inform who is likely to develop the disease, the introduction of ruxolitinib and belumosudil to the paradigm, and future directions with novel strategies in the space. 

cGVHD Paradigm Gains Systemic Options Beyond Steroids, But Real-World Data Are Required