Investigator’s Perspectives on GVHD: The REACH Trials

Yi-Bin Chen, MD

TARGETED THERAPIES IN ONCOLOGY™: Please provide an overview of graft-vs-host disease (GVHD) after allogeneic transplant and the challenges it presents for patients.

CHEN: Allogeneic transplantation is a potential curative modality for many high-risk hematological malignancies and some nonmalignant conditions as well. We believe the therapeutic mechanism of action [MOA] of allogeneic transplant is 2-fold. One, there’s enhanced cytotoxicity from the conditioning regimen that we give before every transplant, but once we ingraft donor hematopoiesis in the recipient, we hope those donor white blood cells can reconstitute, ultimately providing the recipient with an intact immune system. And 2, we hope to cultivate a therapeutic immunological graft vs malignancy effect. This immunological therapeutic mechanism is what we believe to be the dominant MOA in allogeneic transplantation. The issue with this is that transplants are not done from identical twins, so the donor and host are inherently unique allogenic individuals. When the donor immune system grows up in that recipient, there can be an attack on the recipient’s healthy tissues, and this is what GVHD is.

What are the differences between acute and chronic GVHD?

There are generally 2 types of GVHD: acute and chronic. They’re named that way partly because of the timelines when they commonly occur, but also because of their clinical aggressiveness and how long symptoms will remain and how long patients will remain on therapy.

Acute GVHD probably occurs in about 30% to 40% of individuals if we look at transplant patients as a whole—[that’s] the number of patients that we have to act upon or deliver some sort of systemic therapy for. Acute GVHD commonly involves the skin, the GI [gastrointestinal] tract, and the liver, and usually occurs in the first several months after transplantation. It’s important to note that these days, with all kinds of different conditioning regimens and RAF sources and transplant platforms, which have different kinetics of immunoconstitution, GVHD is no longer defined by the first 100 days for acute and afterward for chronic. It’s only defined by clinical manifestations of acute vs chronic.

Chronic GVHD tends to occur in the first few months after transplantation, rarely occurring before the first 3 months. It is less traumatic than acute [GVHD and] its rash is a bit different, not as angry and erythematous but looking more like psoriasis or eczema. It commonly involves the skin as well as the eyes and the mouth, which are more dry eyes−dry mouth syndrome, but chronic GVHD can involve almost any organ in one’s body. The joints can hurt, the muscles can become inflamed, and chronic GVHD also is a state of significant immune dysregulation. Not only do you have the direct attack on the organs that give you the classic clinical manifestations of chronic GVHD, but certain auto-immune phenomena can arise, such as nephrotic syndrome or polymyositis. These are commonly seen autoimmune manifestations in the context of GVHD.

What are the risk factors for acute and chronic GVHD?

The risk factors for GVHD are pretty much the same for both acute and chronic. We’ve classically defined clinical risk factors even before transplant and they start with histocompatibility or HLA [human leukocyte antigen] matching between the donor and the recipient. Other risk factors include an increased intensity of the conditioning regimen, specifically the use of total body radiation, [and] donor sources, in the sense that peripheral blood stem cells will give more GVHD, specifically chronic, when compared to bone marrow. Age of both donor and recipient [is another risk factor], as the older age of either will lead to a higher incidence of GVHD. There is also evidence that a female donor compared with a male donor will lead to an increased incidence of GVHD.
Interestingly, a recent risk factor identified has been the microbiome. This is the diversity of bacteria in one’s GI system or colon and there’s clear evidence, at least from an associative standpoint, that when the microbiome diversity is restricted, that often leads to a higher incidence of complications after transplant, such as GVHD. We haven’t proved a cause and effect, and it may just be a marker of illness, but much research is going on in that regard.

Chronic GVHD seems to follow acute GVHD, meaning that the sequence of events is set very early on. The biggest risk factor for chronic GVHD is prior acute GVHD, and that has been proved in many series throughout the years.

We generally regard acute and chronic GVHD these days as separate diseases. They have distinct clinical manifestations. Acute has the angry erythematous skin, maculopapular skin rash, as well as diarrhea when the lower GI tract is involved. And chronic GVHD looks more like classic autoimmune phenomena, like SjÖgren syndrome, eczema, and psoriasis. That’s because physiologically, we think they morph differently in the immune system. Acute GVHD is far more what we believe to be a direct T-cell engaged activity or a Th1 [T helper type 1]–driven immune response, whereas chronic GVHD is much more Th2 involved. There is involvement in B cells, the humoral immune system, and it’s not uncommon to see a peripheral eosinophilia in these patients as well. Most patients, when we talk about GVHD, usually fall into one box or the other.

What are current best practices for the prevention of GVHD?

Prevention for GVHD is given after any allogeneic transplantation. There are 2 big categories of GVHD prevention. One is graft manipulation, and this is much less common because it involves laboratory expertise and resources but involves taking the donor graft and manipulating it in certain ways. This is commonly referred to as T-cell depletion and can be done in positive selection and selecting for the hematopoietic progenitor cells or [through] negative selection in eliminating a certain subset of cells that may cause GVHD.

The [other,] more common GVHD prevention is with drugs or pharmacological agents. The international framework over the last several decades has been the backbone of calcineurin inhibitors paired with methotrexate or mycophenolate. More recent years have seen the addition of sirolimus [Rapamune] either with or instead of methotrexate, and many centers across the United States and certainly across Europe will add a polyclonal anti–T-cell globulin, often referred to as ATG [antithymocyte globulin], to help in GVHD prevention. There are other agents being studied and being added onto these backbones and those trials are ongoing.

The newer regimen in terms of pharmacological prophylaxis of GVHD that has emerged over the last decade is based around the administration of high doses of posttransplant cyclophosphamide, often given on day 3 and 4 after transplantation. The mechanism here is thought to be elimination of alloreactive cells in that first week as well as preservation of regulatory T cells, and this is generally paired with tacrolimus or sirolimus with mycophenolate. The post-transplant cyclophosphamide regimens were first shown to be very efficacious in haploidentical, or mismatched, transplantation.¹ Now they are being tested in conventionally matched transplantation prospective trials to see if they can replace the standard of care that we commonly use. We anticipate these results over the next few years, and it’s a very exciting time as we continue to make progress.

How is GVHD managed in the frontline setting?

Initial treatment for GVHD, unfortunately, remains high-dose systemic steroids. In general, if we have to treat acute GVHD, we give 1 to 2 mg/kg/day of prednisone or its intravenous [IV] equivalent, depending on the patient’s clinical manifestations. Traditionally, if it’s skin only, we’ve leaned toward 1 mg/kg, and if it involves a lower GI tract or, more rarely, the liver, we generally increase to 2 mg/kg/day, often giving IV because of how sick the patient is. We have tried to improve upon this but have yet to do so. Unfortunately, about 50% of patients will become steroid refractory or need a second-line agent.

What is the definition of refractory in the setting of acute and chronic GVHD?

The definitions of “steroid refractory” have traditionally been the following: either patients get worse in the first 3 days of starting steroids, they don’t get better after at least 1 week, or they do respond [but] another organ develops manifestations; or they do respond, and then upon tapering of steroids their symptoms come back and they flare.

Chronic GVHD also uses systemic steroids. That’s more difficult as well because patients, months after transplant, have usually experienced some sort of comorbidity and tolerate steroids less well at that point. And for chronic GVHD, steroids are [used] for a much longer period of time. The dose is lower. We generally start at maybe 0.5 to 1 mg/kg depending on how aggressive we perceive the disease to be. But once chronic GVHD sets in, there is some that is likely causing irreversible organ damage and patients stay on steroids for a very long time.

A recent abstract from the Chronic Graft Versus Host Disease Consortium would suggest that only a third of patients ever get off steroids for at least a year after starting treatment for chronic GVHD, making it essential that once we start treating patients, we set expectations and understand what we’re treating. Research has also [been devoted to] trying to improve upon therapy for chronic GVHD as well, but initial treatment does remain high-dose steroids. Long-term follow-up shows that about 60% of patients that we start on steroids for chronic GVHD require a second agent. The definitions of steroid refractory for chronic GVHD are not as clear cut given the kinetics of the disease and response. In general, for practical purposes, we wait at least 1 to 2 months when starting an agent to determine if patients are refractory to such treatment to add further treatment.

What available treatments or strategies can be used in patients with steroid-refractory acute GVHD?

For acute GVHD, those who are refractory to first-line steroids, we did not have a standard of care until recently for steroid-refractory disease. Historical therapies often focused on what we believe to be the path of physiology, which was T-cell attack of the host tissues by the donor. The traditional therapies were anti–T-cell therapies that, unfortunately, gave more cumulative immunosuppression. Oftentimes what we dealt with was a lot of opportunistic infection and toxicity with very few patients surviving in the long run.

Modern therapies have focused more on specific pathways of inflammation that we believe are active in GVHD. Some trials are focused on organ resiliency, preservation of organ-specific stem cells, as well as looking at the vascular endothelium and trying to prevent thrombotic microangiopathy [TMA] to improve response rates. But these days, the options we have for patients with steroid-refractory acute GVHD [include] ruxolitinib [Jakafi], which was approved in 2019, the first agent to ever be approved in this space.² Some centers still do use ATG products in low doses. There is some literature [about using] TNF [tumor necrosis factor] antagonists.

We ourselves have used a lot of vedolizumab [Entyvio], which is a monoclonal antibody against α4β7 integrin to modulate lymphocyte trafficking away from the intestinal tract. And there’s been some recent research on microbiome-directed interventions, such as third-party fecal microbiota transplantation, with multiple anecdotes showing success in steroid-refractory acute GVHD.

The MOAs here are all quite varied. Ruxolitinib targets JAK1 and JAK2, which are active in many signaling cascades. They are active in the IO1 and IO6 signaling cascade and they appear to also influence lymphocyte trafficking as well as preservation of regulatory T-cells. I mentioned the MOA of vedolizumab for microbiota transplantation; that all gets back to increasing the diversity of the microbiome and the interactions between the microbiome and your mucosal immune system that shape the immune system at large. With ATG you bluntly remove donor T cells in hopes that that can bring about the right action.

What about treatments for steroid-refractory chronic GVHD?

In chronic GVHD, historically, the treatment options were quite similar. We felt that we just had to suppress the donor immune system, and a lot of patients, again, suffered from opportunistic infection. We need to realize for chronic GVHD that by the time we treat it, there is some irreversible damage, and we should try to only reverse what we can reverse and shape our expectations for ourselves and our patients that way.

But after steroids, we do have an approved agent, ibrutinib [Imbruvica]. That’s a Bruton tyrosine kinase [BTK] inhibitor, which targets the B-cell arm in the immune system. There is evidence that the B-cell arm is active in many patients with chronic GVHD. A lot of exciting laboratory work had shown in male recipients with female donors the formation of these anti H-Y antibodies directed against the Y chromosome, showing there was some B-cell or plasma cell activity. Ruxolitinib has been shown to be quite active in chronic GVHD as well, and we use it very routinely for that indication. There is an agent called belumosudil [Rezurock], made by Kadmon Pharmaceuticals, that recently had exciting results in the ROCKstar clinical trials [(KD025-213; NCT03640481) and was approved] this year.³ And that targets ROCK [Rho-associated coiled-coil kinase], an arm thought to be active in fibrosis.

Please review the patient populations, design, and key safety and efficacy results from the REACH-1 and REACH2 trials.

A lot of the progress over the last few years in GVHD is due to the results we’ve seen from clinical trials involving ruxolitinib and the major REACH-1, REACH2, and REACH3 trials. The company and the investigators really should be applauded for carrying these out. Trials in GVHD are difficult to do. Patients are sick and they’re heterogeneous, but these trials have pushed us a step forward and we hope more progress is on the way.

REACH-1 [NCT02953678] was a phase 2 single-arm trial carried out at several centers across the United States that involved 71 patients with steroid-refractory acute GVHD and treated [them] with ruxolitinib. Patients were given a dose of ruxolitinib of 5 mg twice a day to start, and if after 3 days they tolerated it, the dose was increased to 10 mg twice a day. The primary end point in this trial was 28-day overall response rate [ORR]. That’s the consensually agreed-upon primary end point, as it has been shown that that generally correlates with long-term outcomes of 6-months overall survival [OS] and non-relapse mortality.

The ORR in REACH-1 was 55%, with 27% of patients achieving a complete remission. The best ORR at any time in these patients who received any doses of ruxolitinib was over 73%, and at 6 months the OS rate was about 50% of patients. In this high-risk population, responses were seen across all organ manifestations in general—the skin, GI tract, and the liver.4 All of us who collaborated on this trial or saw the results were impressed with what we had seen. It was on the strength of this study that ruxolitinib was FDA approved for steroid-refractory acute GVHD in patients 12 [years] and older.²

REACH2 [NCT02913261] was a great validation of the REACH-1 results. REACH2 was a phase 3 international trial and it involved 309 patients with steroid-refractory acute GVHD. Patients were randomized to either ruxolitinib at 10 mg twice a day vs a control arm that was summarized as BAT [best available therapy]. The study couldn’t pick 1 control because there is no 1 international standard for treating steroid-refractory acute GVHD. Centers were allowed to choose among 9 commonly used options, and they were combined together to form the BAT control group.

Again, the primary end point was day 28 ORR and this favored ruxolitinib at 62% vs 39%.5 When looking at the secondary end points of durable response rate at day 56, after 8 weeks on the trial, median OS showed a benefit as to what had been seen in REACH- 1, and REACH2 showed that the main adverse events were cytopenias and thrombocytopenia and possibly an increase in the reactivation of cytomegalovirus. These results are impressive.

How has the approval of ruxolitinib for this indication changed treatment sequencing and outcomes for patients with steroid-refractory acute GVHD?

It should be emphasized that the durable response rate at 8 weeks, while it was 40%—about twice as much as the control— still leaves much room for improvement. Much more research has to be done to help these patients optimally. That’s where we stand for steroid-refractory acute GVHD.

More agents are on the way as we do more trials, but the REACH-1 and REACH2 trials have given us a standard. It has led to thinking, as more agents are studied, that we now have a control—that is ruxolitinib—and a benchmark to better design future randomized trials. The approval has given patients more access to an efficacious agent.

Please review the patient population, design, and preliminary safety and efficacy results of the REACH3 trial.

The main study [in chronic GVHD] was REACH3 [NCT03112603], a phase 3 international study involving about 329 patients. The eligible patients were adults with steroid-refractory chronic GVHD, and patients were randomized to ruxolitinib again vs a BAT arm. Investigators were able to choose from a variety of options that they commonly used to treat steroid-refractory chronic GVHD. The primary end point here was a 6-month ORR, as you have to give more time to observe a response and give more time for your agents to work [with chronic GVHD].

Again, the analysis favored patients who received ruxolitinib who had a 50% ORR at 6 months vs 26% in the control arm of BAT.⁶ It’s worth pointing out that a minority of these responses, under 7%, were complete remissions, which is not surprising for chronic GVHD. The secondary end points were failure-free survival, which also favored the ruxolitinib arm significantly, as well as a reduction in symptoms. With chronic GVHD we have to include patient-reported outcomes because that’s hugely important for these patients who will deal with this disease chronically in the long run. On the strength of this study, we [saw] that ruxolitinib [gained] approval from regulatory agencies this year (see pages 20-21).⁷

It has brought about responses in many patients that we treat these days [for whom] we’re able to use the drug. And we believe it has a place in the treatment for chronic GVHD.

What are some remaining unmet needs and what does the future hold for patients with steroid-refractory GVHD?

Looking forward, we need to think about better ways to design studies for acute GVHD. It is clear that not all patients are biologically alike and there are some patients who are going to do well and others who are not. The ability to design trials using these methods of risk stratification will ultimately help improve the field. These biomarkers can, perhaps, help to steer patients toward 1 therapy or another if they can also be predictive of response. That’s the future. It’s taking a population that’s very heterogeneous, like [those who have] acute GVHD, [and] being able to risk stratify them based on some system and conduct such trials.

In the discussions that we have had nationally, what we’re looking at is that patients who are low risk and who are going to do well can get away without steroids and we can use other agents. A cooperative group trial already used sirolimus in this regard, and recently a completed trial also used itacitinib, a JAK1 inhibitor. We’ll see if we can replace steroids for a subset of the population or, perhaps, taper steroids even faster in such patients. For the high-risk patients, I’m not sure any of us think we can get away without steroids at the moment, and perhaps adding a drug to steroids. Maybe [when] trying something like ruxolitinib, which is approved, or any of the other agents being studied, the question is: how do we advance in chronic GVHD.

There are some issues that are similar to acute in the sense that chronic GVHD is a heterogeneous disease, both clinically and biologically. The world of biomarkers for chronic GVHD is a bit behind that for acute. If we’re able to develop some biomarkers that can help restratify those high-risk vs low-risk patients or ultimately can predict which patient will respond to which therapy, those will be huge advances in the field.

A lot of us who look at chronic GVHD need to think about what we tell our patients, not only before transplant but also once we start treatment. We need to frame the expectations of how long symptoms will [last] and what our expectations are, which inherently are to stop the progression first and then to improve. We need to accept that once chronic GVHD has set in, there is some element of organ irreversibility, and we need to acknowledge that with our patients.

Looking at all the clinical trials in chronic GVHD, complete responses are oftentimes in the single digits. That cannot be a realistic end point for this population, at least with the agents we have now. But looking forward, there’s a lot of research going on in all phases of therapy—frontline, refractory, and prevention—and I’m just grateful to be a part of this. It’s an exciting time for GVHD.

_REFERENCES:

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_{2. FDA approves ruxolitinib for acute graft-versus-host disease. FDA. May 24, 2019. Accessed October 4, 2021. https://bit.ly/3uCSAGS}

_{3. FDA approves belumosudil for chronic graft-versus-host disease. FDA. July 16, 2021. Accessed October 4, 2021. https://bit.ly/3A9d8rQ}

_{4. Jagasia M, Perales MA, Schroeder MA, et al. Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label phase 2 trial. Blood. 2020;135(20):1739-1749. doi:10.1182/blood.2020004823}

_{5. Zeiser R, von Bubnoff N, Butler J, et al; REACH2 Trial Group. Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease. N Engl J Med. 2020;382(19):1800-1810. doi:10.1056/NEJMoa1917635}

_{6. Zeiser R, Polverelli N, Ram R, et al; REACH3 Investigators. Ruxolitinib for glucocorticoid-refractory chronic graft-versus-host disease. N Engl J Med. 2021;385(3):228-238. doi:10.1056/NEJMoa2033122}

_{7. FDA approves ruxolitinib for chronic graft-versus-host disease. FDA. September 22, 2021. Accessed October 4, 2021. https://bit.ly/3BfXCvu}