Hematologists and Patients Come Together for Patient-Focused GVHD Discussions


Carrie L. Kitko, MD, and Sagar S. Patel, MD, discuss recent treatment developments and ongoing unmet needs in the graft-vs-host treatment paradigm.

Carrie L. Kitko, MD

Carrie L. Kitko, MD

Although several strides have been made in the treatment of patients with both chronic and acute graft-vs-host disease (GVHD), uncertainties remain regarding the existence of optimal biomarkers that, once identified, may ease diagnoses and tailor therapeutic strategies, according to Carrie L. Kitko, MD, and Sagar S. Patel, MD.

The Second Annual GVHD Day will take place on Saturday, February 17, 2024.1 Hosted by the GVHD Alliance, this virtual event is dedicated to raising awareness for those with this disease, building solidarity with the GVHD community, and spotlighting the voices of those whose lives have been affected by GVHD, including survivors and caregivers. People interested in learning more about GVHD Day and the ways they can show their support can visit the GVHD Alliance Website.

“We’re going to keep trying to find new pathways and new ways of using [agents] to keep improving [patient] outcomes,’ Kitco stated in an interview with OncLive®.

In the same interview, Patel added, “I am hoping to see, particularly in some of these more difficult-to-treat [GVHD] sites, that better activity [is achieved with agents in development].”

Kitko also noted how positive findings from the REACH series of trials continue to support the use of ruxolitinib (Jakafi) in patients with acute and chronic GVHD. For instance, the 2021 FDA approval of this agent for adult patients with chronic GVHD whose disease has progressed on 1 to 2 prior lines of systemic therapy was supported by findings from the phase 3 REACH3 trial (NCT03112603), in which treatment with ruxolitinib elicited an overall response rate (ORR) of 70% (95% CI, 63%-77%) vs 57% (95% CI, 49%-65%) with best available therapy.2

Furthermore, research is ongoing with axatilimab, a monoclonal antibody that may reduce the likelihood of patients developing severe GVHD manifestations. Patel emphasized these as some of the most challenging aspects of the disease for both patients and hematologists. The phase 2 AGAVE-201 trial (NCT04710576) demonstrated that treatment axatilimab led to an ORR of 74% (95% CI, 63%-83%) in patients with chronic GVHD who received the agent at 0.3 mg/kg every 2 weeks.

In the interview, Kitko and Patel expanded on recent developments in the GVHD treatment paradigm that have improved patient outcomes, highlighted unmet needs in GVHD treatment that ongoing research aims to address, and expanded on the importance of raising awareness about GVHD and the ongoing research in this field.

Kitko is an associate professor of pediatrics and hematology/oncology and the medical director of the Pediatric Stem Cell Transplantation Program at Vanderbilt University Medical Center in Nashville, Tennessee, where she also holds an Ingram Professorship in Pediatric Oncology in the Department of Pediatrics.

Patel is a hematologist at the Huntsman Cancer Institute in Salt Lake City, Utah.

OncLive: What are some current unmet needs in GVHD, and why do they exist?

Kitko: [In the GVHD field], we are lucky right now. We have, over the past several years, been granted FDA approval for several medications; 1 for steroid-refractory acute GVHD and 3 for steroid-refractory chronic GVHD. That’s great news for patients. [However], not each of those medicines will work for every patient. We don’t know as much in a clinical trial setting about how to potentially improve outcomes by using combination therapy. Then, what about trying to move some of those treatments earlier in the disease progress as well? Those are areas where we can hopefully see ourselves improving GVHD outcomes by using the tools we already have.

Patel: Unmet needs in GVHD include first-line therapies. We’re still using a lot of steroids, which, although effective, [are associated with] a host of adverse effects [AEs] that can [be] difficult for the patient. That’s one area that’s been difficult to move past, but trials are underway investigating new therapies or combination regimens that can help move the needle there.

The other unmet need has been our ability to find great biomarkers. A lot of work has been done in this arena, [but we still don’t have biomarkers that are] ready for routine clinical practice. [The presence of effective biomarkers] would help from a therapy development perspective and in the treatment of patients as another tool to help make diagnoses and [predict] responses to treatment.

What further work is needed to develop more effective biomarkers in GVHD?

Patel: We are learning with GVHD that there are probably multiple pathways involved. GVHD doesn’t fit into a neat, singular box where a single biomarker would be sensitive and specific enough to that disease process. Trying to separate the background noise of allogeneic stem cell transplant is also difficult. [GVHD undergoes] intrinsic changes with transplant that you have to separate from the disease process. An ideal biomarker would be reliable, sensitive, and specific enough to GVHD.

What data have supported some of the recent regulatory decisions surrounding GVHD treatments?

Kitko: Some of the best data we have are from the series of REACH trials, which [investigated] ruxolitinib, a JAK1/2 inhibitor in both the acute GVHD steroid-refractory setting and after progression on 1 to 2 lines of therapy for chronic GVHD. [Both patient populations were] studied in a randomized way, where patients either received ruxolitinib or what was considered best available therapy, [which comprised] a list of approximately 7 to 8 different commonly used medications in both those scenarios. Those are some of the best data we have [from trials with] a great comparison group– not a historic control– to say patients [who received ruxolitinib achieved] approximately twice the response rate compared with [those who received] the current best available therapies. This supports the use of ruxolitinib [in these populations].

That’s not to say agents such as ibrutinib [Imbruvica] and belumosudil [Rezurock] aren’t also important tools in our toolbox, but [the trials evaluating those agents in GVHD] didn’t have the same comparison [schema and instead included] multiple arms using different doses [of the same agent]. The ORRs reported [with agents other than ruxolitinib] were significantly better than [those observed with] historic controls, but [the trials] didn’t necessarily have contemporary control groups to [verify] that those [seemingly good] outcomes were as helpful as [those seen in] a randomized, controlled trial.

Patel: Some of the later trials, such as the AGAVE-201 trial and the [phase 2] ROCKstar study [NCT03640481], included patients who had been heavily pretreated, [which] reflects what happens in the real world when we have patients with chronic GVHD who are steroid refractory, [are moving] into second, third, or fourth lines of therapy, and still have persistent or progressive disease. It’s always nice to see responses in that population. One would hope [those data] would translate into even better outcomes if those therapies were available in an earlier line.

What ongoing GVHD research has caught your eye?

Kitko: Axatilimab is probably the drug most of us are excited about. What’s been great is the shift away from only thinking of GVHD as a T-cell–mediated complication and recognizing that many arms of the immune system, particularly for chronic GVHD, are probably involved in that process. Finding new agents that target different parts of that potential pathophysiology has been exciting, particularly the thought that axatilimab might have a signal to help against some of the most severe [GVHD] manifestations, [such as] the fibrotic and sclerotic manifestations that are challenging for our patients.

Patel: Even beyond where we have existing drug approvals, [GVHD is a] spectrum. Thinking of chronic GVHD as an inflammatory process [with a] fibrosis element drives a lot of practitioners’ anxieties regarding how much of [the disease will be] reversible before it cements in. In particular, sclerotic skin features or changes in the lungs are hard to reverse.

Some of the drugs that seem to have better activity in those settings are promising. We will probably see some of the newer therapies align as parallel options [so we can] pick the agent that best matches the organs involved. GVHD is heterogeneous from one patient to another.

Given that GVHD is a heterogeneous disease, what is the process of GVHD recognition and diagnosis?

Kitko: There are different stories for acute GVHD vs chronic GVHD. [Regarding] acute GVHD in the early post-transplant period, patients have bright red rashes, crampy belly pain, and watery diarrhea. It’s usually obvious to both the clinician and the patient that something’s going wrong and [GVHD] is easier to point a finger at.

Chronic GVHD is a bit more insidious in its development. A patient [with acute GVHD] might be doing well without signs [of chronic GVHD development], so you taper their immune suppression, and then they come in with skin itching or muscle cramping, but nothing is distinguishing on the exam to nail down the diagnosis. You might be worried this patient might be developing chronic GVHD, but you don’t have that diagnostic feature in front of you to change the disease management.

If I can get my patients off immune suppression, [I want to do that, since] there are downsides to being on that for too long as well. We have to describe to patients that we don’t have [biomarker results from] a blood test. For chronic GVHD, we’re behind in our biomarker understanding.

My best-educated guess is that in a patient who looks well, whose lab [results] look okay, and who is at the right point post-transplant, I [would] try to taper immune suppression and see them back in a month to try again. Sometimes you taper, and they call you back 2 weeks later. [Although the patient was] having vague symptoms, it takes a while until they can say they have a new rash, their mouth is sensitive, or their eyes are super dry. That can be challenging for both the patient and the physician.

Patel: One of the other emerging trends we’re seeing is the incidence of GVHD, both acute and chronic, as it pertains to the use of different prophylaxis regimens. One of the big advances in GVHD, [beyond] the treatment side, [has been in] preventing GVHD to begin with. In many of our patients, we can now use post-transplant cyclophosphamide, which is easy to use in a non-haploidentical donor setting. That strategy has shown significant improvements in GVHD prevention, and there will be a bit of a shift as it has increased uptake amongst transplant centers.

What is the importance of GVHD Day, and how has this initiative impacted the GVHD community?

Patel: GVHD Day is an amazing set of work that’s been in motion for some time by the GVHD Alliance. [This day] helps amplify a [disease that is] relatively rare compared with many [other diseases] one may see in the media. [This work is] particularly important for patients because GVHD is insidious, [and patients] can live a long time with symptoms that can be incredibly debilitating and have a significant impact on their ability to return to school or to work, as well as on their quality of life. Being able to bring together caregivers, survivors, patients, and physicians, [with] a multidisciplinary focus on one platform, is amazing. GVHD Day ties in with a lot of the work we do as transplanters.

Kitko: Although GVHD is rare, and improvements in both our prevention strategies and some of our treatments mean patients are experiencing better outcomes than in the past, we all have patients who, for reasons we don’t understand today, haven’t responded well to those treatments, and are impacted by the debilitating nature of chronic GVHD, in particular. [GVHD Day is a] forum where [patients] can see other people who are going through the same disease or who had a loved one who went through the same disease, and then be connected to the transplant community that’s working hard [to improve treatments]. We’ve made such good progress, but that doesn’t mean we’re going to stop.

What does the future look like for GVHD research?

Kitko: The Mount Sinai Acute GVHD Consortium [MAGIC] has done a lot of work with biomarkers. For chronic GVHD, the biomarkers are not [able to help with] early diagnosis or even risk stratification. There has been work with several biomarkers, but MAGIC is evaluating a combination of 2 biomarkers in an equation that helps risk stratify patients. It’s not ready for primetime at every center, but we have been able to identify patients with high-risk or low-risk GVHD and have run a few clinical trials for low-risk patients [to investigate their likelihood of] avoiding steroids or having decreased complications related to steroids. We have a pediatric-specific study [examining whether patients with low-risk GVHD] can start on a lower dose of steroids and taper more quickly, using the biomarkers to guide this. We’re getting there, and we’re closer [to identifying biomarkers] for acute GVHD than for chronic GVHD.

Patel: Some of the upcoming studies we’ll see will be evolutionary in the sense of using steroids plus other new or existing GVHD treatments. The goal here is to see whether we can use fewer steroids. [The use of steroids in GVHD presents an] interesting dilemma. The reason steroids have been around for so long and have been so effective is that they probably hit a lot of different targets. Sometimes, the dirtier the drug, the better.

[We need to strike] a fine balance between an agent that is targeted and focused against a specific part of the pathway and an agent that hits a lot of different [targets]. Unfortunately, whenever you hit a lot of different [targets], you also [generate] a lot of AEs and potential complications. That’s always been the push and pull. [Data with] some of these combination regimens and therapies, especially in frontline settings, may still show we need some steroids, but maybe not as [many steroids]. That could still be a positive gain for patients.


  1. Second Annual GVHD Day. GVHD Alliance. Accessed February 16, 2024. https://www.gvhdalliance.org/gvhd-day/
  2. FDA approves ruxolitinib for chronic graft-versus-host disease. FDA. September 22, 2021. Accessed February 16, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ruxolitinib-chronic-graft-versus-host-disease
  3. Wolff D, Cutler C, Lee SJ, et al. Safety and efficacy of axatilimab at 3 different doses in patients with chronic graft-versus-host disease (AGAVE-201). Blood. 2023;142(suppl 1):1. doi:10.1182/blood-2023-186963
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