Recognizing cGVHD and When to Make Key Management Decisions

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Chronic graft-vs-host disease (cGVHD) is a heterogenous condition that is the leading cause of nonrelapse mortality in patients who have received allogeneic hematopoietic cell transplantation (HCT) for hematologic malignancies.¹ It occurs when donor lymphocytes cause immune-mediated cellular injury of the recipient’s organs, including skin, gastrointestinal tract, and liver. It can take many forms, and patients who have acute GVHD (aGVHD) are more likely to experience cGVHD as well.

Both aGVHD and cGVHD increase in frequency due to the use of unrelated and/or human leukocyte antigen (HLA)–mismatched donors and peripheral blood stem cells in grafts, though improved prophylactic conditioning regimens can limit their occurrence. The primary treatment for cGVHD is steroid based, but in the past decade, new therapies that target the complex biological mechanisms behind the disease have been advanced for use after steroid failure.

“The goal of treatment is ideally to reverse the manifestations of cGVHD, but in reality, it is to prevent the progression of cGVHD and improve quality of life, functional ability, and other activities of daily life,” Catherine J. Lee, MD, associate professor, clinical research division, Fred Hutch Cancer Center in Seattle, Washington, told participants in a Case-Based Roundtable event she moderated.

Timely action is crucial at each stage of management in patients with cGVHD, from identifying and assessing the severity of disease to determining how and when to start steroid therapy, and when to move to alternative agents. In 2 virtual Case-Based Roundtable discussions, participants shared their insight on how they would approach swift and personalized management of a patient with cGVHD.

Recognizing Manifestations of cGVHD

Because GVHD presents in many forms, and the chronic form can also appear over a long period of time, it is challenging to identify immediately, but rapid intervention is crucial to controlling disease and preventing organ damage. Physician examination alongside patient-reported observations is important to diagnose cGVHD.

In the roundtable events, physicians were asked when they tell patients to report symptoms. Most said within days or weeks of starting therapy, rather than at day 100 or waiting until their next appointment (Poll 1). In an event moderated by Corey S. Cutler, MD, MPH, director of the adult stem cell transplantation program at Dana-Farber Cancer Institute and associate professor of medicine at Harvard Medical School, both in Boston, Massachusetts, he agreed that immediate reporting of symptoms was best. “The longer you wait with symptoms, the more likely they are to progress into something fixed and irreversible,” he said.

Tools such as the Lee Symptom Scale and the National Institutes of Health (NIH) Clinical Scoring of Organ Systems contribute to the assessment of GVHD’s presence and severity. Though the disease is heterogeneous, certain signs such as sclerotic features on the skin are considered diagnostic of cGVHD without the need for biopsy, whereas others are distinctive but not sufficient to confirm diagnosis.² According to Lee during the other event, GVHD of certain organs can be difficult to diagnose. When there is gastrointestinal involvement, patients may report vague issues with multiple causes, and other organs such as the lungs, eyes, and joints are difficult to treat effectively.

For non–transplant specialists, a comprehensive scoring approach to cGVHD can be challenging. “It’s very tough for the community [physician] to do all these scoring systems; it’s beyond us in the short time we have with the patients,” said Jaideep Shenoi, MD, of Skagit Regional Health Cancer Care Center in Mount Vernon, Washington, in Lee’s event. Stressing the importance of the scoring, Cutler pointed out that the mild, moderate, and severe scores have prognostic value for the outcomes of patients.³

Ji-Lian Cai, MD, of Southern California Permanente Medical Group in San Marino, California, said during Lee’s event that he anticipates cGVHD in patients who had aGVHD, and counsels his patients to monitor for anything abnormal and send him a message with pictures. He said he would be wary of symptoms such as fever, skin rash, and weight loss. He was also concerned that patients can be lost to follow-up, which can lead to them being treated in an emergency department that is not prepared to care for patients with cGVHD.

In the other event, Cutler noted that there tend to be interobserver differences in how health care providers grade cGVHD when using the NIH scoring system. Michael Schuster, MD, of Stony Brook University Hospital in New York, said that his practice makes heavy use of taking photos when assessing patients; Cutler said he does the same and this can be helpful in judging features such as the progression of a rash over 4 to 8 weeks. On a similar note, Lee recommended consulting the National Marrow Donor Program (NMDP) photo atlas found at bethematchclinical.org to see examples of various manifestations of cGVHD.⁴ Cutler also recommended the NMDP’s app, including its version for patients that tells them what signs to look for after HCT and when to look for them.

Initiation and Monitoring of Steroids

Once cGVHD is diagnosed and scored, the first-line treatment is with steroids, usually systemic corticosteroids, but sometimes topical versions when indicated, such as for primarily skin or oral disease. Early intervention benefits the patient’s survival as well as their quality of life.

Between 40% and 50% of cGVHD cases are steroid refractory, leading to a need for additional treatment.² Lee said that it is important to recognize early on if patients are not responding to treatment so the physician can move on to the second line and beyond. Steroid intolerance because of toxicity also necessitates moving on from first-line treatment. A third challenge to consider is if patients are steroid dependent and cannot safely be tapered off steroids following a response.

Participants were asked how long they keep a patient on steroids before switching to a second-line therapy. In clinical trials, the definition of steroid-refractory cGVHD was progressive disease for 1 to 2 weeks while on 1 mg/kg daily of prednisone or stable disease with 0.5 mg/kg daily for 1 to 2 months. A majority answered that they would switch if the GVHD persisted for more than 4 weeks on high-dose steroids, though several in each event said they would do so if it persisted for more than 1 week without response (Poll 2).

Cutler explained that the answer to this question has changed as physicians have gained access to effective second-line therapeutics. “A lot of us would have said 4, 6, 8, maybe even 12 weeks before we had good second-line drugs.” Now, physicians may feel more comfortable intervening earlier knowing that nonsteroid options can offer a good chance of response. In Lee’s event, she noted that providers don’t always strictly follow the definitions of steroid-refractory disease, but in her experience, acting between 4 and 8 weeks is normal.

Christopher DiSimone, MD, of Providence Medical Group in Santa Rosa, California, commented in Lee’s event that they should not overlook the toxicity of being on high-dose steroids for a long period, and if patients are having adverse events, they should not need to wait 2 to 4 weeks before switching. “I give 1 to 2 weeks, keep them on for another week, and if I am not seeing any further response, then I’m already thinking of moving on.”

Moving to Second-Line Treatment

The National Comprehensive Cancer Network (NCCN) guidelines list over 15 options for suggested systemic agents for cGVHD.² However, 3 have an FDA approval in this setting: ibrutinib (Imbruvica), ruxolitinib (Jakafi), and belumosudil (Rezurock). These drugs have different mechanisms of action, and there is no consensus on how the approved options may benefit different subgroups of patients.

According to Lee, factors that can shape the choice of therapy include patient tolerability, cost of therapy, physician experience, and convenience of administration. As an example, she said that extracorporeal photopheresis, which was commonly used in the past, has decreased in popularity in larger academic centers as taking a pill is easier than traveling to the center for treatment.

Cutler pointed out that second-line drugs can be used during a steroid taper or until the agent shows response in steroid-dependent disease, especially in the 40% to 50% who have steroid-refractory disease. Using steroids in combination has been investigated in trials, such as with ibrutinib in the phase 3 iNTEGRATE trial (NCT02959944).

The participants were asked which drug they would prefer for a case patient with mild to moderate cGVHD of the skin (Poll 3). The highest proportion of participants selected ruxolitinib, which is the only agent also approved to treat acute GVHD. Participants expressed that they had seen good responses with ruxolitinib as well as with belumosudil.

Cutler surveyed his group on the dose of ruxolitinib; he said he generally starts at 10 mg twice daily unless patients have low blood cell counts. Iris Isufi, MD, of Yale New Haven Health in Connecticut, said she usually does as well but knows others who prefer a lower dose to avoid transfusions. Isufi said it is also a challenge to know when the maximal response is to discontinue ruxolitinib. “I think that’s why many of these patients end up being on these drugs for longer than they have to,” she said.

Evolution of GVHD Management

The transition from steroids to other therapies continues to be the leading challenge in cGVHD. The NCCN recommends clinical trial enrollment when possible so new regimens can be investigated in this area of need.

Cutler anticipated that another agent will be approved by the end of 2024. Axatilimab, a monoclonal antibody targeting CSF-1 receptor on activated macrophages, showed efficacy against late-stage cGVHD in the randomized phase 2 AGAVE-201 study (NCT04710576) in patients with heavily refractory cGVHD.⁵ “We’re hoping to see a fourth drug FDA approved, and that’s pretty good for 7 years of progress; to go from 0 to 4 drugs is changing the game in cGVHD.”

He added that the incidence, prevalence, and characteristics of cGVHD have changed in the last 7 years because of the adoption of posttransplant cyclophosphamide (PTCy) in allogeneic HCT, beginning with its use in HLA-matched mobilized blood cells. Over various trials, PTCy has shown major improvement in GVHD occurrence and severity over other prophylaxis in HLA-matched and mismatched unrelated donors. One recent successful trial was the randomized phase 3 BMT CTN 1703 trial (NCT03959241), which showed the benefit of cyclophosphamide, tacrolimus, and mycophenolate mofetil vs tacrolimus plus methotrexate, with 21.9% cumulative incidence of cGVHD at 1 year in the experimental arm vs 35.1% with the standard prophylaxis.⁶

“If you’re talking about long-term rates of cGVHD under 20%, it does change the equation in terms of the risk-benefit ratio of transplant for a number of patients,” said Cutler. “When you can tell them there’s more than an 80% chance they are cured of their malignancy, that they will not have long-term consequences of transplant, I agree it is a game changer. It has opened transplant to essentially everyone who walks through our door.”

REFERENCES:

1. Hamilton BK. Updates in chronic graft-versus-host disease. Hematology Am Soc Hematol Educ Program. 2021;2021(1):648-654. doi:10.1182/hematology.2021000301

2. NCCN. Clinical Practice Guidelines in Oncology. Hematopoietic cell transplantation, version 1.2024. Accessed May 7, 2024. https://www.nccn.org/ professionals/physician_gls/pdf/hct.pdf

3. Sato T, Ichinohe T, Kanda J, et al. Clinical significance of subcategory and severity of chronic graft-versus-host disease evaluated by National Institutes of Health consensus criteria. Int J Hematol. 2011;93(4):532-541. doi:10.1007/ s12185-011-0820-0

4. Chronic GVHD. National Marrow Donation Program. Accessed May 7, 2024. https://bethematchclinical.org/post-transplant-care/chronic-gvhd/

5. 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

6. Bolaños-Meade J, Hamadani M, Wu J, et al. Post-transplantation cyclophosphamide-based graft-versus-host disease prophylaxis. N Engl J Med. 2023;388(25):2338-2348. doi:10.1056/NEJMoa2215943