Overview of GVHD Types and Symptoms

EP: 1.Patient Profile: A 48-Year-Old Man with Chronic GVHD

EP: 2.Transplant Conditioning Regimens and GVHD Prophylaxis

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EP: 3.Overview of GVHD Types and Symptoms

EP: 4.Therapy Options for Patients with Chronic GVHD

EP: 5.Treatments for Steroid-Refractory Chronic GVHD

EP: 6.Second-Line Approaches to Treating GVHD

EP: 7.Clinical Insights on the Future of GVHD Treatment

Case: A 48-Year-Old Man with Chronic GVHD

• 48-year-old man undergoes myeloablative conditioning followed by matched unrelated donor hematopoietic cell transplant for acute myeloid leukemia w/ tacrolimus + methotrexate as graft versus host disease prophylaxis
  • The donor is a cytomegalovirus seropositive 50-year-old woman with 3 children
• Day +22, acute GvHD of skin emerged, successfully treated with slow steroid taper
• Bone marrow testing performed at 6 months and 12 months post-transplant show AML in complete remission
• 1.5 years post-transplant, new-onset skin changes with hyperpigmentation, lichen-planus and superficial sclerodermatous-like features on lower trunk and lower extremities (not confirmed); 15% BSA involved
• Prednisone initiated, initial dose 0.5 mg/kg/d (max 10 mg/kg per week), then 4-week taper
• After 7 days of prednisone, initial improvement in BSA involvement (now 10% to 15%), with no improvement in range of motion, remained stable thereafter on 0.5 mg/kg every other day

Transcript:

Yi-Bin Chen, MD: Graft-vs-host disease [GVHD] occurs in 2 flavors. We mentioned that the early form is called acute graft-vs-host disease. That generally happens sometime within the first 6 months, and more commonly within the first 3 months after transplantation. We tend to think there are 3 major organs involved: the skin, the GI [gastrointestinal] tract, and the liver.

Skin manifestations include an erythematous skin rash that is usually very symmetrical and is not usually pruritic. Classic areas of involvement include the nape of the neck, the ears, the palms, and the soles of the feet. With the use of different transplant platforms, we’ve seen a lot of heterogeneity. Skin is the most common form and is also the easiest to treat. The GI tract can involve the upper or the lower GI tract. Upper GI symptoms include persistent nausea, anorexia, and vomiting. That tends, in general, to be a bit easier to treat. Some even question the existence of upper tract GI GVHD, with large studies suggesting it may have no influence on the overall outcome. Lower GI disease, by far, is the most worrisome. It’s responsible for the most morbidity and early mortality after allogeneic transplant that is associated with graft-vs-host disease. It presents as voluminous, watery diarrhea. We will quantify the diarrhea to try to understand how well it’s improving. People with lower GI disease will get rehospitalized and often stay in the hospital for several weeks to receive treatment and recover. Hepatic disease, or involvement of the liver, is by far the rarest manifestation. Usually it is just an asymptomatic elevation of liver function tests until it gets into the end stage manifestations.

Chronic graft-vs-host disease can start any time usually after 2 or 3 months, but it typically starts after 6 months. These manifestations are much less dramatic than acute graft-vs-host disease. Part of that is that we’re seeing patients less, so perhaps we don’t notice the subtle changes very much. Chronic graft-vs-host disease can involve almost any organ. It’s a very heterogeneous disease. I’ll mention a few common manifestations: dry eyes, dry mouth, sort of the sicca syndrome. The skin rash remains quite symmetrical, but it’s not so angry and erythematous as with acute disease. It’s a bit scaly. It can resemble eczema or psoriasis. It can have these lichenoid changes and can be a bit more papular. It’s got a silvery feature to it.

Certainly, one of the more serious manifestations is underlying scleroderma of the skin, which is thickening of the skin or fascia, the connective tissue between the skin and the muscles. If that gets severe, it can resemble systemic scleroderma, and can have a huge impact in morbidity. Involvement in the lung, something called bronchiolitis obliterans syndrome, is another difficult-to-treat manifestation. That usually presents very indolently. Diagnosis is often done through imaging, pulmonary function tests, and maybe bronchoscopic biopsy. But if you look in the literature, any organ can technically be involved in chronic graft-vs-host disease, but those are the most common that I listed.

Staging for chronic graft-vs-host disease has evolved throughout the years. It started as a 2-stage system, being limited or extensive. It was quickly realized that there were limitations of that staging, especially to conduct clinical trials. The modern staging for chronic graft-vs-host disease is done by the NIH [National Institutes of Health] consensus system, which assigns scores of 1 to 3 for every organ system that’s involved. Then those scores are added and will stratify patients into mild, moderate, or severe subclasses. Moderate or severe manifestations generally correlate with the need for systemic therapy, but there are exceptions. Some mild cases require systemic therapy, and other moderate cases, maybe if there is only 1 organ involved, such as the eyes or the mouth, you would focus on localized therapies. The staging that the NIH consensus group developed is definitely an advance. It has helped us be able to conduct clinical trials in chronic graft-vs-host disease and has assisted with regulatory approval of several agents. However, the system remains imperfect, and that’s inherent to the nature of the disease.

Judging a response, even judging the severity, still there is a significant element of subjectivity in chronic graft-vs-host disease. Judging a response is oftentimes subjective as well, depending on the manifestations one is trying to compare. Then if you look at the responses by the NIH system, there could be partial responses that are life changing and improve a patient’s quality of life tremendously. There are also partial responses that any patient or provider would not be satisfied with. It’s our job as we go forward to figure out how to best distinguish those responses. We’re really after those responses that improve a patient’s quality of life. There are limitations. It’s still a work in progress. The staging system requires some learning and experience, and takes some time to complete correctly, but that’s where we are right now. I think if you look at our patient in terms of staging, even though the body surface area is a relatively minor amount, they do have some superficial scleroderma, which automatically gives them a skin score of 2. That would put them in the moderate chronic graft-vs-host disease classification.

Transcript edited for clarity.