Graft-Versus-Host Disease

Graft-versus-host disease is a common complication following allogeneic transplants (transplants using donor marrow or blood stem cells). Roughly 20 to 50 percent of patients transplanted with marrow from an HLA-matched1 related donor develop GVHD. Among older patients, and those transplanted with marrow or peripheral blood stem cells from an unrelated or mis-matched donor, the incidence is even higher. GVHD is not a complication associated with autologous transplants.

GVHD is triggered by a type of white blood cell in the donor’s marrow or peripheral blood stem cells called T-cells. The donor T-cells are trained to recognize which cells belong in the donor’s body, and which cells do not. When transplanted into the patient, the T-cells perceive the patient’s organs and tissues as foreign cells, and orchestrate an immune system attack to destroy them.

¹ HLA—human leukocyte antigens—are proteins on the surface of white blood cells that play a critical role in protecting the body against foreign organisms. If certain HLA antigens on the donor’s white blood cells match those of the patient’s, the donor is an HLA match. If they differ, the donor is called a mismatched donor.

Fortunately, most patients experience only a mild or moderate form of the disease that resolves over time with treatment. But for those whose GVHD is more severe, managing this potentially life-threatening complication can be a serious challenge.

There are two types of GVHD: acute and chronic. Patients may experience either type, both or neither.

Acute GVHD

Acute GVHD occurs during the first three months after transplant. The first sign is typically a mild skin rash. The rash may spread or transform into a redness similar to sunburn. In more severe cases, the patient’s skin may blister or peel. Acute GVHD can also affect the liver, stomach and/or intestines, causing cramping, nausea, watery or bloody diarrhea, and/or jaundice (yellowing of the skin and eyes).

Patients at greatest risk for developing acute GVHD are those transplanted with a mis-matched or unrelated donor. A gender mis-match between donor and patient, prior donor pregnancies and older patient age may also increase the risk. For patients undergoing an allogeneic peripheral blood stem cell transplant, the use of cyclosporine alone, rather than a combination of cyclosporine and methotrexate, to prevent GVHD appears to increase the risk of developing acute GVHD.

To lower the likelihood of developing acute GVHD, patients typically receive a combination of cyclosporine and methotrexate, or tacrolimus (FK506, Prograf®) and methotrexate. These drugs weaken the ability of donor T-cells to orchestrate an attack on the patient’s organs and tissues. Several studies have reported a lower incidence of moderate to severe acute GVHD with the tacrolimus/methotrexate combination, than with the cyclosporine/ methotrexate combination.

Other strategies to prevent acute GVHD include use of newer DNA tests, which enable doctors to determine with greater accuracy whether a donor’s marrow type matches the patients, and T-cell depletion—a technique that removes the problematic T-cells from the donor’s marrow or blood stem cells before they are infused into the patient.

Approximately 50 percent of patients who develop acute GVHD can be successfully treated with steroids. Other drugs such mycophenolate mofetil (CellCept®), as well as some newer drugs that disable the proteins on the surface of T-cells that cause acute GVHD, have also shown promise in early clinical trials.

Chronic GVHD

Chronic GVHD develops three or more months after transplant. Patients with chronic GVHD usually experience skin problems that may include a dry itching rash, a change in skin color and tautness or tightening of the skin. Liver abnormalities, dry or burning eyes, dry mouth, mouth sores, infections and stomach irritation are also common symptoms of chronic GVHD.

Less frequently, patients with chronic GVHD experience skin scarring, partial hair loss, pre-mature graying, severe liver problems, vision difficulties, heartburn, stomach pain, difficulty swallowing, weight loss, breathing difficulties and/or a tightening of the tendons in joints that make extending or contracting legs and arms difficult.

Patients who have had acute GVHD are at greatest risk for developing chronic GVHD. Older patients, those transplanted with marrow or stem cells from an unrelated or mis-matched donor, and those transplanted with peripheral blood stem cells rather than bone marrow also have an increased risk of developing chronic GVHD.

Most patients diagnosed with chronic GVHD are first put on alternating doses of cyclosporine and prednisone. If this fails to resolve the problem, the dosage may be adjusted, another immunosuppressive drug added or another experimental therapy may be tried.

Tacrolimus and mycophenolate mofetil (MMF, CellCept®) have both shown some effectiveness in treating patients who have not been helped by cyclosporine and prednisone.

Skin GVHD

Chronic GVHD sometimes causes the skin to tighten–a condition called scleroderma. The addition of acitretin (Soriatane®) to the treatment regimen has helped some patients, while others have benefited from the use of clofazimine (Lamprene®) or hydroxychloroquine (Placquenil®).

PUVA treatments have provided relief to some patients with skin GVHD. Patients are first given the drug psoralen, and are then exposed to ultraviolet light. Although often effective in treating GVHD of the skin, PUVA increases a patient’s risk of later developing a treatable form of skin cancer.

A less toxic alternative is extra corporeal photopheresis (ECP). In this procedure, white blood cells are removed from the patient, incubated with psor-alen, exposed to ultraviolet light, and then reinfused into the patient. In preliminary reports, five of eight patients showed improvement after ECP.

Physical and/or occupational therapy has helped many GVHD patients with scleroderma maintain their flexibility and range of motion. Myofaceal release massage has helped some patients with facial scleroderma.

Other Symptom Relief

Topical steroids such as dexamethasone (Decadron elixir®), fluocinonide (Lidex®) and oral cyclosporine have helped some GVHD patients with mouth sores. PUVA treatments for the mouth is also a treatment possibility.

Dry eyes are common among patients with chronic GVHD. Preservative-free artificial tears, prednisolone eye drops (Predsol®) and chloramphenicol (Chloromycetin®) drops have helped some. Others have experienced relief from tear duct plugs.

A drug called URSO (Actigall®) has helped some patients with chronic GVHD of the liver. For patients whose chronic GVHD has affected the lungs, daclizumab (Zenapax®) may be effective.

Chronic GVHD often causes vaginal strictures, making intercourse painful or impossible. Some patients have found relief using betamethasone ointment applied to the vulva and vagina.

A small number of patients have recently been treated with a drug called etanercept (Enbrel®). Six of the eight patients treated with the drug showed improvement of their skin GVHD following treatment, three reported relief in their joints, and three with lung GVHD improved. “There were no appreciable toxicities with this drug, and the patient’s steroid dose was successfully reduced in several cases,” notes Jean Henslee-Downey MD, director of Alternative Donor Transplants at Indiana Blood and Marrow Transplantation.

Protecting Against Infection is Key

The leading cause of death among patients with chronic GVHD is infection. Chronic GVHD breaks down the barriers such as skin and mucous membranes that normally prevent infectious agents from entering the body. The immunosuppressive drugs that control GVHD, as well as chronic GVHD itself, weaken the body’s infection-fighting immune system.

Patients should be put on drugs to prevent infection, practice good hygiene and be carefully monitored until the chronic GVHD resolves, says Georgia Vogelsang MD, a GVHD specialist at Johns Hopkins Oncology Center in Baltimore. “All patients should receive trimethoprim/sulfamethoxazole (Bactrim®,, Septra®) to protect against pneumocystis carnii, as well as drugs such as penicillin to protect against pneumococcus,” cautions Vogelsang. “Topical antifungals such as Mycelex® troches or nystatin swishes should be used in all patients receiving local steroid therapy for oral GVHD,” she adds.

“The use of systemic anti-fungals such as fluconazole (Diflucan®) and itraconazole (Sporonox®) should also be considered in patients who are on cyclosporine and steroids for long periods of time,” says Rainer Storb MD, GVHD specialist at Fred Hutchinson Cancer Research Center in Seattle.

GVHD’s Psychological Toll

As with most chronic illnesses, GVHD takes a psychological toll on patients and family members alike. Weary of dealing with illness and the other rigors of a transplant, patients often become angry or depressed with the onset of GVHD. The side effects of drugs used to treat GVHD can further stress their already delicate emotional state. Depression, confusion, anxiety, roller coaster-like mood swings and exaggerated feelings of anger, excitement or sadness disproportionate to the situation are common can make the GVHD recovery period a very trying time for patients and their loved ones.

Fortunately, for most patients the effects of GVHD resolve over time. Ongoing research will hopefully uncover new ways to prevent and treat this very challenging disease.

Jons Story