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From OncoLog, April 2013, Vol. 58, No. 4

Photo: Woman with scleroderma
Chronic graft-versus-host disease following allogeneic stem cell transplantation may resemble various autoimmune conditions. The patient above exhibits symptoms of scleroderma: thickening of the skin on the hands with fascial involvement.

Preventing and Treating Graft-Versus-Host Disease After Stem Cell Transplantation

By Kathryn L. Hale

Each year, thousands of patients with hematologic malignancies undergo allogeneic (donor) stem cell transplantation (SCT), which offers a chance at cure. Graft-versus-host disease (GVHD) is a potentially deadly complication of this therapy and occurs in 25%–60% of patients. However, clinicians and researchers are continually working to reduce the rate of GVHD occurrence and improve patient outcomes.

SCT is typically given to patients with a hematologic malignancy such as lymphoma, leukemia, or myeloma after they receive a relatively high dose of chemotherapy or radiation therapy, referred to as the conditioning regimen. The goals of the conditioning regimen are to eradicate the underlying malignancy and to suppress the patient’s immune system so that the donor stem cells are accepted. These treatments—and in some cases, the cancer itself—damage the bone marrow and thus disable the immune system. By reconstituting the stem cells in the bone marrow, SCT restores the patient’s ability to mount an immune response to pathogens. The restored immune system also recognizes and reacts to cancer cells to prevent disease recurrence.

Although allogeneic SCT offers great promise through the development of this “graft-versus-cancer” effect in the transplant recipient, it is not without risks and complications. The most common—and potentially serious—of these is the graft-versus-host (GVH) effect, in which the restored immune system targets the patient’s healthy tissues. This can create the potentially life-threatening complication known as GVHD.

GVHD risk factors

Amin Alousi, M.D., an associate professor in the Department of Stem Cell Transplantation and Cellular Therapy at The University of Texas MD Anderson Cancer Center, oversees clinical research related to the prevention and management of GVHD. “An individual patient’s risk of developing GVHD depends on the presence of a number of risk factors,” he said. “While many risk factors are inherent to the patient and the cancer, the single biggest factor is the donor.”

Donors are selected by human leukocyte antigen (HLA) typing. Historically, siblings were the most common donor source. A sibling, having the same parents as the patient, has a 25% chance of being an exact match.

“Allogeneic SCT from an HLA-matched sibling donor carries the lowest risk of GVHD,” Dr. Alousi said. “Unfortunately, a matched sibling donor often is not available, and we have to turn to alternative donors.” Because family sizes are decreasing in the United States, matched unrelated donors are currently the most common donor source. When a patient lacks a suitable HLA-matched sibling, a search is initiated in the worldwide volunteer donor registry, which lists more than 16 million potential donors. An HLA-matched donor is identified from this registry 30%–50% of the time.

When a matched donor cannot be found in the registry, the transplant team looks at other alternatives: a half-matched family member such as a parent, son or daughter, or haploidentical sibling; an unrelated donor who is not an exact match; or an umbilical cord stem cell transplant, which does not require an exact match. “But when we do that,” Dr. Alousi said, “the risk of GVHD increases. The less matched the donor, the greater the GVHD risk. The greater the risk, the more aggressive we need to be in taking measures to prevent GVHD both during and after the transplant.”

Even a perfect HLA match does not preclude the risk of GVHD, as mismatches of other proteins involved in the immune response confer some risk. Other risk factors include patient age (older patients are more likely than younger patients to develop GVHD) and sex mismatch between donor and recipient (for example, transplantation from a female donor, especially one who has been pregnant, to a male recipient carries a higher risk of GVHD).

Other risk factors for GVHD arise from the patient’s cancer itself. Higher cancer stage and more extensive previous therapy increase the risk of GVHD after SCT. Patients whose cancer has relapsed multiple times, has been heavily treated, or is not in remission at the time of the transplant are also at increased risk of GVHD.

Reducing GVHD risk

Photo: Scleroderma of the trunk
Photo: Scleroderma of the legs
Photo: Scleroderma of the legs
Photo: Patient with lichen planus Photo: Patient with lichen planus
The symptoms of chronic graft-versus-host disease vary greatly and may resemble autoimmune diseases such as scleroderma (A, B, and C) or lichen planus (D and E).
One approach to reducing the risk of GVHD, particularly in patients who are older or have comorbid conditions, is to give a less intensive conditioning regimen. “There’s no one standard conditioning regimen,” Dr. Alousi said. “Rather, we individualize the conditioning regimen to what we think the patient can tolerate. A less intensive conditioning regimen can reduce the risk of GVHD. The problem is that the less intensive regimen may also increase the risk of cancer relapse. It’s a fine line we’re walking.”

Another approach to reducing GVHD risk is to reduce the activity of T lymphocytes—which are largely responsible for the GVH effect—by physically removing them from stem cells before transplantation. According to Dr. Alousi, this approach can reduce the risk of GVHD, but at a great price. “If we remove the T lymphocytes, they’re no longer there to fight infections,” he said. “It slows patients’ recovery and puts them at greater risk of infection that they can’t fight off.”

Dr. Alousi’s research focuses on finding a new strategy that strikes a balance between these two approaches: “We’re looking for an approach that reduces the risk of GVHD while not reducing the graft-versus-cancer effect or the patient’s capacity for fighting infections. Ideally, we want to develop strategies that target the cancer proteins without risking damage to host cells.”

GVHD clinical management


GVHD takes one of two forms: acute or chronic. Acute GVHD usually occurs within the first 100 days after transplantation, whereas chronic GVHD occurs after day 100. Although the risk factors for the two are the same, the underlying mechanisms are believed to differ.

The symptoms of acute and chronic GVHD also differ. Patients with acute GVHD tend to have symptoms that include skin rashes, diarrhea, liver problems, and/or nausea and vomiting. The manifestations of chronic GVHD are notably varied. Chronic GVHD can affect any system of the body and tends to resemble diseases such as scleroderma, lupus erythematosus, and sicca syndrome. Chronic GVHD affects 25%–50% of patients who undergo allogeneic SCT.

According to Dr. Alousi, various means are used to prevent acute GVHD. These typically include an immunosuppressive regimen of one or more drugs such as tacrolimus, cyclosporine, methotrexate, and mycophenolate that begins at the time of the transplant. “As the graft matures, the host becomes more tolerant of it, and we slowly taper the immunosuppressive drugs to allow the donor cells to coexist with the host’s cells,” Dr. Alousi said. “However, about 20% of patients have to stay on the immunosuppressive regimen indefinitely.” Most current approaches for reducing GVHD risk have been more successful in minimizing the risk for acute than for chronic GVHD. However, reducing chronic GVHD risk is an area of active research.

Since GVHD can affect multiple organ systems, its management may require coordination among dermatologists, ophthalmologists, pulmonologists, and other specialists. The management goals for acute or chronic GVHD are to 1) catch it early and stop the process, preventing the disease from worsening; 2) treat symptoms and provide supportive care, minimizing GVHD’s effects on quality of life; and 3) prevent long-term toxic effects from the GVHD therapy.

The only treatment now considered standard for either acute or chronic GVHD is corticosteroids. Because long-term steroid use is linked to many potentially severe toxic effects, including diabetes, increased infection risk, profound muscle weakness, and cancer recurrence, development of alternative therapies is a priority for GVHD specialists.

Current clinical trials for GVHD treatment are investigating combinations of a steroid such as prednisone with other immunosuppressive drugs that will allow lower doses and earlier tapering of the steroid. Some regimens incorporate a technique known as extracorporeal photopheresis to reduce the GVH effect. The patient’s blood is circulated through a device that removes the white blood cells and platelets, treats them with a chemical that is then activated by exposure to ultraviolet light, and returns them to the circulation.

Community physicians key to identifying chronic GVHD


At MD Anderson and most SCT centers in the United States, patients stay in the hospital following SCT until recovering blood cell counts give clear evidence of engraftment, typically about 4 weeks. The patients are then discharged from the hospital and monitored closely by the transplant team until roughly 100 days after the transplant to make sure that their immune system is recovering, that they are not developing infection, and—most important—that they are not developing GVHD. Around day 100, the SCT patients are transitioned to the care of a physician in their home community.

The transplant team at MD Anderson works closely with the community physician. The Stem Cell Transplant Survivorship Clinic, which Dr. Alousi oversees, provides all the needed information to the community physician, who is given tools to help screen for chronic GVHD and information about what to do if GVHD is suspected. The physician can reach the survivorship clinic’s medical staff at any time with questions or concerns.

“We ask the community physician to be our ‘eyes and ears’ with the patient,” Dr. Alousi said. “Chronic GVHD is a clinical diagnosis. It can’t be detected with blood tests or imaging studies. The clinical signs may be very subtle.” The more common symptoms of chronic GVHD include skin rash, dry eyes, mucosal membrane dryness or pain, and joint stiffness. The less common symptoms include jaundice and lung or digestive problems. However, according to Dr. Alousi, chronic GVHD can look like “a hundred different syndromes.”

Quality of life after SCT

Studies have shown that the strongest predictor of long-term quality of life after SCT is the presence or absence of chronic GVHD. Transplant recipients who do not get chronic GVHD tend to have a quality of life similar to other people their age. While chronic GVHD can have a deleterious effect on quality of life, recipients whose chronic GVHD can be controlled tend to have a quality of life similar to those who do not get chronic GVHD. “GVHD and survivorship are very integrated,” Dr. Alousi said. “Helping patients live well after transplantation is in essence preventing or controlling GVHD. My role as a GVHD specialist is also a role in survivorship, in helping patients have the best possible quality of life after the transplant.”

Future research directions


An emerging area of research is the identification of biomarkers for GVHD. An effective biomarker might be able to predict which patients are likely to get GVHD after SCT, which patients who get GVHD are likely to have a more severe case that requires more aggressive therapy, or which patients with acute GVHD are most likely to develop chronic GVHD. An international effort is now under way to find such biomarkers and develop them for clinical use. Some progress has been made in early studies: researchers now know of some blood proteins that might indicate early—before the appearance of symptoms—which patients are developing GVHD. Additional markers are being studied to identify patients who are less likely to respond to standard initial GVHD therapy.

“We haven’t come far enough yet to put these markers to use in the clinic,” Dr. Alousi said. “And a biomarker is worthwhile only if there’s an effective therapeutic approach to act on it. Right now we’re trying to perfect the biomarkers so we can develop the therapies that specifically target them.” Nevertheless, Dr. Alousi said he and his colleagues are optimistic. “We’ve developed several promising strategies, and we’re going to keep at it until we find the ones that work.”

For more information, contact Dr. Amin Alousi at 713-745-8613.

Other articles in OncoLog, April 2013 issue:

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