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Clinical Practice Spotlight: Management of Graft-versus-Host-Disease (GVHD)

  • Advances Doctors Issue 3, Spring 2014
  •  Advances in Hematologic Malignancies Issue 3 Spring 2014

    Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic stem cell transplantation, second only to disease relapse among post-transplant causes of death. GVHD is largely a T-cell-mediated disorder resulting in unregulated inflammation and tissue damage of affected host organs.

    Risk factors for GVHD include greater degree of HLA mismatch between donor and recipient; stem cell source (the risk of GVHD with peripheral blood stem cells is greater than with bone marrow stem cells, which is, in turn, greater than with umbilical cord blood); gender mismatch with the donor; multiparity of a female donor; and more intensive conditioning regimens. GVHD prophylaxis is routine after allogeneic transplant, and here at Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC), we typically use tacrolimus, methotrexate, and sirolimus.

    Acute GVHD affects the skin, gastrointestinal tract, and liver. The classic skin manifestation of acute GVHD is an erythematous maculopapular rash. The most common presentation of gastrointestinaI GVHD is frequent, watery, and voluminous diarrhea. Patients can also have nausea, vomiting, and weight loss. Liver involvement is classically characterized by elevated bilirubin, but elevated transaminases may occur, as well. Biopsy of involved organs can be helpful in establishing diagnosis in ambiguous cases.

    Acute GVHD often occurs within the first three months of transplantation, but late-onset acute GVHD is also possible — especially after reduced-intensity conditioning transplants—and occurs in the context of immunosuppression tapering. Acute GVHD is staged by the extent of organ involvement.

    Initial treatment of acute GVHD is with prednisone at a starting dose of 1-2 mg/kg/day, followed by a slow taper over many months. Examples of second-line therapies include sirolimus, mycophenolate mofetil, extracorporeal photopheresis, and monoclonal antibodies, such as alemtuzumab and daclizumab. Numerous clinical trials are available at DF/BWCC for patients with steroid-resistant GVHD.

    Chronic GVHD can affect many organ systems and is a serious cause of late morbidity after transplantation. It is critical to be vigilant for the signs and symptoms of chronic GVHD, as early intervention is critical to prevent the long-term sequelae of this disease. Ocular involvement presents as dry eyes and a painful, gritty sensation due to corneal abrasion. Oral mucosal involvement includes sensitivity to spicy or hot foods, lichenoid changes, hyperkeratotic features, and ulceration. Skin manifestations include lichenoid and sclerodermatoid rashes; the nails or hair can also be involved. Fascial changes can occur, and can cause joint contractions if severe.

    Early signs of pulmonary involvement by chronic GVHD include shortness of breath, manifesting as a decline in FEV1 on pulmonary function tests. Patients with gastrointestinal involvement may have difficulty swallowing, weight loss, nausea, or vomiting. Liver involvement is marked by elevated liver enzymes and bilirubin. Genital involvement can occur in both women and men.

    Grading of chronic GVHD is done using the National Institutes of Health Consensus Criteria developed in 2005. Initial treatment of chronic GVHD is prednisone, 0.5-1 mg/kg/day, often with tacrolimus. Topical therapy is often applied to the eyes, mouth, skin, and genital areas. The same agents used in acute GVHD are also used in steroid-resistant cases; however, other drugs, such as interleukin-2, rituximab, imatinib, bortezomib, and other investigational agents, are often added.

    Given the complex nature of chronic GVHD, we often involve consulting specialists with an interest in GVHD, including dermatologists, pulmonologists, gynecologists, oral medicine specialists, endocrinologists, ophthalmologists, and gastroenterologists. These DF/BWCC experts have been extremely helpful in the management of our patients.

    GVHD can have a dramatic impact on patients' functional abilities and quality of life. Emotional support is, therefore, also critical for affected patients and their caregivers, and our program provides extensive support services and resources for our patients and their families.

    Melissa Cochran, MS, NPMelissa Cochran, MS, NP  Corey Cutler, MD, MPH, FRCPCCorey Cutler, MD, MPH, FRCPC