Graft versus host disease in allogeneic bone marrow transplants

Rehabilitation Oncology, 1999 by Hyser, Hilary

Introduction

The American Leukemia Society reports that Graft Versus Host Disease (GVHD) affects approximately 50% of allogeneic bone marrow transplant patients and proves fatal in nearly 30% of patients who have clinically significant GVHD. GVHD refers to an acute and/or chronic condition that frequently complicates allogeneic bone marrow transplants. It develops when transplanted immunologically competent donor T-cells identify the patient's body as nonself, and, subsequently, launch an immune system attack on the patient's organs. Because the patient's immune system is suppressed prior to the transplant, it is unable to counter the attack. The risk of GVHD is minimized through careful matching of the recipient and donor HLA markers. The purpose of this article is to discuss GVHD, including the acute and chronic clinical presentation and the implications on physical therapy treatment.

HLA System

The HLA system, or the human leukocyte antigen system, refers to an inherited set of genetic fingerprints (HLA markers) found on the surface of human cells that define a person's tissue type. T-cells utilize the HLA markers to distinguish "self" from "nonself" cells and to summon the immune system to attack and destroy foreign antigens. The greater the disparity between the body's HLA markers and the foreign antigen, the swifter and more vigorous the attack. The success of a bone marrow transplant depends largely on how closely the donor and patient HLA-markers match.

It has been established that the HLA-A, HLA-B, and HLADR loci on white blood cells play an important role in determining the severity of GVHD. To minimize the risk of GVHD, a donor whose HLA type matches that of the patient is best. Because HLA markers are inherited, siblings are more likely to have similar HLA-antigens than unrelated persons. The ideal donor is an identical twin who genetically has the same antigens as the recipient at both the major loci (HLA-A, -B, and -DR) and the less well-known or harder to detect HLA sites. The next best donor is a sibling whose HLA-A, -B, and -DR antigens match those of the patient. A sibling mismatched for one antigen at either the HLA-A, -B or -DR site (a 5 out of 6 antigen match) is also a suitable bone marrow donor. However, when more than one antigen is mismatched, the incidence of severe GVHD significantly increases and long-term survival rates decrease.

Risk Factors

HLA mismatching is the primary risk factor associated with acute GVHD. The National Cancer Institute reports that 70% of patients receiving marrow with 2 mismatched antigens develop significant acute GVHD, as compared to 40% of patients receiving HLA-identical marrow. The prior occurrence of acute GVHD is the most prominent risk factor for developing chronic GVHD. Indeed, 70 to 80% of patients with acute GVHD develops the chronic condition. Other risk factors include an unrelated donor and recipient, a patient 30 years of age or older, a recipient and donor of the opposite sex, and a female donor with 2 or more viable pregnancies.

The results of a 1998 Carlen study indicate a positive correlation between the presence of multiple risk factors and the 5-year incidence of chronic GVHD. The 5-year incidence is 9% when no risk factors are present, 29% with 1 risk factor, 53% with 2 risk factors, 68% with 3 risk factors, and 75% with 4 risk factors.

Acute GVHD

Acute GVHD describes a syndrome, occurring within the first 100 days posta,llogeneic BMT, usually within 30 to 40 days, in which the proliferating transplanted immune competent cells destroy the epithelial cells in the gastrointestinal tract, liver, and skin. The classic clinical presentation of acute GVHD is dermatitis, hepatitis, and gastroenteritis (Table 1). Physicians quantify acute GVHD by, first, clinically staging each individual organ system based on its degree of involvement (Table 2). Then, an overall grade is assigned by combining the clinical stage of each involved organ (Table 3). Clinically significant acute GVHD is defined as an overall grade of II, III, or IV. Both pharmacological and nonpharmacological agents are used to reduce the severity and incidence of acute GVHD.

Pharmacological Agents Immunosuppressive drags, ie, Cyclosporine (alone or in combination with Prednisone and/or Methotrexate), are administered pre- and post-transplant to reduce the incidence and severity of GVHD. These drags may be administered in high doses for several months, particularly if acute GVHD progresses to Stage II or if the patient develops chronic GVHD. Side effects of Cyclosporine may include kidney toxicity, increased body hair growth, and, on rare occasions, neurological problems including seizures, confusion, anxiety, and changes in thought process. Inflammation of the mouth, nose, and/or throat is the most significant potential side effect of Methotrexate. Potential side effects of steroid administration consist of weight gain, fluid retention, elevated blood sugar level, mood swings, and/or confused thinking. Fortunately, the side effects of these drugs are temporary and disappear when drug administration is discontinued.