Graft-versus-host disease (GVHD) represents a significant, perhaps neglected, complication of unrelated bone marrow transplantation, stated Daniel Weisdorf, MD, Professor of Medicine at the University of Minnesota, and Associate Director of the Adult Bone Marrow Transplantation Program, at a symposium on "Clinical Issues in Unrelated Marrow Transplantation" held in association with the recent meeting of the American Society of Hematology. Prolonged immunocompromise is an additional hazard to recipients of unrelated bone marrow transplants.
Typical Case of GVHD
To illustrate the extent of the problem of GVHD, Dr. Weisdorf offered a case example from his practice. A 27-year-old man presented with L3 acute lymphocytic leukemia. After undergoing chemotherapy and entering remission, he received an unrelated donor allogeneic transplant. A B minor mismatched, 50-year-old woman was the donor. The patient received methotrexate(Drug information on methotrexate) and cyclosporine (Sandimmune) for GVHD prophylaxis. Also, GM-CSF (granulocyte macrophage colony-stimulating factor) (Leukine) was initiated for 14 days.
Among the early complications were diarrhea and rash over approximately 25% to 30% of his body (histologically confirmed to be grade-2 GVHD). He was then treated with prednisone(Drug information on prednisone). Even with dosage adjustments of prednisone and cyclosporine, the GVHD persisted (now confirmed to be grade-3 disease), and the rash spread (to more than 80% of his body). High doses of antithymocyte globulin (ATG) and prednisolone(Drug information on prednisolone) were attempted, with a good partial response seen initially; nearly 2 weeks later, the rash flared again. A gradual response was achieved with another course of ATG and methylprednisolone(Drug information on methylprednisolone). Again, with dosage adjustments, grade-2 GVHD was confirmed.
Four months after transplantation, the patient developed Herpes zoster infection and shortly later a basically unexplained cranial nerve palsy with diplopia and some facial weakness. Cyclosporine toxicity was suspected, and so the drug was withdrawn for a time. The patient then developed Pneumocystis carinii pneumonia. Between 6 and 14 months after transplantation, there was no rash; however, when the patient stopped the cyclosporine for 2 weeks, it recurred. Although liver function was normal, he had poor weight gain and severe renal insufficiency.
At 15 months post transplantation, the patient "thinks he is doing well" on the following regimen: continued platelet and sometimes red cell transfusion, erythropoietin(Drug information on erythropoietin) (for the past 4 months), low-dose cyclosporine twice daily, prednisone every other day, and an assortment of antibiotics for prophylaxis.
Such scenarios are not uncommon, Dr. Weisdorf emphasized, and elements of supportive care are equally important to immunosuppression. For instance, patients such as this one require aggressive maintenance of hydration to tolerate cyclosporine. Dietary supplementation is needed because appetite is usually suppressed. Finally, the omission of needless drugs, often causing unrecognized drug interactions, is essential for optimal care of these patients, Dr. Weisdorf warned.
Study Findings on Treatment Response
Dr. Weisdorf reviewed the results of several studies on the treatment outcome of GVHD in patients with unrelated marrow transplants. To begin, he focused on an analysis of 240 allogeneic transplant recipients treated for GVHD. Two thirds of the patients received mismatched unrelated donor transplants and underwent a variety of GVHD prophylactic techniques. Nearly 40% of patients experienced some degree of objective improvement in their symptomatology.
A variety of factors associated with response to GVHD therapy within the first 4 weeks were studied in a multivariate analysis, Dr. Weisdorf explained. The development of gastrointestinal GVHD was the only statistically significant finding. Clinical staging of GVHD was not found to be an independent factor. Furthermore, Dr. Weisdorf indicated that in multivariate analysis, adults and children experienced the same odds ratio of response to treatment.
In a pilot study, initial therapy with ATG for acute GVHD was evaluated. Patients with grades 2 and 3 acute GVHD were treated initially with ATG, at 15 mg/kg twice daily for 5 days, along with an intermediate dose of methylprednisolone (40 mg/m²/d), and were supported with prednisone thereafter. Patients with grade-4 disease were treated with the same dose of ATG and much higher doses (250 mg/m²/d) of methylprednisolone. Of the total 74 patients, 21 received this regimen as primary therapy; the remaining 53 patients received ATG as secondary therapy at a median of 46 days after they failed to respond to prednisone alone. Unrelated donor marrow recipients comprised approximately 50% of patients in the primary group and 50% of patients in the group receiving ATG as secondary therapy. According to Dr. Weisdorf, similar responses were seen in both groups.
Outcome and Survival Data
What factors beyond response to therapy might affect survival? In attempting to answer this question, Dr. Weisdorf pointed to such factors as diagnosis, total body irradiation, different GVHD prophylaxis, and the severity of GVHD. Study findings showed that recipients of matched related donor transplants have a longer survival than do those of unrelated donor transplants. However, some of these factors are associated with better response to evaluation of treatment response at day 28, Dr. Weisdorf added, indicating that such response is almost the only independently significant factor in predicting improved survival. The major difference in survival was seen during the first 6 months after transplantation.
Another reason for poor survival in unrelated donor marrow recipients is infection, said Dr. Weisdorf. In one particular analysis, the risk of late infection after transplantation was studied in 249 consecutive allogeneic transplant recipients between 1989 and 1991. A total of 151 patients received related donor marrow transplants and 98 patients received unrelated bone marrow transplants. All clinically significant infections between 50 days and 2 years after BMT were evaluated and 52% were donor marrow transplants. All clinically significant, microbiologically documented infections treated were evaluated. Of all the infections, nearly 45% were bacterial, approximately 30% were viral, and 10% were fungal.
It was quite surprising, Dr. Weisdorf said, that the related donor marrow recipients suffered more infections soon after transplantation than did unrelated donor marrow recipients and yet a quite low rate of infection nearly 12 months after transplantation. However, in unrelated donor marrow recipients, he added, there was a similar incidence of infection up to 12 months after transplantation, suggesting that their clinically significant immunodeficiency might have led to this ongoing risk of infection.
In conclusion, Dr. Weisdorf posed several questions yet to be addressed. Is early intensive immunosuppressive therapy helpful in controlling the persisting and repeated flaring of GVHD? Can additional supportive care reduce the mortality rate? Is ongoing intravenous immunoglobulin support more important to unrelated than related donor marrow recipients? He closed by saying that we need to develop modified, safer therapy for patients with GVHD and to consider infection prophylaxis up to at least 6 to 12 months after transplantation for recipients of unrelated donor marrow.