Post-Transplantation Complications of Unrelated Bone Marrow

Graft-versus-host disease (GVHD) represents a significant, perhapsneglected, complication of unrelated bone marrow transplantation,stated Daniel Weisdorf, MD, Professor of Medicine at the Universityof Minnesota, and Associate Director of the Adult Bone MarrowTransplantation Program, at a symposium on "Clinical Issuesin Unrelated Marrow Transplantation" held in associationwith the recent meeting of the American Society of Hematology.Prolonged immunocompromise is an additional hazard to recipientsof unrelated bone marrow transplants.

Typical Case of GVHD

To illustrate the extent of the problem of GVHD, Dr. Weisdorfoffered a case example from his practice. A 27-year-old man presentedwith L3 acute lymphocytic leukemia. After undergoing chemotherapyand entering remission, he received an unrelated donor allogeneictransplant. A B minor mismatched, 50-year-old woman was the donor.The patient received methotrexate and cyclosporine (Sandimmune)for GVHD prophylaxis. Also, GM-CSF (granulocyte macrophage colony-stimulatingfactor) (Leukine) was initiated for 14 days.

Among the early complications were diarrhea and rash over approximately25% to 30% of his body (histologically confirmed to be grade-2GVHD). He was then treated with prednisone. Even with dosage adjustmentsof prednisone and cyclosporine, the GVHD persisted (now confirmedto be grade-3 disease), and the rash spread (to more than 80%of his body). High doses of antithymocyte globulin (ATG) and prednisolonewere attempted, with a good partial response seen initially; nearly2 weeks later, the rash flared again. A gradual response was achievedwith another course of ATG and methylprednisolone. Again, withdosage adjustments, grade-2 GVHD was confirmed.

Four months after transplantation, the patient developed Herpeszoster infection and shortly later a basically unexplained cranialnerve palsy with diplopia and some facial weakness. Cyclosporinetoxicity was suspected, and so the drug was withdrawn for a time.The patient then developed Pneumocystis carinii pneumonia.Between 6 and 14 months after transplantation, there was no rash;however, when the patient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 weightgain and severe renal insufficiency.

At 15 months post transplantation, the patient "thinks heis doing well" on the following regimen: continued plateletand sometimes red cell transfusion, erythropoietin (for the past4 months), low-dose cyclosporine twice daily, prednisone everyother day, and an assortment of antibiotics for prophylaxis.

Such scenarios are not uncommon, Dr. Weisdorf emphasized, andelements of supportive care are equally important to immunosuppression.For instance, patients such as this one require aggressive maintenanceof hydration to tolerate cyclosporine. Dietary supplementationis needed because appetite is usually suppressed. Finally, theomission of needless drugs, often causing unrecognized drug interactions,is essential for optimal care of these patients, Dr. Weisdorfwarned.

Study Findings on Treatment Response

Dr. Weisdorf reviewed the results of several studies on the treatmentoutcome of GVHD in patients with unrelated marrow transplants.To begin, he focused on an analysis of 240 allogeneic transplantrecipients treated for GVHD. Two thirds of the patients receivedmismatched unrelated donor transplants and underwent a varietyof GVHD prophylactic techniques. Nearly 40% of patients experiencedsome degree of objective improvement in their symptomatology.

A variety of factors associated with response to GVHD therapywithin the first 4 weeks were studied in a multivariate analysis,Dr. Weisdorf explained. The development of gastrointestinal GVHDwas the only statistically significant finding. Clinical stagingof GVHD was not found to be an independent factor. Furthermore,Dr. Weisdorf indicated that in multivariate analysis, adults andchildren experienced the same odds ratio of response to treatment.

In a pilot study, initial therapy with ATG for acute GVHD wasevaluated. Patients with grades 2 and 3 acute GVHD were treatedinitially with ATG, at 15 mg/kg twice daily for 5 days, alongwith an intermediate dose of methylprednisolone (40 mg/m²/d),and were supported with prednisone thereafter. Patients with grade-4disease were treated with the same dose of ATG and much higherdoses (250 mg/m²/d) of methylprednisolone. Of the total 74patients, 21 received this regimen as primary therapy; the remaining53 patients received ATG as secondary therapy at a median of 46days after they failed to respond to prednisone alone. Unrelateddonor marrow recipients comprised approximately 50% of patientsin the primary group and 50% of patients in the group receivingATG as secondary therapy. According to Dr. Weisdorf, similar responseswere 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 tosuch factors as diagnosis, total body irradiation, different GVHDprophylaxis, and the severity of GVHD. Study findings showed thatrecipients of matched related donor transplants have a longersurvival than do those of unrelated donor transplants. However,some of these factors are associated with better response to evaluationof treatment response at day 28, Dr. Weisdorf added, indicatingthat such response is almost the only independently significantfactor in predicting improved survival. The major difference insurvival was seen during the first 6 months after transplantation.

Another reason for poor survival in unrelated donor marrow recipientsis infection, said Dr. Weisdorf. In one particular analysis, therisk of late infection after transplantation was studied in 249consecutive allogeneic transplant recipients between 1989 and1991. A total of 151 patients received related donor marrow transplantsand 98 patients received unrelated bone marrow transplants. Allclinically significant infections between 50 days and 2 yearsafter BMT were evaluated and 52% were donor marrow transplants.All clinically significant, microbiologically documented infectionstreated were evaluated. Of all the infections, nearly 45% werebacterial, approximately 30% were viral, and 10% were fungal.

It was quite surprising, Dr. Weisdorf said, that the related donormarrow recipients suffered more infections soon after transplantationthan did unrelated donor marrow recipients and yet a quite lowrate of infection nearly 12 months after transplantation. However,in unrelated donor marrow recipients, he added, there was a similarincidence of infection up to 12 months after transplantation,suggesting that their clinically significant immunodeficiencymight have led to this ongoing risk of infection.

In conclusion, Dr. Weisdorf posed several questions yet to beaddressed. Is early intensive immunosuppressive therapy helpfulin controlling the persisting and repeated flaring of GVHD? Canadditional supportive care reduce the mortality rate? Is ongoingintravenous immunoglobulin support more important to unrelatedthan related donor marrow recipients? He closed by saying thatwe need to develop modified, safer therapy for patients with GVHDand to consider infection prophylaxis up to at least 6 to 12 monthsafter transplantation for recipients of unrelated donor marrow.