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 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. 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
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. 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toxicity was suspected, and so the drug was withdrawn for a time.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 (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
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.