A fresh look at an old problem often yields new solutions. Scientists in the Clinical Research Division are finding this philosophy holds true for their efforts to combat graft-vs.-host disease (GVHD), a frequent and sometimes serious complication of the bone-marrow and stem-cell transplants used to treat leukemia and other cancers of the immune system.
During the last three decades, transplantation has developed from a highly experimental treatment to one that offers cure rates of up to 90 percent for some cancers. Along with the evolution of the transplant procedure have come changes in some of the procedure's side effects. That has spurred Fred Hutchinson researchers to propose modifications to the guidelines used by transplant physicians to evaluate GVHD, a venture that promises to improve the care of those who suffer from the complication.
GVHD encompasses a wide spectrum of symptoms, from mild rash to serious damage in the digestive tract. The condition occurs when transplanted immune cells from a donor react against the tissue of a transplant recipient. The effect is due to differences in tissue type between all individuals — even siblings — other than identical twins. Although the reaction can actually be helpful when the targets are cancerous cells, GVHD can wreak havoc on normal tissue, particularly on fast-growing cells like those in the skin and the lining of the mouth and intestines.
Decades of research at Fred Hutchinson have led to improvements in tissue-type matching and new drug therapies that minimize the occurrence and severity of GVHD. In addition, research is underway to devise strategies that eliminate the destructive effects of GVHD on normal tissue while preserving the ability of GVHD to eliminate malignant cells.
Yet despite these advances, GVHD still strikes approximately 70 to 80 percent of transplant recipients. About 20 to 30 percent of these cases are serious enough to endanger survival or cause disability.
The gentler transplant
One major modification of the stem-cell transplant procedure has been the use of the "mini-transplant," a gentler form of the procedure developed at the center that is often used to treat older patients or those medically unfit to withstand a conventional transplant. When GVHD occurs in mini-transplant patients, the onset of the condition is delayed in those individuals compared to patients who receive conventional transplants.
These and other issues require doctors to rethink how GVHD is diagnosed, said Dr. Paul Martin, director of the research component of the center's Long-Term Follow-Up Program. The program tracks the outcome of former patients, some of whom experience GVHD symptoms for years after their transplant.
"The initial classification system for diagnosis of GVHD was established in the 1970s," Martin said. "Although this system still is useful, we'd like to change the way people think about GVHD by proposing some modifications to the existing guidelines."
Improving the accuracy of GVHD diagnosis benefits patients in two ways. First, accurate diagnosis helps doctors tailor treatments more specifically to a transplant recipient's condition. Second, it enables researchers who conduct clinical trials to more precisely and reproducibly assess the extent to which an experimental treatment affects GVHD incidence or severity, which allows quicker delivery of safe and effective new therapies into the mainstream patient population.
"With the current system, grading of GVHD is not highly reproducible among different doctors," Martin said.
To ensure consistency of diagnosis at Fred Hutchinson's transplant clinic at the Seattle Cancer Care Alliance, a single physician assesses GVHD severity. Still, changes in GVHD incidence patterns can occur when new procedures are used to diagnose the disease, as Martin and colleagues discovered when they conducted a retrospective analysis of their transplant patients over the last 15 years.
Those findings, as well as the growing realization among the greater scientific community that refinements to the current system are needed, prompted center researchers to propose new guidelines for GVHD diagnosis and classification.
Historically, doctors have drawn a distinction between the acute form of GVHD, which occurs within three months of transplant, and the chronic form, which begins at three months post-transplant or later. Although each type has some unique symptoms, Martin said that firm lines can't be drawn between the two based on timing alone.
"Symptoms of acute disease can go on for much longer than three months, and symptoms typical of chronic disease can begin before 100 days," he said. "Using the onset and persistence of symptoms as criteria is too ambiguous."
Martin and colleagues propose eliminating duration as a factor in classification and instead suggest that symptoms unique to acute or chronic should be the deciding factor.
Patient care and empowerment
After classifying GVHD as acute or chronic, doctors assign a grade from one to four that reflects the severity of the symptoms. Martin said that this system is also too ambiguous in its current form. His team has proposed that doctors now use the term "serious" to describe cases that meet certain very stringent criteria, such as prolonged hospitalization, significant disability or a specific number of infections, for example. Future discussions among the transplant community at large will be required to establish these criteria.
The ultimate goal, Martin said, is to provide patients with the best care and the maximum amount of information about their condition.
"The current system really doesn't speak to the patient very well," he said. "We've already begun to use some of the proposed guidelines with patients enrolled in clinical trials here. We're now able to inform patients more accurately about what kind of outcome they can expect — information they really want to know."