Earlier this year, Dr. Rainer Storb was eating lunch in his office and poring over thick stacks of transplant patient data when he spotted something that lit up all his synapses at once.
Storb, who is one of the most respected bone marrow transplantation experts in the world and one of the founding members of Fred Hutchinson Cancer Research Center, immediately called a Fred Hutch statistician and put him to work on his hunch.
And sure enough, the data strongly suggested that within the group of patients he was studying, there was a higher rate of graft-vs.-host-disease among those whose white blood cell counts exceeded a certain threshold.
GVHD—and relapse of cancer—are two of the most feared complications stemming from bone marrow and stem cell transplants to treat leukemia and other cancers. From mild rashes to serious damage in the digestive tract, GVHD occurs when transplanted immune cells from a donor react against the tissue of a transplant recipient. In some of the worst cases, GVHD significantly reduces a person’s quality of life or even results in death.
Storb asked himself a question as he looked at the data: Was the transplantation process disturbing natural and healthy bacterial populations in patients’ guts and skin, the epicenters for GVHD?
Within the body of a healthy adult, microbial cells—collectively known as the human microbiome—outnumber human cells 10 to one. But these microscopic communities remain largely unstudied, leaving huge questions unanswered about their influence upon human nutrition, development, physiology, immunity and disease.
For Storb, the potential link between GVHD and a compromised microbiome is filled with possibilities. Could drugs used to fight pathogenic bacteria and viruses in immune-suppressed patients also hurt healthy bacteria, many of which play an important role in immunity, and lead to GVHD?
“We could do a transplant to fight leukemia and other cancers, and we could follow it with a microbiome transplant to bring a patient’s unique microbial population to normal levels, and that may offer a solution for some people with GVHD,” he said. “This is a really exciting lead.”
Storb doesn’t have the funding yet to follow his lead, but his willingness to look at a problem in a completely new way points to how things are done at Fred Hutch, the pioneer of bone marrow and stem cell transplantation and indisputably the world’s major contributor to advances in the field.
Innovative thinking leads to breakthroughs, and at Fred Hutch, researchers are free to take their ideas into new directions.
In nearly four decades of research, Fred Hutch investigators have never stopped asking the tough questions, even when it meant questioning their own work in transplantation.
These questions—and the answers—have led to immense improvements in the transplantation field. It’s this obsessive attention to detail that has contributed to making Fred Hutch into a premier research center with some of the best survival rates in the world for transplant patients at its treatment arm, Seattle Cancer Care Alliance.
With continued advances in technology and medicine, it’s also becoming easier to envision the promise of “precision medicine,” where therapeutic strategies—from what drugs to use to what mutating genes to target—are tailored precisely for each patient fighting cancer, a remarkable shift from one-size-fits-all treatments used in the past.
“For years we have known that when we transplant bone marrow, we are also transplanting the donor’s immune system, and that the transplanted immune system can recognize the patient’s leukemia and help destroy it,” said Dr. Fred Appelbaum, director of Fred Hutch’s Clinical Research Division.
“We have long dreamed of being able to harness this effect and amplify it,” Appelbaum said. “Incredibly, we now have that capability; we are conducting studies in which we are isolating the cells that recognize a patient’s leukemia, manipulating them to increase their numbers and their potency, and using these to treat patients. It’s a very exciting time."
Research saves more lives
Because Dr. George McDonald has been at Fred Hutch since 1988, he knew that transplantation improvements were leading to better outcomes for patients. But as researchers will tell you, intuition is not enough. So he set out to prove it.
“I knew mortality was down, but I didn’t know by how much,” he said.
Dr. George McDonald
McDonald and Gooley looked at transplantation data from 1993 through 1997 and compared it to data from 2003 through 2007. Along with decreased mortality, they also found significant declines in the risks of several complications after transplantation, including severe GVHD, infections caused by viruses, bacteria and fungi, and damage to the lungs, kidney and liver.
“This research and the improved outcomes are the result of a team approach to one of the most complex procedures in medicine,” McDonald said. “Everything we looked at improved a decade after the initial analysis.”
McDonald and Gooley pointed to several changes in clinical practices that were important in reducing risks—with many of these changes spurred by research studies conducted at the Hutchinson Center:
• Careful monitoring of dose adjustments of potent chemotherapy drugs used in transplantation, avoiding too much or too little treatment.
• Use of less intense pre-transplant drugs and radiation conditioning in older patients and in less healthy patients.
• Less use of high-dose systemic immune suppressive drugs to treat acute GVHD.
• Use of the drug ursodiol to prevent liver complications.
• New methods for prevention or early detection of viral and fungal infections.
• Use of more effective and less toxic antifungal drugs to treat serious infections caused by yeast and mold organisms.
• Use of donor blood stem cells instead of bone marrow as the source of donor cells, enabling faster engraftment and return
• More accurate matching of marrow or stem cell donors with unrelated patients.
But this is not enough for Fred Hutch researchers. The relapse of cancer and GVHD remain major concerns, which is why they’re also major areas of investigation.
Understanding why GVHD affects some people has been a long-standing scientific puzzle, making it hard to develop ways to prevent the disease. As Storb seeks a connection between a compromised microbiome and GVHD, his colleagues are looking at other potential causes. Dr. Effie Petersdorf has discovered a genetic component, while Appelbaum is now recommending a significant change in transplantation to help prevent GVHD.
Petersdorf has been seeking to understand what makes someone susceptible to GVHD, which is why she took a closer look at the DNA of more than
Dr. Effie Petersdorf
“The question I wanted to ask was whether there are genes we don’t know about that could be influencing GVHD risk,” she said.
This led to a key insight reported earlier this year: When bone marrow donors and patients have a difference in two key “single-nucleotide polymorphisms” (SNPs)—tiny variations in a person’s DNA—it increases a patient’s risk of suffering GVHD and lowers their odds of survival.
Petersdorf is translating this discovery into a new test that could help match patients with donors who have favorable SNP profiles, improving patients’ chances of avoiding GVHD.
“We’ll be including this test in a new transplant protocol at SCCA later this year,” Petersdorf said. “It could help us do an even better job of finding donors whose cells will benefit patients the most.”
This could be just the beginning. Petersdorf’s next step is to dig beyond SNPs and identify the actual genes that signal whether a person might suffer from GVHD. By improving donor-patient matching even more, this could spare more transplant patients from GVHD, boosting their odds of living longer, happier lives.
Calls for change to reduce risk of GVHD
In another front against GVHD, Appelbaum, one of the world’s leading bone marrow transplant experts, is recommending a significant change to current transplant practices for patients who need marrow or adult stem cells from an unrelated donor to treat hematologic malignancies.
In a recent editorial in The New England Journal of Medicine, Appelbaum wrote that bone marrow—not circulating, peripheral blood, which is the current norm—should be the source for unrelated donor adult stem cells for most patients who require a transplant.
He cited a new study by a former Fred Hutch transplant physician who found a higher incidence of chronic GVHD—53 percent when peripheral blood was the source of stem cells for transplant versus 41 percent from bone marrow.
Dr. Fred Appelbaum
In the meantime, researchers at Fred Hutch continue to make inroads into all facets of transplantation.
“We have some very exciting things going on here,” Storb said. “There was a time when patients spent months at the hospital, not knowing whether they would survive their transplants. Today, some of our patients come in for an afternoon, receive a small dose of radiation and stem cells from a donor, and then they go home.
“Preventing relapse, preventing GVHD, are what we are aiming to accomplish,” he said. “We’re really hustling to control these issues.”