Finding a better (mis)match

Hutch News

Finding a better (mis)match

New way to pair blood stem cell donors with recipients promises to lower risk of potentially devastating transplant side effect

Aug. 28, 2015
Effie Petersdorf speaks at a meeting of the transplant team at Seattle Cancer Care Alliance

Dr. Effie Petersdorf discusses how to implement her recent findings in a meeting of members of the transplant team at Seattle Cancer Care Alliance.

Photo by Robert Hood / Fred Hutch News Service

Sometimes the treatment that is supposed to save your life comes with life-threatening risks itself.

This is the reality of blood stem cell transplantation, a lifesaving therapy developed at Fred Hutchinson Cancer Research Center that can cure blood diseases like leukemia, but which comes with a serious risk of a dangerous complication called graft-vs.-host disease.

Soon, many patients coming to Seattle for transplants will have a lower risk of this outcome thanks to additional genetic testing, which will be built on findings published this month in the New England Journal of Medicine by a team of researchers based at Fred Hutch.

“We’re extremely enthusiastic and excited because it’s something that we feel we should be able to translate” into patient care, said Dr. Effie Wang Petersdorf, the Fred Hutch clinical scientist who led the research. 

Graft-vs.-host disease, or GVHD, occurs when transplanted immune cells turn against their new host’s body. It affects over 70 percent of people who have received transplants from tissue-type–matched unrelated donors. Symptoms range in duration and severity, but in its most serious forms, GVHD can cause terrible pain, organ damage and even death.

Petersdorf said she expects the Fred Hutch Bone Marrow Transplant Program at Seattle Cancer Care Alliance to be able to implement this additional testing in the upcoming months. “We would be the first center in the world using these new concepts to select better donors,” she said.

In their recent study, Petersdorf and her colleagues figured out a way to identify “permissible mismatches” in a tissue-type marker called HLA-DPB1. HLA-DPB1 has long been known to contribute to GVHD if the donor and patient have different versions of this protein, but it is almost impossible to match.

“Now, with these data, I can say, if you can’t find a perfect match, then having a transplant from a donor with a permissible HLA-DPB1 mismatch is almost as good,” Petersdorf said.

Less-than-perfect matching

Twenty-five million people around the world are registered as willing donors of blood stem cells, which grow in the bone marrow and generate all the mature components of the blood and immune system. To find out which potential donor is the best match for any given patient in need of a transplant, a transplant team seeks to match as many as possible of a handful of tissue-type markers called HLA proteins. HLA proteins play a key role in the immune response and in transplant outcomes: Match them all, and the odds go up for a successful transplant.

But even when patients do have a transplant from a donor who matches at all 10 HLA proteins (the current gold standard at the Hutch), they can still get GVHD, with sometimes devastating results.

Mark and Nils Berggren

Mark and Nils Berggren before Nils began feeling symptoms of lymphoma (left) and during Nils' treatment for GVHD at Seattle Children's (right).

Photos courtesy of Mark Berggren

Mark Berggren knows all too well the horror that graft-vs.-host disease can be. His son, Nils, suffered from it for almost a year after receiving a blood stem cell transplant that cured him of his lymphoma.

“He really went through living hell. It was a horrendous thing to watch in anyone, let alone to see your own son go through it,” Berggren said. “Everything they say the disease can do, he went through. He beat them one at a time,” Berggren said, recounting his son’s struggles as the complication manifested itself throughout his young body.

“But in treating the skin problems, he suffered from inflammation of the lungs, and that was just too much,” Berggren said. Nils died in 2014 at age 14.

A key genetic controller revealed

What drives the development of GVHD in fully matched transplants? To find out, Petersdorf and her colleagues set out to explore the uncharted areas of the genome where the HLA genes reside.

Petersdorf’s team carried out a series of methodical experiments over several years that led them, eventually, to zoom in on one area: a DNA variant that controls how much of the HLA-DPB1 protein is produced.  

“When I saw that, I got extremely excited,” Petersdorf said. This particular genetic controller is also known to be involved in the immune response against hepatitis infection, and here it was, somehow involved in GVHD, too.

Even though research by Petersdorf and others has shown that mismatches in HLA-DPB1 increase risk for GVHD, HLA-DPB1 is not included in standard testing to identify a donor–patient match.

Only 15 percent of otherwise fully matched donors are also matched for HLA-DPB1, and prolonging the search for an HLA-DPB1–matched donor runs the risk that the patient’s disease will get worse and they’ll be less likely to survive a transplant, Petersdorf said. So the vast majority of transplants proceed with mismatches in HLA-DPB1.

“The problem is we’ve had no really good way to avoid it,” she said.

But in this study, Petersdorf’s team found a second-best solution for when it isn’t possible to match HLA-DPB1: Just make sure that if there is a mismatch, the patient’s cells only produce a little bit of the mismatched HLA protein. And that’s where the genetic controller comes in.

Petersdorf and colleagues found that when patients and donors were mismatched for HLA-DPB1, patients were less likely to get GVHD if they had low levels of the mismatched HLA-DPB1. But for patients whose mismatched HLA-DPB1 had a high-production controller, GVHD risk soared.

The researchers applied their new knowledge to study DNA samples from 146 transplant patients who had a choice of at least two fully matched unrelated donors under the existing gold-standard system for matching. They found that the majority of patients in this group would have been able to find an acceptable donor when HLA-DPB1 was taken into account — that is, a donor who was either matched for HLA-DPB1 or only mismatched with the patient’s low-production HLA-DPB1 protein (a “permissible mismatch”).

“We now understand that the machinery in our genome that governs protein expression actually has biological significance that’s important to patients. That’s a first,” Petersdorf said. “We have not considered variation in the regions of genes that are responsible for protein expression; up until now, we have been focused on the specific sequence of the protein itself.”

This research “opens up another dimension in matching donors and patients,” said Dr. Claudio Anasetti, who was not involved in this research but was a colleague of Petersdorf at Fred Hutch until 2004. Anasetti is a clinical researcher at Moffitt Cancer Center in Tampa, Florida, who specializes in transplantation of blood-forming stem cells and GVHD research. He said he plans to promote the Hutch team’s findings among his colleagues in the field. He expects that the transplantation program at Moffitt will implement HLA-DPB1 testing based on Petersdorf’s work as soon as possible.

Curing the cure

Petersdorf and members of the transplant-matching team at Fred Hutch’s treatment arm, Seattle Cancer Care Alliance, are currently “in the initial brainstorming period” about how to select potential donors based on their HLA-DPB1 protein , she said.

“This is information we believe can be pretty readily translated to patients who need an unrelated donor in the future, because we can type the gene and avoid choosing high-risk donors,” Petersdorf said.

In addition to clinical implementation, Petersdorf said the next steps for this research are to figure out how HLA-DPB1 works in the context of other HLA mismatches, and the mechanisms through which the genetic controller affects HLA-DPB1 and GVHD risk.

For Mark Berggren, this research and the promise of its swift translation into the clinic offer the kind of advance he and other family members have been hoping for.

“I’m very thrilled to hear these results,” said Berggren, who founded an endowment in Nils’ name to fulfill Nils’ dream of advancing research on GVHD. “If we can cure graft-vs.-host disease, or minimize it, we’re helping cure this cure for cancer and other diseases.”

What do you think of this new development? Tell us about it on our Facebook page.

Mark Berggren’s son, Nils, was diagnosed with anaplastic large cell lymphoma at 12 years old. Nils was successfully treated with a stem cell transplant, but later developed GVHD that took his life.

Do you think you could be the match for someone in need of a transplant of blood-forming stem cells? Learn about joining the donor registry.

Susan Keown, a staff writer at Fred Hutchinson Cancer Research Center, has written about health and research topics for a variety of research institutions, including the National Institutes of Health and the Centers for Disease Control and Prevention. Reach her at skeown@fredhutch.org.

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