More than a year after the blood stem cell transplant for his aggressive leukemia, Ted Ave’Lallemant thought he was easing back into his regular life—more or less. He’d returned to his hometown of Dearbrook, Wisconsin, from Seattle, where he and his family had temporarily lived in 2005 while he received the donated immune cells that would wipe out his cancer. The cancer was gone. He’d gone back to his job as a forester and had started running again.

Then one day after a shower, Ave’Lallemant’s wife noticed something strange on the skin of his lower back.

“It looked like as if you were to take the skin and crunch it up. It started to develop dark lines and it became tough like leather,” Ave’Lallemant said.

It was just a small patch, about 4 inches by 4 inches. But it spread quickly from there, around his torso and to his hips, then down his legs, tightening and restricting the skin and his ability to move normally.

It was scleroderma due to chronic graft-vs-host disease (GVHD), thickening his skin. Chronic GVHD is a common side effect of bone marrow or blood stem cell transplantation where the donor immune cells (the “graft”) attack the patient’s healthy organs in addition to the cancer—in this case, the skin.

“Sclerodermic manifestations of GVHD can be difficult to treat and, when severe, can affect quality of life,” said Dr. Mary Flowers, a GVHD and survivorship researcher at Fred Hutchinson Cancer Research Center and the medical director of the Long-Term Follow-Up Clinical Service for adult transplant patients at Seattle Cancer Care Alliance, Fred Hutch’s clinical care partner.

In this form of chronic GVHD, the skin gets thick and tight, leading to blood flow problems and skin ulcers that can take a long time to heal, Flowers said. In some cases, patients can have trouble bending their joints and even breathing, if the skin around the chest is affected.

Because of side effects like Ave’Lallemant’s, the hard work of research and clinical care doesn’t stop when a patient’s cancer is gone. That’s when survivorship researchers like Flowers step in. Curing cancer goes beyond just eliminating the last cancer cells at all costs, she said. She and her colleagues take a broader view of what cure means for patients.

“The quality of life of our patients is very important,” Flowers said. “The way I look at it, an effective treatment eradicates a disease without causing too much harm. You cannot just measure survival to determine if a treatment is successful, you must also evaluate its potential undesirable effects on quality of life.”

Chronic GVHD is treatable—usually patients are treated first with corticosteroids, but those also come with their own set of side effects.

That’s why Flowers and her colleagues are excited about recent advances in their field—the first drug for chronic GVHD, ibrutinib, was approved by the FDA last summer, after a nationwide clinical trial in which Fred Hutch participated. Flowers expects drugs like ibrutinib, which target specific immune cells involved in the disease, will be a game-changer for patients with chronic GVHD. There are more experimental drugs and prevention methods in trials underway right now that she’s also anticipating will make a big difference.

The cost of a cure

Bone marrow transplantation, developed at Fred Hutch in the 1970s and 1980s, provided the first definitive and reproducible example of the power of the immune system to cure cancer (which is now bearing fruit in the development of more targeted cancer immunotherapy approaches). A transplant of immune cells from another person can do what our own immune cells cannot always do on their own: recognize cancer cells as foreign and eliminate them.

But that cure can come at a cost. For many transplant recipients, those donor cells also see healthy cells as foreign.

Chronic GVHD is caused when transplanted donor immune cells attack the recipient’s healthy cells and tissues. That can lead to skin GVHD, as in Ave’Lallemant’s case, but can affect other organs such as the mouth, eyes, lungs, gut, liver, connective tissues, or some combination. Up to 40% of transplant patients get chronic GVHD, which shows up more than 100 days after the transplant and can last for years or decades, ranging from mildly irritating to debilitating or even deadly. Up to 70% of patients get acute GVHD, which happens much more quickly after transplant and is either resolved with treatment or morphs into the chronic GVHD form.

Ave’Lallemant got both. His doctors at SCCA had told him the acute GVHD, which started in the first few days after his transplant, meant he was also more likely to get the chronic form later on.

“There was an element of surprise because it was so far out,” Ave’Lallemant said. “But it was like, they said I was going to get this, here it finally is.”

His GVHD lasted a long time—he was only able to stop the immune-suppressing drugs that were keeping it at bay last year, 12 years after that tough patch of skin first showed up—but although it did limit his activity, Ave’Lallemant didn’t find it significantly debilitating.

“I can’t really say GVHD has negatively impacted my life … Maybe someone else with the same symptoms would say that it has, but I don’t feel that it has for me,” Ave’Lallemant said. “It’s just part of the package that makes your life different after cancer.”

Understanding chronic GVHD

Until recently, chronic GVHD has proved a tough nut to crack, said Dr. Geoffrey Hill, a transplantation physician and GVHD researcher at QIMR Berghofer Medical Research Institute in Brisbane, Australia. Hill will join the Fred Hutch faculty later this year, where he will hold the José Carreras/E. Donnall Thomas Endowed Chair for Cancer Research.

“From a practical point of view, we haven’t really understood how or why chronic GVHD occurs and what the cellular and molecular mechanisms are that control it,” Hill said.

But in the last few years, there’s been a sea change in understanding the disease, thanks to preclinical research from Hill’s own lab and others that showed how different chronic GVHD is from acute GVHD, in terms of the cells and molecules involved in each disease.

Those findings implied that “treatments used for acute GVHD probably don’t work or won’t work very well for chronic GVHD,” Hill said. “And all clinical evidence is that they don’t.”

Researchers have suspected for a while that certain types of immune cells known as T cells are key players in chronic GVHD, Flowers said. Recently, there’s been a growing appreciation that a different class of immune cells known as B cells also play a role. The newly approved chronic GVHD drug, ibrutinib, works by targeting both types of these GVHD-triggering cells.

Targeted GVHD treatments bring hope

In the study that led to ibrutinib’s approval for treating chronic GVHD, nearly 70% of patients had some relief of their symptoms after taking the drug—and these were patients whose disease had already stopped responding to corticosteroid treatment, which broadly tamps down the immune system and is the standard first line of attack against GVHD.

Studies are now underway testing ibrutinib in combination with corticosteroids as a first-line treatment for chronic GVHD. Corticosteroid treatment comes with so many side effects of its own that even though it is often effective against GVHD, more targeted and less toxic treatments are sorely needed, Flowers said.

“Having a therapy that will decrease the use of corticosteroids remains a major goal for advancing the management of patients with chronic GVHD,” she said.

With the approval of the first therapy for chronic GVHD and the numerous other experimental treatments being tested in clinical trials, there’s a real sense of hope among the GVHD research community and the patients with the disease, said physician-scientist Dr. Stephanie Lee, who directs Fred Hutch’s Research long-term follow-up program in addition to leading the multi-institute chronic GVHD consortium.

As compared to just a few years ago, “we do have more to offer patients in terms of cutting-edge clinical trials and different treatments,” Lee said. “But because the research is pretty early on, we don’t know how well they will work. It hasn’t yet changed how we choose the first-line therapy.”

Does GVHD have to go hand-in-hand with cure?

In the early days of transplantation research, doctors didn’t even realize GVHD could happen, Flowers said. In some of the first transplants performed, researchers saw that patients who’d received donor cells from an identical twin had fewer side effects after the transplant than those who’d gotten a transplant from a non-twin sibling or from an unrelated donor—but those with twin transplants were also much more likely to relapse.

Researchers eventually realized those “side effects,” which they first termed secondary disease and later GVHD, were due to the donor cells attacking healthy tissue. But for a while, they didn’t realize the two attacks—against cancer cells and against the normal cells—could be separated. For many years, doctors told their patients a little GVHD was good, that it meant the transplant was working. Like yin and yang, GVHD went hand-in-hand with an effective transplant—or so the thinking went at the time.

Recently, though, that dogma is shifting. Researchers and physicians are realizing they can divorce the powerful graft-vs-tumor effect, which rids patients of cancer cells, from the damaging and sometimes deadly effects of GVHD. Again, those efforts come back to quality of life for survivors, said Lee.

“When I started in this field 20 years ago, most people were focused on just getting their patients through transplant,” Lee said. “Now, we do want it all. We want them to have good quality of life in addition to not having their disease come back, and a lot of that hinges on whether they get chronic GVHD or not.”

Preventing chronic GVHD

Several research efforts are aimed at preventing GVHD before it even crops up, Lee said. At the Hutch, clinical researcher Dr. Marie Bleakley is leading studies that separate out some immune cells from the donor blood or bone marrow before the transplant. Those clinical trials are based on a growing body of research that has sifted out the specific cells and molecules responsible for triggering GVHD. Bleakley’s studies have shown promising initial results in preventing chronic GVHD, dropping the rates of transplant patients who develop the condition from about 40% to less than 10%.

Researchers have observed that cord blood transplants, using blood cells from donated umbilical cords rather than blood stem cells from adult donors, result in lower levels of moderate to severe chronic GVHD—about 10% to 20% vs 40%. Other studies have also found that giving patients the immune system-suppressing drug cyclophosphamide as a preventive measure drops the risk of chronic GVHD by about 50%. Flowers and her colleagues recently found that in addition to lower rates of chronic GVHD, the disease was shorter in recipients of cord blood transplant and in those who had received cyclophosphamide.

Hill’s clinical work also focuses on GVHD prevention, building off the preclinical studies he and others led identifying the specific cells that drive the disease.

“What I’m really interested in is trying to develop prevention strategies for GVHD that involve much more targeted therapies,” he said. “That’s where I see the field moving, away from broadly immune-suppressive drugs and more toward targeted immune suppression that don’t have the same side effects.”

The next phase—getting even more targeted

Researchers are also coming to understand that different patients’ diseases may be even more distinct from each other than they’d previously realized.

“The real question now is, ‘Is all chronic GVHD the same?’ and it’s probably not,” Hill said. “So one treatment’s probably not going to fit all in chronic GVHD.”

Understanding the differences will entail identifying specific proteins and cells that are active in an individual patient, and tailoring that patient’s treatments accordingly. That will involve new blood tests to predict which treatment a given patient is likely to respond to, Hill said. But in parallel, researchers are also trying to identify targeted treatments that may work better for specific organs affected by GVHD, Lee said.

She and her colleagues at the Hutch are poised to launch a number of clinical trials testing therapies specifically for patients with just one form of chronic GVHD, such as scleroderma or lung GVHD.

In the coming years, “I think we’ll see even more targeting of specific kinds of chronic GVHD,” Lee said. “We won’t just treat all people with chronic GVHD the same. Instead, we’ll use markers in their blood and what organs are involved to intelligently select a treatment based on the kind of chronic GVHD they have.”

Those differences are likely part of the reason that combating chronic GVHD has proven so difficult, Lee said.

“Recent years have been exciting, but I wish I could point to a breakthrough that will work for most people. It’s just a very hard disease,” she said. “But there’s been a lot that’s happened the last couple years that makes me hopeful we’ll have better treatments ahead.”