Gentler treatment for many with graft-vs.-host disease

A new study finds halving standard steroid dose treats most acute GVHD just as well; could limit dangerous side effects
Dr. Marco Mielcarek
Dr. Marco Mielcarek, a clinical researcher at Fred Hutch, led a new study testing the effectiveness of lower doses of prednisone for patients with acute graft-vs.-host disease. Photo by Robert Hood / Fred Hutch News Service

For cancer patients who’ve undergone bone marrow transplantation, graft-vs.-host disease can seem like a cruel irony. The donor immune cells that fought off their cancer now attack other body parts, leading to painful skin rashes, digestive troubles and sometimes liver problems.

Up to 70 percent of transplant recipients develop acute GVHD, which crops up within the first few months of transplantation. And 40 percent get chronic GVHD, which can evolve from acute GVHD or appear on its own and is often more severe and can last for years.

As if the double whammy of a treatment-induced disease after cancer wasn’t enough, the standard medication for GVHD – the steroid prednisone – carries its own host of potentially serious side effects, including an increased risk of dangerous infections in patients whose immune systems have already taken a major hit from the transplant procedure.

So doctors have to balance the risk of out-of-control GVHD with minimizing prednisone’s side effects, said Dr. Marco Mielcarek, a clinical researcher at Fred Hutchinson Cancer Research Center who led a new study testing lower doses of prednisone in patients with acute GVHD.

Along with rendering transplant patients even more vulnerable to infection, prednisone can cause severe muscle wasting, especially in the elderly, and mood swings and it increases blood sugar levels, which sometimes triggers diabetes and high blood pressure.

“If one could minimize [these side effects], that would be very much wanted,” Mielcarek said. “And nobody had tried to go really low on the prednisone.”

Since prednisone is potentially dangerous at high doses, especially when given over long periods, the standard course of treatment starts at a relatively high dose and then tapers to lower doses within a matter of days, weeks or sometimes months, depending on how quickly patients’ symptoms resolve.

But the starting dose was partly set based on the drug’s use in other medical conditions, Mielcarek said. “We don’t really know what the optimal starting dose of prednisone is [for acute GVHD].”

Half a dose as effective for most patients

In their new study, published Feb. 14 in the journal Haematologica, Mielcarek and his colleagues found that halving starting prednisone doses in 164 patients was just as effective for most people with acute GVHD.

For patients who present at the clinic with moderate GVHD, which is 75 to 80 percent of those with the disease, the study’s findings were so definitive that they will change the standard treatment at Seattle Cancer Care Alliance, Fred Hutch’s treatment arm, where Mielcarek treats transplant patients. These patients, who can have nausea, vomiting, mild to moderate diarrhea and rashes, were no more likely to require additional treatments for their GVHD, progress to more severe stages or die from their disease than those who started at the higher dose. To Mielcarek’s knowledge, no other centers are using such low doses as standard of care for acute GVHD.

Before the study, those patients received starting daily doses of 1 milligram of prednisone per kilogram of body weight. This means that a patient who weighed 155 pounds would start out taking 70 mg every day. Mielcarek and his colleagues found that a daily starting dose of 0.5 mg per kg worked just as well.

For those who present with severe GVHD, the remaining 20 to 25 percent of patients with acute GVHD, the study results weren’t quite as straightforward. These patients have much more serious symptoms including abdominal cramping, severe diarrhea and rashes that cover more than half of their skin. They normally receive 2 mg per kg of body weight per day as a starting dose; the study compared that dose to 1 mg per kg of body weight.

The lower dose of prednisone seemed to work just as well for patients with severe GVHD involving the stomach and intestines. But patients with severe GVHD of the skin who started on the lower dose often needed additional treatments to keep the GVHD in check. So for now, SCCA will recommend using the higher starting dose for most patients with severe GVHD, in particular those with skin symptoms.

Elderly patients may benefit the most

Mielcarek is keen to minimize prednisone’s potentially toxic side effects in his clinic, where he’s seeing more and more elderly cancer patients. So-called “mini-transplants,” a gentler version of bone marrow transplantation first pioneered at Fred Hutch, brought the curative treatment to an older population that could not tolerate the traditional, more toxic treatments used to prepare patients for transplantation.

So for that group of patients, studies like this are especially important, Mielcarek said.

“For more elderly people, the toxicity becomes exceedingly difficult to tolerate if they get GVHD and need prednisone,” he said. “We have to make a real effort to use treatments that can be tolerated by patients in their 60s and 70s.”

The study’s other authors are Fred Hutch clinical research nurse Terry Furlong and clinical researchers Drs. Barry Storer, Margaret Green, George McDonald, Paul Carpenter, Mary Flowers, Rainer Storb, Michael Boeckh and Paul Martin.

Rachel Tompa is a former staff writer at Fred Hutchinson Cancer Center. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Follow her on Twitter @Rachel_Tompa.

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