Bone marrow transplants are one of cancer care's striking successes, but they have a dark side: The transplanted cells can turn on patients, attacking their skin and organs.
This potentially deadly side effect, called graft-versus-host disease, strikes several thousand each year. The last decade has brought little progress in battling it.
Last month brought another blow, as the Food and Drug Administration rejected orBec, the new drug closest to market. But orBec's manufacturer is pledging additional research to satisfy the FDA's concerns. And it joins a list of other promising experiments into ways to ease the misery -- from novel stem-cell infusions to drugs that block immune cells run amok.
The burst of research comes none too soon, as a long-lasting form of graft-versus-host disease is on the rise.
"I love my doctors, but they throw up their hands," says Stephen Dugan, 54, of Radnor, Pa.
A transplant four years ago saved Dugan from cancer. Two months later he barely survived a harsh bout of graft-versus-host disease; now he battles a less severe but chronic form.
When someone receives a transplanted organ, the big fear is that their own immune system will attack the new "foreign" tissue. Graft-versus-host disease is the opposite problem. It occurs when patients receive donated bone marrow or the stem cells that produce it from someone else's immune system. Sometimes the donor's T cells, whose job is to hunt foreign invaders, attack the recipient's body.
It happens in at least half of the more than 6,000 Americans who receive allogeneic -- or donated -- marrow or stem-cell transplants every year. Many times, the disease is mild or moderate, causing skin rashes or blistering, vomiting, liver or lung damage. One case in five is life-threatening. A particularly dangerous form ravages the stomach and intestines, causing unremitting vomiting and diarrhea.
The only treatment: Super-high doses of the steroid prednisone for weeks, to suppress out-of-control immune cells and the inflammation they cause. But the treatment's side effects are severe, even deadly: Patients fall prey to infections; it debilitates bone and muscle until some become bedridden; and it can cause violent mood swings. Plus, about half of seriously ill patients fail to improve, prompting doctors to add other steroids.
"They're our best friends but our greatest enemies," says Dr. Steven Pavletic of the National Institutes of Health, referring to prednisone and its cousins.
Treatments that aim to calm graft-versus-host disease without that steroid toxicity are now in advanced testing:
* OrBec is a milder kind of steroid, a pill version of the beclomethasone that asthma patients have long inhaled. Dr. George McDonald of Seattle's Fred Hutchinson Cancer Research Center reformulated the drug to coat the gastrointestinal tract, not roam the body.
Adding orBec to standard prednisone seemed to improve survival, a year after gut graft-versus-host disease first struck, by 45%. But because of a statistical issue with the research, the FDA told Dor BioPharma, orBec's manufacturer, to show more evidence that orBec works. The company pledged to do so, and has a different Phase III trial under way -- to see if giving orBec with the transplant can prevent gut graft-versus-host disease in the first place.
* The experimental drug Prochymal aims to soothe the disease without suppressing immunity. It's made of a different kind of stem cell, mesenchymal cells, which are damaged during a bone marrow transplant. But when donated ones are infused into patients' bodies, they steer to wherever graft-versus-host disease is attacking and "change the chemical environment and basically put the brakes on," says Dr. Hans Klingemann, bone marrow transplant chief at Tufts New England Medical Center. He is independent safety monitor for Osiris Therapeutics' studies of the drug.
In a small study, adding Prochymal to steroid treatment doubled chances of a complete recovery. A large Phase III trial is trying to confirm that effect.
* Johns Hopkins University researchers are studying whether two doses of an old cancer drug, cyclophosphamide, at the time of transplant could prevent the disease. The drug is thought to block the function of bad-acting immune cells, while allowing the rest of the immune system to rebuild after the transplant. Of roughly 100 patients tested so far, 65% have needed no further anti-graft-versus-host disease protection. Larger studies at other hospitals are about to begin.