Researchers fighting bone marrow cell rejection

WASHINGTON -- 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.

The potentially deadly side effect with the unwieldy name of graft-versus-host disease, or GVHD, 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 the new drug closest to market.

But that drug, called orBec, isn't dead. Its manufacturer is pledging additional research to satisfy 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.

Increasing problem

The burst of research comes none too soon, as a long-lasting form of GVHD is on the rise.

When someone receives a transplanted organ, the big fear is that their own immune system will attack the new "foreign" tissue. GVHD is the opposite problem. It occurs when patients receive donated bone marrow or the stem cells that produce it, pieces of someone else's immune system. Sometimes the donor's T cells, whose job is to hunt foreign invaders, become super-aggressive and 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, GVHD is mild or moderate, causing skin rashes or blistering, vomiting, liver or lung damage. But one of every five cases is life-threatening. A particularly dangerous form ravages the stomach and intestines, causing unremitting vomiting and diarrhea.

The only treatment: 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. In addition, about half of seriously ill patients fail to improve, prompting doctors to frantically add other steroids.

Drugs being tested

Now in advanced testing are treatments that aim to calm GVHD without that body-wide steroid toxicity:

• 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 GVHD first struck, by 45 percent.
• The experimental drug Prochymal aims to soothe the source of GVHD's inflammation without suppressing immunity. It's made of a different kind of stem cell, mesenchymal cells. Your own mesenchymal cells are damaged during a bone marrow transplant. But when donated ones are infused into patients' bodies, they steer to wherever GVHD is attacking. There, overly aggressive T cells spur high levels of chemicals called cytokines that in turn inflame tissue.

* Johns Hopkins University researchers are studying if two doses of an old cancer drug, cyclophosphamide, at the time of transplant could prevent GVHD anywhere in the body. It's a drug thought to block the function of only bad-acting immune cells, while allowing the rest of the immune system to build back up after the transplant. Of roughly 100 patients tested so far, 65 percent have needed no further anti-GVHD protection, says Dr. Leo Luznik of Hopkins Kimmel Cancer Center. Larger studies at other hospitals are about to begin.