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My Bone Marrow Transplant

Pain is inevitable, suffering is optional.

An existing drug dramatically  reduced the most serious complications of bone marrow transplants, University  of Pennsylvania researchers are reporting
The finding could  someday point the way toward an entirely new method of preventing the body  from “rejecting” transplanted organs of all kinds in the
future, experts  said.
The work demonstrates a possible new approach to transplants of  donated bone marrow, said Joseph Antin, a professor of medicine at Harvard,  who was
not involved with the study.
“It is the first time that someone has  tried to do this, which makes it fascinating in itself,” Antin said. “Now what  we need to do is confirm it” and compare how patients fare with and without  the drug in a randomized trial.
Antin chairs a committee in the Blood and  Marrow Transplantation Clinical Trials Network that will design such a trial  that could begin in a year or so.
For decades, transplants of nearly all  organs have been possible only with the use of powerful medications that  suppress the immune system so that it
doesn’t attack the alien organ. But  those immunosuppressant drugs can be toxic to other parts of the body and  leave recipients vulnerable to dangerous infections, often for the rest of  their lives.
Rather than searching for better immunosuppressant drugs, the  Penn researchers asked a different question: “What if we let the immune cells  do their job” – attacking cancers and other diseases “and we just tell them  where to go and where not to go?” said Ran Reshef, lead author of the paper published Thursday in the New England Journal of Medicine.
It turns out  that the traffic signal already exists. It is maraviroc, a drug that has been  on the market for five years to treat HIV.
The bone marrow study evaluated  only 35 patients, and the first-time finding must be replicated in larger and  longer trials. Whether the mechanism would work with transplants of other  organs is at this point hypothetical.
Still, several independent  researchers said the concept is sound, and the problem it tries to solve –  organ rejection – is major.
“Transplant surgeons would love to do two  things: to operate during the day” and avoid rejection, said Cataldo Doria,  director of transplantation at
Thomas Jefferson University Hospital, who, like  others, praised the study as “promising.”
The Penn study tested the HIV  drug for prevention of graft-versus-host disease, the most serious  complication of donor bone marrow transplants. About 10,000 Americans a year  receive these transplants, often after other treatments for leukemia and other  cancers have failed.
Because the bone marrow creates immune cells along  with blood cells, a transplant imports a new immune system to use against the  cancer. To the donated immune system, the recipient’s entire body is  alien.
Attacks on organs create graft-versus-host disease in 30 percent to  70 percent of patients.
After the researchers added maraviroc to the  standard immune-suppressing regimen for 33 days, they found that just 6  percent of the patients developed a severe form of the disease; typically, 22  percent would have.
After one year, 15 percent of the patients developed  severe disease, compared with the normal 29 percent. There were few side  effects. The early-phase trial had been intended to test only the safety of  the drug. “We didn’t really expect to see any efficacy results,” said Reshef,  who said the finding “was amazing even to us.”
If future trials are  successful, he and others predicted that maraviroc could become a supplement  to standard therapy for donor bone marrow transplants, probably not a  replacement.
Maraviroc is made by Pfizer, which won approval of the drug  for HIV in 2007. It did not initiate the Penn study but contributed funding,  as did the National Institutes of Health, the Leukemia and Lymphoma Society,  and other groups. A Pfizer spokeswoman said the company would not speculate  about the findings.
The drug treats a specific type of HIV by blocking the  path, known as a CCR5 receptor, that the virus uses to enter immune  cells.
For graft-versus-host disease, the researchers took advantage of an entirely different mechanism, known as chemotaxis, which controls where and  when
cells move around the body.
Just as traffic lights along South Broad  Street must be turned on by an electrical current before they can direct cars  to, say, Citizens Bank Park, the CCR5 receptors on cell surfaces must receive  specific chemical signals called chemokines to direct the immune cells to the  liver.
Maraviroc is known as a CCR5 antagonist because it attaches to the  same receptors and blocks the chemokines, leaving the cells without direction  and
protecting vital organs such as the liver from  attack.
Graft-versus-host disease is most severe in the liver and gut; CCR5  is involved with trafficking immune cells to those same organs.
After a  donor bone marrow transplant, immunosuppressive drugs typically are tapered  off as the new immune system adapts. By contrast, transplants of
“solid”  organs, such as the liver, kidney, and heart, require lifelong suppression of  the immune system to avoid attacks on the new organs.
The trial did not  investigate whether using a drug to block the CCR5 or other receptors would  work with those organs, but researchers said the concept would be the  same.
“There have been laboratory experiments that suggest that that’s  true,” said David L. Porter, a senior author of the Penn paper and director of Penn’s blood and marrow transplantation program. And studies have found that people with a particular deletion in their CCR5 receptor are less likely than others to reject a transplanted kidney, he said.
In an unrelated study  published last month, researchers at Jefferson used maraviroc to prevent  highly aggressive breast cancer cells from being
trafficked – in this case,  metastasizing – to other organs in mice, where they can kill.
Marcel Van  den Brink, the head of hematological oncology at Memorial Sloan-Kettering  Cancer Center in New York, noted that the concept of “blocking
trafficking”  has been pursued since the 1990s but this is the first trial that appears to  have had success.
For solid organs, “I think it is possible,” he said,  “maybe for the same organs that showed [positive results] here, such as the  gut and liver.”
Daniel Weisdorf, director of the adult bone marrow  transplantation program at the University of Minnesota Medical Center, said  research still needed
to prove that it was the trafficking mechanism rather  than something else that caused what he termed “very interesting and  promising” findings for
bone marrow transplants.
“If there is directed  signaling that tells lymphocytes to go to a kidney and attack a transplanted  kidney,” he said, then something like this “might work really  well.”


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