HIV Drug Reduces Graft-versus-Host Disease in Bone Marrow Transplant Patients
July 11, 2012 - PHILADELPHIA - An HIV drug that redirects immune cell traffic significantly reduces the
incidence of a dangerous complication that often follows bone marrow transplants for blood cancer patients, according to research from
the Perelman School of Medicine at the University of Pennsylvania that will
be published today in the New England Journal of Medicine . The findings represent a new tactic for the prevention of
graft-versus-host disease (GvHD), which afflicts up to 70 percent of transplant patients and is a leading cause of
deaths associated with the treatment.
Allogeneic bone marrow transplantation - also known as stem cell transplantation - involve the transfusion of a matched
donor's blood stem cells to rebuild the patient's bone marrow after treatment has eliminated both the defective blood cells associated
with their cancer and their healthy blood cells.
"It appears that our new approach allows us to prevent some patients from developing GvHD by redirecting immune cells
away from certain sensitive organs that they could harm," says lead author Ran Reshef, MD ,
an assistant professor in the division of Hematology-Oncology and a member of the Hematologic Malignancies Research Program at
Penn's Abramson Cancer Center. "This is a novel way for us to try to decrease treatment-related complications among bone marrow transplant
patients without also reducing their new immune system's ability to attack their cancer."
Typically, patients receive immunosuppressive drugs following their transplant to lower the risk of developing
graft-versus-host disease (GvHD), which occurs when the newly transplanted immune cells attack healthy tissue they perceive
as foreign. But since patients' own immune systems must be wiped out in order to receive their transplants, those drugs
leave patients even more vulnerable to life-threatening infections and to a relapse of their cancer. The Penn team
found that treatment with the HIV drug maraviroc dramatically reduced the incidence of GvHD in organs where
it is most dangerous - the liver and gut -- without compromising any other function of the immune system.
The findings, which involved repurposing maraviroc -- approved for HIV treatment in 2007 -- could represent a breakthrough
for prevention of GvHD. Reshef and his co-authors showed that the drug is safe in BMT patients who receive stem cells from a healthy
donor, and that a brief course of the drug led to a 73 percent reduction in severe forms of GvHD in the first six months after
transplant, compared with the incidence rate typically seen in similar patients who do not receive maraviroc.
"Just like in real estate, immune responses are all about location, location, location," Reshef says. "Cells of the immune
system don't move around the body in a random way. There is a synchronized and well orchestrated process whereby cells express particular
receptors on their surface that allow them to respond to small proteins called chemokines, which direct the immune cells to specific
organs where they are needed -- or in the case of GvHD, to where they cause damage. We're using maraviroc, which was initially
designed to prevent certain types of HIV from entering healthy cells in the body, as a traffic signal to direct the donor's
immune cells away from those places in the body where they might cause GvHD."
Thirty-eight patients with blood cancers, including acute myeloid leukemia, myelodysplastic syndrome, lymphoma,
myelofibrosis and others, were enrolled in the trial. All patients received the standard GvHD prevention drugs tacrolimus and
methotrexate, plus a 33-day course of maraviroc that began two days before transplant. In the first 100 days after
transplant, none of the patients treated with maraviroc developed GvHD in the gut or liver, which are the most
severe forms of the illness. At six months, only six percent of patients treated with maraviroc had severe
graft-versus-host disease, only three percent had it in their liver, and nine percent had it in their
gut. Among similar patients who receive standard drugs without maraviroc, rates of severe GvHD six
months after transplant are 22 percent, with liver and gut involvement seen in 15 and 27 percent
of patients, respectively. At one year, the benefit of maraviroc appeared to be partially
sustained, with a cumulative incidence of severe GvHD of only 15 percent, as opposed to
29 percent in patients who receive standard therapy.
Based on these data, the research team plans to try a longer treatment regimen with maraviroc in future studies, to see if they could
prolong the protective effect.
The differential impact of maraviroc on the liver and gut indicates that the drug is working as expected, by limiting the movement
of immune cells called T lymphocytes to specific organs in the body. Maraviroc works by blocking the CCR5 receptor on lymphocytes,
preventing the cells from trafficking to certain organs. The researchers saw no effect on skin GvHD, so they theorize that the
CCR5 receptor might be more important for recruiting lymphocytes into the liver and the gut than for the skin.
Maraviroc treatment did not appear to increase treatment-related toxicities in these patients, nor did it alter the relapse rate of
their underlying disease or risk of infection, and it did not slow the amount of time it took for patients' new immune systems to
engraft in their bodies.
David Porter, MD , professor of Medicine and director of Blood and Marrow Transplantation in the Abramson Cancer Center, and
Robert Vonderheide, MD, DPhil , associate professor of Medicine and Associate Director for Translational Research at the
Abramson Cancer Center, are the senior authors of the study.
Funding support for this investigator-initiated trial comes from the Abramson Cancer Center, the Leukemia and Lymphoma Society, the
American Society of Hematology, the National Cancer Institute and the National Heart, Lung, and Blood Institute of the National
Institutes of Health (K24-CA117879, P30-CA16520, and U01-HL069286), the American Society of Clinical Oncology, and Pfizer, the
maker of maraviroc.
Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions
of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman
School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of
Pennsylvania Health System, which together form a $4.3 billion enterprise.
The Perelman School of Medicine is currently ranked #2 in U.S. News & World Report's survey of research-oriented medical
schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $479.3
million awarded in the 2011 fiscal year.
The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania
-- recognized as one of the nation's top 10 hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; and Pennsylvania
Hospital - the nation's first hospital, founded in 1751. Penn Medicine also includes additional patient care facilities and services
throughout the Philadelphia region.
Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities.
In fiscal year 2011, Penn Medicine provided $854 million to benefit our community.
Source: Penn Medicine: University of Pennsylvania
"Reproduced with permission - Penn Medicine: University of Pennsylvania"
Penn Medicine: University of Pennsylvania
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