HIV Drug Reduces Graft-versus-Host Disease in Stem Cell Transplant Patients, Penn Study Shows
New Approach Redirects Lymphocytes From Harming Vital Organs, Without Dangers of Immunosuppression
Abstract #1011 -- Inhibition of Lymphocyte Trafficking Using a CCR5 Antagonist - Final Results of a Phase I/II Study.
December 13, 2011 -(SAN DIEGO)- An HIV drug that redirects immune cell traffic appears to significantly reduce the dangerous complication
graft-versus-host disease (GvHD) in blood cancer patients following allogeneic stem cell transplantation (ASCT), according to new research
from the Perelman School of Medicine at the University of Pennsylvania that will
be presented today at the 53rd American Society of
Hematology Annual Meeting. Standard GvHD treatments suppress the immune system, reducing - but not eliminating - the
risk of developing the common problem. In the current trial, treatment with the HIV drug maraviroc dramatically reduced
the incidence of GvHD in organs where it is most dangerous -- without compromising the immune system and leaving
patients more vulnerable to severe infections.
"There hasn't been a change to the standard of care for GvHD since the late 1980s, so we're very excited about these results, which
exceeded our expectations," says 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 . "Until now, we thought that only extreme suppression of the immune system
can get rid of GvHD, but in this approach we are not killing immune cells or suppressing their activity, we are just preventing them from
moving into certain sensitive organs that they could harm."
Reshef and colleagues will present results showing that maraviroc is safe and feasible in ASCT patients - those who receive stem cells
from a healthy donor -- and that a brief course of the drug led to a 73 percent reduction in severe GvHD in the first six months after
transplant, compared with a matched control group treated at Penn during the same time period (6 percent developed severe
GvHD vs. 22 percent, respectively).
"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 very distinct and well orchestrated process whereby cells express particular
receptors on their surface that allow them to respond to small proteins called chemokines. The chemokines direct the immune cells
to specific organs, where they are needed, or in the case of GvHD, to where they cause damage."
Thirty-eight patients with blood cancers, including acute myeloid leukemia, myelodysplastic syndrome, lymphoma, myelofibrosis, and
others, enrolled in the phase I/II 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. By contrast, 12.5 percent of patients in the control group developed
GvHD in the gut and 8.3 percent developed it in the liver within 100 days of their transplant.
The differential impact of maraviroc on those organs indicates that the drug is working as expected, by limiting the movement of
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 sending lymphocytes into the liver and the gut than for the skin.
After 180 days, the benefit of maraviroc appeared to be partially sustained in patients and the cumulative incidence of gut and
liver GvHD rose only to 8.8 percent and 2.9 percent, respectively. The cumulative incidence in the control group, however,
remained higher, at 28.4 percent for gut and 14.8 percent for liver GvHD. Based on those data, the research team plans to
try a longer treatment regimen with maraviroc to see if they could prolong the protective effect.
Maraviroc treatment did not appear to increase treatment-related toxicities in these patients, nor did it alter the relapse rate
of their underlying disease.
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 Pfizer, the makers of maraviroc, the Leukemia and Lymphoma Society,
the American Society of Hematology, and the National Institutes of Health (K24-CA117879).
The findings will be presented at 8:30 AM PST on Tuesday, December 13, in the Manchester Grand Hyatt San Diego's Douglas Pavilion A.
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 billion enterprise.
Penn's Perelman School of Medicine is currently ranked #2 in U.S. News & World Report's survey of research-oriented medical schools
and among the top 10 schools for primary care. The School is consistently among the nation's
top recipients of funding from the National Institutes of Health, with $507.6 million awarded in the 2010 fiscal year.
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System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top
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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
2010, Penn Medicine provided $788 million to benefit our community.
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