Vorinostat, a drug currently approved by the FDA to treat certain types of cancer, cuts in half the serious and often deadly side-effects following a lifesaving bone marrow transplant. These findings were presented on Dec. 9th, 2012 at the 54th Annual Meeting of the American Society of Hematology by researchers at the University of Michigan Comprehensive Cancer Center. Researchers illustrated how vorinostat combined with standard medications resulted in 21 percent of patients developing graft-vs.-host disease compared to 42 percent of patients who typically develop this condition with standard medications alone.
Hematopoietic Stem Cell Transplantation (HSCT):
HSCT is the primary form of treatment for many patients with blood disorders; it involves the transplantation of healthy blood-forming stem cells from the bone marrow, circulating blood, or umbilical cord blood to replace damaged, disease-causing cells in recipients. Despite the therapeutic benefits of HSCT, half of all patients who receive transplants from a related donor develop acute Graft-versus-host disease (GVHD).
Graft-versus-host Disease (GVHD):
GVHD is a challenging, and life-threatening condition occurring when the newly transplanted cells identify and treat the patient’s normal cells as foreign invaders. The new immune cells then attack the recipient’s own cells, and begin to damage the patient’s organs. GVHD is the most serious complication from transplant therapy that seriously limits the ability to offer transplants more broadly.
Over the past 20 years, HSCT patients have received prophylactic therapy to prepare their bodies for the procedure, and to help manage their subsequent immune response. While this series of drugs is designed to help reduce patients’ risk of developing GVHD, it also compromises their immune systems, leaving them vulnerable to serious infections and complications.
This strategy has remained mostly unchanged for the past 20 years.
Vorinostat Discovery & How It Works:
Vorinostat belongs to a new class of anti-cancer drugs known as histone deacetylase inhibitors (HDACi). These drugs have demonstrated an ability to “turn off” an enzyme that leads to inflammation, a major contributor to GVHD. To test this hypothesis, researchers initiated the current study to evaluate whether vorinostat might reduce the risk of acute GVHD when added to current prophylactic regimens.
To test this hypothesis, researchers enrolled 45 patients undergoing matched related donor HSCT from transplant centers at the University of Michigan in Ann Arbor, Mich. and Washington University in St. Louis to compare results of a standard regimen with vorinostat to historical controls. The focus of the trial was to aim for an incidence of mild to severe GHVD in no more than 25 percent of patients, compared to the 42 percent seen in the past with standard regimen.
Prior to transplantation, patients received oral vorinostat combined with standard preventive treatments. This regimen continued during, and for 100 days after transplantation. Once the treatments were complete, a lower incidence rate of GVHD was shown in patients – a 22 % incidence rate, which was far lower than their historical controls of 42%. In addition there were lower rates of severe (grade 3-4) GVHD (4% vs. 19% in controls) and transplant-related mortality at one year (13% vs. 19% in controls). There were no differences in rates of infectious complications or incidence of relapse, indicating that vorinostat helped reduce the risk of GVHD in patients without further compromising their immune systems.
Vorinostat Research and Development:
“In order to increase the use of transplants and make them safer for more patients who need them, we need to see if this treatment approach may be successful in patients who receive stem cells from unrelated donors, and whether it may work among patients who are at high risk for severe GVHD. Moreover, we would like to confirm our findings in a larger, Phase III clinical trial.” said Pavan Reddy, MD, senior author and Co-Director of the University of Michigan Bone Marrow Transplant and Hematologic Malignancies Program, who has been studying this approach in the lab for eight years.
“Vorinostat has a dual effect as an anti-cancer and an anti-inflammatory agent. That’s what’s potentially great about using it to prevent graft-vs.-host, because it may also help prevent the leukemia from returning,” says lead study author Sung Choi, M.D., assistant professor of pediatrics at the University of Michigan Medical School. “This study has us cautiously excited that there may be a potential new way to prevent this condition.”.
Vorinostat CAS# 149647-78-9 is available for R&D purposes, and supplied by LGM Pharma. LGM Pharma offers complete consultative support throughout every stage of drug development.
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