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Addition of Zolinza to HSCT conditioning could reduce GVHD
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ATLANTA — The administration of the histone deacetylase inhibitor vorinostat in matched related donor reduced-intensity conditioning allogeneic hematopoietic stem cells transplants could be an effective approach to reduce graft-versus-host disease, according to study results presented at the 2012 American Society of Hematology Meeting and Exposition.
Prior early-stage studies have indicated that histone deacetylase inhibitors (HDACi) may safely reduce the risk of GVHD in patients.
Translating these experimental observations from murine models to a first-in-human clinical trial, Pavan Reddy, MD, co-director of the University of Michigan Bone Marrow Transplant and Hematologic Malignancies Program, and colleagues enrolled 47 patients in a phase 1/phase 2 trial to determine whether the addition of vorinostat (Zolinza, Merck) to standard GVHD prophylaxis regimen consisting of mycophenolate mofetil and tacrolimus could reduce the risk of acute GVHD.
The primary endpoint of the study was the cumulative incidence of grade 2-4 acute GVHD. Researchers established a target risk of 25%, which would represent a statistically significant improvement over the 48% risk experienced by historical controls.
The control group consisted of patients who underwent matched related donor reduced-intensity conditioning allogeneic HSCT and received standard GVHD prophylaxis with tacrolimus and mycophenolate mofetil.
Eligibility criteria included adult patients with a hematologic malignancy for which reduced-intensity conditioning HSCT was considered appropriate and had an available 7/8 or 8/8 human leukocyte antigen match-related donor. Patients with CLL and lymphoma must have been in complete/partial response or had stable disease.
During the study, participants received fludarabine 40 mg/m2 for 4 days, busulfan 3.2 mg/kg for 2 days and mycophenolate mofetil for 29 days. Tacrolimus levels were maintained between 8-12 ng/mL through day 56, and then tapered off by day 180 in the absence of GVHD.
Vorinostat was administered orally from day 10 to day 100.
Following treatment, patients who received vorinostat exhibited a significantly lower incidence of GVHD than their historical controls (22% vs. 48%). They also had lower rates of grade 3/grade 4 GVHD (4% vs. 19% in controls), as well as transplant-related mortality at 1 year (13% vs. 19% in controls).
There were no differences in rates of infectious complications or incidence of relapse, indicating that vorinostat might have helped reduce the risk of GVHD in patients without further compromise.
“While GVHD remains a challenging complication that affects a large proportion of patients who receive stem cell transplants, we are encouraged by these results that suggest a reduction in both the incidence and severity of this life-threatening condition,” Reddy said. “In order to increase the use of transplants and make them safer for more patients who need them, we need to see if this approach may be successful in patients who receive stem cells from unrelated donors, who are at a high risk for severe GVHD.”
Eventually the investigators hope to confirm their findings in a larger phase 3 trial, Reddy said.
For more information:
Choi SW. Abstract #740. Presented at: the 2012 ASH Annual Meeting and Exposition; Dec. 8-11, 2012; Atlanta.
Disclosure: The researchers report no relevant financial disclosures.
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Vanderson Rocha, MD, PhD
This study is significant because we are trying to change this idea that only immunosuppressive treatment is important for the prevention of graft versus host disease (GVHD). There are some biological studies focusing on other drugs of the same class, which have been found to be effective in increasing some blood cells of transplant recipients that will, in fact, decrease the severity of GVHD, and at the same time, also fight against cancer cells. In addition, there are European studies currently under discussion for treatment of chronic GVHD using this class of drugs.
As we learn more about the biology and therapeutic use of hematopoietic stem cells to cure blood disorders, we are able to refine our traditional approaches to reduce complications and deliver better patient benefits. We are finding that hematopoietic stem cells can be programmed in ways we previously did not think possible, a discovery that may lead to the development of important new therapeutic strategies.
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