|By PR Newswire||
|December 9, 2012 10:00 AM EST||
ATLANTA, Dec. 9, 2012 /PRNewswire-USNewswire/ -- Studies of stem cell biology and transplant approaches presented today at the 54th Annual Meeting of the American Society of Hematology (ASH) illustrate how the use of advanced modeling techniques is optimizing stem cells to treat patients with blood disorders, as well as the potential of enhanced treatment strategies to improve the success rate of hematopoietic stem cell (HSC) transplantation for these patients.
Hematopoietic stem cell transplantation is effectively used today as a form of "replacement" therapy for patients with hard-to-treat blood conditions, providing healthy HSCs to help patients whose bodies cannot properly fight infection or disease on their own. While transplants often lead to long-term remission for many patients, researchers are now challenging traditional assumptions in an effort to further improve success rates while minimizing the remaining risks associated with transplantation.
"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," said Vanderson Rocha, MD, PhD, moderator of the press conference and Professor of Hematology of Oxford University, United Kingdom. "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."
This press conference will take place on Sunday, December 9, at 10:00 a.m. EST.
Targeting Histone Deacetylases as a New Strategy for Graft Versus Host Disease Prevention [Abstract 740]
New research shows that the addition of the oral anti-cancer agent vorinostat to standard therapy given before, during, and after hematopoietic stem cell transplantation (HSCT) may safely reduce the incidence and severity of a challenging complication called graft-versus-host disease (GVHD).
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 (allogeneic HCT) develop acute GVHD, a life-threatening condition occurring when the newly transplanted cells identify the recipient's body as foreign and attack the recipient's own cells.
Currently, HSCT patients receive prophylactic therapy before and after transplant 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. Recent research has sought to determine ways to improve patients' initial immune response to transplanted cells as well as promote faster immune recovery after transplant.
Recent early-stage studies have demonstrated that a class of anti-cancer drugs known as histone deacetylase inhibitors (HDACi) may safely reduce the risk of GVHD in patients. These drugs have demonstrated an ability to "turn off" an enzyme that leads to inflammation, a major contributor to GVHD that develops as a byproduct of patients' intense immune response to HSCT. Based on those early results, researchers initiated the current study to evaluate whether one drug in this class, vorinostat, might reduce the risk of acute GVHD when added to current 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 primary endpoint of the single-arm, Phase I/II trial was the cumulative incidence of grade 2-4 acute GHVD (grade 1 is mildest; grade 4 is most severe). They aimed for an incidence of no more than 25 percent, compared with historical average rates of 42 percent.
Patients participating in the study received oral vorinostat daily in addition to standard preventive treatments prior to, during, and for 100 days after transplantation. After treatment, these patients had a significantly lower incidence of GVHD than their historical controls (22 % vs. 42%) and had 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.
"While GVHD remains a challenging complication that affects a large proportion of patients who receive stem cell transplants, we are encouraged by the significant reduction in both the incidence and severity of this life-threatening condition that we observed in this trial," said Pavan Reddy, MD, senior author and Co-Director of the University of Michigan Bone Marrow Transplant and Hematologic Malignancies Program. "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."
Sung W. Choi, MD, lead author, will present this study in an oral presentation on Monday, December 10, at 4:45 p.m. EST at the Georgia World Congress Center in Room C108-C109, Level 1, Building C.
No Survival Advantage after Double Umbilical Cord Blood (UCB) Compared to Single UCB Transplant in Children with Hematological Malignancy: Results of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0501) Randomized Trial [Abstract 359]
A study evaluating the efficacy of hematopoietic stem cell (HSC) transplants using single versus double units of transfused umbilical cord blood (UCB) for children with hematologic malignancies finds that the single unit approach remains the gold standard, refuting the notion that "more is better" in this clinical setting.
UCB contains a high concentration of HSCs with a unique immune profile that permits a high degree of human leukocyte antigen (HLA, proteins on white blood cells that determine compatibility between donor and recipient) mismatch, making it an increasingly popular source of HSCs for transplants. Questions remain, however, regarding the optimal quantity of transplanted umbilical cord stem cells. Previous research has found that double UCB transplant (the co-infusion of two partially HLA-matched units) is effective, particularly for adults for whom a single UCB unit is inadequate. Since prior research has connected cell quantity with survival, researchers hypothesized that a double UCB transplant may be superior to the use of a single unit in children with blood cancer for whom two units were available.
For this study, a team of researchers within the Blood and Marrow Transplant Clinical Trials Network examined whether the use of two units of UCB would offer a significant advantage in overall survival and other transplant outcomes such as blood and marrow recovery time, risks of acute and chronic graft-versus-host disease (GVHD), and transplant-related mortality and relapse.
As part of the multi-center, Phase III trial, 224 pediatric acute leukemia patients were randomized to receive either a single- or double-unit UCB transplant. After a median of 25 months of follow-up, nearly all patients (92%) in both study arms were in remission, with similar overall survival rates at one year post transplant between the groups (71% vs. 66% for the single vs. double unit, respectively). Overall, outcomes were similar between the groups, including disease-free survival (68% vs. 64% in single vs. double) and rates of relapse (12% vs. 14%), suggesting the double UCB transplant did not offer additional therapeutic benefit. While both study arms had the same overall rate of GVHD (57% each), patients who received a double UCB transplant experienced a higher risk of severe (grade 3-4) GVHD (23% vs. 14% for single unit patients), possibly attributed to the greater number of transplanted HSC.
"Our findings, though unexpected, affirm that the standard transplant approach of a single umbilical cord blood unit is optimal so long as the unit offers a sufficient number of cells. The study also demonstrated that a double umbilical cord blood transplant, while not better than a single cord blood transplant, can be an effective strategy among mainly adult patients for whom a single unit of cells is insufficient," said John Wagner, MD, lead author and Director of the Pediatric Blood and Marrow Transplant Program at the University of Minnesota in Minneapolis. "With this in mind, we need to focus our efforts on the development of new strategies that will enhance the speed of engraftment and immune recovery – and the double umbilical cord blood model may be a useful tool for achieving that goal."
Dr. Wagner will present this study in an oral presentation on Monday, December 10, at 8:00 a.m. EST at the Georgia World Congress Center in Room B312-313a, Level 3, Building B.
Prolonged Strenuous Exercise Expands the Population of Developmentally Early Stem Cells in Bone Marrow (BM) and Mobilizes them into Peripheral Blood – Novel Evidence that Strongly Supports a Positive Effect of Physical Activity on Extension of Life Span at the Level of Stem Cells [Abstract 584]
Researchers have demonstrated through a mouse model study that the beneficial effect of exercise on lifespan may be specifically related to the increase of a certain type of primitive stem cell believed to play an important role in tissue and organ regeneration.
Established research cites the benefit of exercise in reducing the risk of disease and managing chronic conditions, and studies have already shown that physical activity helps to mobilize stem cells, or move them from the bone marrow into the bloodstream. Taking this one step further, researchers focused their study on investigating the activity of the primitive stem cells (known as very small embryonic-like stem cells or VSELs) to directly assess whether strenuous exercise could increase the presence of a pool of developmentally early and highly potent stem cells in the blood stream. They hypothesized that the increased presence of these stem cells in the blood stream may enhance the rejuvenation of organs and tissues and potentially extend the lifespan.
To test their hypothesis, the team exposed the mice to various periods of strenuous exercise on rotating wheels (short-term at 1 day, mid-term at 14 days, and long-term at 6 months). The length of exercise was positively correlated to the counts of these primitive cells in their bone marrow and circulating blood, with the greatest increase in overall counts being in the group with the longest exercise exposure. The team also found similar correlations between the rates of exercise and the active function of genes that assist in organ and tissue regeneration. The data show that prolonged, strenuous exercise in mice is associated with the increased quantity of these important primitive stem cells in the bone marrow and their movement into the bloodstream.
"These data makes a compelling argument that exercise may not only prevent health issues that tend to emerge as people age, but may also help improve the body's ability to heal damaged tissue and organs," said Mariusz Ratajczak, MD, PhD, senior author and Director of the Stem Cell Institute at the James Graham Brown Cancer Center of the University of Louisville in Kentucky. "Additional studies need to be conducted to better define the role of these early stem cells in healing tissue damage, extending the lifespan, and maintaining health during the aging process, as well as to understand how we might be able to harness them for further therapeutic benefit."
Maciej Tarnowski, PhD, lead author, will present this study in an oral presentation on Monday, December 10, at 3:00 p.m. EST at the Georgia World Congress Center in Room C101, Level 1, Building C.
American Society of Hematology 54th Annual Meeting
The study authors and moderator will be available for interviews after the press conference or by telephone. Additional press briefings will take place throughout the meeting on new targeted treatment for chronic lymphocytic leukemia (CLL) and hard-to-treat blood disorders, efforts to reduce toxicity and improve survival for blood cancer therapy, and strategies to increase the efficacy and safety of treatments for clotting disorders. For the complete annual meeting program and abstracts, visit www.hematology.org/2012abstracts. Follow ASH (@ASH_hematology) on Twitter (use the hashtag #ASH12 when posting tweets about the meeting) and on Facebook at www.facebook.com/AmericanSocietyofHematology for the most up-to-date information about the 2012 ASH Annual Meeting.
The American Society of Hematology (ASH) (www.hematology.org) is the world's largest professional society of hematologists dedicated to furthering the understanding, diagnosis, treatment, and prevention of disorders affecting the blood. For more than 50 years, the Society has led the development of hematology as a discipline by promoting research, patient care, education, training, and advocacy in hematology. The official journal of ASH is Blood (www.bloodjournal.org), the most cited peer-reviewed publication in the field, which is available weekly in print and online.
SOURCE American Society of Hematology
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