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Late-Breaking Data Highlighting Research Advances in Several Blood Disorders to Be Presented At the American Society of Hematology Annual Meeting

SAN FRANCISCO, Dec. 6 /PRNewswire-USNewswire/ -- Four studies highlighting late-breaking research advances in the treatment of cancer and sickle cell disease will be presented today at the 50th Annual Meeting of the American Society of Hematology in San Francisco, CA.

Results from a study examining the ability of an investigational agent to improve endothelial dysfunction, a malfunction in the inner lining of blood vessels, in patients with sickle cell disease will be featured at a press conference on Saturday, December 6, at 9:30 a.m. "Abnormal function of the cells lining blood vessels may contribute to the complications of sickle cell disease. Disruption in the synthesis of nitric oxide, an important regulator of blood vessel relaxation, contributes to these abnormalities," said Nancy Berliner, M.D., 2009 ASH President and Chief of Hematology at Brigham and Women's Hospital in Boston and co-moderator of the press conference on the advances in screening and treatment for sickle cell disease. "This study showcases a novel investigational treatment that aims at improving nitric oxide production and reducing endothelial dysfunction."

Three other late-breaking studies showcasing treatment advances in blood cancers will be highlighted during a press conference on Saturday, December 6, at 2:00 p.m. This press conference will feature the results of a study examining the use of a rituximab-based combination therapy regimen for improving progression-free survival and complete response rates in patients with relapsed or refractory chronic lymphocytic leukemia, the first large-scale study examining mortality rates in patients with cancer taking erythropoiesis-stimulating agents (ESAs) for the treatment of anemia, and the discovery of a new tumor suppressor gene in patients with myeloproliferative disorders.

"There is now additional evidence concerning the use of ESAs in patients with cancer. Last year, ASH collaborated with the American Society of Clinical Oncology to release an evidence-based clinical practice guideline on the use of ESAs, and the findings of this study are consistent with the guideline's recommendations," said Samuel Silver, M.D., Chair of the ASH Subcommittee on Reimbursement, and Professor of Internal Medicine at the University of Michigan in Ann Arbor, MI. "However, we plan to reconvene the guideline panel to determine whether any updates should be made as a result of these new data." Dr. Silver will be available at the ASH press conference on treatment advances in leukemia and lymphoma to respond to questions on this important practice issue.

"The results of two other large-scale studies presented at the meeting may also affect the way we treat patients with advanced chronic lymphocytic leukemia," said Linda Burns, M.D., moderator of the press conference and Professor of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN. "These studies validate the role of fludarabine, cyclophosphamide, and rituximab combination therapy as the new standard of treatment for this type of leukemia, regardless of previous treatment regimens."

Rituximab, Fludarabine, and Cyclophosphamide(R-FC) Prolongs Progression-Free Survival in RelapsedorRefractoryChronic Lymphocytic Leukemia (CLL) Compared with FCAlone: Final Results From the International Randomized Phase III REACH Trial [LBA-1]

Tadeusz Robak, M.D., Ph.D., Medical University, Lodz, Poland

*Abstract LBA-1 is being presented on Saturday, December 6, at 2:00 p.m. at the ASH press conference on treatment advances in leukemia and lymphoma. The embargo for this abstract will break at that time.

Results from this multinational phase III study demonstrate that the combination of fludarabine, cyclophosphamide, and rituximab (FCR) provides a 10-month improvement in progression-free survival and a near doubling of complete response rates in patients with relapsed or refractory chronic lymphocytic leukemia.

A total of 552 patients from 17 countries with relapsed or refractory chronic lymphocytic leukemia were randomized to receive six 28-day cycles of fludarabine (25 mg/m^2 intravenously on days 1 to 3) and cyclophosphamide (250 mg/m^2 intravenously on days 1 to 3) alone (FC) or in combination with rituximab (FCR) (375 mg/m^2 rituximab intravenously at the start of first cycle and 500 mg/m^2 on day 1 for all subsequent cycles). Patients previously had received an average of one previous treatment regimen, including a single-agent alkylator therapy (66 percent), a purine-analog therapy (16 percent), or combination chemotherapy treatments (18 percent). The primary endpoint of the study was progression- free survival.

Patients in the FCR arm achieved a 30.6-month progression-free survival compared with 20.6 months in the FC arm, translating into a significant 10-month increase in progression-free survival for FCR combination therapy. The overall response rate was significantly higher in the FCR arm (70 percent) as compared with the FC arm (58 percent), because of superior complete-response rates in the FCR arm (24 percent versus 13 percent, respectively). While median overall survival in the FC arm was reached at 53 months, it had not yet been reached in the FCR arm.

While Grade 3 and 4 adverse events were more prevalent in the FCR arm (80 percent) as compared with the FC arm (74 percent), serious adverse events were similar in each treatment arm (50 percent versus 48 percent, respectively). Overall, the FCR combination showed a favorable risk-benefit profile and did not reveal any new or unexpected safety concerns.

TET2 is a Novel Tumor SuppressorGene Inactivated in Myeloproliferative Neoplasms: Identification of a Pre-JAK2 V617FEvent [LBA-3]

Francois Delhommeau, M.D., Saint-Antoine Hospital,Paris, France

*Abstract LBA-3 is being presented on Saturday, December 6, at 2:00 p.m. at the ASH press conference on treatment advances in leukemia and lymphoma. The embargo for this abstract will break at that time.

This research unveiled a new tumor suppressor gene called TET2 (Ten-Eleven Translocation-2), which is altered in 14 percent of patients with myeloproliferative disorders, providing scientists with a greater understanding of the underlying biology of these conditions, as well as a potential target for the development of future treatments.

All blood cells start out as hematopoietic, or blood-forming, stem cells and have the potential to become mature red blood cells, white blood cells, or platelets. Myeloproliferative disorders develop when the DNA of a stem cell is altered in the bone marrow, causing the overproduction of some blood cells.

Previous research has detected mutations in other genes -- JAK2 and MPL -- in the blood stem cells of patients with myeloproliferative disorders. These JAK2 and MPL defects cause the overproduction of mature malignant blood cells, but multiple lines of evidence suggest that these are not the only molecular lesions responsible for abnormalities in the stem cell in these disorders. Greater analysis of blood cell development in myeloproliferative disorders with the JAK2 V617Fmutation led researchers to identify two subsets of patients. The first subset of patients (85 percent) had an overproduction of malignant cells mainly dependent on the late stages of blood cell differentiation, far downstream from the stem cell. In contrast, a second subset of patients (15 percent) had an early expansion of very immature malignant progenitor cells, close to the stem cell.

Researchers then hypothesized that the second subset of patients had a pre-existent molecular defect able to promote the early expansion of the malignant cells. With high-resolution arrays, researchers were able to identify one single gene, TET2, which belongs to a family of three genes of unknown function.

Researchers then further analyzed cells in five patients with TET2mutations, which demonstrated that TET2 defects target hematopoietic stem cells. Moreover, they show that in these five patients TET2 inactivation precedes the JAK2 V617Fmutation, suggesting that this new molecular lesion could be an early event in cancer stem cell formation.

To further test these findings, researchers sequenced TET2in 181 unselected JAK2 V617F patients with myeloproliferative disorders. TET2 mutations were found in 25 of the 181 patients, resulting in an overall 14 percent frequency.

Tetrahydrobiopterin (6R-BH4): Novel Therapy forEndothelial Dysfunction in Sickle Cell Disease


Lewis Hsu, M.D., Ph.D., Drexel University, Philadelphia, PA

*Abstract LBA-5 is being presented on Saturday, December 6, at 9:30 a.m. at the ASH press conference on advances in screening and treatment for sickle cell disease. The embargo for this abstract will break at that time.

The results of this phase II study showed that the investigational oral agent tetrahydrobiopterin is safe and well-tolerated. The drug appears to improve endothelial dysfunction -- the inability of blood vessels to dilate properly -- in patients with sickle cell disease.

Tetrahydrobiopterin, an essential enzyme involved in the production of nitric oxide, plays a key protective role in the cardiovascular system. In patients with sickle cell disease, inflammation and production of superoxide (a highly reactive form of oxygen) in blood vessels may decrease levels of tetrahydrobiopterin, creating a deficiency. Restoring tetrahydrobiopterin levels could potentially improve endothelial function, alleviating this complication associated with sickle cell disease.

A total of 27 patients with sickle cell disease were treated every four weeks with escalating doses of tetrahydrobiopterin (2.5, 5, 10, and 20 mg/kg/day). The primary endpoint of the study was the overall safety and efficacy of tetrahydrobiopterin as measured by a non-invasive fingertip test (PAT) that scores endothelial dysfunction. A value of less than or equal to 1.67 represents endothelial dysfunction. At the start of the study, 18 patients had abnormal mean PAT scores (1.33 ± 0.17) and nine patients had normal mean PAT scores (2.09 ± 0.31).

More than one-third (67 percent) of patients with abnormal PAT scores achieved statistically significant dose-dependent improvements in endothelial dysfunction over 16 weeks of tetrahydrobiopterin treatment (2.5 mg/kg: 24 percent improvement; 5mg/kg: 31.2 percent improvement; 10 mg/kg: 39.9 percent improvement; and, 20 mg/kg: 56.6 percent improvement). Patients with normal PAT scores showed no improvement with therapy, which is consistent with the mechanism of action of tetrahydrobiopterin.

This was designed as a safety study, and additional studies in larger numbers of patients will be needed to confirm these preliminary data on the use of tetrahydrobiopterin for the treatment of endothelial dysfunction in patients with sickle cell disease.

Recombinant Human Erythropoiesis Stimulating Agents in Cancer Patients: IndividualPatient Data Meta-Analysis on Behalf of the EPO IPD Meta-Analysis Collaborative Group [LBA-6]

Julia Bohlius, M.D., MScPH, University of Bern, Bern, Switzerland

*Abstract LBA-6 is being presented on Saturday, December 6, at 2:00 p.m. at the ASH press conference on treatment advances in leukemia and lymphoma. The embargo for this abstract will break at that time.

Results of this first large-scale study examining how survival rates are affected by the use of erythropoiesis-stimulating agents (ESAs) for the treatment of anemia in patients with cancer showed that ESAs increased on-study mortality and worsened overall survival, confirming previous studies that have suggested that ESAs may negatively affect the overall health of these patients.

In order to assess the effect of ESAs on mortality, a meta-analysis was conducted of 13,933 patients with cancer enrolled in 53 randomized, controlled clinical trials comparing epoetin alfa, epoetin beta, and darbepoetin alfa plus red blood cell transfusions versus red blood cell transfusions alone for the prevention or treatment of anemia during or after receiving anticancer therapy. Thirty-eight of these trials, which included 10,441 patients, used chemotherapy as the anticancer regimen.

The primary endpoints of the study were on-study mortality and overall survival in patients with cancer receiving chemotherapy, including all studies where more than 70 percent of patients enrolled received chemotherapy, and all patients with cancer regardless of the type of anticancer therapy. On-study mortality was defined as death from any cause between the date of being randomized in the clinical trial and 28 days following the end of the treatment phase of the study. Overall survival was defined as death from any cause between the date of randomization and longest amount of follow-up available. All analyses were pre-specified in a peer-reviewed protocol, and an independent steering committee agreed on all analyses and interpretations.

The study found that in all patients with cancer, the use of ESAs increased on-study mortality by 17 percent (factor 1.17) and worsened overall survival by 6 percent (1.06). For patients undergoing chemotherapy, the increase in on-study mortality and overall survival was less pronounced (10 percent, or factor 1.10, and 4 percent, or factor 1.04, respectively). This study found that the risks associated with ESAs must be balanced against the benefits for the individual patient when treating chemotherapy -- induced anemia.

American Society of Hematology 50thAnnual Meeting

The study authors and press program moderator will be available for interviews after the press conference or by telephone. Additional press briefings will take place throughout the meeting on combating blood clots, therapeutic strategies for platelet disorders, and improvements in stem cell therapies.

The American Society of Hematology ( is the world's largest professional society concerned with the causes and treatment of blood disorders. Its mission is to further the understanding, diagnosis, treatment, and prevention of disorders affecting blood, bone marrow, and the immunologic, hemostatic, and vascular systems, by promoting research, clinical care, education, training, and advocacy in hematology. In September, ASH launched Blood:The Vital Connection (, a credible online resource addressing bleeding and clotting disorders, anemia, and cancer. It provides hematologist-approved information about these blood conditions including risk factors, preventative measures, and treatment options. A cornerstone of this public awareness campaign is a new documentary by award-winning filmmaker Joseph Lovett called "Blood Detectives," which will air on the Discovery Health cable network on December 19, 2008, at 7:00 p.m. ET/PT and again at 12:00 midnight. The show focuses on hematologists as they work to unravel medical mysteries and save lives.

SOURCE American Society of Hematology
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