Leukemia and myeloproliferative disorders are serious and often deadly blood cancers. Research presented today at the 51st Annual Meeting of the American Society of Hematology introduces potential new treatment options and improved diagnostic methods for patients suffering from acute promyelocytic leukemia, chronic myeloid leukemia, infant acute lymphoblastic leukemia, and myelofibrosis that are based on a better understanding of the underlying genetic causes of these conditions.“Researchers are committed to improving the survival of patients with blood cancers and other bone marrow disorders like myelofibrosis,” said Richard A. Larson, MD, Professor of Medicine at the University of Chicago. ?We hope that the results of these studies will help us develop safer and more effective treatments, especially in those hard-to-treat conditions where we currently do not have many options.”Long-Term Follow-Up and Optimized Dosing Regimen of INCB018424 in Patients With Myleofibrosis: Durable Clinical, Functional, and Symptomatic Reponses with Improved Hematological Safety [Abstract #756]Myelofibrosis is a serious bone marrow disease that disrupts the body?s normal production of blood cells and results in extensive scarring of the bone marrow. It can lead to severe anemia, weakness, fatigue, and often an enlarged spleen and liver with debilitating constitutional symptoms. Currently, there are no approved treatment options for patients with myelofibrosis and average life expectancy is 5-7 years. Recent evidence indicates that exaggerated Janus activated kinase (JAK) signaling plays an important role in the pathogenesis of myelofibrosis. Researchers at The University of Texas M. D. Anderson Cancer Center in Houston examined INCB018424, an investigational oral selective inhibitor of JAK1 and JAK2 enzymes, to determine its safety and effectiveness as a treatment option for these patients. Preliminary results (Verstovsek, ASH 2008) have demonstrated that INCB018424 may shrink enlarged spleens and improve other disease-related symptoms in patients with myelofibrosis.Study authors enrolled 155 patients with either primary myelofibrosis or myelofibrosis occurring after polycythemia vera (a rare blood disease in which the body overproduces red blood cells), or essential thrombocythemia (a rare blood disease in which the body overproduces platelets). Patients received an individually optimized dose of 10 mg, 15 mg, or 25 mg of INCB018424 twice a day. Efficacy of INCB018424 was assessed by taking MRI (magnetic resonance imaging) measurements of spleen size at one, three, and six months. To measure the effect of INCB018424 on myelofibrosis-related symptoms, patients were surveyed about the impact of the treatment on their health and well-being. The impact of INCB018424 on exercise capacity was measured with a standardized six-minute-walk test at the start of the study and after one, three, and six months of therapy.The data revealed that an individually optimized dosing regimen of INCB018424, with starting doses of 10 or 15 mg twice-a-day and increased or decreased doses depending on each patient?s needs, resulted in improved quality of life and disease symptoms, reduction in spleen size, and a better hematologic safety profile than previously observed at a higher starting dose of 25 mg twice-a-day (maximum tolerated dose). Treatment with INCB018424 resulted in a rapid reduction of spleen volume and was evident as early as one month and lasted beyond six months of therapy. Specifically, 48 percent of patients had spleen volume reduction of greater than or equal to 35 percent after six months of treatment. Treatment with INCB018424 also resulted in improvements in the six-minute-walk test, with median increases from baselines of 33, 58, and 70 meters after one, three, and six months of therapy, respectively. Spleen response was associated with greater improvements in exercise capacity and reduced fatigue. Finally, a great majority of patients improved their health and well-being while on therapy with INCB018424.”Myelofibrosis is a serious disease that has few therapeutic options,” said lead author Srdan Verstovsek, MD, PhD, Associate Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas M. D. Anderson Cancer Center in Houston. “While the treatment approach for these patients has been mostly in the form of palliative care, INCB018424 may provide patients with the first-ever treatment option that is designed to work on the underlying cause of this disease.”Dr. Verstovsek will present this study in the Plenary Scientific Session on Monday, December 7, at 5:45 p.m. in Room 393-396.Specific MLL Partner Genes in Infant Acute Lymphoblastic Leukemia (ALL) Associated With Outcome Are Linked to Age and White Blood Cell Count (WBC) at Diagnosis: A Report on the Children?s Oncology Group (COG) P9407 Trial [Abstract #907]Infants with leukemia remain one of the most challenging populations to treat in all of pediatric oncology. Leukemia, of which the most common form in children is acute lymphoblastic leukemia (ALL), is the most widespread cancer in children and in infants less than one year old. Most infants less than one year old with ALL respond poorly to chemotherapy drugs and have a much lower survival rate than do older children. One factor associated with poor outcomes in infant ALL is the MLL translocation, a molecular abnormality in which the MLL gene on chromosome 11 breaks and then becomes joined with one of a number of different ?partner? genes on other chromosomes. In collaboration with the Children?s Oncology Group (COG), researchers from the Children?s Hospital of Philadelphia determined the specific partner genes involved in MLL translocations among cases of ALL in infants enrolled in the clinical trial COG P9407 for the treatment of infant ALL. The researchers then assessed how different MLL partner genes affected outcome and studied how they were related to other classical prognostic factors, including age and white blood cell count at diagnosis. This research was funded by SCOR grant 7372-07 from the Leukemia & Lymphoma Society.A total of of 221 infants with ALL were enrolled in the COG P9407 trial. Researchers used several methods (e.g., Southern blot analysis, reverse transcriptase polymerase chain reaction (RT-PCR), fluorescence in situ hybridization (FISH), etc.) to identify MLL translocations and specific partner genes at the levels of the genes and chromosomes. Statistical tests were then used to determine how MLL translocations with different partner genes affected the prognosis, and their relationships to classical prognostic factors.The COG researchers found that the leukemia cells of 74 percent of infants with ALL had an MLL translocation and that the most common partner genes of MLL were AF4, ENL, and AF9. The two most common partner genes of MLL, AF4 (located on chromosome 4) and ENL (located on chromosome 19), negatively affected patient survival. Better outcomes were observed when the MLL gene fused with AF9, located on chromosome 9. The outcome was far worse when AF4 or ENL occurred as partner genes in MLL translocations in cases of ALL in younger infants who were less than 90 days old at diagnosis. In addition, translocations fusing MLL with AF4 were associated with a higher white count, whereas translocations fusing MLL with AF9 were associated with a lower white blood cell count. These new associations of specific MLL partner genes with age and white blood cell count indicate how disease biology and the classical prognostic factors in infant ALL are integrally connected.”The ability to characterize acute lymphoblastic leukemia based on specific partner genes may provide a new way to determine whether infants with ALL in which the partner genes of MLL are different will benefit from specific types of treatment,” said senior author Carolyn A. Felix, MD, Professor of Pediatrics at the Children?s Hospital of Philadelphia. “We hope that these findings will help lead to the development of new, molecularly targeted therapies for infants with leukemi
a.”Dr. Blain W. Robinson will present this study in an oral session on Tuesday, December 8, at 7:30 a.m. in Room E-3.

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