Researchers identify genes that may be associated with prognosis in pediatric leukemia
(WASHINGTON, DC, August 25, 2003) – A panel of 35 genes have been identified whose expression may be associated with prognosis and response to treatment in pediatric patients with acute myeloid leukemia (AML), according to a study published in the September 1st issue of Blood. At the time of diagnosis, hematologists may be able to use these genes to predict pediatric patient outcomes. Additionally, these genes and their pathways may serve as molecular targets for new therapeutic strategies to prevent relapse of pediatric AML.
AML occurs in both children and adults, although there are some distinct characteristics that distinguish pediatric and adult AML. In children, the primary treatment for AML is chemotherapy, sometimes followed by bone marrow/stem cell transplantation. Most patients with AML enter complete remission after treatment with chemotherapy, but a large number of patients relapse with resistant disease. The prediction of a patient's risk of treatment failure, or even disease relapse, at the time of diagnosis is important for the optimum selection of treatment strategies, such as additional rounds of conventional chemotherapy, stem cell transplantation, or novel experimental therapies.
The 35 genes found were unexpected, and did not correspond to known prognostic genes. Moreover, they were identified independently of currently used classification methods, such as microscopic appearance or specific cytogenetic abnormalities. Additional factors associated with poor prognosis are advanced age, high white blood cell count, extramedullary mass, and a history of blood disorders, such as myelodysplastic syndrome.
Researchers from the Cancer Genomics Division of the National Cancer Center Research Institute in Tokyo, Japan, enrolled 54 pediatric AML patients, all less than 15 years of age. Samples of either bone marrow or peripheral blood were collected and classified at the time of diagnosis. Patients in the study were treated with chemotherapy, and 53 patients entered complete remission, 16 of which were treated with stem cell transplants.
In order to identify the genes, investigators randomly selected nine good prognosis patients from the 19 patients who experienced a complete response for more than three years, and nine poor prognosis patients from the 18 patients who experienced induction failure or relapse within one year from the first complete response. Complete response was defined as less than five percent of blasts (abnormal, immature white blood cells) in the bone marrow, and induction failure was defined as no complete response within three months from the start of treatment. Researchers asked whether or not each gene was expressed differentially between the two comparison groups of patients, and identified 133 genes. To confirm that these 133 genes were actually related to prognosis, investigators analyzed whether these same 133 genes predicted clinical response in the remaining patients in the test sample. Clustering analysis of the genes separated the 54 patients into two groups – those who experienced poor prognosis (27 high-risk patients, including all poor prognosis patients and one good prognosis patient) and those who experienced remission (27 low-risk patients plus the four controls, including eight good prognosis patients). Additional statistical tests confirmed the significantly different event-free survival between the two groups.
Further analysis honed down the initial group of 133 genes to a smaller subset of 35 genes, whose expression levels clearly separated the patients into high- and low-risk groups. Through this analysis, six patients from the high-risk group were reclassified as low-risk, and two patients in the low-risk group were reclassified as high-risk. Significant differences were again seen in the event-free survival between the two groups.
"While the prognosis for pediatric patients with acute myeloid leukemia has improved steadily over the past 25 years, there are still too many children who either do not respond to treatment or whose disease returns," according to Stephen Emerson, M.D., Ph.D., Francis C. Wood Professor in Medicine and Chief of Hematology/Oncology at the University of Pennsylvania. "The results of this study offer hope to patients that hematologists may be able to not only more accurately predict their treatment outcome, but hopefully in the near future will be able to use these genes to develop targeted treatment programs that will even better improve children's chances for cure from AML."
Acute myeloid leukemia is a cancer of the blood-forming tissue, primarily the bone marrow and lymph nodes, and is divided into several subtypes. Early symptoms of AML may include fever, chills, bleeding or bruising easily, swollen lymph nodes, and other symptoms similar to those of the flu, such as feeling weak or tired all the time, with aching bones or joints. According to the American Cancer Society, an estimated 10,500 new cases of AML (both pediatric and adult) will be diagnosed in 2003, and an estimated 7,800 children and adults will die of the disease.
Blood, the Journal of the American Society of Hematology, is the most cited peer-reviewed publication in the field. All articles undergo rigorous peer review and are selected for publication on the basis of the originality and quality of the work described. As a special service to researchers and clinicians, accepted papers are made available online about three months ahead of print as "First Edition Papers." Blood is issued to Society members and other subscribers twice per month, available in print and online at www.bloodjournal.org.