Data on leukemia are outlined in reports from the United States and Spain

04-20-2006

Data on leukemia are outlined in reports from the United States and Spain.

Study 1: In a recently published article, scientists in the United States reported that the overexpression of the ETS-related gene, ERG, predicts a worse outcome in acute myeloid leukemia (AML) with normal karyotype.

G. Marcucci and colleagues, The Ohio State University, wrote that the study was undertaken, "To test the prognostic significance of ERG expression in cytogenetically normal primary AML."

"Pretreatment blood samples from 84 cytogenetically normal AML patients aged less than 60 years, who were characterized for BAALC expression, FLT3 internal tandem duplication (ITD), and MLL partial tandem duplication (PTD) and uniformly treated on Cancer and Leukemia Group B 9621 protocol, were analyzed for ERG expression by real-time reverse transcriptase polymerase chain reaction."

"Patients were divided into quartiles according to ERG levels and were compared for clinical outcome. High-density oligonucleotide arrays were used to identify genes differentially expressed between high and low ERG expressers," the researchers explained.

"With a median follow-up of 5.7 years, patients with the upper 25% of ERG expression values had a worse cumulative incidence of relapse (CIR; p<.001) and overall survival (OS; p=.011) than the remaining patients. In a multivariable analysis, high ERG expression (p<.001) and the presence of MLL PTD (p=.027) predicted worse CIR."

Marcucci and coinvestigators wrote, "With regard to OS, an interaction was observed between expression of ERG and BAALC (p=.013), with ERG overexpression predicting shorter survival only in low BAALC expressers (p=.002). ERG overexpression was an independent prognostic factor even when the unfavorable group of FLT3 ITD patients lacking an FLT3 wild-type allele was included."

"High ERG expression was associated with upregulation of 112 expressed-sequenced tags and named genes, many of which are involved in cell proliferation, differentiation, and apoptosis."

"ERG overexpression in AML patients with normal cytogenetics predicts an adverse clinical outcome and seems to be associated with a specific molecular signature," concluded the scientists.

Marcucci and colleagues published their study in Genetics (Overexpression of the ETS-related gene, ERG, predicts a worse outcome in acute myeloid leukemia with normal karyotype: a Cancer and Leukemia Group B study. J Clin Oncol, 2005;23(36):9234-42).

For additional information, contact G. Marcucci, Department of Internal Medicine, Division of Hematology and Oncology, Comprehensive Cancer Center, The Ohio State University, Columbus OH 43210, USA.

Study 2: Tamibarotene could be used to treat relapsed or refractory acute promyelocytic leukemia (APL).

"APL is a form of acute myeloid leukemia (AML) caused by a specific chromosomal translocation: t(15;17). This translocation creates a fusion between the promyelocytic (PML) leukemia gene and the retinoic acid receptor alpha (RAR alpha) gene to arrest the maturation of myeloid cells at the promyelocytic stage, leading to increased proliferation of promyelocytes," scientists reported in the journal Drugs of the Future.

"These accumulate in the bone marrow and peripheral blood, replacing normal blood cells. All-trans-retinoic acid (ATRA) therapy targets the transforming activities of the PML-RAR alpha fusion gene. Tamibarotene, a novel RAR alpha agonist, was recently approved and launched in Japan for the treatment of relapsed or refractory APL," announced S.L. Davies and colleagues, Prous Science.

"In vitro, it successfully induces PML differentiation and maturation, deterring PML proliferation. In in vivo studies, the compound demonstrated antitumor activity and good tolerability. Clinical investigations revealed its efficacy in APL patients who had relapsed from ATRA-induced complete remission, as well as a milder side effect profile compared to previous treatment."

The researchers concluded, "Tambarotene therefore represents a novel and promising therapy for APL."

Davies and colleagues published their study in Drugs of the Future (Tamibarotene - Leukemia therapy refinoid RAR alpha agonist. Drug Future, 2005;30(7):688-693).

Additional information can be obtained by contacting S.L. Davies, Prous Science, POB 540, Barcelona 08080, Spain.

Study 3: Researchers examined the effects of sample source and test methodology on the prognosis of acute myelogenous leukemia (AML).

"Numerous studies have analyzed the expression and prognostic importance of various proteins in AML. We sought to determine whether the sample source and methodology used to measure protein expression affect the results obtained," scientists writing in the journal Leukemia reported.

"To determine the importance of sample source, we used Western blotting to compare the expression of 8 proteins and phosphoproteins in the leukemia blast-enriched fraction of 118 blood- and 108 marrow-derived samples, including 37 paired samples. To determine the importance of methodology, the expression of 5 proteins was measured in 20 paired samples by Western blotting, laser scanning cytometry (LSC), and flow cytometry," explained S.M. Kornblau and colleagues, M.D. Anderson Cancer Center.

"The mean expression and range of expression in blood- and marrow-derived samples were statistically identical for all eight proteins. Expression measurements for the 37 paired blood and marrow samples also had very high statistical correlation. The LSC and flow cytometry data had the highest concordance when compared using Kolmogorov-Smirnoff D-stats (range of R values, .8 -1.0)."

"High concordance was also observed between the LSC and flow cytometry results when the percentage of cells positive for expression was dichotomized into positive or negative expression. However, there was less correlation between LSC and flow cytometry when the actual percentages of positive cells were compared. The majority of discordant situations involved samples that were positive by flow cytometry but negative by LSC," noted the investigators.

"The correlation between Western blotting signal intensity and the percentage of expression-positive cells measured by LSC or flow cytometry varied by protein but was limited when there was little heterogeneity in expression by either method."

The researchers concluded, "Provided that leukemia blast-enriched fractions were analyzed, the blood- and marrow-derived samples had identical protein expression. There was good concordance of results between flow cytometry and LSC, which share similar technology, but more limited correlation between these methods and Western blotting."

Kornblau and colleagues published their study in Leukemia (Comparative analysis of the effects of sample source and test methodology on the assessment of protein expression in acute myelogenous leukemia. Leukemia, 2005;19(9):1550-1557).

Additional information can be obtained by contacting S.M. Kornblau, University of Texas, M.D. Anderson Cancer Center, Sect Molecular Hematology & Therapy, Dept. Blood & Marrow Transplantation, Box 448, 1515 Holcombe Blvd., Houston, TX 77030, USA.

Keywords: Houston, Texas, United States, Acute Myelogenous Leukemia, Blood, Diagnosis, Diagnostics, Flow Cytometry, Laser Scanning Cytometry, Marrow, Prognosis, Prognostics, Protein Expression, Proteins, Proteomics, Western Blotting, Sample Source, Test Methodology.

This article was prepared by Clinical Oncology Week editors from staff and other reports. Copyright 2006, Clinical Oncology Week via NewsRx.com.