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Proffered Abstract (Plenary Session): Monitoring Response During Cancer Therapy

A novel biomarker to diagnose and monitor acute myelogenous leukemia

Panacea Pharmaceuticals, Inc., Gaithersburg, MD and Institute for Hematology and Blood Transfusion, Prague, Czech Republic

Abstract

PR-6

Background: Acute myelogenous leukemia (AML) is characterized by the rapid proliferation of immature leukocytes (blasts) in patient peripheral blood (PB). Initial diagnosis of AML relies upon blood cell counts and detection of cytomorphological changes in leukocytes found in the PB and bone marrow (BM). Treatment of AML begins with induction chemotherapy resulting in complete remission (CR) in 60-80% of all patients. CR is defined as the absence of leukemic cells in both the PB and BM as detected by cytomorphological assessment. Due to the lack of sensitivity of these methods, small numbers of diseased cells may persist resulting in disease relapse. Thus, in most cases multiple rounds of chemotherapy may be recommended. A specific molecular marker for minimum residual disease (MRD) would be of great benefit in determining prognosis, optimal post-remission therapy, effectiveness of therapy and as an early indicator of disease relapse. Human aspartyl (aspariginyl) ß-hydroxylase (ASPH) is a highly specific biomarker for cancer. Increased ASPH expression has been detected at the protein and mRNA levels specifically in tumor cells. Over-expression of ASPH results in its translocation to the cellular surface where it is a potential target for antibody-based cancer therapy. The primary goal of this work was to investigate the utility of ASPH gene expression levels as a marker for MRD in AML.Methods: Expression levels of ASPH were determined by real-time quantitative polymerase chain reaction (RQ-PCR) analysis of leukocytes isolated from fresh whole blood at diagnosis and compared to healthy donors. Expression levels in treated patients who attained CR were also determined. Results: At diagnosis, patients (n=22) displayed increased expression of the ASPH transcript (~8.6-fold, p<0.0002) when compared to healthy donors (n=15). Increased levels of ASPH expression were detected in multiple AML subtypes. On average, ASPH expression decreased in treated patients (n=27) to essentially normal levels, however a broader range of values was detected and it remains to be determined if higher values correlate with disease relapse.Conclusions: These results suggest that ASPH expression represents a molecular marker for AML that is broadly applicable over multiple disease subtypes and may be helpful in monitoring remission. ASPH expression is easily determined from PB leukocytes and may replace BM biopsy as a monitoring tool. Thus, determination of ASPH expression levels may enhance the diagnosis and monitoring of AML.