Expression of topoisomerase (topo) II in adult acute myeloid leukemia (AML): Relationships to immunophenotype and treatment outcomes.

Abstract

6564 Background: Anthracyclines used in the treatment of AML target topo II. Topo II α and β are genetically distinct with different expression (expr) patterns and cellular distribution. While topo IIα has been associated with increased proliferation and an adverse prognosis in AML, there is no information regarding topo IIβ. This study examined the relationships of topo IIα and β expr to immunophenotype (IP), multidrug resistant (MDR) phenotype and outcomes in adult AML. Methods: 230 pts with non-M3 AML by FAB criteria who received frontline ara‐C/daunomycin (AD) therapy during the years 1992-98 on studies SWOG-9031, ‐9126, ‐9333 or ‐9500 were included (median age 63 years [18-88], WBC 29x109/L [0.8-274]). RT-PCR of RNA from marrow blasts was run with topo IIα and β specific primers (ABI PRISM 7900HT). Topo IIα and β expr in pts, normalized to internal standard β2‐microglobulin, was measured by log (fold-change) relative to the Kasumi AML cell line. Treatment outcomes - complete response (CR), resistant disease (RD), and relapse-free and overall survival (RFS, OS) - were analyzed by logistic or Cox regression. Results: Topo IIα and β data were available for 211 pts. Topo IIα expr in pts ranged from 298-fold less to 91-fold more than in the Kasumi AML cell line, but was not significantly correlated with any pt characteristic, IP or treatment outcome in uni- or multivariate analysis. In contrast, topo IIβ ranged from only 9‐fold less to 10-fold more than the cell line, but was associated with higher blast percentage in marrow (P=0.0001) or blood (P=0.0055); higher CD7 (P=0.0071); and lower CD14 (P<0.0001) and CD54 (P<0.0001) in multivariate regression analysis. In 105 pts with MDR data, topo IIβ was also inversely correlated with Rhodamine efflux (P<0.0001) and CD11c (P=0.0010). However after adjusting for prognostic factors, topo IIβ was not significantly related to any outcome, nor did topo IIβ interact significantly with any prognostic factors. Conclusions: Topo IIβ expr reflects aspects of disease biology, such as highly proliferative disease (higher blasts), IP and MDR, and thus may not be an independent variable influencing outcome in adult AML pts treated with anthracycline-based therapy.