1. ¹Department of Hematology and Oncology, Georg-August-University Goettingen, Germany
2. ²Department of Genetic Epidemiology, Georg-August-University Goettingen, Germany
3. ³Institute of Cell Biology, University Hospital Essen, Germany
4. ⁴Department of Hematology, University Hospital Essen, University of Duisburg-Essen, Germany

Correspondence: Dr R Schroers, Department of Hematology and Oncology, Georg-August-University Goettingen, Robert-Koch-Strae 40, D-37099 Goettingen, Germany. Fax: +49 551 39 8587; E-mail: R.Schroers@medizin.uni-goettingen.de; Dr J Dürig, Department of Hematology, University Hospital Essen, Hufelandstrae 55, D-45122 Essen, Germany. Fax: +49 201 723 2304; E-mail: jan.duerig@uni-essen.de

Received 20 December 2004; Accepted 29 December 2004; Published online 10 March 2005.

Abstract

Prognostic predictions in B-cell chronic lymphocytic leukemia (B-CLL) at early clinical stage are based on biological disease parameters, such as ZAP-70 and CD38 protein levels, genomic aberrations as well as immunoglobulin variable heavy chain gene (IgV_H) mutation status. In the current study, ZAP-70 and CD38 expressions were examined by flow cytometry in 252 patients with B-CLL. Cytoplasmic ZAP-70 expression in more than 20% (ZAP-70⁺) and surface CD38 expression on more than 30% (CD38⁺) of B-CLL cells were associated with an unfavorable clinical course. The levels of ZAP-70 and CD38 did not change over time in the majority of patients where sequential samples were available for analysis. Combined analysis of ZAP-70 and CD38 yielded discordant results in 73 patients (29.0%), whereas 120 patients (47.6%) were concordantly negative and 59 patients (23.4%) were concordantly positive for ZAP-70 and CD38 expression. Median treatment-free survival times in patients whose leukemic cells were ZAP-70⁺CD38⁺ was 30 months as compared to 130 months in patients with a ZAP-70^-CD38^- status. In patients with discordant ZAP-70/CD38 results, the median treatment-free survival time was 43 months. Thus, ZAP-70 and CD38 expression analyses provided complementary prognostic information identifying three patient subgroups with good, intermediate and poor prognosis. Over-representation of high-risk genomic aberrations such as 17p deletion or 11q deletion and distribution of the IgV_H mutation status in B-CLL discordant for ZAP-70/CD38 pointed toward a distinct biologic background of the observed disease subgroups. This finding was also supported by microarray-based gene expression profiling in a subset of 35 patients. The expression of 37 genes differed significantly between the three groups defined by their expression of ZAP-70 and CD38, including genes that are involved in regulation of cell survival and chemotherapy resistance.