Combined analysis of ZAP-70 and CD38 expression as a predictor of disease progression in B-cell chronic lymphocytic leukemia

Georg-August-Universität Göttingen, Göttingen, Lower Saxony, Germany
Leukemia (Impact Factor: 10.43). 06/2005; 19(5):750-8. DOI: 10.1038/sj.leu.2403707
Source: PubMed


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.

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Available from: Lorenz Trümper, Apr 17, 2014
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    • "Kaplan–Meier analysis of the patients showed significantly lower TDP (4.5 months) in patients with higher ZAP-70, CD38 expression and carrying del 17p, while those with negative CD38, ZAP-70 and del 17p had a TDP of 16.7 months, whereas TDP was 8.2 months in patients with two parameters positive, and was 12 months in patients with cells positive for one parameter only. Similar results were previously shown by other investigators [23] who added that over representation of the high-risk genomic aberration 17p deletion in B-CLL discordant for CD38/ZAP-70 pointed towards a distinct biologic background of the observed disease subgroups. This finding was also supported by gene expression profiling where the expression of 37 genes differed significantly between the groups defined by their expression of ZAP-70 and CD38, including genes that are involved in regulation of cell survival and chemotherapy resistance [13]. "
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    ABSTRACT: Prognostic markers as CD38 and ZAP-70 and specific chromosomal abnormalities as del 17p have now been developed to refine the risk of progressive disease in chronic lymphocytic leukemia (CLL). This study analyzed 40 recently diagnosed, untreated B-CLL patients for CD38 and ZAP-70 expression by flow cytometry and for del 17p by conventional cytogenetics (CCG) and by fluorescence in situ hybridization (FISH) technique to evaluate their effect on the clinical course of CLL and as risk factors for disease progression in addition to their impact on response to treatment and disease outcome. Twenty healthy age- and sex-matched subjects were included as a control. The results revealed that CD38 and ZAP-70 expression were detected in 42.5% and 47.5% of cases, respectively. They were associated with an unfavorable clinical course. Higher levels were significantly associated with increased risk of unfavorable response to treatment (P = 0.003), with poor clinical outcome (P = 0.0001). Del 17p was detected in 35% of cases by FISH technique and in 7.5% by CCG. The deletion was significantly associated with progressive clinical course; poor response to treatment (P = 0.007) but not with disease outcome (P = 0.103).
    Preview · Article · Jun 2012 · Egyptian Journal of Medical Human Genetics
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    • "As this is a difficult and expensive test to perform routinely in clinical laboratories, surrogate markers such as zeta associated protein 70 (ZAP70) and CD38 expression have been evaluated.12–15 The use of a combination of both CD38 expression and ZAP70 can classify CLL patients in to 2 risk groups with a double negative result equating to an excellent prognosis and double positive a poor prognosis.16 "
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    ABSTRACT: The management of chronic lymphocytic leukemia (CLL) has evolved dramatically in the last decade. For the first time, clinical intervention has been shown to alter the natural history of the disease. Considerable efforts are focussing on better patient selection and response prediction, and it is expected that the publication of the first 200 CLL genomes will spark new insights into risk stratification of CLL patients. Besides, many new agents are being evaluated on their own and in combination therapy in early and late Phase clinical studies. Here, we provide a general clinical introduction into CLL including diagnosis and prognostic markers followed by a summary of the current state-of-the-art treatment. We point to areas of continued clinical research in particular for patients with co-morbidities and highlight the challenges in managing refractory disease.
    Full-text · Article · Mar 2012 · Clinical Medicine Insights: Oncology
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    • "However, expression within the two subgroups of del11q and trisomy 12 increased significantly. This observation was similar to the findings by other investigators (Kienle et al., 2005; Schroers et al., 2005; Krober et al., 2006). Comparison of means and standard deviations for the cytogenetic subgroups and the control group illustrated that standard deviations for the del13q subgroup and the control group were much smaller than those of del11q and trisomy 12 subgroups. "
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    ABSTRACT: Chromosomal abnormalities and ZAP70 expression profile are two major independent prognostic markers in B-cell chronic lymphocytic leukemia. We investigated a possible correlation between these two markers. ZAP70 expression using real-time RT-PCR was examined in 20 B-cell chronic lymphocytic leukemia patients with del13q14, 13 patients with del11q22, 15 patients with trisomy 12, and 16 patients with no detected chromosomal abnormalities. Molecular analysis revealed that ZAP70 expression in the del13q subgroup was the same as in the control group, while it increased 2.78-fold in the del11q subgroup and 2.95-fold in the trisomy 12 subgroup, compared to the 15 cases in the control group. Comparison of the mean and standard deviation of the ZAP70 expression profile within the subgroups showed it to be highly variable among the individuals of the del11q and trisomy 12 subgroups, versus tight clustering for the del13q subgroup. Therefore, there is a correlation between del13q aberration, which has good prognosis with normal levels of ZAP70 expression. Due to a high degree of variation, no conformity is seen for del11q and trisomy 12 subgroups, making this grouping poor for prognostic discrimination. As a result, neither of these markers can serve as sole discriminators to determine the course of the disease; the use of both markers improves prognostic assessment.
    Full-text · Article · Jan 2011 · Genetics and molecular research: GMR
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