Relative Value of ZAP-70, CD38, and Immunoglobulin Mutation Status In Predicting Aggressive Disease In Chronic Lymphocytic Leukemia (original) (raw)
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Prognostic significance of combined analysis of ZAP70 and CD38 in chronic lymphocytic leukemia
American Journal of Hematology, 2007
The clinical heterogeneity that characterizes chronic lymphocytic leukemia (CLL) poses critical questions concerning the identification of high risk patients. Unmutated IgV H genes, CD38 and ZAP-70 expression have emerged as the most useful tools in identifying aggressive CLL. The simultaneous expression of ZAP-70 and CD38 in 157 patients with CLL has been evaluated. Fifty-seven patients (36%) were positive for ZAP-70 and 46 patients (29%) were positive for CD38. Both molecules were highly correlated and predictive of the clinical course of the disease. According to the simultaneous evaluation of ZAP-70 and CD38, patients were divided into three groups. In 81 patients (52%), there was a negative concordance of both molecules (ZAP-70 À /CD38 -); in 27 patients (17%) there was a positive concordance (ZAP-70 1 /CD38 1 ); in 49 patients (31%) there was a discordant expression (ZAP-70 1 /CD38and ZAP-70 -/CD38 1 ). A comparison of the clinical and laboratory data showed in ZAP-70 1 /CD38 1 patients a significantly higher bone marrow and peripheral blood lymphocytosis, lower hemoglobin levels, more advanced clinical stage, and higher number of unmutated IgV H status with respect to the other two groups. Furthermore, ZAP-70 1 /CD38 1 patients displayed a much shorter treatment-free interval (median 12 months vs 42 months in discordant patients and not reached in ZAP-70 -CD38patients). These results prove that the concomitant evaluation of ZAP-70 and CD38 expression allows the separation of CLL patients in prognostic subgroups and suggest that their simultaneous assessment should become an integral component of the CLL diagnostic grid. Am. J. Hematol. 82:787-791, 2007. V V C 2007 Wiley-Liss, Inc.
Leukemia, 2005
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 þ ) and surface CD38 expression on more than 30% (CD38 þ ) 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 þ CD38 þ was 30 months as compared to 130 months in patients with a ZAP-70 À CD38 À 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.
Leukemia, 2007
Zeta-associated protein-70 (ZAP-70), mostly assessed by flowcytometry (FC), recently emerged as reliable prognostic factor in chronic lymphocytic leukaemia (CLL) at presentation. We evaluated ZAP-70 expression in 156 CLL patients by immunohistochemistry (IHC) on formalin-fixed bone marrow (BM) biopsies at diagnosis. At presentation, 117 patients (75%) were with Binet stage A, 27 (17%) stage B and 12 (8%) stage C. Median follow-up was 61 months (range 6-242). ZAP-70 was expressed in neoplastic lymphocytes of 69 patients (44%). Concordance between ZAP-70 by IHC and ZAP-70 by FC, immunoglobulin heavy chain variable genes (IGHV) mutational status and CD38 expression was found in 41/46 (89%), 41/49 (80%) and in 60/88 (68%) tested cases, respectively. ZAP-70 expression significantly correlated with advanced Binet stage (B-C), diffuse BM infiltration, increased lactate dehydrogenase (LDH) and b2-microglobulin serum levels and lymphocyte doubling time o12 months. ZAP-70 positivity was significantly related to poorer time to progression (median 16 months vs 158 of ZAP-70-negative cases) (Po0.0001) and overall survival (median 106 months vs not reached) (P ¼ 0.0002); this correlation was confirmed at multivariate analysis. ZAP-70 expression correlated with poorer outcome also when evaluated only in the 117 stage A patients. In conclusion, immunohistological detection of ZAP-70 on formalin-fixed BM biopsies at diagnosis appears a useful methodological approach to identify patients with poor prognosis in CLL.
Frequency of Zap-70 and CD38 in Newly Diagnosed Cases of B-Cell Chronic Lymphocytic Leukemia
Research Article, 2019
Amongst all chronic lymphoproliferative disorders B-CLL is the most common. Clinical behavior of CLL is very variable and in order to identify the clinical spectrum there is a need for risk adaptive prognostic markers which will further facilitate in management strategy. Currently available molecular biomarkers ZAP-70 & CD-38 have gain much interest in providing useful prognostic information in patients diagnosed as B-CLL.
Turkiye Klinikleri Journal of Medical Sciences, 2014
Chronic lymphocytic leukemia (CLL) is one of the most common leukemia type among adults in the industrialized countries. Due to the nature of CLL, it is important to recognize patients with a more rapid course of disease. The goal of our study was to study ZAP70 and CD38 antibodies along with immunglobulin heavy chain variable region (IgVH) mutation status, which have been associated with rapid progression and aggressive clinical course in CLL, and to correlate the expression of these molecules with patterns of bone marrow infiltration. M Ma at te er ri ia al l a an nd d M Me et th ho od ds s: : We included 84 bone marrow biopsy samples into the study to determine ZAP70 and CD38 status using immunohistochemistry. Expression patterns for both antibodies were then correlated with the bone marrow infiltration patterns. We also analyzed IgVH mutations in 20 patients using DNA obtained from paraffin-embedded formalin-fixed bone marrow biopsies. These findings were then correlated with immunohistochemical results. R Re es su ul lt ts s: : We identified a positive correlation between the expression patterns of ZAP70 and CD38, factors that were previously identified as poor prognostic factors (p<0.001). However, there was no correlation between these two markers and IgVH mutation status (p=1.000 and p=0.931). In addition, we showed a statistically significant positive correlation with ZAP70 immunostaining, and the necessity for an early intervention (p=0.046). ZAP70 and CD38 expressions were statistically significantly correlated with the diffuse pattern infiltration of bone marrow (p<0.001 and p<0.001, respectively). C Co on nc cl lu us si io on n: : Despite small number of our patients, the findings of our study suggested that ZAP70 and CD38 expression patterns as well as IgVH mutation status might be helpful to determine the course of the disease, and the risk of progression. Particularly ZAP70 immunopositive patients appear to have a faster disease progression, and may require earlier intervention and a closer follow up.
ZAP-70 expression is associated with increased risk of autoimmune cytopenias in CLL patients
American Journal of Hematology, 2010
words count=192 Text words count=3125 Tables=3 Figure=4 ABSTRACT Autoimmune cytopenias (AIC) are frequent in CLL patients, but risk factors and prognostic relevance of these events are controversial. Data about the influence on AIC of biological prognostic markers, as ZAP-70, are scanty. We retrospectively evaluated AIC in 290 CLL patients tested for ZAP-70 expression by immunohistochemistry on bone marrow biopsy at presentation. They were 185 males, median age 63 years, 77.9% Binet stage A, 17.6% B and 4.5% C. AIC occurred in 46 patients (16%): 31 autoimmune haemolytic anaemias, 10 autoimmune thrombocytopenias, 4 Evans syndromes and 1 pure red cell aplasia. Of the 46 cases of AIC, 37 (80%) occurred in ZAP-70positive patients and 9 (20%) in ZAP-70negatives. ZAP-70 expression (HR=7.42; 95%CI:2.49-22.05) and age >65 years (HR=5.41; 95%CI:1.67-17.49) resulted independent risk factors for AIC. Among the 136 patients evaluated for ZAP-70 expression and IGHV status the occurrence of AIC was higher in ZAP-70positive/IGHVunmutated cases (35%) than in patients ZAP-70negative/IGHVmutated (6%) or discordant for the two parameters (4%) (P<0.0001). In ZAP-70 positive patients occurrence of AIC negatively influenced survival (HR=1.75; 95% CI: 1.06-2.86).