One of the most intriguing features of chronic lymphocytic leukemia (CLL) is its clinical heterogeneity. The mutational status of immunoglobulin heavy chain variable region (IgVH) genes is one of the most powerful predictors of overall survival (OS) and progression-free survival (PFS). The expression of the tyrosine kinase ZAP-70 in CLL cells has been proposed as a surrogate marker for the mutational status of IgVH genes. Recent reports suggest that ZAP-70 over-expression is an independent prognostic factor for shorter OS and PFS. There is little information about correlation between ZAP-70 expression and other clinical and biological features in CLL. The aims of this study are 1) to evaluate prospectively ZAP-70 expression in a series of CLL patients; 2) to correlate this with clinical stage, lymphocyte morphology, CD38 expression and chromosomal abnormalities detected by FISH and 3) to analyze the independent prognostic value of ZAP-70 in predicting time to first treatment (treatment free interval, TFI). ZAP-70 expression was analyzed using four-colour flow cytometry (as described by

Crespo et al,
NEJM
2003
;
348
:
1764
–75
). 201 previously untreated CLL patients were evaluated at diagnosis (32%) or during the disease course. Amongst them, 143 patients were entered in the LRF CLL4 trial. Clinical stage at the time of the study was A in 92 patients (A progressive in 46), B in 63 and C in 46. 28% were ZAP-70 positive (+) (cut-off ≥ 20% of CD5/CD19+ cells). ZAP-70 positivity was associated with prevalence of stage B/C at diagnosis (p=0.004), CLL with >10% prolymphocytes (CLL/PL) or atypical morphology (p<0.001), CD38 positivity (regardless of the cut-off point) (p<0.001), trisomy12 (p=0.001), del(6)(q21) (p=0.05) or no detectable abnormalities (0.002). ZAP-70 negative (−) cases presented more often with del(13)(q14) (p<0.001). There were no significant differences in the frequency of del(11)(q23) or delp53 between ZAP-70(+) and ZAP-70(−) cases. Median time from diagnosis to first treatment (treatment free interval, TFI) was 17.7 months for ZAP-70(+) and 44.6 months for ZAP-70(−) cases (p<0.001). The presence of the following parameters was associated with short TFI in univariate analysis: male sex (p=0.02), atypical morphology (p=0.02), clinical stage B/C (p<0.001), ZAP-70(+) (p<0.001), CD38+ (p<0.001), absence of del(13)(q14) (p<0.001), presence of delp53 (p=0.05). Multivariate analysis is being performed. In conclusion, we document a significant correlation between ZAP-70 over-expression in CLL and other adverse prognostic factors (such as CD38 and advanced stage), provide new data concerning its association with cytogenetic abnormalities detected by FISH and demonstrate the prognostic value of ZAP-70 expression.

Topics:
chronic b-cell leukemias, chronic lymphocytic leukemia, zap-70 kinase, atypical, prognostic factors, disease progression, flow cytometry, immunoglobulin heavy chains, protein tyrosine kinase, surrogate markers

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2005, The American Society of Hematology
2004
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