ZAP-70 and Prognosis in CLL

January 20, 2004

Lancet. 2004 Jan 10; 363(9403): 105-11.

ZAP-70 expression and prognosis in chronic lymphocytic leukaemia.

Orchard JA, Ibbotson RE, Z, Wiestner A, Rosenwald A, PW,

Hamblin TJ, Staudt LM, Oscier DG.

Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK

Background: Chronic lymphocytic leukemia (CLL) is a heterogeneous

disease; many patients never need treatment, whereas some have poor

outcomes. New treatments, which can induce complete remissions, allow

patients with poor outlook to be treated while they are still

asymptomatic. Whether or not the IgVH gene is mutated is the best

predictor of clinical outcome, but this assay is unsuited to the

routine laboratory.

The gene coding for ZAP-70, a tyrosine kinase protein normally

expressed in T and NK cells, has been shown by gene-expression

profiling to be differentially expressed between patients with

mutated and unmutated IgVH genes. We assessed whether ZAP-70 could be

used as a prognostic marker in CLL.

Methods: We developed a flow cytometry assay for ZAP-70 protein

expression and investigated its concordance with ZAP-70 mRNA

expression, IgVH gene mutational status, and clinical outcome in 167

patients with CLL.

Findings: We showed high concordance between ZAP-70 protein

expression and IgVH gene mutations. 108 patients (65%) had mutated

IgVH genes and were ZAP-70 negative; 46 (28%) had unmutated IgVH

genes and were ZAP-70 positive. Findings were discordant in 13

patients: six (4%) had mutated IgVH genes but were ZAP-70 positive,

and seven (4%) had unmutated IgVH genes and were ZAP-70 negative.

Expression of mRNA showed 97% concordance with ZAP-70 protein.

Median survival was 24.4 years (95% CI 15.1-33.8) in ZAP-70 negative

patients and 9.3 years (7.0-11.5) in those who were ZAP-70 positive

(hazard ratio 5.5, 2.8-.8).

Interpretation: ZAP-70 protein, which can be measured by flow

cytometry in the general laboratory, is a reliable prognostic marker

in CLL, equivalent to that of IgVH gene mutational status.

PMID: 14726163 [PubMed - in process]

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