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Journal of Clinical Oncology, Vol 24, No 19 (July 1), 2006: pp. 3219-3220 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.06.3271
In ReplyDepartment of Internal Medicine, University of Ulm, Ulm, Germany We have evaluated the association of zeta-associated protein 70 (ZAP-70) expression as assessed by flow cytometry according to Crespo et al,1 genomic aberrations, the VH mutation status, and V3-21 usage in chronic lymphocytic leukemia (CLL).2 ZAP-70 expression and VH mutation status were strongly associated in CLL without additional genetic high-risk features as defined by the absence of 11q or 17p deletion and V3-21 usage (concordance, 84%). In contrast, the proportion of discordant cases was significantly higher (39%), if such additional genetic high-risk features were present. Discordant cases with V3-21 usage were almost exclusively ZAP-70 positive and VH mutated (89%), whereas all but one of the discordant cases with high-risk aberrations were ZAP-70 negative and VH unmutated (92%). Shanafelt et al assessed ZAP-70 by the method of Rassenti et al3 in 234 CLL patients. Their CLL cohort was characterized by typical low-risk features, such as a high proportion of VH mutated cases (65%), a low proportion of V3-21 using cases (3%), and a low proportion of cases with 11q or 17p deletion (14%). In contrast to our results as well as other groups who analyzed CLL patients with mainly low-risk features and found ZAP-70/VH status concordance rates greater than 90%,1,4 the ZAP-70/VH status concordance was only 71% in the series of Shanafelt et al. Despite the high discordance rate in their measurements, Shanafelt et al reproduce the major points of our report: they confirm a higher ZAP-70/VH status concordance rate in the absence of 11q deletion, 17p deletion, or V3-21 usage. They also find the discordance mode VH unmutated/ZAP-70 negative in the majority of discordant cases (67%) in the group with 11q or 17p deletion (no V3-21). They observed a balanced distribution among the modes of discordance in the absence of 11q, 17p deletion, or V3-21 usage as described in our data set. In addition, our observation has been independently reproduced by Dicker et al,5 who analyzed ZAP-70 expression by quantification of mRNA. Among 100 CLL patients, 20 patients showed discordant ZAP-70/VH status. Among these, nine patients were VH unmutated with low ZAP-70 expression and seven of these nine patients exhibited adverse cytogenetic features. A peculiar feature in the series of Shanafelt et al is the fact that the majority of V3-21 using cases were VH unmutated and all their V3-21 cases were ZAP-70 negative. These findings are in contrast to other published series: the majority of reported V3-21 cases are mutated and ZAP-70 expression has been frequently detected by different methods in cases with mutated V3-21 rearrangements, which also supports our data.4-9 We agree with Shanafelt et al that interlaboratory standardization of the ZAP-70 flow cytometry assay has been challenging and may account for some of the differences between our studies. In addition, specific features of the patient cohort analyzed by Shanafelt et al such as a high proportion of low risk patients, the relatively low numbers of 11q, 17p deletion, and V3-21 using cases as well as the peculiar characteristics of their V3-21 cases could also account for the differences observed. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Crespo M, Bosch F, Villamor N, et al: ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med 348:1764-1775, 2003 2. Kröber A, Bloehdorn J, Hafner S, et al: Additional genetic high-risk features such as 11q deletion, 17p deletion, and V3-21 usage characterize discordance of ZAP-70 and VH mutation status in chronic lymphocytic leukemia. J Clin Oncol 24:969-975, 2006 3. Rassenti LZ, Huynh L, Toy TL, et al: ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. N Engl J Med 351:893-901, 2004 4. Orchard JA, Ibbotson RE, Davis Z, et al: ZAP-70 expression and prognosis in chronic lymphocytic leukemia. Lancet 363:105-111, 2004[CrossRef][Medline] 5. Dicker F, Ebenbichler C, Mann K, et al: Analysis with the LightCycler System identifies a highliy significant correlation between ZAP-70 mRNA expression and immunoglobulin variable heavy chain gene mutational status in chronic lymphocytic leukemia. Blood 106:911a, 2005 (abstr 3259) 6. Thorselius M, Kröber A, Murray F, et al: Strikingly homologous immunoglobulin gene rearrangements and poor outcome in VH3-21-utilizing chronic lymphocytic leukemia independent of geographical origin and mutational status. Blood 107:2889-2894, 2006 7. Wiestner A, Rosenwald A, Barry TS, et al: ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile. Blood 101:4944-4951, 2003 8. Letestu R, Le Garff-Tavernier M, Vaur D, et al: Analysis of B-CLL with discordant ZAP-70 expression and IgVH mutational status. Blood 106:348a, 2005 (abstr 1194) 9. Kienle D, Benner A, Kröber A, et al: Distinct gene expression patterns in chronic lymphocytic leukemia defined by usage of specific VH genes. Blood 107:2090-2093, 2006
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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