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Previous Volume 351:893-901 August 26, 2004 Number 9 Next

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ABSTRACT

Background The course of chronic lymphocytic leukemia (CLL) is variable. In aggressive disease, the CLL cells usually express an unmutated immunoglobulin heavy-chain variable-region gene (IgV_H) and the 70-kD zeta-associated protein (ZAP-70), whereas in indolent disease, the CLL cells usually express mutated IgV_H but lack expression of ZAP-70.

Methods We evaluated the CLL B cells from 307 patients with CLL for ZAP-70 and mutations in the rearranged IgV_H gene. We then investigated the association between the results and the time from diagnosis to initial therapy.

Results We found that ZAP-70 was expressed above a defined threshold level in 117 of the 164 patients with an unmutated IgV_H gene (71 percent), but in only 24 of the 143 patients with a mutated IgV_H gene (17 percent, P<0.001). Among the patients with ZAP-70–positive CLL cells, the median time from diagnosis to initial therapy in those who had an unmutated IgV_H gene (2.8 years) was not significantly different from the median time in those who had a mutated IgV_H gene (4.2 years, P=0.07). However, the median time from diagnosis to initial treatment in each of these groups was significantly shorter than the time in patients with ZAP-70–negative CLL cells who had either mutated or unmutated IgV_H genes (P<0.001). The median time from diagnosis to initial therapy among patients who did not have ZAP-70 was 11.0 years in those with a mutated IgV_H gene and 7.1 years in those with an unmutated IgV_H gene (P<0.001).

Conclusions Although the presence of an unmutated IgV_H gene is strongly associated with the expression of ZAP-70, ZAP-70 is a stronger predictor of the need for treatment in B-cell CLL.

Source Information

From the Chronic Lymphocytic Leukemia Research Consortium (L.Z.R., L.H., T.L.T., L.C., M.J.K., J.G.G., D.S.N., I.W.F., K.R.R., J.C.B., N.E.K., A.G., T.J.K.); University of California, San Diego, La Jolla (L.Z.R., L.H., T.L.T., L.C., A.G., T.J.K.); M.D. Anderson Cancer Center, Houston (M.J.K.); Dana–Farber Cancer Institute, Boston (J.G.G., D.S.N.); Kimmel Cancer Center, Johns Hopkins, Baltimore (I.W.F.); Long Island Jewish Medical Center, New Hyde Park, N.Y. (K.R.R.); Ohio State University, Columbus (J.C.B.); Mayo Clinic, Rochester, Minn. (N.E.K.); and Howard Hughes Medical Institute, University of California, San Francisco, San Francisco (A.W.).

Address reprint requests to Dr. Kipps at 9500 Gilman Dr., UCSD School of Medicine, La Jolla, CA 92093, or at tkipps{at}ucsd.edu.

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• Ghia, E. M., Rassenti, L. Z., Widhopf, G. F., Neuberg, D. S., Keating, M. J., Wierda, W. G., Gribben, J. G., Brown, J. R., Flinn, I. W., Rai, K. R., Byrd, J. C., Kay, N. E., Greaves, A. W., Kipps, T. J. (2006). Study of VH3-21 in a Large Cohort of Chronic Lymphocytic Leukemia Patients Reveals Evidence for Antigen Selection and Confirms Its Predictive Value for Early Disease Progression.. ASH ANNUAL MEETING ABSTRACTS 108: 2774-2774 [Abstract]  
• Rassenti, L. Z., Neuberg, D. S., Huynh, L., Wierda, W. G., Gribben, J. G., Brown, J. R., Flinn, I. W., Rai, K. R., Byrd, J. C., Kay, N. E., Greaves, A. W., Kipps, T. J. (2006). Relative Value of CD38 and ZAP-70 Versus Immunoglobulin Mutation Status in Predicting Early Disease Progression in Chronic Lymphocytic Leukemia.. ASH ANNUAL MEETING ABSTRACTS 108: 2778-2778 [Abstract]  
• Shanafelt, T. D., Witzig, T. E., Fink, S. R., Jenkins, R. B., Paternoster, S. F., Smoley, S. A., Stockero, K. J., Nast, D. M., Flynn, H. C., Tschumper, R. C., Geyer, S., Zent, C. S., Call, T. G., Jelinek, D. F., Kay, N. E., Dewald, G. W. (2006). Prospective Evaluation of Clonal Evolution During Long-Term Follow-Up of Patients With Untreated Early-Stage Chronic Lymphocytic Leukemia. JCO 24: 4634-4641 [Abstract] [Full Text]  
• Frey, U. H., Nuckel, H., Sellmann, L., Siemer, D., Kuppers, R., Durig, J., Duhrsen, U., Siffert, W. (2006). The GNAS1 T393C Polymorphism Is Associated with Disease Progression and Survival in Chronic Lymphocytic Leukemia.. Clin. Cancer Res. 12: 5686-5692 [Abstract] [Full Text]  
• Balakrishnan, K., Nimmanapalli, R., Ravandi, F., Keating, M. J., Gandhi, V. (2006). Forodesine, an inhibitor of purine nucleoside phosphorylase, induces apoptosis in chronic lymphocytic leukemia cells. Blood 108: 2392-2398 [Abstract] [Full Text]  
• Shanafelt, T. D., Byrd, J. C., Call, T. G., Zent, C. S., Kay, N. E. (2006). Narrative review: initial management of newly diagnosed, early-stage chronic lymphocytic leukemia.. ANN INTERN MED 145: 435-447 [Abstract] [Full Text]  
• Yee, K. W. L., O'Brien, S. M. (2006). Chronic Lymphocytic Leukemia: Diagnosis and Treatment. Mayo Clin Proc. 81: 1105-1129 [Abstract] [Full Text]  
• Del Principe, M. I., Del Poeta, G., Buccisano, F., Maurillo, L., Venditti, A., Zucchetto, A., Marini, R., Niscola, P., Consalvo, M. A. I., Mazzone, C., Ottaviani, L., Panetta, P., Bruno, A., Bomben, R., Suppo, G., Degan, M., Gattei, V., de Fabritiis, P., Cantonetti, M., Lo Coco, F., Del Principe, D., Amadori, S. (2006). Clinical significance of ZAP-70 protein expression in B-cell chronic lymphocytic leukemia. Blood 108: 853-861 [Abstract] [Full Text]  
• Koller, C., Bekele, B. N., Zhou, X., Park, C., Estrov, Z., O'Brien, S., Keating, M., Jilani, I., Giles, F. J., Kantarjian, H. M., Albitar, M. (2006). Plasma thrombopoietin compared with immunoglobulin heavy-chain mutation status as a predictor of survival in chronic lymphocytic leukemia. Blood 108: 1001-1006 [Abstract] [Full Text]  
• Deglesne, P.-A., Chevallier, N., Letestu, R., Baran-Marszak, F., Beitar, T., Salanoubat, C., Sanhes, L., Nataf, J., Roger, C., Varin-Blank, N., Ajchenbaum-Cymbalista, F. (2006). Survival response to B-cell receptor ligation is restricted to progressive chronic lymphocytic leukemia cells irrespective of zap70 expression.. Cancer Res. 66: 7158-7166 [Abstract] [Full Text]  
• Shanafelt, T. D., Jelinek, D., Tschumper, R., Schwager, S., Nowakowski, G., DeWald, G. W., Kay, N. E. (2006). Cytogenetic Abnormalities Can Change During the Course of the Disease Process in Chronic Lymphocytic Leukemia. JCO 24: 3218-3219 [Full Text]  
• Krober, A., Dohner, H., Stilgenbauer, S. (2006). In Reply. JCO 24: 3219-3220 [Full Text]  
• Tsimberidou, A.-M., O'Brien, S., Khouri, I., Giles, F. J., Kantarjian, H. M., Champlin, R., Wen, S., Do, K.-A., Smith, S. C., Lerner, S., Freireich, E. J., Keating., M. J. (2006). Clinical Outcomes and Prognostic Factors in Patients With Richter's Syndrome Treated With Chemotherapy or Chemoimmunotherapy With or Without Stem-Cell Transplantation. JCO 24: 2343-2351 [Abstract] [Full Text]  
• Richardson, S. J., Matthews, C., Catherwood, M. A., Alexander, H. D., Carey, B. S., Farrugia, J., Gardiner, A., Mould, S., Oscier, D., Copplestone, J. A., Prentice, A. G. (2006). ZAP-70 expression is associated with enhanced ability to respond to migratory and survival signals in B-cell chronic lymphocytic leukemia (B-CLL). Blood 107: 3584-3592 [Abstract] [Full Text]  
• Khan, I. H., Mendoza, S., Rhyne, P., Ziman, M., Tuscano, J., Eisinger, D., Kung, H.-J., Luciw, P. A. (2006). Multiplex Analysis of Intracellular Signaling Pathways in Lymphoid Cells by Microbead Suspension Arrays. Mol. Cell. Proteomics 5: 758-768 [Abstract] [Full Text]  
• Buhl, A. M., Jurlander, J., Jorgensen, F. S., Ottesen, A. M., Cowland, J. B., Gjerdrum, L. M., Hansen, B. V., Leffers, H. (2006). Identification of a gene on chromosome 12q22 uniquely overexpressed in chronic lymphocytic leukemia. Blood 107: 2904-2911 [Abstract] [Full Text]  
• Potter, K. N., Mockridge, C. I., Neville, L., Wheatley, I., Schenk, M., Orchard, J., Duncombe, A. S., Packham, G., Stevenson, F. K. (2006). Structural and Functional Features of the B-Cell Receptor in IgG-Positive Chronic Lymphocytic Leukemia.. Clin. Cancer Res. 12: 1672-1679 [Abstract] [Full Text]  
• Krober, A., Bloehdorn, J., Hafner, S., Buhler, A., Seiler, T., Kienle, D., Winkler, D., Bangerter, M., Schlenk, R. F., Benner, A., Lichter, P., Dohner, H., Stilgenbauer, S. (2006). 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. JCO 24: 969-975 [Abstract] [Full Text]  
• Borkhardt, A., Fuchs, U., Tuschl, T., Chng, W. J., Calin, G. A., Cimmino, A., Croce, C. M. (2006). MicroRNA in chronic lymphocytic leukemia.. NEJM 354: 524-525 [Full Text]  
• Binet, J.-L., Caligaris-Cappio, F., Catovsky, D., Cheson, B., Davis, T., Dighiero, G., Dohner, H., Hallek, M., Hillmen, P., Keating, M., Montserrat, E., Kipps, T. J., Rai, K., for the International Workshop on Chronic Lymphocy, (2006). Perspectives on the use of new diagnostic tools in the treatment of chronic lymphocytic leukemia. Blood 107: 859-861 [Abstract] [Full Text]  
• Byrd, J. C., Gribben, J. G., Peterson, B. L., Grever, M. R., Lozanski, G., Lucas, D. M., Lampson, B., Larson, R. A., Caligiuri, M. A., Heerema, N. A. (2006). Select High-Risk Genetic Features Predict Earlier Progression Following Chemoimmunotherapy With Fludarabine and Rituximab in Chronic Lymphocytic Leukemia: Justification for Risk-Adapted Therapy. JCO 24: 437-443 [Abstract] [Full Text]  
• Chiorazzi, N., Ferrarini, M. (2006). Evolving View of the In-Vivo Kinetics of Chronic Lymphocytic Leukemia B Cells. ASH Education Book 2006: 273-278 [Abstract] [Full Text]  
• Montserrat, E. (2006). New Prognostic Markers in CLL. ASH Education Book 2006: 279-284 [Abstract] [Full Text]  
• Chiaretti, S., Guarini, A., De Propris, M. S., Tavolaro, S., Intoppa, S., Vitale, A., Iacobelli, S., Elia, L., Ariola, C., Ritz, J., Foa, R. (2006). ZAP-70 expression in acute lymphoblastic leukemia: association with the E2A/PBX1 rearrangement and the pre-B stage of differentiation and prognostic implications. Blood 107: 197-204 [Abstract] [Full Text]  
• Nabhan, C., Bitran, J. D. (2005). Chronic Lymphocytic Leukemia: To Transplant or Not to Transplant... That Is the Question?. JCO 23: 8126-8127 [Full Text]  
• Marasca, R., Maffei, R., Morselli, M., Zucchini, P., Castelli, I., Martinelli, S., Fontana, M., Ravanetti, S., Curotti, M., Leonardi, G., Cagossi, K., Partesotti, G., Torelli, G. (2005). Immunoglobulin Mutational Status Detected through Single-Round Amplification of Partial VH Region Represents a Good Prognostic Marker for Clinical Outcome in Chronic Lymphocytic Leukemia. J. Mol. Diagn. 7: 566-574 [Abstract] [Full Text]  
• Calin, G. A., Ferracin, M., Cimmino, A., Di Leva, G., Shimizu, M., Wojcik, S. E., Iorio, M. V., Visone, R., Sever, N. I., Fabbri, M., Iuliano, R., Palumbo, T., Pichiorri, F., Roldo, C., Garzon, R., Sevignani, C., Rassenti, L., Alder, H., Volinia, S., Liu, C.-g., Kipps, T. J., Negrini, M., Croce, C. M. (2005). A MicroRNA Signature Associated with Prognosis and Progression in Chronic Lymphocytic Leukemia. NEJM 353: 1793-1801 [Abstract] [Full Text]  
• Montserrat, E. (2005). Fighting CLL cells: deciphering the enemy. Blood 106: 2226-2226 [Full Text]  
• Castro, J. E., Prada, C. E., Loria, O., Kamal, A., Chen, L., Burrows, F. J., Kipps, T. J. (2005). ZAP-70 is a novel conditional heat shock protein 90 (Hsp90) client: inhibition of Hsp90 leads to ZAP-70 degradation, apoptosis, and impaired signaling in chronic lymphocytic leukemia. Blood 106: 2506-2512 [Abstract] [Full Text]  
• Oppezzo, P., Vasconcelos, Y., Settegrana, C., Jeannel, D., Vuillier, F., Legarff-Tavernier, M., Kimura, E. Y., Bechet, S., Dumas, G., Brissard, M., Merle-Beral, H., Yamamoto, M., Dighiero, G., Davi, F., for the French Cooperative Group on CLL, (2005). The LPL/ADAM29 expression ratio is a novel prognosis indicator in chronic lymphocytic leukemia. Blood 106: 650-657 [Abstract] [Full Text]  
• Petlickovski, A., Laurenti, L., Li, X., Marietti, S., Chiusolo, P., Sica, S., Leone, G., Efremov, D. G. (2005). Sustained signaling through the B-cell receptor induces Mcl-1 and promotes survival of chronic lymphocytic leukemia B cells. Blood 105: 4820-4827 [Abstract] [Full Text]