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Original Article
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Volume 351:893-901 August 26, 2004 Number 9
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ZAP-70 Compared with Immunoglobulin Heavy-Chain Gene Mutation Status as a Predictor of Disease Progression in Chronic Lymphocytic Leukemia
Laura Z. Rassenti, Ph.D., Lang Huynh, B.S., Tracy L. Toy, B.S., Liguang Chen, M.D., Ph.D., Michael J. Keating, M.D., John G. Gribben, M.D., Ph.D., Donna S. Neuberg, Sc.D., Ian W. Flinn, M.D., Ph.D., Kanti R. Rai, M.D., John C. Byrd, M.D., Neil E. Kay, M.D., Andrew Greaves, B.S., Arthur Weiss, M.D., Ph.D., and Thomas J. Kipps, M.D., Ph.D.

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 by Hamblin, T. J.

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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 (IgVH) and the 70-kD zeta-associated protein (ZAP-70), whereas in indolent disease, the CLL cells usually express mutated IgVH 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 IgVH 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 IgVH gene (71 percent), but in only 24 of the 143 patients with a mutated IgVH 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 IgVH gene (2.8 years) was not significantly different from the median time in those who had a mutated IgVH 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 IgVH 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 IgVH gene and 7.1 years in those with an unmutated IgVH gene (P<0.001).

Conclusions Although the presence of an unmutated IgVH 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.


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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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