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Blood, 1 September 2008, Vol. 112, No. 5, pp. 1923-1930.
Prepublished online as a Blood First Edition Paper on June 24, 2008; DOI 10.1182/blood-2007-05-092882.
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Submitted May 29, 2007
Accepted May 30, 2008
Relative value Of ZAP-70, CD38, and immunoglobulin mutation status in predicting aggressive disease in chronic lymphocytic leukemia
Laura Z Rassenti, Sonia Jain, Michael J. Keating, William G. Wierda, Michael R. Grever, John C. Byrd, Neil E. Kay, Jennifer R. Brown, John G. Gribben, Donna S. Neuberg, Feng He, Andrew W. Greaves, Kanti R Rai, and Thomas J Kipps*
Hematology/Oncology, Moores Cancer Ctr, University of California, San Diego, La Jolla, CA, United States
Division of Biostatistics and Bioinformatics, University of California, San Diego, La Jolla, CA, United States
Department of Leukemia, University of Texas, Houston, TX, United States
James Cancer Institute, Ohio State University, Columbus, OH, United States
Department of Hematology, Mayo Clinic, Rochester, MN, United States
Dana Farber Cancer Institute, Boston, MA, United States
Hematology, Barts and The London School of Medicine, London, United Kingdom
Hematology/Oncology, Long Island Jewish Medical, New Hyde Park, NY, United States
* Corresponding author; email: tkipps{at}ucsd.edu.
Leukemia-cell expression of ZAP-70, CD38, or unmutated immunoglobulin heavy-chain-variable region genes (U-IGHV) each is associated with aggressive disease in patients with chronic lymphocytic leukemia (CLL). To assess the relative strength of each marker we defined thresholds for designating a case as positive for CD38 or ZAP-70 in a test cohort of 307 patients and used these data-defined criteria to stratify patients in an independent cohort of 705 patients. Multivariable analysis revealed that ZAP-70 was the strongest risk factor. Knowledge of the IGHV mutation status or CD38 did not improve our ability to predict the time to first treatment except for ZAP-70-negative cases, which could be segregated into two groups of intermediate-risk or low-risk disease based upon whether they expressed unmutated or mutated IGHV. ZAP-70 maintained its high relative prognostic value for the subset of patients with early-stage, asymptomatic disease, including patients evaluated within one year of diagnosis. Although it is premature to recommend therapy based on these risk factors, patients with ZAP-70-positive CLL cells should be monitored closely for disease progression as they have a median time from diagnosis to requiring intial therapy by standard criteria of approximately three years.
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