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Prospective Evaluation of Clonal Evolution During Long-Term Follow-Up of Patients With Untreated Early-Stage Chronic Lymphocytic Leukemia

Tait D. Shanafelt, Thomas E. Witzig, Stephanie R. Fink, Robert B. Jenkins, Sarah F. Paternoster, Stephanie A. Smoley, Kimberly J. Stockero, Danielle M. Nast, Heather C. Flynn, Renee C. Tschumper, Susan Geyer, Clive S. Zent, Tim G. Call, Diane F. Jelinek, Neil E. Kay, Gordon W. Dewald

From the Mayo Clinic College of Medicine, Department of Internal Medicine, Division of Hematology, Department Pathology, Division of Cytogenetics, Department of Immunology, Division of Biostatistics, Mayo Clinic, Rochester, MN

Address reprint requests to Tait D. Shanafelt, MD, 200 First Street SW, Mayo Clinic, Rochester, MN 55905

PURPOSE: Retrospective studies suggest cytogenetic abnormalities detected by interphase fluorescent in situ hybridization (FISH) can identify patients with chronic lymphocytic leukemia (CLL) who will experience a more aggressive disease course. Other studies suggest that patients may acquire chromosome abnormalities during the course of their disease. There are minimal prospective data on the clinical utility of the widely used hierarchical FISH prognostic categories in patients with newly diagnosed early-stage CLL or the frequency of clonal evolution as determined by interphase FISH.

PATIENTS AND METHODS: Between 1994 and 2002, we enrolled 159 patients with previously untreated CLL (83% Rai stage 0/I) on a prospective trial evaluating clonal evolution by FISH. Patients provided baseline and follow-up specimens for FISH testing during 2 to 12 years.

RESULTS: Chromosomal abnormalities detected by FISH at study entry predicted overall survival. Eighteen patients experienced clonal evolution during follow-up. The rate of clonal evolution increased with duration of follow-up with only one occurrence in the first 2 years (n = 71; 1.4%) but 17 occurrences (n = 63; 27%) among patients tested after 5+ years. Clonal evolution occurred among 10% of ZAP-70–negative and 42% of ZAP-70–positive patients at 5+ years (P = .008).

CONCLUSION: This clinical trial confirms prospectively that cytogenetic abnormalities detected by FISH can predict overall survival for CLL patients at the time of diagnosis, but also suggests that many patients acquire new abnormalities during the course of their disease. Patients with higher ZAP-70 expression may be more likely to experience such clonal evolution. These findings have important implications for both clinical management and trials of early treatment for patients with high-risk, early-stage CLL.

Supported by grants from Vysis Inc, Des Plaines, IL (G.D., R.J., T.W.), and Grants No. NCI K12 CA90628 and NCI Lymphoma SPORE CA97274 (S.F.).

Presented at the 47th Annual Meeting of the American Society of Hematology, Atlanta, GA, December 10-13, 2005.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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