Originally published as JCO Early Release 10.1200/JCO.2006.08.3089 on February 5 2007

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Comprehensive Assessment of Genetic and Molecular Features Predicting Outcome in Patients With Chronic Lymphocytic Leukemia: Results From the US Intergroup Phase III Trial E2997

Michael R. Grever, David M. Lucas, Gordon W. Dewald, Donna S. Neuberg, John C. Reed, Shinichi Kitada, Ian W. Flinn, Martin S. Tallman, Frederick R. Appelbaum, Richard A. Larson, Elisabeth Paietta, Diane F. Jelinek, John G. Gribben, John C. Byrd

From the Eastern Cooperative Oncology Group; Cancer and Leukemia Group B; Southwest Oncology Group; Division of Hematology-Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH; Department of Cytogenetics, Mayo Clinic; Mayo Clinic College of Medicine, Rochester, MN; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA; Burnham Institute for Medical Research, La Jolla, CA; Department of Oncology, Johns Hopkins University, Baltimore, MD; Division of Hematology-Oncology, Northwestern University Feinberg School of Medicine; The University of Chicago, Chicago IL; Fred Hutchinson Cancer Research Center, Seattle, WA; Our Lady of Mercy Comprehensive Cancer Center, Bronx, NY; and Barts and The London School of Medicine, London, United Kingdom

Address reprint requests to Michael R. Grever, MD, 215 Means Hall, 1654 Upham Dr, Columbus, OH 43210; e-mail: michael.grever{at}osumc.edu

Purpose: Genomic features including unmutated immunoglobulin variable region heavy chain (IgV_H) genes, del(11q22.3), del(17p13.1), and p53 mutations have been reported to predict the clinical course and overall survival of patients with chronic lymphocytic leukemia (CLL). In addition, ZAP-70 and Bcl-2 family proteins have been explored as predictors of outcome.

Patients and Methods: We prospectively evaluated the prognostic significance of a comprehensive panel of laboratory factors on both response and progression-free survival (PFS) using samples and data from 235 patients enrolled onto a therapeutic trial. Patients received either fludarabine (FL; n = 113) or fludarabine plus cyclophosphamide (FC; n = 122) as part of a US Intergroup randomized trial for previously untreated CLL patients.

Results: Complete response (CR) rates were 24.6% for patients receiving FC and 5.3% for patients receiving FL (P = .00004). PFS was statistically significantly longer in patients receiving FC (median, 33.5 months for patients receiving FC and 19.9 months for patients receiving FL; P < .0001). The occurrence of del(17p13.1) (hazard ratio, 3.428; P = .0002) or del(11q22.3) (hazard ratio, 1.904; P = .006) was associated with reduced PFS. CR and overall response rates were not significantly different based on cytogenetics, IgV_H mutational status, CD38 expression, or p53 mutational status. Expression of ZAP-70, Bcl-2, Bax, Mcl-1, XIAP, Caspase-3, and Traf-1 was not associated with either clinical response or PFS.

Conclusion: These results support the use of interphase cytogenetic analysis, but not IgV_H, CD38 expression, or ZAP-70 status, to predict outcome of FL-based chemotherapy. Patients with high-risk cytogenetic features should be considered for alternative therapies.

published online ahead of print at www.jco.org on February 5, 2007.

Supported by National Institutes of Health Grants No. R01 CA 88647 (M.R.G.) and U10 CA 101140, and R21 CA 101332 (J.C.B.).

Presented in part at annual meetings of the American Society of Hematology, December 6-10, 2002 (Philadelphia, PA), December 6-9, 2003 (San Diego, CA), and December 4-7, 2004 (San Diego, CA); and at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA.

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

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