Originally published as JCO Early Release 10.1200/JCO.2005.03.1021 on December 12 2005

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Select High-Risk Genetic Features Predict Earlier Progression Following Chemoimmunotherapy With Fludarabine and Rituximab in Chronic Lymphocytic Leukemia: Justification for Risk-Adapted Therapy

From the Division of Hematology-Oncology, Departments of Internal Medicine and Pathology, The Ohio State University, Columbus, OH; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; CALGB Statistical Center, Durham, NC; Department of Medicine, The University of Chicago, Chicago, IL

Address reprint requests to John C. Byrd, MD, Division of Hematology-Oncology, Starling Loving Hall, Room 302, The Ohio State University, Columbus, OH 43210; john.byrd{at}osumc.edu

Purpose Several new prognostic factors predicting rapid disease progression in chronic lymphocytic leukemia (CLL) have been identified, including unmutated Ig V_H mutational status, del(11)(q23), del(17)(p13.1), and p53 mutations. To date, the impact of these same prognostic factors have not been examined relative to treatment outcome with chemoimmunotherapy.

Methods We examined the impact of these new prognostic factors on predicting treatment outcome in symptomatic, untreated CLL patients who received chemoimmunotherapy with fludarabine and rituximab as part of a completed, randomized phase II study, Cancer and Leukemia Group B (CALGB) 9712.

Results Eighty-eight patients treated as part of CALGB 9712 had detailed prognostic factor assessment performed. Using Ig V_H mutational status to classify risk, there was no association between complete response rate with either unmutated Ig V_H mutational status or high-risk interphase cytogenetics. However, the median progression-free survival (PFS; P = .048) and overall survival (OS; P = .01) were shorter among the Ig V_H unmutated patients as compared with the Ig V_H mutated patients. Using the hierarchical classification of Döhner, PFS (P = .005) and OS (P = .004) were significantly longer as the classification moved from high risk [del (11)(q22.3) or del (17)(p13.1)] to low risk.

Conclusion These data demonstrate that high-risk CLL patients characterized by Ig V_H unmutated ( 98%) or high-risk interphase cytogenetics, including either del(17p) or del(11q), appear to have a shorter PFS and OS with chemoimmunotherapy. Larger prospective studies will be required to determine the independent influence of Ig V_H mutational status and interphase cytogenetics on treatment outcome.

Supported in part by grants from the National Cancer Institute (CA31946) to the Cancer and Leukemia Group B (Richard L. Schilsky, MD, Chairman), R21CA101332, and UO1CA101140. Support from the Leukemia and Lymphoma Society of America (J.C.B.), and D. Warren Brown Foundation (J.C.B.).

J.C.B. is a clinical scholar of the Leukemia and Lymphoma Society of America.

The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute.

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

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