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Blood. 2014 May 22;123(21):3247-54. doi: 10.1182/blood-2014-01-546150. Epub 2014 Mar 20.

Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial.

Author information

1
Department of Internal Medicine III, Ulm University, Ulm, Germany;
2
Department of Internal Medicine III, Ulm University, Ulm, Germany; Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, and Department of Medicine V, University of Heidelberg, Heidelberg, Germany;
3
Department of Hematology Oncology, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, University of Pavia, Italy;
4
Second Department of Medicine, University Hospital of Schleswig-Holstein, Campus Kiel, Kiel, Germany;
5
Department of Internal Medicine III, Ulm University, Ulm, Germany; Cooperation Unit "Mechanisms of Leukemogenesis," German Cancer Research Center, Heidelberg, Germany;
6
Department of Hematology, Medical University of Vienna, Vienna, Austria;
7
Roche Molecular Systems, Pleasanton, CA;
8
Pharmaceuticals Division, F. Hoffmann-La Roche Ltd., Basel, Switzerland;
9
Pharmaceuticals Division, F. Hoffmann-La Roche Ltd., Basel, Switzerland; Department of Internal Medicine I, University Hospital Cologne, Cologne, Germany;
10
Division of Molecular Genetics, German Cancer Research Center, Heidelberg, Germany;
11
Department of Internal Medicine I, University Hospital Cologne, Cologne, Germany; Department I of Internal Medicine, Klinikum Schwabing, Munich, Germany; and.
12
Department of Internal Medicine I, University Hospital Cologne, Cologne, Germany;
13
Institute for Medical Statistics and Epidemiology, Technical University Munich, Munich, Germany.

Abstract

Mutations in TP53, NOTCH1, and SF3B1 were analyzed in the CLL8 study evaluating first-line therapy with fludarabine and cyclophosphamide (FC) or FC with rituximab (FCR) among patients with untreated chronic lymphocytic leukemia (CLL). TP53, NOTCH1, and SF3B1 were mutated in 11.5%, 10.0%, and 18.4% of patients, respectively. NOTCH1(mut) and SF3B1(mut) virtually showed mutual exclusivity (0.6% concurrence), but TP53(mut) was frequently found in NOTCH1(mut) (16.1%) and in SF3B1(mut) (14.0%) patients. There were few significant associations with clinical and laboratory characteristics, but genetic markers had a strong influence on response and survival. In multivariable analyses, an independent prognostic impact was found for FCR, thymidine kinase (TK) ≥10 U/L, unmutated IGHV, 11q deletion, 17p deletion, TP53(mut), and SF3B1(mut) on progression-free survival; and for FCR, age ≥65 years, Eastern Cooperative Oncology Group performance status ≥1, β2-microglobulin ≥3.5 mg/L, TK ≥10 U/L, unmutated IGHV, 17p deletion, and TP53(mut) on overall survival. Notably, predictive marker analysis identified an interaction of NOTCH1 mutational status and treatment in that rituximab failed to improve response and survival in patients with NOTCH1(mut). In conclusion, TP53 and SF3B1 mutations appear among the strongest prognostic markers in CLL patients receiving current-standard first-line therapy. NOTCH1(mut) was identified as a predictive marker for decreased benefit from the addition of rituximab to FC. This study is registered at www.clinicaltrials.gov as #NCT00281918.

PMID:
24652989
DOI:
10.1182/blood-2014-01-546150
[Indexed for MEDLINE]
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