title: Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial.
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.
authors.affiliation: Department of Internal Medicine III, Ulm University, Ulm, Germany;
authors.forename: Stephan
authors.initials: S
authors.lastname: Stilgenbauer
authors.affiliation: Department of Internal Medicine III, Ulm University, Ulm, Germany;
authors.forename: Andrea
authors.initials: A
authors.lastname: Schnaiter
authors.affiliation: Department of Internal Medicine III, Ulm University, Ulm, Germany;
authors.forename: Peter
authors.initials: P
authors.lastname: Paschka
authors.affiliation: 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;
authors.forename: Thorsten
authors.initials: T
authors.lastname: Zenz
authors.affiliation: Department of Hematology Oncology, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, University of Pavia, Italy;
authors.forename: Marianna
authors.initials: M
authors.lastname: Rossi
authors.affiliation: Department of Internal Medicine III, Ulm University, Ulm, Germany;
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
authors.affiliation: Department of Internal Medicine III, Ulm University, Ulm, Germany;
authors.forename: Andreas
authors.initials: A
authors.lastname: Bühler
authors.affiliation: Second Department of Medicine, University Hospital of Schleswig-Holstein, Campus Kiel, Kiel, Germany;
authors.forename: Sebastian
authors.initials: S
authors.lastname: Böttcher
authors.affiliation: Second Department of Medicine, University Hospital of Schleswig-Holstein, Campus Kiel, Kiel, Germany;
authors.forename: Matthias
authors.initials: M
authors.lastname: Ritgen
authors.affiliation: Second Department of Medicine, University Hospital of Schleswig-Holstein, Campus Kiel, Kiel, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Kneba
authors.affiliation: Department of Internal Medicine III, Ulm University, Ulm, Germany;
authors.forename: Dirk
authors.initials: D
authors.lastname: Winkler
authors.affiliation: Department of Internal Medicine III, Ulm University, Ulm, Germany;
authors.forename: Eugen
authors.initials: E
authors.lastname: Tausch
authors.affiliation: Department of Internal Medicine III, Ulm University, Ulm, Germany;
authors.forename: Patrick
authors.initials: P
authors.lastname: Hoth
authors.affiliation: Department of Internal Medicine III, Ulm University, Ulm, Germany;
authors.forename: Jennifer
authors.initials: J
authors.lastname: Edelmann
authors.affiliation: Department of Internal Medicine III, Ulm University, Ulm, Germany; Cooperation Unit "Mechanisms of Leukemogenesis," German Cancer Research Center, Heidelberg, Germany;
authors.forename: Daniel
authors.initials: D
authors.lastname: Mertens
authors.affiliation: Department of Internal Medicine III, Ulm University, Ulm, Germany;
authors.forename: Lars
authors.initials: L
authors.lastname: Bullinger
authors.affiliation: Department of Internal Medicine III, Ulm University, Ulm, Germany;
authors.forename: Manuela
authors.initials: M
authors.lastname: Bergmann
authors.affiliation: Department of Internal Medicine III, Ulm University, Ulm, Germany;
authors.forename: Sabrina
authors.initials: S
authors.lastname: Kless
authors.affiliation: Department of Internal Medicine III, Ulm University, Ulm, Germany;
authors.forename: Silja
authors.initials: S
authors.lastname: Mack
authors.affiliation: Department of Hematology, Medical University of Vienna, Vienna, Austria;
authors.forename: Ulrich
authors.initials: U
authors.lastname: Jäger
authors.affiliation: Roche Molecular Systems, Pleasanton, CA;
authors.forename: Nancy
authors.initials: N
authors.lastname: Patten
authors.affiliation: Roche Molecular Systems, Pleasanton, CA;
authors.forename: Lin
authors.initials: L
authors.lastname: Wu
authors.affiliation: Pharmaceuticals Division, F. Hoffmann-La Roche Ltd., Basel, Switzerland;
authors.forename: Michael K
authors.initials: MK
authors.lastname: Wenger
authors.affiliation: Pharmaceuticals Division, F. Hoffmann-La Roche Ltd., Basel, Switzerland; Department of Internal Medicine I, University Hospital Cologne, Cologne, Germany;
authors.forename: Günter
authors.initials: G
authors.lastname: Fingerle-Rowson
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center, Heidelberg, Germany;
authors.forename: Peter
authors.initials: P
authors.lastname: Lichter
authors.affiliation: Department of Hematology Oncology, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, University of Pavia, Italy;
authors.forename: Mario
authors.initials: M
authors.lastname: Cazzola
authors.affiliation: Department of Internal Medicine I, University Hospital Cologne, Cologne, Germany; Department I of Internal Medicine, Klinikum Schwabing, Munich, Germany; and.
authors.forename: Clemens M
authors.initials: CM
authors.lastname: Wendtner
authors.affiliation: Department of Internal Medicine I, University Hospital Cologne, Cologne, Germany;
authors.forename: Anna M
authors.initials: AM
authors.lastname: Fink
authors.affiliation: Department of Internal Medicine I, University Hospital Cologne, Cologne, Germany;
authors.forename: Kirsten
authors.initials: K
authors.lastname: Fischer
authors.affiliation: Institute for Medical Statistics and Epidemiology, Technical University Munich, Munich, Germany.
authors.forename: Raymonde
authors.initials: R
authors.lastname: Busch
authors.affiliation: Department of Internal Medicine I, University Hospital Cologne, Cologne, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Hallek
authors.affiliation: Department of Internal Medicine III, Ulm University, Ulm, Germany;
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
mesh_terms: D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use; D000963:Antimetabolites / Q000627:therapeutic use; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D003520:Cyclophosphamide / Q000627:therapeutic use; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics*; D011379:Prognosis; D000072260:RNA Splicing Factors; D051881:Receptor, Notch1 / Q000235:genetics*; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics*; D000069283:Rituximab; D016019:Survival Analysis; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D014740:Vidarabine / Q000627:therapeutic use
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000963:Antimetabolites; D018906:Antineoplastic Agents, Alkylating; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D051881:Receptor, Notch1; D017413:Ribonucleoprotein, U2 Small Nuclear; C112491:SF3B1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000069283:Rituximab; D003520:Cyclophosphamide; D014740:Vidarabine