title: Development of a comprehensive prognostic index for patients with chronic lymphocytic leukemia.
abstract: In addition to clinical staging, a number of biomarkers predicting overall survival (OS) have been identified in chronic lymphocytic leukemia (CLL). The multiplicity of markers, limited information on their independent prognostic value, and a lack of understanding of how to interpret discordant markers are major barriers to use in routine clinical practice. We therefore performed an analysis of 23 prognostic markers based on prospectively collected data from 1948 CLL patients participating in phase 3 trials of the German CLL Study Group to develop a comprehensive prognostic index. A multivariable Cox regression model identified 8 independent predictors of OS: sex, age, ECOG status, del(17p), del(11q), IGHV mutation status, serum β2-microglobulin, and serum thymidine kinase. Using a weighted grading system, a prognostic index was derived that separated 4 risk categories with 5-year OS ranging from 18.7% to 95.2% and having a C-statistic of 0.75. The index stratified OS within all analyzed subgroups, including all Rai/Binet stages. The validity of the index was externally confirmed in a series of 676 newly diagnosed CLL patients from Mayo Clinic. Using this multistep process including external validation, we developed a comprehensive prognostic index with high discriminatory power and prognostic significance on the individual patient level. The studies were registered as follows: CLL1 trial (NCT00262782, http://clinicaltrials.gov), CLL4 trial (ISRCTN 75653261, http://www.controlled-trials.com), and CLL8 trial (NCT00281918, http://clinicaltrials.gov).
authors.affiliation: Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, University of Cologne, Cologne, Germany;
authors.forename: Natali
authors.initials: N
authors.lastname: Pflug
authors.affiliation: Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, University of Cologne, Cologne, Germany;
authors.forename: Jasmin
authors.initials: J
authors.lastname: Bahlo
authors.affiliation: Department of Internal Medicine, Division of Hematology, Mayo Clinic, Rochester, MN;
authors.forename: Tait D
authors.initials: TD
authors.lastname: Shanafelt
authors.affiliation: Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, University of Cologne, Cologne, Germany;
authors.forename: Barbara F
authors.initials: BF
authors.lastname: Eichhorst
authors.affiliation: Department I of Internal Medicine, Hospital München-Schwabing, Munich, Germany;
authors.forename: Manuela A
authors.initials: MA
authors.lastname: Bergmann
authors.affiliation: Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, University of Cologne, Cologne, Germany;
authors.forename: Thomas
authors.initials: T
authors.lastname: Elter
authors.affiliation: Cochrane Hematological Malignancies Group, University of Cologne, Cologne, Germany;
authors.forename: Kathrin
authors.initials: K
authors.lastname: Bauer
authors.affiliation: Institute of Clinical Chemistry, University Hospital of Cologne, Cologne, Germany;
authors.forename: Gebhart
authors.initials: G
authors.lastname: Malchau
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN;
authors.forename: Kari G
authors.initials: KG
authors.lastname: Rabe
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: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.affiliation: Department of Internal Medicine I, Division of Hematology and Haemostaseology and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria;
authors.forename: Ulrich
authors.initials: U
authors.lastname: Jäger
authors.affiliation: Hämatologische und Onkologische Schwerpunktpraxis, Erlangen, Germany;
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Eckart
authors.affiliation: Department III of Internal Medicine, University Hospital of Salzburg, Salzburg, Austria; and.
authors.forename: Georg
authors.initials: G
authors.lastname: Hopfinger
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 I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, University of Cologne, Cologne, Germany;
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Fink
authors.affiliation: Department I of Internal Medicine, Hospital München-Schwabing, Munich, Germany;
authors.forename: Clemens-Martin
authors.initials: CM
authors.lastname: Wendtner
authors.affiliation: Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, University of Cologne, Cologne, Germany;
authors.forename: Kirsten
authors.initials: K
authors.lastname: Fischer
authors.affiliation: Department of Internal Medicine, Division of Hematology, Mayo Clinic, Rochester, MN;
authors.forename: Neil E
authors.initials: NE
authors.lastname: Kay
authors.affiliation: Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, University of Cologne, Cologne, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Hallek
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D017326:Clinical Trials, Phase III as Topic; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000145:classification* / Q000175:diagnosis* / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic
chemical_list: D014408:Biomarkers, Tumor