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Development of a comprehensive prognostic index for patients with chronic lymphocytic leukemia

Natali Pflug, Jasmin Bahlo, Tait D. Shanafelt, Barbara F. Eichhorst, Manuela A. Bergmann, Thomas Elter, Kathrin Bauer, Gebhart Malchau, Kari G. Rabe, Stephan Stilgenbauer, Hartmut Döhner, Ulrich Jäger, Michael J. Eckart, Georg Hopfinger, Raymonde Busch, Anna-Maria Fink, Clemens-Martin Wendtner, Kirsten Fischer, Neil E. Kay and Michael Hallek

Key points

  • A prognostic tool for CLL patients with high discriminatory power in comparison to the conventional clinical staging systems.

  • Allowing prognostication on the individual patient level independent of clinical stage.

Abstract

Besides 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 III trials of the German CLL Study Group to develop a comprehensive prognostic index. A multivariable Cox regression model identified eight 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 four 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 multi-step process including external validation, we developed a comprehensive prognostic index with high discriminatory power and prognostic significance on the individual patient level. 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.

  • Submitted February 14, 2014.
  • Accepted April 16, 2014.