Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia

Blood. 2013 Feb 21;121(8):1403-12. doi: 10.1182/blood-2012-09-458265. Epub 2012 Dec 13.


The identification of new genetic lesions in chronic lymphocytic leukemia (CLL) prompts a comprehensive and dynamic prognostic algorithm including gene mutations and chromosomal abnormalities and their changes during clonal evolution. By integrating mutational and cytogenetic analysis in 1274 CLL samples and using both a training-validation and a time-dependent design, 4 CLL subgroups were hierarchically classified: (1) high-risk, harboring TP53 and/or BIRC3 abnormalities (10-year survival: 29%); (2) intermediate-risk, harboring NOTCH1 and/or SF3B1 mutations and/or del11q22-q23 (10-year survival: 37%); (3) low-risk, harboring +12 or a normal genetics (10-year survival: 57%); and (4) very low-risk, harboring del13q14 only, whose 10-year survival (69.3%) did not significantly differ from a matched general population. This integrated mutational and cytogenetic model independently predicted survival, improved CLL prognostication accuracy compared with FISH karyotype (P < .0001), and was externally validated in an independent CLL cohort. Clonal evolution from lower to higher risk implicated the emergence of NOTCH1, SF3B1, and BIRC3 abnormalities in addition to TP53 and 11q22-q23 lesions. By taking into account clonal evolution through time-dependent analysis, the genetic model maintained its prognostic relevance at any time from diagnosis. These findings may have relevant implications for the design of clinical trials aimed at assessing the use of mutational profiling to inform therapeutic decisions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Baculoviral IAP Repeat-Containing 3 Protein
  • DNA Mutational Analysis
  • Education, Medical, Continuing
  • Female
  • Genetic Testing
  • Humans
  • Inhibitor of Apoptosis Proteins / genetics*
  • Kaplan-Meier Estimate
  • Leukemia, Lymphocytic, Chronic, B-Cell / diagnosis
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
  • Leukemia, Lymphocytic, Chronic, B-Cell / mortality*
  • Male
  • Models, Genetic
  • Myeloid Differentiation Factor 88 / genetics
  • Phosphoproteins / genetics*
  • Prognosis
  • RNA Splicing Factors
  • Receptor, Notch1 / genetics*
  • Ribonucleoprotein, U2 Small Nuclear / genetics*
  • Risk Factors
  • Tumor Suppressor Protein p53 / genetics*
  • Ubiquitin-Protein Ligases


  • Inhibitor of Apoptosis Proteins
  • MYD88 protein, human
  • Myeloid Differentiation Factor 88
  • NOTCH1 protein, human
  • Phosphoproteins
  • RNA Splicing Factors
  • Receptor, Notch1
  • Ribonucleoprotein, U2 Small Nuclear
  • SF3B1 protein, human
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • BIRC3 protein, human
  • Baculoviral IAP Repeat-Containing 3 Protein
  • Ubiquitin-Protein Ligases