Monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia

N Engl J Med. 2008 Aug 7;359(6):575-83. doi: 10.1056/NEJMoa075290.


Background: A diagnosis of chronic lymphocytic leukemia (CLL) requires a count of over 5000 circulating CLL-phenotype cells per cubic millimeter. Asymptomatic persons with fewer CLL-phenotype cells have monoclonal B-cell lymphocytosis (MBL). The goal of this study was to investigate the relation between MBL and CLL.

Methods: We investigated 1520 subjects who were 62 to 80 years of age with a normal blood count and 2228 subjects with lymphocytosis (>4000 lymphocytes per cubic millimeter) for the presence of MBL, using flow cytometry. Monoclonal B cells were further characterized by means of cytogenetic and molecular analyses. A representative cohort of 185 subjects with CLL-phenotype MBL and lymphocytosis were monitored for a median of 6.7 years (range, 0.2 to 11.8).

Results: Monoclonal CLL-phenotype B cells were detected in 5.1% of subjects (78 of 1520) with a normal blood count and 13.9% (309 of 2228) with lymphocytosis. CLL-phenotype MBL had a frequency of 13q14 deletion and trisomy 12 similar to that of CLL and showed a skewed repertoire of the immunoglobulin heavy variable group (IGHV) genes. Among 185 subjects presenting with lymphocytosis, progressive lymphocytosis occurred in 51 (28%), progressive CLL developed in 28 (15%), and chemotherapy was required in 13 (7%). The absolute B-cell count was the only independent prognostic factor associated with progressive lymphocytosis. During follow-up over a median of 6.7 years, 34% of subjects (62 of 185) died, but only 4 of these deaths were due to CLL. Age above 68 years and hemoglobin level below 12.5 g per deciliter were the only independent prognostic factors for death.

Conclusions: The CLL-phenotype cells found in the general population and in subjects with lymphocytosis have features in common with CLL cells. CLL requiring treatment develops in subjects with CLL-phenotype MBL and with lymphocytosis at the rate of 1.1% per year.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Aged
  • Aged, 80 and over
  • B-Lymphocytes / immunology*
  • Cohort Studies
  • DNA Mutational Analysis
  • Disease Progression
  • Female
  • Genes, Immunoglobulin*
  • Genetic Markers
  • Germ-Line Mutation*
  • Hemoglobins / analysis
  • Humans
  • Immunoglobulin Heavy Chains / genetics*
  • Kaplan-Meier Estimate
  • Leukemia, Lymphocytic, Chronic, B-Cell / immunology*
  • Leukemia, Lymphocytic, Chronic, B-Cell / mortality
  • Lymphocyte Count
  • Lymphocytosis / immunology*
  • Male
  • Middle Aged
  • Phenotype
  • Precancerous Conditions / immunology*
  • Prognosis
  • Reference Values


  • Genetic Markers
  • Hemoglobins
  • Immunoglobulin Heavy Chains