Chronic Lymphocytic Leukemia - CLL

Chronic Lymphocytic Leukemia - CLL

 

Chronic lymphocytic leukemia (CLL) is characterized by small lymphocytes in the bone marrow, blood and lymphoid tissues.  It is the most common form of leukemia in adults in the United States.

Epidemiology

  • Incidence – 2-3/100,000
  • Age – median 70 years
    • 80% diagnosed ≥60 years
  • Sex – M:F; 2.8:1

Risk Factors

  • Family member with CLL

Clinical Presentation

  • 25-50% are asymptomatic – found to have lymphocytosis on complete blood count
  • Constitutional symptoms – night sweats, weight loss, fatigue
  • Adenopathy
    • Hepatomegaly
    • Lymph nodes – most commonly cervical, supraclavicular, axillary
    • Splenomegaly
  • Extranodal disease – uncommon
    • Central nervous system
    • Gastrointestinal tract
    • Lungs
    • Renal
  • Complications – large-cell transformation (Richter syndrome)

Diagnosis

  • Based on modification of National Cancer Institute (NCI) information; bone marrow is not necessary if characteristic phenotype is present
Criteria for the Diagnosis of Chronic Lymphocytic Leukemia a
Criteria NCI-WG 1996 WCLL 2005
Peripheral blood lymphocytes (x109/L) >5 Not specified b
Morphology Not specified Small, mature lymphocytes without visible nucleoli; smudge cells are characteristic
Immunophenotype of lymphocytes ≥1 B-cell marker (CD19, CD20 or CD23) and CD5 positivity in the absence of other pan-T-cell marker

Monoclonal expression of either kappa or gamma chain

Low-density surface Ig

 ≥1 B-cell marker (CD19, CD20 or CD23) and CD5 positivity in the absence of other pan-T-cell marker

Monoclonal expression of either kappa or gamma chain

Low-density surface Ig
Atypical cells (e.g., prolymphocytes) <55% and/or <15 x 109/L <55% and/or <15 x 109/L
Duration of lymphocytosis None required Not specified but needs to be chronic
Bone marrow lymphocytes (%) ≥30 Bone marrow evaluation not requiredc
a IWCLL = International Workshop on Chronic Lymphocytic Leukemia; NCI-WG = National Cancer Institute-sponsored Working Group

bA lower value than 5x109/L is acceptable provided there is a chronic, absolute increase in blood lymphocytes with the characteristic morphology and immunophenotype

c Bone marrow evaluation is no longer required for diagnosis but useful to determine the extent and pattern of involvement and clarification of the etiology of cytopenias
(Used with permission from Mayo Clin Prc.  Yee and O'Brien, 2006, 1106)

Differential Diagnosis

  • Benign causes – infections, thyrotoxicosis, Addison disease, postsplenectomy
  • Malignant – non-Hodgkin lymphoma transformed, plasma cell dyscrasias, Sézary syndrome, other leukemias

Disease Monitoring and Staging

  • ZAP-70 – correlated with poor outcome if present
    • Highly correlated to the immunoglobulin variable heavy chain (IgVH) gene mutation
  • Flow cytometry followup – to detect minimal residual disease
  • CD38 >30% expression – poor outcome
  • Beta 2-microglobulin – elevation associated with poor prognosis
  • Chromosome analysis – complex and unbalanced translocations associated with poor prognosis
  • FISH panel for prognostic stratification
    • p53 (17p) deletion – unfavorable and associated with resistance to fludarabine, alkylator, and possibly rituximab
    • ATM (11q) deletion – unfavorable
    • Trisomy 12 – neutral
    • 13q14 deletion – favorable