Chronic Lymphocytic Leukemia - CLL

Key Points

Chronic Lymphocytic Leukemia Prognostic Markers

The diagnosis of CLL generally requires finding >5,000 CLL type cells per microliter of peripheral blood. CLL cells typically express CD19, weak CD20, and CD23 along with CD5 which is usually assessed by flow cytometry immunophenotyping (Leukemia/Lymphoma Phenotyping, Whole Blood 0096299).

Cytogenetic, molecular, and flow cytometric testing play an important role in prognostication of CLL patients.

For molecular markers in CLL, see table below

Diagnosis

Indications for Testing

• Adult with persistent, unexplained lymphocytosis of ≥3 months duration on CBC; lymphadenopathy

Laboratory Testing

• Initial testing – CBC with differential, platelets, lactate dehydrogenase (LD) concentration
• Serum testing – monoclonal antibody panels (minimal)
  • B-CLL – kappa/lambda, CD5/CD19, CD23, CD10, FMC-7
  • T-CLL – CD3/CD4, CD3/CD8, CD5, CD7, CD25, CD30
• Diagnosis based on lymphocytosis, morphology, and immunophenotyping (CD5+, CD19+, CD20 [weak], CD23+, CD10-)
• CLL FISH panel may aid in diagnosis (consider ordering for t(11;14) IGH/CCND)
  • CLL can mimic mantle cell lymphoma

Histology

• Bone marrow sampling – not necessary if characteristic phenotype, consistent cytology is present, and CBC is normal (based on IWCLL 2008 recommendations)

  • If performed, typically hyper- or normo-cellularity, nodular or diffuse pattern of lymphocytic infiltration in >10% of nucleated cells
  • Consider immunophenotyping, if marrow obtained
  • Immunohistochemistry – p53 (KRAS) positivity may correlate with genetic p53 mutation

Prognosis

• SNP microarray testing – preferred test for cytogenetics; may not detect low level clones
• FISH testing also used
• Prognostic factors for CLL

  Factor	Outcome
  	Good	Poor
  Stage (Rai and Binet systems)	Rai 0, I Binet A	Rai II, III, IV Binet B or C
  Lymphocyte morphology	Typical	Atypical
  Lymphocyte doubling time	Low	Elevated
  Serum markers
  LD	Normal	Elevated
  Beta-2 microglobulin	Normal	Elevated
  Thymidine kinase	Normal	Elevated
  Soluble CD23	Normal	Elevated
  Cytogenetics (FISH, SNP microarray)
  Genetic abnormalities	Normal diploid del(13)(q14) only	del(17)(p13.1)* del(11)(q22.3) Trisomy 12+
  Molecular Markers (FISH, PCR)
  CD38 expression	<30%	≥30%
  ZAP70 expression	<20%	≥30%
  IGVH gene mutation	>2%	≤2%
  Note: p53 and KRAS mutations are associated with therapy resistance to alkylating agents, fludarabine, and tyrosine kinase inhibitors (eg, rituximab)

Differential Diagnosis

• Benign
  • Infection
  • Postsplenectomy
  • Reactive lymphocytosis
• Malignant
  • Other non-Hodgkin lymphoma
  • Sézary syndrome
  • Other leukemia (ALL)

Monitoring

Clinical Background

Chronic lymphocytic leukemia (CLL) is characterized by small lymphocytes in the bone marrow, blood, and lymphoid tissues. CLL is the most common form of leukemia in U.S. adults and represents 40% of all adult leukemias in Western countries.

Epidemiology

• Incidence – 4.2/100,000 (SEER data 2007)
• Age – median 79 years
  • 80% diagnosed ≥60 years
  • Rare in patients <50 years (~10% of cases)
• Sex – M>F, 2.8:1
• Ethnicity – lower risk in Chinese, Japanese, and Filipino ethnicities

Risk Factors

• Family member with CLL
  • First-degree relative has threefold risk of developing CLL or other lymphoid neoplasm

Clinical Presentation

• CLL principally involves bone marrow and blood; 25-50% of patients present as asymptomatic with lymphocytosis found on complete blood count
  • Disease may remain indolent for several years until treatment required
• Small lymphocytic leukemia (SLL) – different manifestation of CLL if nodes principally involved
  • SLL has similar biology and history to CLL; same treatment approach
• Monoclonal B-cell lymphocytosis (MBL) – asymptomatic patient with <5,000 circulating CLL phenotype cells/mL³ and no node involvement
  • Precedes development of CLL
  • MBL estimated to be present in 5% of adults ≥50 years; however, general screening for MBL not recommended
  • MBL with lymphocytosis >4,000 CLL phenotype cells per microliter progresses into CLL at a rate of 1% per year
• 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)
  • Autoimmune cytopenias (autoimmune hemolytic anemia, immune thrombocytopenic purpura, pure red cell aplasia)

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
CBC with Platelet Count and Automated Differential 0040003 Method: Automated Cell Count/Differential	Initial test to determine degree of lymphocytosis
Lactate Dehydrogenase, Serum or Plasma 0020006 Method: Quantitative Enzymatic	Use for CLL prognostication
Chromosome Analysis, Bone Marrow 2002292 Method: Giemsa Band	Detect chromosome abnormalities in bone marrow Complex abnormalities and unbalanced translocations are associated with a poorer prognosis
Chromosome Analysis, Leukemic Blood 2002290 Method: Giemsa Band	Detect chromosome abnormalities in peripheral blood Complex abnormalities and unbalanced translocations are associated with a poorer prognosis
CD19 by Immunohistochemistry 2005114 Method: Immunohistochemistry	Aid in histologic diagnosis of B-cell leukemia/lymphoma Stained and returned to client pathologist for interpretation; consultation available if needed

Diagnostic Algorithm

  Lymphoma Leukemia Phenotyping Testing Algorithm