Chronic Lymphocytic Leukemia - CLL

Key Points

CLL Prognostic Markers

The diagnosis of CLL generally requires detection of >5,000 CLL-type cells per microliter of peripheral blood. CLL cells typically express CD19, weak CD20, and CD23 (B-cell antigens), along with CD5 (a T-cell antigen); these are usually assessed by flow cytometry immunophenotyping.

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

Diagnosis

Indications for Testing

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

Laboratory Testing

• Initial testing – CBC with differential, platelets, lactate dehydrogenase (LD) concentration
  • Diagnosis of CLL requires ≥5,000 lymphocytes/µL
• Serum testing – monoclonal antibody panels (minimal)
  • B cell – kappa/lambda, CD5, CD10, CD19, CD23, FMC7
  • T cell – CD3, CD4, CD5, CD6, CD7, CD8, CD25, CD30
• Diagnosis based on lymphocytosis, morphology, and immunophenotyping (CD5+, CD19+, CD20 [weak], CD23+, CD10-)
• CLL FISH panel may aid in diagnosis
  • CLL must be differentiated from mantle cell lymphoma – consider ordering testing for t(11;14) IGH/CCND

Histology

• Bone marrow sampling – unnecessary 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 TP53 gene mutation

Prognosis

• SNP microarray testing – preferred test for detection of genomic abnormalities; may not detect low-level clones
• Fluorescence in situ hybridization (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%
  IGVH gene mutation	>2%	≤2%
  Note: TP53 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 leukemias (eg, ALL)

Monitoring

• Flow cytometry and fluorescence in situ hybridization (FISH) used for follow-up to detect minimal residual disease (MRD)
  • Cytogenomic microarray not recommended for MRD
• Infectious disease screening prior to and during therapy
  • Hepatitis B – identify infection prior to initiating CD20 monoclonal antibody therapy
    • Monitor all patients with positive test result who are receiving therapy
  • Cytomegalovirus (CMV) antibodies – high risk of CMV reactivation with tyrosine kinase inhibitor (TKI) therapy
    • Monitor every 2-3 weeks in patients using alemtuzumab
  • Herpes simplex virus (HSV) and Pneumocystis jirovecii – risk of reactivation of these infections in patients with HIV who undergo therapy
    • HSV and P. jirovecii testing as indicated

Background

Epidemiology

• Incidence – 4/100,000 (Hallek, 2015)
• Age – median 67-72 years (Hallek, 2015)
  • 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

Pathophysiology

• Specific subtypes
  • Small lymphocytic leukemia (SLL) – different manifestation of CLL if nodes are principally involved
    • SLL has similar biology and  same treatment approach
  • Monoclonal B-cell lymphocytosis (MBL) – asymptomatic patient with <5,000 circulating CLL phenotype cells per microliter and no node involvement
    • Precedes development of CLL
    • MBL estimated to be present in 5% of adults ≥50 years; however, general screening for MBL is not recommended
    • MBL with lymphocytosis >4,000 CLL phenotype cells per microliter progresses into CLL at a rate of 1% per year

Clinical Presentation

• CLL principally involves bone marrow and blood
  • Majority of patients present as asymptomatic with lymphocytosis found on CBC
  • Disease may remain indolent for several years until treatment is required
• Symptoms
  • Constitutional symptoms – night sweats, weight loss, fatigue
  • Adenopathy – most patients have some degree of adenopathy at presentation
    • Hepatosplenomegaly
    • Lymph nodes – most commonly cervical, supraclavicular, axillary
  • 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)