What is the recommended initial evaluation and treatment approach for lymphocytosis in a 70-year-old man?

Diagnostic Approach to Lymphocytosis in a 70-Year-Old Man

The initial evaluation of lymphocytosis in a 70-year-old man should include complete blood count with differential, peripheral blood immunophenotyping, and FISH analysis for cytogenetic abnormalities, as these are essential for distinguishing between benign causes, monoclonal B-cell lymphocytosis (MBL), and chronic lymphocytic leukemia (CLL). 1

Initial Diagnostic Workup

Laboratory Evaluation

• Complete blood count with differential to confirm sustained lymphocytosis (≥5 × 10^9 cells/L)
• Peripheral blood smear to assess lymphocyte morphology (small, mature lymphocytes suggest CLL)
• Immunophenotyping of peripheral blood to determine:
  • CLL immunophenotype: CD5+, CD19+, CD20+ (low), CD23+, sIg low, CD79b low, FMC7– 2, 1
  • Atypical CLL: CD19+, CD5+, bright CD20+, lack CD23 3
  • Non-CLL phenotype: CD5-negative 3
• Additional blood tests:
  • LDH, bilirubin, serum protein electrophoresis
  • Direct Coombs test (to evaluate for autoimmune hemolytic anemia)
  • Beta-2 microglobulin (prognostic marker)
  • Hepatitis B, C, and HIV serology 2

Genetic and Molecular Testing

• FISH analysis for cytogenetic abnormalities, particularly:
  • del(17p)/TP53 mutation (poor prognosis)
  • del(11q) (intermediate prognosis)
  • Trisomy 12 (intermediate prognosis) 2, 1
• IGHV mutation status (if CLL is confirmed) 2, 1

Physical Examination and Imaging

• Careful palpation of all lymph node areas
• Assessment of liver and spleen size
• Chest X-ray
• Consider CT scan of neck, thorax, abdomen, and pelvis if clinically indicated (not routine) 2

Differential Diagnosis

Benign Causes of Lymphocytosis

• Viral infections (EBV, CMV, HIV)
• Stress or acute illness
• Medications
• Smoking

Malignant/Clonal Causes

1. Monoclonal B-cell lymphocytosis (MBL)

   • B-cell count <5 × 10^9/L
   • No signs or symptoms of lymphoproliferative disorder
   • Stratified as:
     • Low-count MBL (<0.5 × 10^9/L): generally no lymphocytosis, minimal progression risk
     • High-count MBL (≥0.5 × 10^9/L): 1-2% annual risk of progression to CLL requiring therapy 3

2. Chronic Lymphocytic Leukemia (CLL)

   • B-cell count ≥5 × 10^9/L with characteristic immunophenotype
   • Staging using Binet or Rai systems:
     • Binet A/Rai 0-I: Early stage
     • Binet B/Rai II: Intermediate stage
     • Binet C/Rai III-IV: Advanced stage 2

3. Other Lymphoproliferative Disorders

   • Mantle cell lymphoma (requires cyclin D1 staining or t(11;14) detection)
   • Follicular lymphoma
   • Marginal zone lymphoma
   • Hairy cell leukemia 2

Management Approach

For MBL

• Low-count MBL: No specific follow-up required
• High-count MBL: Regular monitoring with CBC every 6-12 months 3

For CLL

1. Early-stage disease without symptoms (Binet A/Rai 0-I without active disease)

   • "Watch and wait" approach with monitoring every 3 months initially, then extending intervals if stable 2, 1

2. Treatment indications (any of the following):

   • Progressive marrow failure (anemia, thrombocytopenia)
   • Massive or symptomatic splenomegaly
   • Massive nodes or progressive/symptomatic lymphadenopathy
   • Progressive lymphocytosis with doubling time <6 months
   • Autoimmune complications unresponsive to corticosteroids
   • Constitutional symptoms (night sweats, weight loss, fatigue) 1

3. Treatment options based on fitness and genetic profile:

   • For fit elderly patients without del(17p)/TP53 mutation:

     • Bendamustine + rituximab (BR) (consider dose reduction to 70 mg/m²) 2
     • R-CVP (rituximab, cyclophosphamide, vincristine, prednisone) 2

   • For elderly patients with comorbidities:

     • Dose-reduced BR or R-CVP
     • Chlorambucil + anti-CD20 antibody 2

   • For patients with del(17p)/TP53 mutation:

     • Ibrutinib (preferred first-line therapy) 2
     • Idelalisib + rituximab (for relapsed/refractory disease) 2

Important Considerations and Pitfalls

• Avoid treating based on absolute lymphocyte count alone without clinical symptoms or disease progression 1
• Do not mistake lymphocytosis caused by BTK inhibitors (ibrutinib) for disease progression - this is an expected effect and usually resolves over time 2
• Be vigilant for Richter's transformation (transformation to aggressive lymphoma) in patients with rapidly enlarging lymph nodes, B symptoms, or rising LDH 1
• Consider infections and autoimmune complications which are common in CLL patients and may require specific management 1
• Distinguish between autoimmune cytopenias and marrow infiltration as causes of low blood counts, as management differs 1

Follow-up Recommendations

• For asymptomatic MBL/CLL: Clinical examination and blood counts every 3-12 months
• For patients on treatment: More frequent monitoring based on therapy and toxicity profile
• Consider pneumococcal and influenza vaccination for all patients 1