What is the treatment approach for asymptomatic Chronic Lymphocytic Leukemia (CLL)?

Treatment of Asymptomatic CLL

The standard treatment approach for asymptomatic Chronic Lymphocytic Leukemia (CLL) is a watch-and-wait strategy, as early intervention with chemotherapy has not shown survival benefits. 1

Diagnostic Criteria and Staging

• CLL diagnosis is established through blood counts, blood smears, and immunophenotyping of circulating B-lymphocytes showing a clonal B-cell population with CD5 and typical B-cell markers 2
• Staging is performed using either the Rai or Binet staging systems:
  • Binet A: Hb ≥100 g/l, platelets ≥100×10⁹/l, <3 involved lymphoid sites
  • Binet B: Hb ≥100 g/l, platelets ≥100×10⁹/l, ≥3 involved lymphoid sites
  • Binet C: Hb <100 g/l, platelets <100×10⁹/l
  • Rai 0 (low-risk): Lymphocytosis only
  • Rai I-II (intermediate-risk): Lymphocytosis with lymphadenopathy and/or organomegaly
  • Rai III-IV (high-risk): Lymphocytosis with anemia and/or thrombocytopenia 1

Management of Asymptomatic CLL

Watch and Wait Strategy

• Previous studies have consistently shown that early treatment with chemotherapeutic agents does not translate into a survival advantage in patients with early-stage CLL 1
• The standard approach for asymptomatic patients with early-stage disease (Binet A and B without active disease; Rai 0, I, and II without active disease) is a watch-and-wait strategy 1
• This approach is recommended regardless of prognostic markers 3

Follow-up Protocol

• Initial monitoring: All patients should be seen at 3-monthly intervals during the first year 1
• Subsequent monitoring: After the first year, patients can be followed every 3-12 months depending on disease burden and dynamics 1, 4
• Each follow-up visit should include:
  • Complete history and physical examination with careful palpation of all lymph node areas, spleen, and liver
  • Complete blood cell count with differential 1, 4
• Special attention should be paid to the appearance of autoimmune cytopenias (autoimmune hemolytic anemia, autoimmune thrombocytopenia), which occur in 10-15% of CLL patients 1
• Routine imaging during the watch-and-wait period is not recommended unless there are clinical symptoms 1

Criteria for Treatment Initiation

Treatment should only be initiated when there is evidence of active disease, defined by at least one of the following criteria:

1. Progressive marrow failure (development or worsening of anemia and/or thrombocytopenia)
2. Massive (≥6 cm below left costal margin) or progressive or symptomatic splenomegaly
3. Massive (≥10 cm in longest diameter) or progressive or symptomatic lymphadenopathy
4. Progressive lymphocytosis with ≥50% increase over 2 months, or lymphocyte doubling time of <6 months
5. Autoimmune complications poorly responsive to corticosteroids
6. Symptomatic or functional extranodal involvement
7. Disease-related symptoms (unintentional weight loss, significant fatigue, fever, night sweats) 1

Risk Stratification

• Routine evaluation of del(17p), TP53 mutation, and IGHV status in early and asymptomatic stage is not recommended 1
• These genetic markers should be assessed before treatment initiation to guide therapy choice 1
• Patients with del(17p) or TP53 mutations have poorer outcomes and require different treatment approaches when therapy is indicated 1, 3

When Treatment Becomes Necessary

When treatment criteria are met, options will depend on:

• Patient fitness and comorbidities
• Presence of high-risk genetic features (particularly del(17p) or TP53 mutations)
• For most patients, current standard first-line treatments include:
  • BTK inhibitors (e.g., ibrutinib) 5, 3
  • BCL2 inhibitor (venetoclax) often in combination with anti-CD20 antibodies
  • Chemoimmunotherapy for selected patients 2

Common Pitfalls and Caveats

• Avoid premature treatment initiation based solely on anxiety or high-risk prognostic markers in the absence of active disease criteria 1, 3
• Do not confuse lymphocytosis due to infections or steroid administration with disease progression 1
• Remember that factors other than CLL can cause symptoms like fatigue, weight loss, or night sweats; these should be excluded before attributing them to CLL and initiating treatment 1
• Regular monitoring for secondary malignancies is important as CLL patients have an increased risk 1
• Recognize that the watch-and-wait approach may be challenging psychologically for patients, requiring appropriate education and support 6