Does chronic lymphatic leukemia (CLL) always require immediate treatment?

Does Chronic Lymphocytic Leukemia Always Require Treatment?

No, chronic lymphocytic leukemia (CLL) does not always require treatment—in fact, most patients diagnosed with early-stage disease should not be treated immediately, as early treatment with any agent has not been shown to improve overall survival. 1, 2

Watch-and-Wait is Standard for Early Disease

The watch-and-wait approach remains the standard of care for asymptomatic, early-stage CLL patients (Binet stage A and B without active disease; Rai 0, I, and II without active disease). 1, 2

• Multiple studies over decades have definitively shown that early treatment with chemotherapeutic agents does not translate into a survival advantage in patients with early-stage CLL. 1, 2

• Even with novel targeted agents like ibrutinib, a recent phase III clinical trial in asymptomatic patients with Binet stage A and unfavorable-risk CLL confirmed no overall survival benefit when starting treatment early, despite demonstrating longer time to next treatment. 2

• Approximately 80% of newly diagnosed CLL patients present with early-stage disease that does not meet criteria for immediate treatment. 3

When Treatment Must Be Initiated

Treatment should only be started when patients develop "active disease" as defined by specific criteria—not based on diagnosis alone or prognostic factors. 1, 2

At least one of the following criteria must be met to initiate therapy:

1. Progressive marrow failure: Development or worsening of anemia (hemoglobin <100 g/L) and/or thrombocytopenia (platelets <100 × 10⁹/L), though stable thrombocytopenia does not automatically require intervention. 1

2. Massive or progressive splenomegaly: Spleen extending ≥6 cm below the left costal margin, or progressive/symptomatic enlargement. 1, 2

3. Massive or progressive lymphadenopathy: Lymph nodes ≥10 cm in longest diameter, or progressive/symptomatic enlargement. 1, 2

4. Progressive lymphocytosis: Increase of 50% over 2 months, or lymphocyte doubling time <6 months (only in patients with initial counts >30 × 10⁹/L). Exclude other causes like infections or steroid use. 1, 2

5. Autoimmune complications: Anemia or thrombocytopenia poorly responsive to corticosteroids. 1

6. Symptomatic extranodal involvement: Affecting skin, kidney, lung, or spine. 1

7. Constitutional symptoms: Fever, night sweats, or weight loss attributable to CLL (after excluding other causes like infections or secondary malignancies). 1, 2

Critical Pitfall: Prognostic Factors Are Not Treatment Indications

A common mistake is initiating treatment based on high-risk prognostic factors alone—this is explicitly not recommended. 1, 2

• Prognostic factors such as del(17p), TP53 mutations, unmutated IGHV status, and complex karyotype predict time to progression but should NOT be used as indications for treatment in asymptomatic patients. 2

• These markers should be assessed before treatment to guide therapy selection, not to decide whether to treat. 1

• Even patients with del(17p) or TP53 mutations should not receive treatment until they develop symptoms or meet criteria for active disease. 2

• Absolute lymphocyte count alone, regardless of how elevated, is not an indication for treatment. 2, 4

Monitoring Strategy During Watch-and-Wait

Patients with early-stage CLL require regular monitoring with blood cell counts and clinical examinations every 3-12 months. 1, 2

• In the first year after diagnosis, 3-monthly intervals should be applied for all patients. 1

• Physical examination should include careful palpation of lymph nodes, liver, and spleen. 2

• Routine imaging during the watch-and-wait period is not recommended unless clinical symptoms develop. 1

• Attention to development of symptoms that would indicate need for treatment is crucial during follow-up. 2

Treatment Options When Disease Becomes Active

When treatment is indicated, several options exist depending on patient characteristics and molecular profile. 2, 5, 6

• For patients with del(17p) or TP53 mutations, BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib) are preferred as first-line therapy since these patients are resistant to chemoimmunotherapy. 2, 5, 6

• For patients without del(17p) or TP53 mutations, options include venetoclax plus obinutuzumab, BTK inhibitor monotherapy, or chemoimmunotherapy (depending on age, fitness, and IGHV status). 2, 5, 6

• For physically fit patients younger than 65 years with mutated IGHV, chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab remains a standard option. 5