What is the next step in management for a patient with progressive chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) with increasing white blood cell (WBC) and lymphocyte counts?

Next Steps in Management for Progressive CLL/SLL

For this patient with progressive CLL showing lymphocyte doubling time of less than 6 months, the next step should be to order FISH testing for del(17p), TP53 mutation analysis, and IGHV mutation status to guide treatment selection.

Assessment of Disease Progression

The patient demonstrates clear evidence of progressive disease based on the following:

• Progressive lymphocytosis with WBC increasing from 13.6 (11/2023) to 31.2 (current)
• Lymphocyte count increasing from 18.62 to 25.27 over approximately 5 months
• Lymphocyte doubling time of less than 6 months (criterion #4 for active disease)

According to the International Workshop on CLL guidelines 1, progressive lymphocytosis with an increase of more than 50% over a 2-month period or lymphocyte doubling time (LDT) of less than 6 months is a clear indication for initiating treatment.

Recommended Diagnostic Workup

Before initiating treatment, the following tests should be ordered:

1. Genetic/Molecular Testing:

   • FISH analysis for del(17p), del(11q)
   • TP53 mutation analysis
   • IGHV mutation status
   • CpG-stimulated karyotyping

2. Disease Burden Assessment:

   • CT scan of chest, abdomen, and pelvis to evaluate lymphadenopathy
   • Complete blood count with differential
   • Comprehensive metabolic panel
   • Serum immunoglobulin levels

3. Functional Assessment:

   • Evaluation of comorbidities
   • Creatinine clearance
   • Performance status assessment

Rationale for Testing

The ESMO and NCCN guidelines 1, 2 emphasize that genetic testing, particularly for del(17p), TP53 mutations, and IGHV status, is crucial before initiating treatment as these factors significantly influence treatment selection:

• Patients with del(17p) or TP53 mutations have poor responses to conventional chemotherapy and require BTK inhibitors (ibrutinib, acalabrutinib, or zanubrutinib) as first-line therapy 1, 2
• IGHV mutation status helps determine whether time-limited or continuous therapy is more appropriate 1
• Presence of del(11q) may also influence treatment choice 1

Common Pitfalls to Avoid

1. Initiating treatment based solely on absolute lymphocyte count: The guidelines clearly state that "the absolute lymphocyte count should not be used as the sole indicator for treatment" 1, 2. Treatment should be based on established criteria for active disease.

2. Failing to perform genetic testing before treatment selection: Without knowledge of del(17p), TP53 mutation, or IGHV status, inappropriate treatment selection could lead to suboptimal outcomes 2.

3. Overlooking assessment of comorbidities: Patient fitness and comorbidities significantly impact treatment tolerability and selection 1.

4. Neglecting to evaluate for autoimmune cytopenias: These can complicate CLL management and may require specific interventions 1.

Once the genetic testing results are available, treatment can be selected based on the patient's specific risk profile, age, and comorbidities, with BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib) or venetoclax-based regimens being the current standard of care for most patients with CLL requiring treatment 3.