What are the diagnostic criteria and treatment options for Chronic Lymphocytic Leukemia (CLL)?

Diagnostic Criteria and Treatment Options for Chronic Lymphocytic Leukemia (CLL)

The diagnosis of CLL requires ≥5000 monoclonal B lymphocytes/µl in peripheral blood for at least 3 months with a characteristic immunophenotype (CD5+, CD19+, CD20+ low, CD23+, surface immunoglobulin low, CD79b low) confirmed by flow cytometry. 1

Diagnostic Criteria

Essential Diagnostic Elements

• Lymphocytosis: ≥5000 monoclonal B lymphocytes/µl persisting for at least 3 months 1
• Characteristic immunophenotype:
  • CD5+, CD19+, CD20+ (low), CD23+ (required markers) 1
  • Additional features: surface immunoglobulin (sIg) low, CD79b low, restricted kappa or lambda light chains, FMC7 typically negative 1
• Morphology: Small, mature-appearing lymphocytes with narrow cytoplasm border, dense nucleus lacking discernible nucleoli, and partially aggregated chromatin 1

Additional Diagnostic Evaluation

• Physical examination with careful palpation of all lymph node areas 2
• Laboratory tests: LDH, bilirubin, serum protein electrophoresis, Coombs test 2
• Chest X-ray 2
• Cytogenetic analysis by FISH (especially for del(17p), del(11q), del(13q), trisomy 12) 1
• Differential diagnosis against mantle cell lymphoma using CD23 status, FISH for t(11;14) translocation, and cyclin D1 staining 1

Important Distinctions

• Bone marrow biopsy is not required for diagnosis but recommended before initiating therapy to evaluate unexplained cytopenias 1
• CT scans are not routinely required but may be used for baseline assessment in clinical trials 1

Staging and Risk Assessment

Staging Systems

1. Binet Staging System (commonly used in Europe) 2, 1:

   • Stage A: Hb ≥10.0 g/dl, platelets ≥100×10⁹/l, <3 lymph node regions
   • Stage B: Hb ≥10.0 g/dl, platelets ≥100×10⁹/l, ≥3 lymph node regions
   • Stage C: Hb <10.0 g/dl and/or platelets <100×10⁹/l

2. Rai Staging System 1:

   • Stage 0: Lymphocytosis only
   • Stage I: Lymphocytosis + lymphadenopathy
   • Stage II: Lymphocytosis + hepatomegaly/splenomegaly ± lymphadenopathy
   • Stage III: Lymphocytosis + anemia
   • Stage IV: Lymphocytosis + thrombocytopenia

Prognostic Factors

• Cytogenetic abnormalities by FISH (del(17p), del(11q), del(13q), trisomy 12) 1
• TP53 mutations 3
• Immunoglobulin heavy chain variable region (IGHV) mutational status 3
• CD38 and ZAP70 expression 2

Treatment Approach

When to Initiate Treatment

• Watch and wait strategy for early-stage asymptomatic disease (Binet stage A, Rai 0-II without symptoms) 2, 4
• Treatment indications (active disease criteria) 2, 3:
  • Significant B symptoms (fever, night sweats, weight loss)
  • Progressive lymphadenopathy, splenomegaly, or hepatomegaly
  • Progressive lymphocytosis with doubling time <6 months
  • Cytopenias not caused by autoimmune phenomena

First-Line Treatment Options

1. For patients with del(17p) and/or TP53 mutation:

   • Second-generation BTK inhibitors (acalabrutinib, zanubrutinib) administered indefinitely 3, 4
   • Ibrutinib as an alternative BTK inhibitor 5, 4

2. For patients without del(17p)/TP53 mutation with mutated IGHV:

   • Time-limited therapy with BCL2 inhibitor (venetoclax) in combination with anti-CD20 antibody (obinutuzumab) for 1 year 3, 4

3. For patients with unmutated IGHV:

   • Either continuous BTK inhibitor therapy or fixed-duration BCL2 inhibitor-based therapy 3
   • Consider individual factors such as potential toxicities, drug interactions, and patient preference 3

4. For very frail patients:

   • Supportive care 3

Treatment for Relapsed/Refractory Disease

• Consider alternative regimen if relapse occurs within 3 years of initial treatment 6
• Options include:
  • Alternative BTK inhibitor if not previously used 4
  • Venetoclax-based regimen if not previously used 4
  • Noncovalent BTK inhibitor (pirtobrutinib) after failure of covalent BTK inhibitors and venetoclax 4
  • PI3K inhibitors (idelalisib, duvelisib) with close monitoring for autoimmune conditions and infections 4
  • CAR-T cell therapy (lisocabtagene maraleucel) for multiple relapses 4
  • Allogeneic hematopoietic cell transplant remains an option after targeted agents 4

Important Considerations

• CLL and small lymphocytic lymphoma (SLL) are the same disease with different presentations and should be treated the same way 3
• Targeted therapies (BTK inhibitors, BCL2 inhibitors) have largely replaced traditional immunochemotherapy in most treatment scenarios 3, 4
• Fixed-duration therapies are gaining prominence as they are cost-effective, may avoid resistance development, and offer treatment-free intervals 6
• Patients require ongoing monitoring for infectious, autoimmune, and malignant complications 7
• The optimal sequencing of targeted therapies remains to be determined 6
• Management of patients who are double-refractory to both BTK and BCL2 inhibitors remains challenging 6