Treatment Guideline Chart

Chronic lymphocytic leukemia (CLL) is a malignant, chronic lymphoproliferative disorder characterized by proliferation and accumulation of monoclonal B-cells in the bone marrow, peripheral blood, lymph nodes, liver and spleen.

It is the most common form of adult leukemia in the Western world but rare in Asians.

Exact etiology is unknown but usually associated with genetic aberrations and lesions.


Chronic%20lymphocytic%20leukemia Management

Follow Up

  • Patients should be re-evaluated every 6 months within the 1st year of diagnosis
    • For patients with early asymptomatic disease, follow-up at 3-monthly intervals is recommended within the 1st year, then every 3-12 months thereafter depending on patient’s status
  • Physical examination and blood exams are used for assessment of treatment response
    • Bone marrow biopsy and aspirate should be conducted on patients in clinical trials

Response Criteria for Chronic Lymphocytic Leukemia (CLL) by the International Workshop Group on CLL (IWCLL)

  • Complete response should include all of the following, at least 2 months after treatment completion:
    • Peripheral blood lymphocyte count <4 x 109/L
    • Normal blood counts without growth factor support [neutrophils ≥1.5 x 109/L, platelets ≥100 x 109/L, hemoglobin (Hb) ≥11 g/dL]
    • No enlarged lymph nodes (≥1.5 cm in diameter)
    • No splenomegaly or hepatomegaly
    • No CLL-related constitutional symptoms (eg weight loss, fever, night sweats)
    • Bone marrow is normocellular for age without typical CLL lymphocytes and B-lymphoid nodules
  • Partial response criteria include:
    • ≥2 of the following within 2 months after completion of therapy:
      • ≥50% reduced peripheral blood lymphocyte count compared to baseline
      • ≥50% reduced lymphadenopathy compared to baseline
      • ≥50% reduction in liver/spleen size if previously enlarged in baseline findings
    • ≥1 of the blood count normalized or increased by ≥50% prior to treatment initiation:
      • Platelet count ≥100 x 109/L or ≥50% improved compared to baseline
      • Hb concentration ≥11 g/dL or ≥50% improved compared to baseline
      • Neutrophil count ≥1.5 x 109/L or >50% improved compared to baseline
  • Disease progression involves any of the following:
    • Lymphocyte count, lymphadenopathy, splenomegaly or hepatomegaly increased by 50% from baseline
    • Presence of new lesions or transformation to more aggressive forms
    • Occurrence of cytopenias contributing to CLL progression (≥2 g/dL Hb and >50% platelet count decreased from baseline)
  • Stable disease is defined as disease without complete or partial response but without disease progression
  • Minimal residual disease (MRD)
    • Detects malignant clones by flow cytometry or quantitative polymerase chain reaction
    • Most important predictor of overall survival and progression-free survival after chemoimmunotherapy

    Maintenance Therapy

    • Treatment with Lenalidomide after completion of initial therapy may be considered for high-risk CLL patients without del(17p)/TP53 mutation (MRD ≥10-2 or ≥10-4 and <10-2 with unmutated IGHV)
    • Treatment with Lenalidomide or Ofatumumab may be considered in CLL patients with refractory/relapsed disease with complete or partial response after completion of 2nd-line therapy
    • For patients previously treated with Ibrutinib being considered for Acalabrutinib treatment, Bruton's tyrosine kinase (BTK) mutation analysis should be considered; BTK mutation-positive patients may be unresponsive to Acalabrutinib therapy

    Second-line and Subsequent Therapy

    • Relapsed disease occurs when disease progression appears ≥6 months after initial complete or partial response
    • Refractory disease is when a patient fails to achieve a response or disease progression occurs within 6 months of the last treatment dose

    Second-line and Subsequent Therapy

    • Depends on the presence of del(17p)/TP53 mutation, patient’s age, and presence of comorbidities
    • Patients without del(17p)/TP53 mutation, ≥65 years old or <65 years old with significant comorbidities
      • Acalabrutinib1
      • Dose-dense Rituximab4
      • Duvelisib2 
      • High-dose Methylprednisolone (HDMP) + Rituximab or Obinutuzumab3
      • Ibrutinib1 
      • Idelalisib ± Rituximab2
      • Lenalidomide ± Rituximab2
      • Obinutuzumab2
      • Ofatumumab2
      • Rituximab + Bendamustine3 
      • Rituximab + Chlorambucil2
      • Venetoclax2 
      • Venetoclax + Rituximab1
      • Zanubrutinib2
    • CLL without del(17p)/TP53 mutation <65 years old without significant comorbidities
      • Acalabrutinib1  
      • Alemtuzumab ± Rituximab4
      • Bendamustine + Rituximab2 
      • Bendamustine, Rituximab + Ibrutinib4
      • Duvelisib2  
      • Ibrutinib1
      • Idelalisib ± Rituximab2
      • FC + Ofatumumab4
      • FCR(Fludarabine, Cyclophosphamide, Rituximab)
      • HDMP + Rituximab or Obinutuzumab3
      • Lenalidomide ± Rituximab2 
      • Obinutuzumab2  
      • Ofatumumab2
      • Venetoclax2
      • Venetoclax + Rituximab1
      • Zanubrutinib2
    • CLL with del(17p)/TP53 mutation
      • Acalabrutinib1  
      • Alemtuzumab ± Rituximab4
      • Duvelisib2
      • HDMP + Rituximab
      • Ibrutinib1
      • Idelalisib ± Rituximab2
      • Lenalidomide ± Rituximab2
      • Ofatumumab2,5 
      • Venetoclax2
      • Venetoclax + Rituximab1
      • Zanubrutinib2 

    1Indicated as Category 1 by the National Comprehensive Cancer Network (NCCN).
    2Indicated as Category 2A by the NCCN.
    3Indicated as Category 2B by the NCCN.
    4Indicated as Category 3 by the NCCN.
    5Not recommended for patients with lymph nodes >5 cm.

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