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.


Follow Up

  • Patients should be re-evaluated every 6 months within the 1st year of diagnosis
  • Physical examination & blood exams are used for assessment of treatment response
    • Bone marrow biopsy & aspirate should be conducted on patients in clinical trials

Response Criteria for 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 >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 <30% lymphocytes, clonal cells absent in flow cytometry
  • Partial response criteria includes ≥2 of the following within 2 months duration:
    • ≥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
      • Hgb 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 chronic lymphocytic leukemia progression (>2 g/dL hemoglobin & >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
  • Maintenance Therapy

  • Treatment w/ Lenalidomide after completion of initial therapy may be considered for high-risk CLL patients w/ or without del(17p)/TP53 mutation (MRD ≥10-2 or ≥10-4 & <10-2 w/ unmutated IGHV)
  • Treatment w/ Lenalidomide or Ofatumumab may be considered in CLL patients w/ refractory/relapsed disease w/ complete or partial response after completion of 2nd-line therapy
  • Management of Relapse

    • 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

    Management of Refractory or Relapsed Chronic Lymphocytic Leukemia

    • Depends on the presence of del(17p)/TP53 mutation, patient’s age, & presence of comorbidities
    • Frail patients without del(17p)/TP53 mutation or ≥65 years old & younger with significant comorbidities
      • Acalabrutinib2 
      • Ibrutinib1
      • Idelalisib + Rituximab1
      • Idelalisib2
      • Ofatumumab2
      • Obinutuzumab2
      • Reduced-dose FCR2(Fludarabine, Cyclophosphamide, Rituximab)
      • Reduced-dose PCR2(Pentostatin, Cyclophosphamide, Rituximab)
      • High dose Methylprednisone + Rituximab2
      • Rituximab + Chlorambucil2
      • Bendamustine +/- Rituximab2
      • Lenalidomide +/- Rituximab2
      • Alemtuzumab +/- Rituximab2
      • Dose-dense Rituximab3
      • Venetoclax2 
      • Venetoclax + Rituximab1
      •  Ibrutinib, Bendamustine, Rituximab3
      • Idelalisib, Bendamustine, Rituximab
    • Chronic lymphocytic leukemia without del(17p)/TP53 mutation <65 years old without significant comorbidities
      • Acalabrutinib2  
      • Ibrutinib1
      • Idelalisib + Rituximab1
      • Idelalisib2
      • Ofatumumab2
      • Obinutuzumab2
      • FCR2(Fludarabine, Cyclophosphamide, Rituximab)
      • PCR2(Pentostatin, Cyclophosphamide, Rituximab)
      • Bendamustine +/- Rituximab2
      • FC + Ofatumumab2
      • High dose Methylprednisone + Rituximab2
      • OFAR2 (Oxaliplatin, Fludarabine, Cytarabine, Rituximab)
      • Lenalidomide +/- Rituximab2
      • Alemtuzumab +/- Rituximab2
      • RCHOP2 (Cyclophosphamide, Doxorubicin, Vincristine, Prednisone)
      • Venetoclax2
      • Venetoclax + Rituximab1
      • Ibrutinib, Bendamustine, Rituximab3
      • Idelalisib, Bendamustine, Rituximab3
    • Chronic lymphocytic leukemia with del(17p)/TP53 mutation
      • Acalabrutinib2  
      • Ibrutinib1
      • Idelalisib + Rituximab2
      • Idelalisib2
      • Ofatumumab2,5
      • Lenalidomide +/- Rituximab2
      • Alemtuzumab +/- Rituximab2
      • OFAR2(Oxaliplatin, Fludarabine, Cytarabine, Rituximab)
      • High dose Methylprednisone + Rituximab2
      • Venetoclax2
      • Venetoclax + Rituximab1

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

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