Chronic Myeloid Leukemia (CML)

Background

• CML is a clonal hematopoietic stem cell disorder characterized by presence of the Philadelphia chromosome, which has 3 distinct phases:
  • chronic phase (most patients present in this phase)
  • accelerated phase
  • blast phase
• CML most commonly affects adults.
• The annual age-adjusted incidence of CML is about 1-2 per 100,000 persons/year.
• Exposure to ionizing radiation is a risk factor for the development of CML.
• Patients with newly diagnosed Philadelphia chromosome-positive CML in chronic phase with adequate tyrosine kinase inhibitor (TKI) therapy typically have similar prognosis to general population without CML. Patients in blast phase generally have poor prognosis, with reported overall survival < 1 year. The most important prognostic factors are age, spleen size, and myeloblast, platelet, eosinophil, and basophil counts.

Evaluation

• About 50% of patients are asymptomatic and diagnosed incidentally when abnormalities are noticed on blood tests and physical examination. If present, most common signs and symptoms of CML include splenomegaly, anemia, leukocytosis, as well as nonspecific symptoms such as fatigue, weight loss, and malaise.
• Initial evaluation for diagnosis involves obtaining a complete blood count with differential showing excessive granulocytosis with left shift of granulopoiesis (Strong recommendation).
• Confirmation of diagnosis is made by metaphase bone marrow cytogenetics to detect the Philadelphia chromosome (t[9;22][q34;q11]) and by reverse transcriptase polymerase chain reaction (RT-PCR) of peripheral blood or bone marrow to detect BCR-ABL1 fusion transcripts (Strong recommendation).
• Perform morphologic evaluation (Strong recommendation) to determine the proportion of myeloblasts, promyelocytes, and basophils in bone marrow and/or peripheral blood to differentiate chronic phase from accelerated phase and blast phase.
• Following diagnosis:
  • Perform risk stratification (Strong recommendation).
  • For patients in accelerated or blast phase, additional evaluations include
    • BCR-ABL1 kinase domain mutational analysis (Strong recommendation) with next-generation sequencing-based myeloid gene mutation panel (Weak recommendation)
    • flow cytometry to determine leukemic cell lineage (Weak recommendation)
    • human leukocyte antigen (HLA) testing if considering allogeneic hematopoietic stem cell transplantation (HSCT) (Weak recommendation)

Management

Management in Chronic Phase

• For initial management:
  • TKIs are the standard management strategy; options include:
    • imatinib 400 mg once daily (preferred option for low-risk disease only) (Strong recommendation)
    • bosutinib 400 mg once daily (preferred option regardless of risk) (Strong recommendation)
    • dasatinib 100 mg once daily (preferred option regardless of risk) (Strong recommendation)
    • nilotinib 300 mg twice daily (preferred option regardless of risk) (Strong recommendation)
  • For patients with sustained deep molecular response fulfilling stringent criteria, consider TKI discontinuation.
  • For patients during pregnancy, consider watch and wait strategy if active management is not indicated, or management with interferon if needed later during pregnancy. TKI should be avoided, especially during the first trimester, given higher risk of miscarriage and fetal abnormalities. While TKI should be avoided throughout pregnancy, if needed later in pregnancy, potential risks to the fetus and risks associated with TKI avoidance on disease response should be carefully evaluated.
• Further management depends on response to first-line TKIs.
  • For patients with optimal response to first-line TKIs, continuation of current TKIs (Weak recommendation) with continuous monitoring of response and toxicities (Strong recommendation).
  • For patients with disease resistant to current TKI, perform BCR-ABL1 kinase domain mutation analysis (Strong recommendation). Management strategies depend on TKI resistance and BCR-ABL1 kinase domain mutation status.
    • For imatinib-resistant disease, switch to a second-generation TKI (bosutinib, dasatinib, or nilotinib) (Strong recommendation).
    • For disease resistant to second-generation TKI, switch to alternative second-generation TKI as guided by the BCR-ABL1 mutation status or a third-generation TKI (ponatinib) (Strong recommendation)
    • For patients resistant and/or intolerant to ≥ 2 prior TKIs, consider ponatinib (Strong recommendation), asciminib (Weak recommendation), or omacetaxine (Weak recommendation).
    • Consider allogeneic HSCT as a management option, especially for patients who are resistant and/or intolerant to ≥ 2 prior TKIs, have BCR-ABL1 T315I mutation and fail to respond to ponatinib, or are at high risk of progression to accelerated or blast phase (Weak recommendation), or have inadequate recovery of normal hematopoiesis.

Management in Accelerated or Blast Phase

• For patients with accelerated phase CML, consider induction therapy followed by allogeneic HSCT if possible, especially if the response to induction therapy is not sufficient (Weak recommendation).
  • The preferred induction therapy is a second- or third-generation TKI (options are based on BCR-ABL1 kinase domain mutation status), such as
    • bosutinib (Weak recommendation)
    • dasatinib (Weak recommendation)
    • nilotinib (Weak recommendation)
    • ponatinib (Weak recommendation)
  • Other induction therapy options include
    • imatinib (Weak recommendation)
    • omacetaxine (for patients with progression to accelerated phase only, but not for patients who present with accelerated phase) (Weak recommendation)
• For patients with blast-phase CML, offer TKI-based induction therapy followed by allogeneic HSCT (Strong recommendation).
  • For lymphoid disease:
    • perform induction therapy with TKI in combination with either chemotherapy used in acute lymphocytic leukemia or corticosteroids (Strong recommendation)
    • consider lumbar puncture and central nervous system (CNS) prophylaxis (Weak recommendation), given risk of CNS involvement
  • For myeloid disease, offer induction therapy with either TKI in combination with chemotherapy used in acute myeloid leukemia or TKI alone (Strong recommendation).

Response Assessment and Surveillance

• Regular response monitoring for tyrosine kinase inhibitor involves
  • complete blood count with differential every 15 days until complete hematologic response, and then every 3 months thereafter (Strong recommendation)
  • quantitative polymerase chain reaction (qPCR) using International Scale (IS) at least every 3 months initially (Strong recommendation)
  • metaphase bone marrow cytogenetics at time of TKI failure, loss of response, or at 3 and 6 months initially (Strong recommendation)
  • BCR-ABL1 kinase domain mutation analysis at time of TKI failure, loss of response, or progression to accelerated or blast phase (Strong recommendation)
  • fluorescence in situ hybridization (FISH) if metaphase bone marrow cytogenetics is not analyzable or normal, or if molecular response is not assessable (Strong recommendation)
• To monitor response after allogeneic HSCT, consider qPCR every 3 months for 2 years, and then every 3-6 months thereafter (Weak recommendation).