Chronic myelogenous leukemia (CML) is a malignant myeloid disorder characterized by the presence of a distinctive cytogenetic abnormality known as the Philadelphia chromosome.

Exposure to ionizing radiation is the only known risk factor with median presentation at age >50 years old.

Three phases of the disorder are chronic, accelerated and blast.

Choice of therapy is influenced by age, availability of a donor, comorbidities and phase of CML.

Chronic%20myeloid%20leukemia Diagnosis


Phases of Chronic Myeloid Leukemia

Chronic Phase (CP)

  • Sometimes termed as chronic stable phase and the phase that is easily controlled with oral agents
  • Defined as <10% of blasts in the peripheral blood and bone marrow

Accelerated Phase (AP)

  • Criteria for defining accelerated phase by the World Health Organization (WHO) (≥1 of the following):
    • 10-19% blasts in the peripheral blood smear or in the nucleated bone marrow cells
    • ≥20% basophils in the peripheral blood
    • Persistent thrombocytopenia (<100,000/µL platelets) that is unrelated to therapy
    • Persistent thrombocytosis (>1,000,000/µL platelets) that are unresponsive to therapy
    • Progressive splenomegaly and increased white cell count (>10 x 109/L) that is unresponsive to therapy
    • Cytogenetic evolution (chromosomal abnormalities other than Ph chromosome during therapy)
    • Hematologic resistance to 1st-line tyrosine kinase inhibitors (TKI) therapy
    • Hematologic, cytogenic, or molecular indications of resistance to 2 sequential tyrosine kinase inhibitors
    • ≥2 mutations in BCR-ABL1 during tyrosine kinase inhibitors therapy 
  • Modified criteria used at MD Anderson Cancer Center
    • ≥15% and 30% peripheral blood blasts
    • ≥30% combined peripheral blood blasts and promyelocytes
    • ≥20% peripheral blood basophils
    • ≤100 x 109/L platelet count unrelated to therapy
    • Clonal evolution in Ph+ cells

Blast Phase (BP)

  • Disease progression may occur in patients without a preceding accelerated phase of chronic myeloid leukemia (AP-CML) and are refractory to treatment
  • Criteria for defining blast phase by the WHO
    • ≥20% blasts in the peripheral blood smear or bone marrow blasts
    • Presence of large foci or clusters of blasts in bone marrow biopsy
    • Presence of extramedullary blast infiltrates 
  • Criteria used by the International Bone Marrow Transplant Registry
    • ≥30% blasts in the blood, marrow, or both
    • Presence of extramedullary infiltrates of leukemic cells

Physical Examination

  • Complete history and physical examination including the size of the spleen and liver

Laboratory Tests

  • Complete blood count (CBC) with differential and platelet count
  • Biochemical profile including hepatitis B serology, cholesterol, lipase, hemoglobin A1c
  • Electrocardiogram (ECG)

Peripheral Blood Smear (PBS)

  • Absolute basophilia and eosinophilia as well as leukocytosis (approximately 100,000/µL)
  • Presence of mature metamyelocytes (“leukemic hiatus” or myelocyte bulge)
    • A classic finding in chronic myeloid leukemia

Bone Marrow Aspirate and Biopsy

  • Used as initial workup and for the detection of other chromosomal abnormalities that cannot be detected on peripheral blood fluorescence in situ hybridization (FISH)
  • Reveals a granulocytic hyperplasia with maturation pattern, increased reticulin fibrosis and vascularity, widened areas of immature neutrophils, decreased erythroid islands, presence of dwarf megakaryocytes, decreased iron-laden macrophages and increased cell turnover with pseudo-Gaucher cell and sea-blue histiocytes
  • Morphologic review contains percentage of the blast and basophils

Genetic Tests

  • Cytochemistry
    • Differentiates myeloid from lymphoid blasts in blastic phase of chronic myeloid leukemia
  • Cytogenetics
    • The test that initially discovered the Ph chromosome with the use of May-Grünwald-Giemsa (MGG) banded metaphase chromosomes
      • If Ph positive and BCR-ABL1 positive, a chronic or an advanced phase of chronic myeloid leukemia is confirmed
      • If Ph negative and BCR-ABL1 negative, the patient should be evaluated for other diseases than chronic myeloid leukemia
  • Fluorescence in situ hybridization (FISH) analysis
    • Used to detect the chromosomal position of the BCR and ABL1 genes in preparations containing metaphase chromosome
    • Also used in the utilization of the interphase cells in the bone marrow or peripheral blood
      • Presence of co-localization of the BCR and ABL probes indicates the presence of fused BCR-ABL1 genes
  • Quantitative reverse transcription-polymerase chain reaction (QPCR) using International Scale (IS)
    • Uses primers to amplify the DNA fragment from the mRNA transcripts of BCR-ABL1 genes
    • Can detect fusion of e1a2, e13a2 (b2a2), e14a2 (b3a2) and e19a2 genes
  • Other chromosomal abnormalities related to chronic myeloid leukemia (eg trisomy 8, trisomy 19, duplication of the Ph chromosome, isochromosome 17q)
    • Also known as additional clonal cytogenetic aberrations (ACAs)
    • Have poorer progression-free survival (PFS) and overall survival (OS)

Human Leukocyte Antigen (HLA) Testing

  • If the patient is considered for allogenic hematopoietic stem cell transplantation (HCT)


Determination of Risk Score

Sokal Prognostic Score

  • Spleen size, percent blasts, age and platelet count >700,000/µL are used as variables
  • Low risk: <0.8
  • Intermediate risk: 0.8 - 1.2
  • High risk: >1.2

Hastford (EURO) Score

  • Developed for patients receiving Interferon therapy
  • Adds eosinophilia and basophilia to the other variables
  • Low risk: ≤780
  • Intermediate risk: >780 - ≤1480
  • High risk: >1480

European Treatment and Outcome Study (EUTOS)

  • Developed in 2011; identifies 2 risk groups with different probabilities of complete cytogenetic response (CCyR) within 18 months post-therapy 
  • Scoring based on the percentage of basophils and size of the spleen
  • Additional studies may be needed to confirm importance of EUTOS in predicting clinical outcomes of patients receiving tyrosine kinase inhibitors therapy
  • Low risk: ≤87
  • High risk: >87

EUTOS Long-term Survival (ELTS) Score

  • Newest scoring system developed in 2016 by the European LeukemiaNet to distinguish 3 risk groups with significantly different probabilities of dying of chronic myeloid leukemia 
  • Scoring based on the percentage of basophils, size of the spleen and Sokal age
  • Low risk: ≤1.5680
  • Intermediate risk: >1.5680 but ≤2.2185
  • High risk: >2.2185
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