chronic%20myeloid%20leukemia
CHRONIC MYELOID LEUKEMIA

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.

Diagnosis

Phases of Chronic Myeloid Leukemia

Chronic phase (CP)

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

Accelerated phase (AP)

  • Criteria for defining accelerated phase by the World Health Organization (≥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 & 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% & 30% peripheral blood blasts
    • ≥30% combined peripheral blood blasts & promyelocytes
    • ≥20% peripheral blood basophils
    • ≤100 x 109/L platelet count unrelated to therapy
    • Clonal evolution

Blast phase (BP)

  • Disease progression may occur in patients without a preceding accelerated phase of chronic myeloid leukemia (AP-CML) & are refractory to treatment
  • Criteria for defining blast phase by the World Health Organization
    • ≥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 & physical examination including the size of the spleen

Laboratory Tests

  • Complete blood count (CBC) with differential & platelet count

Peripheral blood smear (PBS)

  • Absolute basophilia & 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 & biopsy

  • Used as initial workup & 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 & vascularity, widened areas of immature neutrophils, decreased erythroid islands, presence of dwarf megakaryocytes, decreased iron-laden macrophages & increased cell turnover with pseudo-Gaucher cell & sea-blue histiocytes
  • Morphologic review contains percentage of the blast & 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 & BCR-ABL1 positive, a chronic or an advanced phase of chronic myeloid leukemia is confirmed
      • If Ph negative & 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 & 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 & ABL probes indicates the presence of fused BCR-ABL1 genes

Genetic tests

  • 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) & 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) & 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 & platelet count >700,000/µL are used as variables
  • Hastford or Euro Score
    • Developed for patients receiving Interferon therapy
    • Adds eosinophilia & basophilia to the other variables
  • European Treatment and Outcome Study (EUTOS) Score
    • Scoring that is based on the percentage of basophils & size of the spleen
    • Additional studies may be needed to confirm importance of European Treatment and Outcome Study (EUTOS) in predicting clinical outcomes of patients receiving tyrosine kinase inhibitors therapy
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