12. Chronic Myeloid Leukemia (CML) Characteristics

CML results from an acquired (somatic) mutation that leads to a clonal myeloproliferative expansion of what type of cells

transformed, primitive hematopoietic progenitor cells

CML is expression of what

BCR-ABL related to the presence of Philadelphia Chromosome

How does the Philadelphia chromosome get made

• translocation between the long arms of chromosomes 9 and 22 t(9;22)

• This joining of a portion of the ABL gene of chromosome 9 and the BCR gene of chromosome 22 leads to the formation of the BCR-ABL fusion oncogene

• The changed chromosome 22 is known as the “Philadelphia chromosome” (Ph+)

BCR-ABL gene lead to production of the BCR-ABL protein, what is BCR-ABL protein?

an abnormal tyrosine kinase

How does the BCR-ABL tyrosine avoid apoptosis?

BCR-ABL tyrosine kinase has an ATP binding site which can transfer a phosphate group to a protein substrate causing a signalling cascade for CML cells to proliferate and avoid apoptosis

with a multitude of CML cells (immature myeloid precursor cells) that develop overpopulate the bone marrow, what happens to functional cells?

healthy functional cells (functional WBC, platelets, RBC) are crowded out

How many patients are asymptomatic due to the initial indolent phase of the disease

half

CML Signs & Symptoms

• Splenomegaly (up to half of patients)

  • The spleen is a storage site for white blood cells. Some patients may have early satiety (due to splenomegaly), anorexia, unexplained weight loss

• Impact on hematopoiesis (other cell lines from bone marrow)

  • Patients may have bone pain and/or fatigue

• Leukocytosis (WBC > 25):

  • Some patients may have leukostasis (WBC >100)

  • Leukostasis can allow infiltration of WBCs into tissues of major organs, compromising the organ’s ability to function normally

    • infiltration of lungs or CNS, visual disturbances, stroke, or MI

Diagnosis of CML

bone marrow biopsy (like a medical apple corer)

Tests to Understand CML Diagnosis

• Hematopathologist reviews the samples from the bone marrow and peripheral blood to confirm disease and phase

• Cytogenetics

  • Review of the chromosomes in the cells from the bone marrow sample – is the philadelphia chromosome present?

• Molecular Testing

  • Q-RT-PCR (Quantitative Reverse Transcriptase Polymerase Chain Reaction)

  • Very sensitive and is able to quantitatively measures the BCR-ABL gene

• Chronic, Accelerated, or Blast Crisis?

• These tests take some time!

Chronic Phase (CP) CML 

• < 10% blasts in the peripheral blood or bone marrow

• often asymptomatic 

• Duration w/o treatment: 3 to 5 years

Accelerated Phase (AP) CML

• 10 to 19% blasts in peripheral blood and/or nucleated bone marrow cells

• Anemia, bone pain

• B symptoms (fever, night sweats, and weight loss) may occur.

• Duration without treatment: few months

Blast Crisis (BC) CML

• ≥ 20% blasts in peripheral blood white blood cells or nucleated bone marrow cells

• Symptoms similar to acute leukemia

• Duration w/o treatment: days to weeks before death without treatment. cause of death is typically infection or hemorrhage

Leukostasis definition

• a life-threatening complication of hyperleukocytosis (extremely high white blood cell counts),

• WBC count > 100

Anti-leukemic therapy for leukostasis

Hydroxyurea

Hydroxyurea MOA and dose

• Inhibits RNA reductase which blocks DNA synthesis

  • prevents conversion of ribonucleotides to deoxyribonucleotides

  • just treats WBCs, kills WBCs indiscriminately and cause cell contents to leak out into blood

• 20-40 mg/kg/day in divided doses

• Continue until WBC count in is control and CML therapy is initiated

Does hydroxyurea affect course of disease?

Hydroxyurea is not Ph+ specific so will not affect course of disease

What should you give hydroxyurea with to prevent TLS?

Hydroxyurea will cause massive cell breakdown. Give with allopurinol to prevent TLS

Other uses of hydroxyurea

used for other myeloproliferative neoplasms such as polycythemia vera and essential thrombocytosis