Chronic Myeloid Leukemia (CML) : Causes, Pathogenesis, Lab findings, Symptoms & Treatment

Chronic Myeloid Leukemia CML : Overview, Pathogenesis, Lab findings, Symptoms & Treatment


  • Chronic Myeloid Leukemia CML is a type of Cancer (Blood cancer) in which Bone marrow excessively (Uncontrolled & unregulated) produce WBC.
  • It is a type of myeloproliferative disorder.
  • Chronic myeloid (myelogenous, myelocytic, granulocytic) leukaemia comprises about 20% of all leukaemias and its peak incidence is seen in 3rd and 4th decades of life.
  • Both sexes are affected equally.


Pathogenesis of Chronic Myeloid Leukemia CML is as following :

  • CML is always associated with the presence of a BCR-ABL fusion gene.
    In about 95% of cases, the BCR-ABL gene is the product of a balanced (9;22) translocation that involves fusion of BCR (breakpoint cluster region) gene on chromosome 22 ( 22q11 ) with ABL (named after Abelson murine leukaemia virus) gene located on chromosome 9 ( 9q34 ). The fusion product so formed is termed “Ph chromosome t(9;22) (q34;11), BCR/ABL” which is characeristic for CML.
    In the remaining 5% of cases, a BCR-ABL fusion gene is created by cytogenetically cryptic or complex rearrangements involving more than two chromosomes.
  • The BCR-ABL fusion gene is present in granulocytic, erythroid, megakaryocytic, and B cell precursors, and in some cases T cell precursors as well, indicating that the tumor arises from a transformed hematopoietic stem cell.
  • The BCR-ABL gene encodes a fusion protein consisting of portions of BCR and the tyrosine kinase domain of ABL.
  • Normal myeloid progenitors depend on signals generated by growth factors and their receptors for growth and survival.
    The growth factor dependence of CML progenitors is greatly decreased by constitutive signals generated by BCR-ABL that mimic the effects of growth factor receptor activation.
  • Importantly, because BCR-ABL does not inhibit differentiation, the early disease course is marked by excessive hematopoiesis.
  • Although the BCR-ABL fusion gene is present in multiple lineages, for unclear reasons the pro-growth effects of BCR-ABL are confined mainly to the granulocyte and megakaryocyte lineages.

Lab findings & Morphology

The diagnosis of Chronic Myeloid Leukemia CML is generally possible on blood picture alone. However, bone marrow, cytochemical stains and other investigations are of help.

  • BLOOD PICTURE : The peripheral blood findings are highly characteristic. The typical blood picture in a case of CML at the time of presentation shows the following Features:
    – Anaemia : Anaemia is usually of moderate degree and is normocytic normochromic in type. Occasional normoblasts may be present.
    – White blood cells : Characteristically, there is marked leucocytosis (approximately 200,000/μl or more at the time of presentation). The circulating cells are predominantly neutrophils, metamyelocytes, and myelocytes, but basophils and eosinophils are also prominent and platelets are usually increased.
    – Platelets : Platelets are usually increased.
  • BONE MARROW EXAMINATION : Examination of marrow aspiration yields the following results:
    – Cellularity : The bone marrow is hypercellular owing to increased numbers of granulocytic and megakaryocytic precursors.
    – Myeloid cells : The myeloid cells predominate in the bone marrow with increased myeloid-erythroid ratio.
    – Erythropoiesis : Erythropoiesis is normoblastic but there is reduction in erythropoietic cells.
    – Megakaryocytes : Megakaryocytes are conspicuous but are usually smaller in size than normal.
    – Cytogenetics : Cytogenetic studies on blood and bone marrow cells show the characteristic chromosomal abnormality called Philadelphia (Ph) chromosome seen in 90-95% cases of CML. Ph chromosome is formed by reciprocal balanced translocation between part of long arm of chromosome 22 and part of long arm of chromosome 9{(t(9;22) (q34;11)} forming product of fusion gene, BCR/ ABL.
  • CYTOCHEMISTRY : The only significant finding on cytochemical stains is reduced scores of neutrophil alkaline phosphatase (NAP) which helps to distinguish CML from myeloid leukaemoid reaction in which case NAP scores are elevated. However, NAP scores in CML return to normal with successful therapy, corticosteroid administration and in infections.
  • OTHER INVESTIGATIONS : A few other accompanying findings are seen in CML:
    – Elevated serum B12 and vitamin B12 binding capacity.
    – Elevated serum uric acid (hyperuricaemia).

Clinical symptoms

The onset of CML often is insidious, as the initial symptoms usually are nonspecific (e.g., easy fatigability, weakness, weight loss). Some of the common presenting manifestations are as under:

  • Features of anaemia such as weakness, pallor, dyspnoea and tachycardia.
  • Symptoms due to hypermetabolism such as weight loss, lassitude, anorexia, night sweats.
  • Splenomegaly is almost always present and is frequently massive. In some patients, it may be associated with acute pain due to splenic infarction.
  • Bleeding tendencies such as easy bruising, epistaxis, menorrhagia and haematomas may occur.
  • Less common features include gout, visual disturbance, neurologic manifestations and priapism.
  • Juvenile CML (A distinctive variant of CML seen in children) is more often associated with lymph node enlargement than splenomegaly.
  • Other features are frequent infections, haemorrhagic manifestations and facial rash.

Sometimes the first symptom is a dragging sensation in the abdomen caused by splenomegaly. On occasion it may be necessary to distinguish CML from a “leukemoid reaction,” a dramatic elevation of the granulocyte count in response to infection, stress, chronic inflammation, and certain neoplasms. This distinction can be achieved definitively by testing for the presence of the BCR-ABL fusion gene, which can be done by karyotyping, fluorescence in situ hybridization, or PCR assay.


The approach of modern therapy in CML is targetted at removal of all malignant clones of cells bearing BCR/ABL fusion protein, so that patient reverts back to prolonged non-clonal haematopoiesis i.e. molecular remission from disease. This is achievable by the following approaches:

  • Imatinib oral therapy
  • Allogenic bone marrow (stem cell) transplantation
  • Interferon-α.
  • Chemotherapy
  • Splenic irradiation
  • Splenectomy
  • Leucopheresis

Drug of choice as well as treatment of choice for Chronic Myeloid Leukemia CML is a tyrosine kinase inhibitor Imatinib mesylate.

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