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Diagnosing Chronic Myeloid Leukemia

Medical editor Tobias Gedde-Dahl d.y. MD
Oslo University Hospital


Chronic myeloid leukemia (CML) is a clonal myeloproliferative stem cell disease which is distinguished by an increased number of mature and immature granulocytes in peripheral blood, bone marrow, with increased granulocytopoiesis and splenomegaly.

The disease is defined by the presence of the BCR-ABL fusion gene. This anomaly is probably necessary and sufficient for the development of chronic myeloid leukemia.


  • Suspicion of chronic myeloid leukemia


  • Confirm the diagnosis
  • Identify risk group for disease progression
  • Choose the correct treatment and follow-up care


By definition, the BCR-ABL fusion gene is always present in chronic myeloid leukemia.

In over 95% of cases, the BCR-ABL chimera gene is present on chromosome 22, t(9;22)(q34,q11)  . The resulting chromosome 9 achieves an elongation of the long arm, which is not apparent when looking at the chromosomes during cell division under a microscope (karyotyping, cytogenetic examination). In contrast, the resulting chromosome 22 becomes conspicuously shortened in its long arm. This may be seen during cytogenetic examination.

The short chromosome 22 received the name Philadelphia chromosome (Ph) after the location of its discovery.

In chronic myeloid leukemia without visible Ph, the BCR-ABL gene is often created by translocations involving more chromosomes than chromosome 9 and 22. In these cases, the karyotype changed in a way that a typical Ph is not recognized. Polymerase chain reaction analyses (PCR) will catch the presence of BCR-ABL regardless of where the gene is located in the genome. This is the most sensitive method for finding the fusion gene.

In rare cases, clinical and laboratory findings may be consistent with chronic myeloid leukemia without finding Ph or BCR-ABL. These cases are classified as atypical chronic myeloid leukemia and represent another disease entity.

The Philadelphia chromosome is not only found in chronic myeloid leukemia. It is also present in about 20% of adults and 2–5% of children with acute lymphatic leukemia.

The ABL gene always splits between exon 1 and exon 2 from the rest of chromosome 9, while the BCR gene can break in multiple places from chromosome 22. The consequence is that in different patients, there can be different lengths of the fusion gene and thereby the fusion protein. The normal fusion protein of chronic myeloid leukemia is 210 kD (p210). Chronic myeloid leukemia can sometimes have a benign course and is then often associated with a longer form, p230. Ph+ acute lympatic leukemia, which is an aggressive disease, is often found in a shorter form, p190.

The ABL protein is a tyrosine kinase enzyme, which when transcribed from chromosome 9, is under "strict control" by the N-terminus which has a self-inhibiting effect on the tyrosine kinase activity. When the gene moves to chromosome 22, the N-terminus of the protein is derived from the BCR gene. This does not have a self-inhibiting effect on the tyrosine kinase activity. Consequently, there is uninhibited tyrosine kinase activity. Phosphorylation of tyrosine is an important mechanism for intracellular signaling and we know that the tyrokinase BCR-ABL affects many signal pathways which are important for cell division, cell differentiation, ahesion, apoptosis, and transcription regulation. 

It is striking that the p190 BCR-ABL gene, often found in acute lymphatic leukemia, has a higher tyrosine activity than p210 BCR-ABL, which is most common in chronic myloid leukemia. The gene p230 BCR-ABL has the lowest tyrosine activity and is associated with a less aggressive clinical course. It appears the degree of tyrosine kinase activity is of importance for the aggressiveness of the disease.


Many CML patients are diagnosed before they develop symptoms during health checks or routine blood tests. Leukocytosis and an enlarged spleen cause suspicion of the disease.

Patient history and clinical examinations

Survey general leukemia symptoms and hyperviscosity symptoms which can occur in chronic myeloid leukemia.

Blood tests

  • Hb
  • Leukocytes with differentiation
  • Thrombocytes
  • S-LD
  • Uric acid
  • Liver tests
  • Renal function tests
  • BCR-ABL mutation analysis

Blood smear

  • Morphological assessment

Bone marrow aspirate/biopsy

  • Morphological assessment
  • Cytogenetic examination 


Typical findings are leukocytosis and the clinical examination often uncovers splenomegaly.

Usually, the neutrophile granulocytes and myelocytes in peripheral blood are > 50 x 109/l (blood resembles bone marrow) . The thrombocyte value may be elevated, normal, or low and anemia is present. 

Basophilia is very common. The bone marrow is abundant with cells and is dominated by granulocytopoeisis which completely matures in the chronic phase.

The diagnosis is confirmed by the presence of the Philadelphia chromosome in the cytogenetic analysis of bone marrow/peripheral blood and detection of BCR-ABL from PCR analysis in peripheral blood.


As soon as the diagnosis is confirmed, treatment is started.

Prognostic factors

Risk assessments tied to the expected disease outcome, treatment, and probability for reaching the treatment goal with the treatment alternatives, is central to handling of the patient.

The disease phase, age, thrombocyte count, spleen size, and number of blasts in peripheral blood are risk factors forming the basis for separating patients into the following prognosis groups:

  • high risk of progression
  • intermediary risk for progression
  • low risk for progression

Individual treatment plans should be made. Good objective information and patient involvement in decisions where uncertainty is the greatest is very important.

Cytogenetic changes such as deletions on the derivative chromosome 9 and other cytogenetic changes in the Ph+ clone are negative prognostic indicators. This data is important for what strategy is chosen at the time of diagnosis and for sub-optimal response to treatment.

Monitoring the disease

Chronic myeloid leukemia and its treatment effect can be monitored on three levels:

Hematological response

  • Leukocytes < 10 x 109/l
  • Thrombocytes < 450 x 109/l
  • < 5 % myelocytes in blood
  • No blasts or promyelocytes in blood
  • < 20 % basophile granulocytes in blood
  • No extramedullary manifestations

Cytogenetic response

  • Complete cytogenetic response (CCyR) – 0 % Ph+
  • Partial cytogentic reponse (PCYR) – 1-35 % Ph+
  • Major cytogenetic response (MCyR) – PCyR + CCyR (0-35 % Ph+)
  • Minor cytogenetic response – 36-65 % Ph+
  • Minimal cytogenetic response – 66-95 % Ph+

Cytogenetic response and the amount of bone marrow cells which are Ph+ are examined by freezing mitogen-stimulated cells in metaphase. At least 20 metaphases (cell divisions) should be examined.

Molecular response

  • Complete – BCR-ABL transcript not detectable  
  • Major – BCR-ABL transcript ≤ 0,1%

PCR techniques measure BCR-ABL in the blood as a percent of the total ABL transcript. One hundred percent is the average of BCR-ABL transcript divided by the total ABL transcript x 100 in a reference population on 30 newly diagnosed CML patients. A result of 0.1% equals a 1000 fold reduction (3 log) of the transcript amount in relation to the reference population's average value and is expressed as "major molecular response." The concept "complete molecular response" in practice means the level is below the method's level of detection, which is usually reached by a 4-5 fold reduction of the BCR-ABL transcript.  

The degree of cytogenetic and molecular response at a given point in time has shown to be a very good surrogate marker for progression-free survival.

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