Approach

Many patients are asymptomatic, and diagnosis often follows incidental detection on full blood count (FBC) when ordered for other reasons.[31] Most patients present in the chronic phase.

If present, symptoms typically include malaise, fever, weight loss, abdominal discomfort, and night sweats. Peripheral smear, bone marrow biopsy, and cytogenetic and/or molecular studies confirm the diagnosis.

History

About 50% of patients are asymptomatic.[31] In such cases, diagnosis follows incidental detection of an elevated white blood cell (WBC) count.[1][31][32] In the US, incidence peaks between 65 and 74 years of age with a slight male predominance.[13]

Patients may report systemic symptoms such as fever, chills, malaise, weight loss, and night sweats. They may report localised symptoms such as left upper quadrant discomfort or fullness. Excessive bruising, either spontaneous or from minor trauma, is common.[11] Uncommon symptoms include shortness of breath on exertion, epistaxis, arthralgia, and sternal tenderness.

Physical examination

The most common physical examination finding is splenomegaly (20% to 40%).[31][32] The spleen may be just palpable at the left costal margin or, with extreme enlargement, may fill the left side of the abdomen and extend to the right iliac fossa. Hepatomegaly may be present with a soft, ill-defined lower edge, but it is less common.[11][31] Pallor of the mucous membranes due to anaemia may be noted but is uncommon. Retinal haemorrhages may rarely be present.[31]

Investigations

FBC is the first test to order.[5]

The vast majority of patients with chronic myeloid leukaemia (CML) have an elevated WBC count, and half have a WBC count >100 x 10⁹/L (100 x 10³/microlitre or 100,000/microlitre).[32] Anaemia and thrombocytosis may be present.[32][33]

A peripheral smear shows that most WBCs are neutrophils, with a left shift (a spectrum of circulating immature myeloid forms); basophil and eosinophil counts are also commonly elevated.

A complete metabolic profile is also recommended.[5] Potassium, lactate dehydrogenase, and uric acid may be elevated due to extensive cell turnover. Pseudohyperkalaemia, from thrombocytosis and/or leukocytosis, may be observed.[34]

Bone marrow evaluation and molecular analysis

CML is confirmed by the presence of the Philadelphia (Ph) chromosome, t(9;22)(q34;q11). Several methods are employed.

  • Bone marrow aspiration and biopsy for cytogenetic analysis: performed in all patients to establish the presence of the Ph chromosome, and to confirm the phase of CML.[5][35]​ In addition to the Ph chromosome, bone marrow cytogenetic analysis can detect additional chromosomal abnormalities (ACAs) in Ph-positive and Ph-negative cells, which may have negative prognostic impact. Analysis of 20-25 metaphase cells is recommended.[5][35]

  • Molecular analysis using quantitative reverse transcription polymerase chain reaction (qRT-PCR) on peripheral blood: should be carried out at initial work-up to establish the presence of quantifiable BCR::ABL1 mRNA transcripts. Laboratories should report qRT-PCR results according to an international scale (IS).[36] qRT-PCR is highly sensitive and it is the only quantitative method of assessing molecular response to therapy; regular qRT-PCR monitoring is recommended following diagnosis.[5][35]

  • Fluorescence in situ hybridisation (FISH): performed on bone marrow aspirate or peripheral blood to identify BCR::ABL1 rearrangements. Used if bone marrow cytogenetic evaluation is not possible or if results of cytogenetics and qRT-PCR differ. It is sometimes used as an initial screening test or, if qRT-PCR is not available, for disease monitoring. FISH cannot detect ACAs.[5][35]

Mutational analysis

Performed to identify mutations associated with tyrosine kinase inhibitor (TKI) resistance. BCR::ABL1 kinase domain mutation analysis (using next-generation sequencing) should be carried out for patients with chronic-phase disease who have an inadequate response to TKI therapy, and for patients diagnosed with or who progress to advanced disease.[5][35]

Next-generation sequencing with a myeloid mutation panel may be considered in patients with no identified BCR::ABL1 kinase domain mutations to detect low-level BCR::ABL1 kinase domain mutations or BCR::ABL1-independent resistance mutations.[5][35]

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