What is the diagnostic approach and treatment for Chronic Myeloid Leukemia (CML)?

Diagnosis of Chronic Myeloid Leukemia

The diagnosis of CML is straightforward and requires demonstration of the Philadelphia chromosome or BCR-ABL1 fusion gene in a patient with characteristic peripheral blood findings showing excessive granulocytosis with left shift of granulopoiesis. 1, 2

Initial Clinical Presentation

The typical presentation includes:

• Excessive granulocytosis with left shift showing immature granulocytes (myelocytes, metamyelocytes, myeloblasts) in peripheral blood 1
• White blood cell count often exceeds 100 × 10⁹/L at presentation 2
• Basophilia and eosinophilia are commonly present 1, 2
• Thrombocytosis frequently occurs 1
• Splenomegaly is present in >50% of cases, though 50% of patients remain asymptomatic 1

Confirmatory Diagnostic Testing

Cytogenetic Analysis

Bone marrow cytogenetics must be performed to detect the t(9;22)(q34;q11) translocation (Philadelphia chromosome, 22q-) and identify any additional chromosomal abnormalities 1, 2. This balanced translocation results in juxtaposition of the ABL1 gene from chromosome 9 with the BCR gene on chromosome 22, creating the BCR-ABL1 fusion gene 1.

Molecular Testing

• Qualitative RT-PCR on peripheral blood or bone marrow identifies the BCR-ABL1 transcript type, typically e13a2 or e14a2 2
• Quantitative RT-PCR establishes baseline BCR-ABL1 transcript levels on the International Scale (IS) for future monitoring 2, 3

Special Circumstances

In 5% of cases where the Philadelphia chromosome cannot be detected by standard cytogenetics, confirmation depends on FISH or RT-PCR to identify the BCR-ABL1 fusion. 1 These patients should be treated identically to Philadelphia-positive patients, as therapeutic response is comparable 1.

Complete Baseline Diagnostic Workup

The ESMO and NCCN guidelines mandate the following comprehensive evaluation 2:

History and Physical Examination

• Palpation for splenomegaly and hepatomegaly 2
• Assessment of constitutional symptoms 2

Laboratory Studies

• Complete blood count with differential 2
• Comprehensive chemistry profile 2
• Hepatitis B panel (required before TKI therapy) 2

Bone Marrow Studies

• Aspirate for morphology and cytology 2
• Biopsy for histology and assessment of fibrosis 2
• Cytogenetics to detect additional chromosomal abnormalities beyond the Philadelphia chromosome 2

Molecular Studies

• Qualitative RT-PCR to identify transcript type 2
• Quantitative RT-PCR to establish baseline BCR-ABL1 levels on the International Scale 2

Disease Phase Classification

The European LeukemiaNet (ELN) criteria should be used for phase classification, as these definitions have been employed in almost all clinical trials assessing TKI efficacy. 1

Chronic Phase (90-95% of patients at diagnosis)

• <15% blasts in peripheral blood and bone marrow 1, 2

Accelerated Phase

• 15-29% blasts in peripheral blood or bone marrow 1, 2
• >20% basophils in blood 1
• Thrombocytosis >1000 × 10⁹/L uncontrolled by therapy OR thrombocytopenia <100 × 10⁹/L unrelated to therapy 1
• Any new clonal chromosomal aberration during therapy 1

Blast Phase

• ≥30% blasts in peripheral blood or bone marrow 1, 2
• Extramedullary blast involvement (excluding liver and spleen) 1
• Myeloid blast crisis accounts for 70-80% of cases, while lymphoid blast crisis represents 20-30% 4

Critical Diagnostic Pitfalls

Patients with clinical features of CML but no detectable Philadelphia chromosome or BCR-ABL1 rearrangement represent atypical CML (Philadelphia-negative, BCR-ABL1-negative) according to WHO classification and constitute a separate disease entity requiring different management 1.

BCR-ABL1 positive cells are genetically unstable and prone to develop additional genomic abnormalities, leading to transformation from chronic to accelerated or blast phase through either BCR-ABL1-dependent mechanisms (kinase domain mutations) or BCR-ABL1-independent factors (additional cytogenetic aberrations causing clonal evolution) 1.