What is the diagnosis and treatment of Chronic Myeloid Leukemia (CML)?

Diagnosis of Chronic Myeloid Leukemia

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

Clinical Presentation

• Most patients (>50%) present with splenomegaly on physical examination, though approximately 50% are asymptomatic at diagnosis 1
• The median age at diagnosis is 60-65 years in Europe, with an incidence of 10-15 cases per million per year 1
• Constitutional symptoms may include fatigue, weight loss, and early satiety (from splenomegaly), though many cases are discovered incidentally on routine blood work 1

Essential Laboratory Findings

• Complete blood count typically reveals marked leukocytosis, often exceeding 100 × 10⁹/L, with a characteristic left shift showing immature granulocytes including myelocytes, metamyelocytes, and myeloblasts 1, 2
• Basophilia and eosinophilia are commonly present in the peripheral blood differential 1, 2
• Thrombocytosis is frequently observed at presentation 1

Confirmatory Molecular and Cytogenetic Testing

The diagnostic workup must include three complementary testing modalities to confirm CML and establish baseline disease burden:

1. Conventional Cytogenetics (Bone Marrow)

• Detects the Philadelphia chromosome t(9;22)(q34;q11) in 85-90% of cases at diagnosis 1
• A minimum of 20-25 metaphases should be analyzed to ensure detection of additional chromosomal abnormalities (ACAs) 1
• Approximately 7% of chronic phase cases present with ACAs, which may confer inferior prognosis 1
• Bone marrow aspirate is preferred over peripheral blood for cytogenetic analysis 1

2. Fluorescence In Situ Hybridization (FISH)

• FISH is mandatory when conventional cytogenetics shows insufficient metaphases or normal karyotype, as 1-5% of cases have cryptic BCR-ABL1 fusions not visible on standard karyotyping 1
• FISH detects BCR and ABL1 gene juxtaposition in interphase cells, making it useful when metaphases are unavailable 1

3. Molecular Testing (RT-PCR)

• Qualitative RT-PCR identifies the specific BCR-ABL1 transcript type (typically e13a2 or e14a2, formerly known as b2a2 or b3a2) 1, 2
• Quantitative RT-PCR (RQ-PCR) establishes baseline BCR-ABL1 transcript levels on the International Scale (IS), which is essential for subsequent monitoring 2, 3
• RT-PCR can be performed on peripheral blood or bone marrow and is highly sensitive 1

Complete Baseline Diagnostic Workup

The following comprehensive evaluation should be completed before initiating therapy:

• History and physical examination focusing on splenomegaly, hepatomegaly, and constitutional symptoms 2
• Complete blood count with differential 2
• Comprehensive metabolic panel including liver and renal function 2
• Hepatitis B panel (required before starting tyrosine kinase inhibitor therapy) 2
• Bone marrow aspirate and biopsy for:
  • Morphology and cytology to assess blast percentage 2
  • Histology and assessment of fibrosis 2
  • Cytogenetics (20-25 metaphases) to detect ACAs 1, 2
• Qualitative RT-PCR to identify BCR-ABL1 transcript type 2
• Quantitative RT-PCR to establish baseline BCR-ABL1 levels on International Scale 2

Disease Phase Classification at Diagnosis

Over 90% of patients are diagnosed in chronic phase (CP), which is defined by specific criteria 1, 2:

Chronic Phase Criteria

• <15% blasts in peripheral blood and bone marrow 2
• <30% blasts plus promyelocytes combined 1
• <20% basophils in peripheral blood 1
• Platelet count >100 × 10⁹/L (unless related to therapy) 1

Accelerated Phase Criteria

• 15-29% blasts in peripheral blood or bone marrow 1, 2
• >20% basophils in peripheral blood 1
• Persistent thrombocytopenia (<100 × 10⁹/L) or thrombocytosis unrelated to therapy 1
• Clonal cytogenetic evolution (new chromosomal abnormalities in addition to Philadelphia chromosome) 1

Blast Phase/Blast Crisis Criteria

• ≥30% blasts in peripheral blood or bone marrow (ELN criteria) or ≥20% blasts (WHO criteria) 1, 2
• Extramedullary blast infiltration 1, 2
• 70-80% of blast phase cases are myeloid phenotype, resembling acute myeloid leukemia 4

Critical Diagnostic Pitfalls

Philadelphia-negative, BCR-ABL1-negative cases should NOT be diagnosed as CML but rather as atypical CML or other myeloproliferative neoplasms according to WHO classification 1

In 5-10% of cases, variant translocations involve chromosomes 9q34 and 22q11 plus additional chromosomes, but these patients should be treated identically to standard Philadelphia-positive cases 1

Cases with cryptic BCR-ABL1 fusions (1-5%) cannot be diagnosed by conventional cytogenetics alone, necessitating FISH or RT-PCR confirmation 1

All diagnostic testing should be performed in ISO15189-accredited laboratories participating in external quality assurance schemes to ensure standardization and reproducibility 1