What are the diagnostic criteria and treatment options for Chronic Myeloid Leukemia (CML)?

Diagnosis of Chronic Myeloid Leukemia (CML)

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

Essential Diagnostic Criteria

Initial Blood Work

• Complete blood count with differential showing excessive granulocytosis with typical left shift of granulopoiesis (immature granulocytes including myelocytes and metamyelocytes) 1
• White blood cell count often exceeds 100 × 10⁹/L at presentation 1
• Basophilia is common, and eosinophils may be prominent 1

Confirmatory Testing - The Gold Standard

Confirmation of diagnosis is obtained by identifying the Philadelphia chromosome (22q-) or BCR-ABL1 transcripts in peripheral blood or bone marrow cells. 1

The diagnostic workup must include:

• Bone marrow cytogenetics to detect the t(9;22)(q34;q11) translocation and identify any additional chromosomal abnormalities 1
• Qualitative RT-PCR on blood or bone marrow to identify the BCR-ABL1 transcript type (typically e13a2 or e14a2, also known as b3a2 and b2a2) 1
• Quantitative RT-PCR (qPCR) to establish baseline BCR-ABL1 transcript levels on the International Scale (IS) 1

Alternative Testing When Standard Methods Fail

In 5% of cases where the Philadelphia chromosome cannot be detected by conventional cytogenetics:

• Fluorescence in situ hybridization (FISH) with dual probes for BCR and ABL1 genes confirms the BCR-ABL1 fusion 1
• Reverse transcriptase PCR (RT-PCR) detects BCR-ABL1 transcripts 1
• These Philadelphia-positive but cytogenetically cryptic patients should be treated identically to standard Ph+ patients, as therapeutic response is comparable 1

Critical Distinction: Philadelphia-Negative Disease

Patients with clinical features of CML but no Philadelphia chromosome or BCR-ABL1 rearrangement represent atypical CML, a separate disease entity requiring different management. 1 Do not treat these patients with tyrosine kinase inhibitors designed for BCR-ABL1+ CML.

Bone Marrow Evaluation

When Bone Marrow Biopsy is Essential

Bone marrow aspirate and biopsy are recommended at diagnosis for morphologic and cytogenetic evaluation. 1

Bone marrow biopsy is particularly critical (essential in 25% of patients) when: 2

• Blast counts from aspirate smears are misleading or inadequate
• There is suspicion of accelerated phase (AP) or blast phase (BP) disease
• Assessment of myelofibrosis is needed (high-grade myelofibrosis is more frequent in AP/BP disease, p=0.0005) 2
• Identification of disease phase requires histologic confirmation (needed in 75% of BP cases, p=0.001) 2

Bone Marrow Findings at Diagnosis

• Increased cellularity due to proliferation of myelopoiesis in all stages with predominance of mature forms 1
• Blast percentage <15% in blood and bone marrow defines chronic phase by ELN criteria 1
• Moderate to marked reticulin fibrosis in 30% of cases 1
• Smaller than normal megakaryocytes with hypolobulated nuclei 1

Disease Phase Classification

Chronic Phase (CP) - 90-95% at Diagnosis

Most patients (90-95%) present in chronic phase, which is defined by <15% blasts in blood and bone marrow according to ELN criteria. 1

Accelerated Phase (AP)

ELN criteria (used in clinical trials): 1

• 15-29% blasts in peripheral blood or bone marrow

Blast Phase (BP)

ELN criteria: 1

• ≥30% blasts in peripheral blood or bone marrow
• Extramedullary blast involvement (excluding liver and spleen)

The ELN definition should be used as the basis for treatment decisions, as it has been employed in almost all clinical trials assessing tyrosine kinase inhibitor efficacy. 1

Complete Baseline Diagnostic Workup

According to ESMO and NCCN guidelines, the initial evaluation must include: 1

1. History and physical examination with specific attention to:

   • Palpation of spleen (splenomegaly present in 40-50% of cases) 1
   • Hepatomegaly (less common than splenomegaly) 1
   • Constitutional symptoms (fatigue, weight loss, malaise) 1

2. Laboratory studies:

   • Complete blood count with differential 1
   • Chemistry profile 1
   • Hepatitis B panel 1

3. Bone marrow studies:

   • Aspirate for morphology and cytology 1
   • Biopsy for histology and assessment of fibrosis 1
   • Cytogenetics (karyotype) to detect additional chromosomal abnormalities 1

4. Molecular studies:

   • Qualitative RT-PCR to identify transcript type 1
   • Quantitative RT-PCR to establish baseline BCR-ABL1 levels 1

Common Pitfalls to Avoid

• Do not rely solely on peripheral blood FISH - interphase FISH can have a false-positive rate of 1-5% depending on the probe used 1
• Do not skip bone marrow evaluation if there is any suspicion of advanced phase disease or if adequate aspirate cannot be obtained 2
• Do not perform baseline BCR-ABL1 mutation analysis in newly diagnosed chronic phase CML, as this has not been proven to provide information on optimal treatment selection 1
• Do not confuse atypical CML (Ph-negative, BCR-ABL1-negative) with Philadelphia-positive CML, as they are distinct disease entities requiring different treatment approaches 1