How to manage a suspected case of Chronic Myeloid Leukemia (CML)?

Management of Suspected Chronic Myeloid Leukemia (CML)

For a suspected case of CML, immediately obtain a complete blood count with differential, bone marrow aspirate and biopsy with cytogenetics, and quantitative RT-PCR for BCR::ABL1 to confirm diagnosis before initiating tyrosine kinase inhibitor therapy. 1

Initial Clinical Evaluation

History and Physical Examination

• Assess for constitutional symptoms including fever, night sweats, weight loss, and bone pain 1
• Palpate the spleen for splenomegaly, which is present in the majority of CML cases 1, 2
• Evaluate for hepatomegaly and any cutaneous lesions 1, 2
• Obtain hepatitis B panel before initiating therapy, as reactivation can occur with treatment 1, 2

Laboratory Workup

• Complete blood count with differential typically shows WBC count often exceeding 100 × 10⁹/L with left shift including myelocytes and metamyelocytes, plus basophilia and eosinophilia 2
• Chemistry profile to assess baseline organ function 1, 2
• Peripheral blood smear examination to evaluate granulocytosis pattern and presence of immature cells 1, 2

Confirmatory Diagnostic Testing

Bone Marrow Studies (Essential)

Bone marrow aspirate and biopsy are mandatory for diagnosis and should include: 1

• Morphologic evaluation to assess cellularity, dysplasia, and blast percentage 1, 2
• Conventional cytogenetic analysis of at least 20-25 metaphases to detect t(9;22)(q34;q11) Philadelphia chromosome and identify additional chromosomal abnormalities (ACAs) 1
• Bone marrow biopsy sections stained with hematoxylin-eosin, CD34+ immunostaining, and Gomori's silver impregnation for fibrosis 1

Molecular Testing (Critical)

Quantitative RT-PCR must be performed on peripheral blood or bone marrow to: 1

• Establish baseline BCR::ABL1 transcript levels on the International Scale (IS) for future monitoring 1, 2
• Identify the specific transcript type (typically e13a2 or e14a2, encoding p210 protein) as this is crucial for accurate molecular monitoring 1
• Screen for atypical BCR::ABL1 variants (e1a2, e6a2, e8a2, e19a2, e13a3, e14a3) which occur in 1-2% of cases 1

Alternative Diagnostic Approaches

If bone marrow evaluation is not immediately feasible: 1

• FISH on peripheral blood with dual probes for BCR and ABL1 genes is acceptable for initial diagnosis, though it has a 1-5% false-positive rate depending on the probe used 1
• Double-fusion FISH has lower false-positive rates and can detect variant translocations 1
• However, bone marrow cytogenetics should still be obtained as soon as possible to detect ACAs, which have prognostic significance 1

Critical Exclusions

Rule Out Other Myeloid Neoplasms

The following must be excluded before confirming CML diagnosis: 1

• BCR::ABL1-negative cases should be classified as another myeloid neoplasm based on hematological and molecular features 1
• Chronic myelomonocytic leukemia (CMML) by excluding bcr/abl fusion gene and PDGFRA/PDGFRB rearrangements 1
• MDS/MPN with eosinophilia by testing for PDGFRA and PDGFRB rearrangements in cases with eosinophilia 1

Assess for Reactive Causes

• Exclude infectious diseases that can cause leukocytosis 1
• Rule out solid tumors that may cause reactive monocytosis or granulocytosis 1

Disease Phase Classification

Determine the phase of CML at diagnosis, as this impacts prognosis and treatment: 1, 2

• Chronic phase (90-95% of cases at diagnosis): <15% blasts in blood and bone marrow 2
• Accelerated phase: 15-29% blasts in peripheral blood or bone marrow 2
• Blast phase: ≥30% blasts in peripheral blood or bone marrow, or extramedullary blast involvement 2

Prognostic Assessment

High-Risk Features at Diagnosis

Identify high-risk additional chromosomal abnormalities (ACAs) in Ph-positive cells: 1

• Major-route ACAs: +Ph, +8, i(17q), +19 are associated with longer time to achieve complete cytogenetic remission and major molecular response 1
• Other high-risk ACAs: +21, +17, -7/7q-, 3q26.2, 11q23 rearrangements, and complex karyotypes 1
• These ACAs are associated with shorter progression-free and overall survival with imatinib therapy 1

Risk Stratification Scores

• Calculate EUTOS Long-Term Survival Score (ELTS) to identify high-risk patients who may benefit from more aggressive initial therapy 1

Pre-Treatment Preparation

Cardiovascular Assessment

Before initiating TKI therapy, evaluate cardiovascular risk factors: 1, 3

• Obtain baseline ECG to assess for QT prolongation, especially if considering nilotinib or ponatinib 3
• Assess for pre-existing cardiovascular disease including coronary artery disease, cerebrovascular disease, and peripheral arterial disease 1, 3
• Screen for cardiovascular risk factors including diabetes, hypertension, and hyperlipidemia 3

Pulmonary Assessment

• Evaluate for pre-existing lung disorders or uncontrolled hypertension if considering dasatinib, due to pleural effusion risk 1, 3
• Screen for pulmonary arterial hypertension (PAH) as dasatinib can cause or worsen this condition 1, 3

Additional Pre-Treatment Considerations

• Assess renal function as dose adjustments may be needed with renal insufficiency 3
• For women of childbearing potential, ensure effective contraception as TKIs are teratogenic 3
• Review concomitant medications for potential drug interactions, particularly with dasatinib and anticoagulants 1

Common Diagnostic Pitfalls

Atypical BCR::ABL1 Variants

Laboratories using limited RT-PCR screens (only p210 or p210 plus p190) may miss up to 2% of bona fide CML cases with atypical fusions. 1

• If a limited transcript screen is performed, the clinical report must clearly state that atypical BCR::ABL1 fusions would not have been detected 1
• Low levels of BCR::ABL1 mRNA at diagnosis may signal the presence of a co-existing BCR::ABL1-negative hematological neoplasm 1

Cryptic BCR::ABL1 Fusions

1-5% of CML cases have cryptic BCR::ABL1 fusion without cytogenetically-visible involvement of chromosomes 9 or 22. 1

• These cases arise by small double recombination events that insert ABL1 into BCR 1
• They cannot be diagnosed by conventional cytogenetics alone and require FISH or RT-PCR 1

Low-Level e1a2 Expression

Most e13a2/e14a2 CML cases express low levels of e1a2 transcripts (>1000x lower than p210), which should not be misinterpreted as p190 CML. 1

• P190 CML should only be diagnosed when e1a2 expression is at a level consistent with the burden of pre-treatment disease 1

Specimen Handling

Sample Storage

• Store bone marrow cells for possible further molecular analysis in centers with certified tissue banks 1
• This allows for future testing if atypical features emerge or if additional molecular characterization is needed 1

Laboratory Quality Standards

• All diagnostic tests should be conducted in appropriately accredited laboratories (e.g., ISO15189.2022) 1
• Testing laboratories should participate in external quality assurance (EQA) schemes 1