What are the diagnostic criteria and management options for Chronic Myeloid Leukemia (CML), including relevant lab values and treatment indications?

Chronic Myeloid Leukemia: Diagnostic Criteria and Management

Diagnostic Criteria

CML diagnosis requires detection of the Philadelphia chromosome t(9;22)(q34;q11) and/or BCR::ABL1 fusion gene in the appropriate clinical setting. 1

Essential Laboratory Findings

• Complete blood count typically shows WBC >100 × 10⁹/L with left shift of granulopoiesis including metamyelocytes, myelocytes, and promyelocytes, with basophilia and eosinophilia commonly present 1, 2
• Peripheral blood differential reveals excessive granulocytosis with immature forms (myelocytes, metamyelocytes), few or occasional myeloblasts, and frequent thrombocytosis 1, 2
• Severe anemia is rare at presentation 1

Confirmatory Testing Algorithm

Bone marrow aspirate and biopsy with cytogenetics is the gold standard for diagnosis, analyzing minimum 20-25 metaphases to detect t(9;22)(q34;q11) and identify additional chromosomal abnormalities (ACAs) 1

Alternative diagnostic approaches when bone marrow is not feasible:

• FISH on peripheral blood using dual-color dual-fusion BCR-ABL1 probes can substitute for cytogenetics, though it has 1-5% false-positive rate depending on probe used 1
• Qualitative RT-PCR identifies BCR::ABL1 transcript type (e13a2/e14a2 encoding p210, or rarely e19a2 encoding p230, or e1a2 encoding p190) 1, 2
• Quantitative RT-PCR (qPCR) establishes baseline BCR::ABL1 transcript levels on International Scale (IS) for subsequent monitoring 1, 2

Important caveat: 85-90% of cases show standard Philadelphia chromosome on cytogenetics, 5-10% have variant translocations, and 1-5% have cryptic BCR::ABL1 fusion not visible cytogenetically 1

Disease Phase Classification

Chronic phase (90-95% of presentations): <15% blasts in blood and bone marrow, no extramedullary disease, basophils <20%, platelets 100-1000 × 10⁹/L 1, 2, 3

Accelerated phase: 15-29% blasts in peripheral blood or bone marrow per European LeukemiaNet criteria 2

Blast phase: ≥30% blasts in blood/bone marrow or extramedullary blast involvement per ELN (≥20% per WHO) 1, 2, 3

Risk Stratification

Calculate prognostic risk using EUTOS Long-Term Survival Score (ELTS), which is simpler and has greater prognostic value in TKI-treated patients than older Sokal or EURO scores 1

High-risk additional cytogenetic abnormalities (ACAs) at diagnosis include: +Ph, +8, i(17q), +19, +21, +17, -7/7q-, 3q26.2, 11q23 rearrangements, and complex karyotypes, which predict longer time to complete cytogenetic remission and shorter progression-free survival 1

Management

First-Line Treatment

Four TKIs are FDA-approved for first-line chronic phase CML: imatinib, dasatinib, bosutinib, and nilotinib, with asciminib also approved 3, 4, 5

All four TKIs are equivalent if the aim is survival improvement, as 10-year survival now approaches that of age-matched general population (1-2% annual CML-related mortality versus historical 10-20%) 3, 4, 5

Second-generation TKIs (dasatinib, nilotinib, bosutinib) achieve deeper and faster molecular responses but without survival advantage over imatinib, likely due to effective salvage options 4, 5, 6

TKI Selection Strategy

For younger patients with high-risk disease aiming for treatment-free remission, favor second-generation TKIs due to higher rates of deep molecular response 4

For older patients or those with significant comorbidities, consider agent-specific toxicity profiles:

• Dasatinib: pleural effusion risk 7, 3
• Nilotinib: arterio-occlusive events (myocardial infarction, stroke, peripheral artery disease) 3
• Bosutinib: gastrointestinal disturbance 3
• Ponatinib: arterio-occlusive events, pancreatitis (increased amylase/lipase) 3
• Asciminib: pancreatitis, increased amylase/lipase 3

Monitoring During Treatment

Quantitative RT-PCR on peripheral blood every 3 months to assess BCR::ABL1 transcript levels on International Scale 1

Bone marrow cytogenetics required at follow-up (peripheral blood insufficient) to detect cytogenetic relapse or emergence of ACAs 1

Management of Treatment Failure

Second-line options after first-line TKI failure include alternative second- or third-generation TKIs 4, 5, 6

For T315I "gatekeeper" mutation (resistant to all TKIs except three): use ponatinib, asciminib, or olverembatinib 4, 5

Allogeneic stem cell transplantation indicated for:

• Resistance to ≥2 TKIs in chronic phase 4, 5, 6
• All patients with accelerated phase or blast phase CML 4, 5, 6
• Cure rates range 20-60% depending on disease phase at transplant 3

For older patients failing all TKIs who maintain chronic phase: continue most effective/least toxic TKI daily, with or without addition of hydroxyurea, omacetaxine, azacitidine, decitabine, or cytarabine to maintain long-term survival 4, 5, 6

Hematologic Toxicity Management

Myelosuppression is universal with all TKIs, with higher frequency in advanced phase disease 7, 8

For imatinib-induced neutropenia (ANC <1.0 × 10⁹/L): temporarily discontinue until ANC ≥1.5 × 10⁹/L, then resume at starting dose 8

Grade 3/4 cytopenias managed with dose reduction or interruption, with median duration of neutropenic episodes 2-3 weeks and thrombocytopenic episodes 2-4 weeks 8

Critical Pitfall

Medication adherence is essential to maintain treatment responsiveness - non-adherence is a major cause of suboptimal response and should be assessed at every visit 3