Chronic Myeloid Leukemia (CML)

Definition

There is no BCR-ABL-negative CML. "Atypical CML" and chronic neutrophilic leukemia are genetically distinct entities.

• Goldman-Cecil Medicine, p. 1938

Molecular Biology

• p210^BCR-ABL1^ (Major BCR, e13a2/e14a2): Most common in CML (~95%)
• p190^BCR-ABL1^ (Minor BCR, e1a2): Found in ~2/3 of Ph+ ALL, rare in CML
• p230^BCR-ABL1^ (Micro BCR, e19a2): Rare, associated with an indolent course

• Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 583

Epidemiology

• Accounts for ~15% of all leukemias
• Annual incidence: ~2 per 100,000; ~9,000 new cases/year in the US
• Median age at diagnosis: 55-65 years (slight male predominance, M:F ~1.6:1)
• Only 3% of patients are under 20 years
• CML prevalence is rising: before TKI therapy, median survival was 3-6 years; with modern TKIs, annual mortality is reduced to ~1-2%, and US prevalence is projected to plateau at ~450,000 by 2040
• No familial associations - not increased in twins or relatives of patients
• Ionizing radiation exposure (nuclear accidents, high-dose RT) does increase risk; peaks 5-10 years post-exposure
• Harrison's Principles of Internal Medicine 22E, p. 878

Disease Phases

1. Chronic Phase (CP)

• Asymptomatic accumulation of differentiated myeloid cells in marrow, spleen, and blood

• 75% of cases in the developed world are diagnosed here (often incidentally on routine CBC)

• Peripheral blood shows leukocytosis (often >100,000 cells/μL), with the full granulocytic spectrum: neutrophils, bands, metamyelocytes, myelocytes, eosinophils, basophilia (characteristic)
• Blasts typically <10% in blood
• Platelets often elevated, sometimes markedly
• Symptoms (if any): fatigue, weight loss, left upper quadrant discomfort/early satiety (splenomegaly), anemia

2. Accelerated Phase (AP)

• Increasing anemia and thrombocytopenia, rising basophilia
• Additional cytogenetic abnormalities (e.g., trisomy 8, isochromosome 17q, duplication of Ph chromosome)
• ELN definition: peripheral/BM blasts 15-30%; WHO definition: 10-20%

3. Blast Phase / Blast Crisis (BP)

• Resembles acute leukemia; ELN: blasts ≥30%; WHO: blasts ≥20%
• Myeloid blast crisis in ~70% of cases
• Lymphoid (pre-B cell) blast crisis in ~25% - evidence of pluripotent HSC origin
• Blast crisis is triggered by acquired mutations in transcriptional regulators (e.g., RUNX1, IKZF1)

Morphology

Diagnosis

1. Characteristic blood/BM findings (leukocytosis with granulocytic spectrum, basophilia)
2. Detection of the BCR-ABL1 rearrangement by one of:
   • Cytogenetics: visualizes the Ph chromosome (90%+ of cases)
   • FISH: detects cryptic rearrangements; more sensitive than karyotype
   • RT-PCR / quantitative PCR (qPCR): most sensitive; used for monitoring

Important: ~10% of cases have cytogenetically complex/cryptic rearrangements - the Ph chromosome is absent but BCR-ABL1 is detectable by FISH or PCR.

• Washington Manual of Medical Therapeutics, p. 866

Treatment

Tyrosine Kinase Inhibitors (TKIs)

• 2nd-gen TKIs are 30-300x more potent than imatinib
• Ponatinib and asciminib are active against the T315I "gatekeeper" mutation (the most resistant kinase domain mutation)
• Asciminib is a STAMP inhibitor (Specifically Targeting the ABL Myristoyl Pocket) - a mechanistically distinct approach from ATP-competitive TKIs
• Harrison's Principles of Internal Medicine 22E, p. 882

Response Milestones (Treatment Monitoring)

• CHR: normalization of CBC + absence of splenomegaly
• CCyR: absence of Ph chromosome metaphases on cytogenetic analysis
• MMR (MR3.0): BCR-ABL1 ≤0.1% (IS)
• Deep molecular response (MR4.5): BCR-ABL1 ≤0.0032% - threshold for considering treatment-free remission (TFR)

Treatment-Free Remission (TFR)

Blast Phase Management

Other Agents

• Omacetaxine mepesuccinate: a protein synthesis inhibitor; option for TKI-resistant disease (including T315I)
• Asciminib (STAMP inhibitor): approved for T315I mutation and after ≥2 prior TKIs
• HSCT: now reserved primarily for blast phase or multiple TKI failures

Survival - TKI Era

• Pre-TKI era (<1982): Only 8% survived 10 years
• TKI era (2001-present): ~95% CML-related survival at 10 years; ~92% accounting for CML/SCT-related deaths; ~86% overall survival
• Accelerated phase: Median survival improved from 28 to 88 months with TKIs
• Blast phase: Still poor prognosis; median survival only 5-7 months, marginally improved with TKIs

Differential Diagnosis

• Leukemoid reaction: elevated WBC but with left shift from infection/inflammation; BCR-ABL1 negative; high LAP (leukocyte alkaline phosphatase) score vs. very low in CML
• Other myeloproliferative neoplasms (PV, ET, PMF): BCR-ABL1 negative; JAK2/CALR/MPL mutations
• Atypical CML: morphologically similar but BCR-ABL1 negative; distinct genetics (often SETBP1, CSF3R)
• Chronic neutrophilic leukemia: CSF3R mutations; distinct entity

Recent Evidence (2024-2026)

1. Ponatinib vs. asciminib after 2nd-generation TKI failure in CP-CML: matching-adjusted indirect comparison showing comparable activity (Garcia-Gutierrez et al., Front Oncol, 2024 - PMID 39634261)
2. TKI toxicity burden: Patient-reported toxicity symptoms during TKI treatment - systematic review and meta-analysis highlighting that symptom burden is significant and often underreported (Smit et al., Support Care Cancer, 2025 - PMID 40317312)
3. TKI + anticoagulant combinations: Safety systematic review for CML patients requiring anticoagulation (Gameil et al., Oncology, 2026 - PMID 41525412)

Summary Table