Chronic Myeloid Leukemia (CML): Causes, Symptoms, Diagnosis and Treatment — Overview, Diagnosis & Treatment Options | MyMedicPlus

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm universally defined by the Philadelphia chromosome (Ph) — t(9;22)(q34;q11.2) translocation producing the BCR-ABL1 fusion oncogene. It comprises approximately 15% of adult leukemias, with approximately 9,000 new cases per year in the US. Three clinical phases: chronic (CML-CP, most common at diagnosis), accelerated (CML-AP), and blast crisis (CML-BC).

The Philadelphia chromosome (BCR-ABL1 fusion) is the universal defining molecular event, arising from a reciprocal translocation between chromosomes 9 and 22. BCR-ABL1 constitutively activates tyrosine kinase signaling, driving myeloid proliferation and suppressing apoptosis. No established hereditary predisposition. Prior ionizing radiation (high dose) modestly increases risk. Most cases are sporadic.

Chronic phase: often asymptomatic, discovered incidentally on routine CBC showing marked leukocytosis. When symptomatic: fatigue, night sweats, splenomegaly (left upper quadrant fullness or pain from massive spleen enlargement), weight loss, and pallor. Blast phase mimics acute leukemia with severe cytopenias, susceptibility to infections, bleeding, and organ infiltration.

CBC with differential shows leukocytosis (often 50,000-200,000/μL), basophilia, eosinophilia, and left shift (myelocytes, metamyelocytes). Bone marrow biopsy with cytogenetics confirms Philadelphia chromosome. Quantitative BCR-ABL1 RT-PCR (IS: International Scale) is the gold standard for diagnosis and molecular response monitoring. ABL1 kinase domain mutation testing at resistance. ELN 2020 milestones define optimal response: BCR-ABL1 ≤10% at 3 months, ≤1% at 6 months, ≤0.1% at 12 months.

First-line TKI therapy: imatinib (400 mg daily, 1st generation), dasatinib or nilotinib (2nd generation with faster deeper responses), bosutinib (2nd generation, less neutropenia). Third-line: ponatinib (for T315I 'gatekeeper' mutation). Asciminib (STAMP inhibitor, allosteric binding) for 3rd-line or T315I-mutated CML. Treatment-free remission (TFR) is achievable in approximately 40-50% of deep molecular responders (MR4.5) after ≥3 years of TKI therapy. Allogeneic SCT only for blast crisis or highly refractory disease.

CML-CP treated with TKI: 10-year OS exceeds 85-90%, approaching the life expectancy of the general population — a landmark achievement of targeted oncology. CML blast phase: 5-year OS approximately 20%, still poor. Achievement of deep molecular response (MR4.5) is the prerequisite for attempting treatment-free remission. CML represents one of the greatest successes in modern molecular oncology.