Overview
CML is defined by the Philadelphia chromosome (BCR-ABL fusion). Treatment with tyrosine kinase inhibitors (TKIs) has transformed CML from a fatal disease to a chronic condition with near-normal life expectancy. First-line options include imatinib, dasatinib, nilotinib, and bosutinib. Treatment goals include achieving complete cytogenetic response and major molecular response.
Epidemiology & Impact
Chronic myeloid leukemia (CML) accounts for approximately 15% of adult leukemias, with about 9,280 new cases expected in the United States in 2025. The median age at diagnosis is 64 years, with a slight male predominance. CML is among the greatest success stories in targeted cancer therapy — 5-year survival has improved from approximately 30% in the pre-imatinib era to over 90% today, approaching the survival of the age-matched general population. CML prevalence continues to increase as patients live longer with the disease, with an estimated 150,000 or more Americans currently living with CML. The only well-established risk factor is prior exposure to ionizing radiation (as demonstrated in atomic bomb survivors). Most cases present in chronic phase and are diagnosed incidentally or through nonspecific symptoms like fatigue and splenomegaly.
Molecular Biology & Biomarkers
CML is defined by the Philadelphia chromosome — a reciprocal translocation t(9;22)(q34;q11) that creates the BCR-ABL1 fusion oncoprotein. This constitutively active tyrosine kinase drives uncontrolled myeloid proliferation and is both the molecular hallmark and the therapeutic target of the disease. The BCR-ABL1 transcript level, measured by quantitative PCR (qPCR), serves as the primary tool for monitoring treatment response. Key response milestones include early molecular response (BCR-ABL1 ≤10% at 3 months), major molecular response (MMR, BCR-ABL1 ≤0.1%), and deep molecular response (MR4.0 or MR4.5). Resistance to tyrosine kinase inhibitors is most commonly mediated by point mutations in the BCR-ABL1 kinase domain, with the T315I "gatekeeper" mutation conferring resistance to all first- and second-generation TKIs but sensitivity to ponatinib and asciminib. CML that transforms to blast crisis acquires additional genetic alterations including TP53 mutations, IKZF1 deletions, and RUNX1 mutations.
Evolving Treatment Landscape
Imatinib (Gleevec), the first rationally designed targeted cancer therapy, transformed CML from a fatal disease to a chronic manageable condition and earned a Nobel Prize for its discoverer. Second-generation TKIs — dasatinib, nilotinib, and bosutinib — offer faster and deeper responses and are now commonly used first-line, particularly in patients aiming for treatment-free remission (TFR). Asciminib (Scemblix), a first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor, works through a completely different mechanism than ATP-competitive TKIs and has shown superiority over bosutinib in the ASC4FIRST trial. Ponatinib remains essential for patients with the T315I mutation. Perhaps the most remarkable development in CML is treatment-free remission: patients who achieve sustained deep molecular response can safely discontinue TKI therapy under close monitoring, with approximately 50% maintaining remission indefinitely. This has transformed the treatment goal from lifelong therapy to potential functional cure.