Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm driven by a defining genetic lesion: the Philadelphia chromosome. This results from a reciprocal translocation between chromosomes 9 and 22, producing the BCR-ABL1 fusion gene. The BCR-ABL1 tyrosine kinase is constitutively active, triggering downstream signaling pathways that promote increased proliferation, impaired apoptosis, and altered differentiation of hematopoietic cells. Clinically, CML often evolves through distinct phases: a chronic phase that may be indolent, an accelerated phase characterized by rising counts and symptoms, and a blast phase resembling acute leukemia.
The disease biology of CML centers on continuous BCR-ABL1 signaling through pathways such as RAS/MAPK, PI3K/AKT, and JAK/STAT. These signals increase cell-cycle progression and survival, while also altering the bone marrow microenvironment and immune responses. In untreated disease, the cumulative risk of progression rises over time, but the advent of targeted therapy has dramatically improved outcomes. Even when hematologic parameters appear stable, molecular persistence of BCR-ABL1 can occur, making depth of molecular response a critical treatment endpoint.
Diagnosis begins with clinical context and routine blood counts. Many patients present with leukocytosis, thrombocytosis, and a left shift on peripheral smear, along with possible splenomegaly. The confirmatory diagnostic step is detection of BCR-ABL1. Conventional cytogenetics can identify the Philadelphia chromosome, while fluorescence in situ hybridization (FISH) detects the fusion at the cellular level. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) is used to measure BCR-ABL1 transcripts on the International Scale, enabling sensitive monitoring of treatment response and residual disease. Bone marrow examination may be performed for baseline assessment and to characterize phase, particularly if blasts increase or cytogenetic evolution is suspected.
Treatment has been transformed by tyrosine kinase inhibitors (TKIs). First-generation TKIs such as imatinib revolutionized care by competitively inhibiting BCR-ABL1 kinase activity. Second- and third-generation TKIs (e.g., dasatinib, nilotinib, bosutinib, ponatinib) provide greater potency and can overcome certain resistance mechanisms. TKI selection depends on patient factors, side-effect profiles, comorbidities, and prior response. Resistance in CML can be due to BCR-ABL1 kinase domain mutations, altered drug transport/efflux, amplification of BCR-ABL1, or inadequate drug exposure. Therefore, mutation analysis may guide therapy after suboptimal response.
Response is assessed using a stepwise framework: hematologic response (normalization of blood counts), cytogenetic response (reduction of Philadelphia-positive cells), and molecular response (quantitative BCR-ABL1 transcript reduction). Milestones such as major molecular response and deeper responses indicate lower risk of progression. Monitoring frequency is typically higher early during treatment and may be extended when stable deep responses are achieved. In select patients with sustained deep molecular response, discontinuation strategies under strict surveillance may be considered in specialized settings, though relapse risk remains and requires rapid re-initiation of TKIs.
Allogeneic hematopoietic stem cell transplantation (HSCT) remains a potentially curative option but is reserved for particular circumstances due to treatment-related mortality and morbidity. HSCT is considered when patients have advanced-phase disease, experience TKI failure with progression, or show high-risk features that predict poor outcomes with further TKI therapy alone. The rationale is immune-mediated graft-versus-leukemia effects, enabled by recognition of leukemic antigens by donor-derived immune cells. However, HSCT carries risks including graft-versus-host disease, infections, organ toxicity, and relapse. Reduced-intensity conditioning regimens have expanded eligibility for older or medically fragile patients, but long-term follow-up is essential.
Supportive care is integral across the treatment continuum. Management of anemia, thrombocytopenia, infection risk, and symptom burden supports adherence and improves quality of life. Monitoring for TKI-specific adverse effects is essential: imatinib can cause edema and muscle cramps; dasatinib is associated with pleural effusions in some patients; nilotinib may increase metabolic risk and vascular events; ponatinib is linked with thrombotic complications. Regular assessment, dose adjustments, and interdisciplinary care help mitigate these risks.
From a public health perspective, CML illustrates the impact of molecularly targeted medicine. Early diagnosis and timely initiation of TKI therapy can yield long survival and, for some patients, functional normalization of life expectancy. Nonetheless, achieving and maintaining molecular control requires ongoing monitoring, management of resistance, and careful consideration of HSCT in high-risk or refractory cases. Source: [Creator/Source]
Cure Leukaemia: This Fundraiser Friday, we’re celebrating Mark! After being diagnosed with CML in 2017 and receiving a life-saving stem cell transplant, Mark has become an incredible supporter of Team CL. He’s completed our London 2 Paris ride multiple times and is even crewing the event right. #breaking
— @CureLeukaemia May 1, 2026
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