Chronic myeloid leukemia (CML) is a type of myeloproliferative neoplasm involving hematopoietic stem cells that results in overexpression of cells of myeloid lineage, especially granulocytes. It is caused by a reciprocal translocation between chromosomes 9 and 22, resulting in the formation of the Philadelphia chromosome, which contains the BCR-ABL1 fusion gene. The BCR-ABL1 fusion gene encodes a hybrid tyrosine kinase with increased enzymatic activity that leads to unregulated proliferation of hematopoietic stem cells. These cells subsequently differentiate into mature myeloid cells, resulting in CML. CML has three distinct phases: the chronic phase (CP-CML), the accelerated phase (AP-CML), and the blast phase (BP-CML, also referred to as blast crisis. Patients with CP-CML may be asymptomatic or present with nonspecific symptoms (e.g., fever, weight loss, night sweats) and splenomegaly. AP-CML is characterized by complications secondary to the suppression of other hematologic cell lines (e.g., thrombocytopenia, anemia, recurrent infections), and the clinical picture of BP-CML is similar to that of acute leukemia. Important diagnostic features in BP-CML are severe leukocytosis (with leukocyte counts as high as 500,000/mm3), basophilia, and . The most effective treatment for CML is targeted therapy with tyrosine kinase inhibitors (TKIs). This class of drug has revolutionized the efficacy of treatment and greatly improved the prognosis of patients with CML.
Epidemiological data refers to the US, unless otherwise specified.
- Reciprocal translocation between chromosome 9 and chromosome 22 → formation of the Philadelphia chromosome t(9;22) → fusion of the ABL1 gene (chromosome 9) with the BCR gene (chromosome 22) → formation of the BCR-ABL gene → encodes a BCR-ABL non-receptor tyrosine kinase with increased enzyme activity
- Result: inhibits physiologic apoptosis and increases mitotic rate → uncontrolled proliferation of functional granulocytes
|Malignancy||Detection of Philadelphia translocation|
Genetic changes and clinical course
- Additional chromosomal changes and mutations of tumor suppressor genes and oncogenes (p53, Rb1, or Ras), which emerge during the course of the disease, are responsible for the progression from chronic to accelerated phase and, ultimately, the transition to acute leukemia.
- Can persist for up to 10 years and is often subclinical
- When symptomatic, features include:
- Erythrocytopenia: anemia
- Neutropenia: infection and fever
- Extreme pleocytosis
- Extreme splenomegaly : palpable in lower left quadrant or pelvic cavity
The blast crisis is the terminal stage of CML.
- Symptoms resemble those of .
- Rapid progression of bone marrow failure → , bone pain
- Severe malaise
- Subtypes :
- Clinicians should maintain a high index of suspicion if patients present with the following:
- Initial diagnostic workup should include:
- Diagnostic confirmation: identification of the Philadelphia chromosome and/or the BCR-ABL1 fusion gene.
- Evaluate patients without the Philadelphia chromosome or the BCR-ABL1 fusion gene for other myeloproliferative disorders.
Initial evaluation 
- CBC and peripheral blood smear
- Further laboratory studies
- Bone marrow aspiration and biopsies
Diagnostic confirmation 
Diagnostic confirmation relies on the detection of the Philadelphia chromosome and/or the BCR-ABL1 gene or its transcripts in the bone marrow or peripheral blood. These tests are usually repeated to assess response to treatment.
- Cytogenetic testing: used to confirm the presence of the BCR-ABL1 fusion gene and/or the Philadelphia chromosome, and identify additional genetic mutations
Molecular testing: quantitative RT-PCR 
- Highly sensitive detection and quantification of cells with BCR-ABL1 transcripts
- Especially useful to assess treatment response and remission status
Definitions of CML phases 
AP-CML and BP-CML have characteristic laboratory parameter values (e.g., the proportion of blast cells in peripheral blood or bone marrow). Some definitions also include further genetic mutations and responsiveness to treatment.
- Significantly increased proportion of blast cells
- Additional genetic mutations are often present.
- Blast phase
The presence of additional mutations is associated with more advanced stages of CML (i.e., AP-CML or BP-CML) and can cause resistance to targeted therapy. 
BP-CML is a life-threatening condition that is clinically similar to acute leukemia. It should be recognized early and treated immediately.
- Pretreatment: individualized evaluation in consultation with a hematologist-oncologist
- Chronic phase
- Accelerated phase
- Blast phase: Treatment is similar to that of acute leukemia.
Targeted therapy: tyrosine kinase inhibitors 
- Indication: all patients with CML, regardless of the phase
Mechanism of action
- Selective inhibition of tyrosine kinase (e.g., by blocking its ATP binding site): inhibits tyrosine phosphorylation of downstream signaling proteins (no phosphate transfer from ATP to tyrosine residues)
- Disruption of the BCR-ABL1 pathway: inhibits proliferation and induces apoptosis in BCR-ABL1-positive cells
- Special considerations
TKIs are the primary drug class used to treat CML.
Further treatment options 
- Adjunctive medical treatment
- Systemic chemotherapy: indicated in BP-CML and certain cases of AP-CML
- Allogeneic HSCT: Should be considered in patients with TKI-resistant CML and certain patients in advanced phases (AP-CML or BP-CML)
|Differential diagnosis between leukemoid reaction and myeloproliferative neoplasms|
|Disease||CBC and peripheral blood smear||LAP score||Genetics/cause|
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|Chronic myeloid leukemia|| |
|Leukemoid reaction || |
The differential diagnoses listed here are not exhaustive.