What abnormalities are characteristic of Chronic Myeloid Leukemia (CML)?

From the Guidelines

Chronic myelogenous leukemia (CML) is characterized by the presence of the Philadelphia chromosome, resulting from a reciprocal translocation between chromosomes 9 and 22, creating the BCR-ABL fusion gene, which is the primary driver of the disease's pathogenesis, as noted in the most recent study by 1.

Key Abnormalities

The key abnormalities associated with CML include:

• The Philadelphia chromosome, which is present in 90-95% of CML cases at diagnosis, as reported by 1
• A reciprocal translocation between chromosomes 9 and 22, resulting in the BCR-ABL fusion gene, as described by 1
• Elevated white blood cell count, often exceeding 100,000 cells/μL, with a full spectrum of myeloid cells at different maturation stages visible in the peripheral blood
• Hypercellularity with myeloid hyperplasia in the bone marrow
• Basophilia, eosinophilia, and thrombocytosis
• Splenomegaly due to extramedullary hematopoiesis

Additional Cytogenetic Abnormalities

Additional cytogenetic abnormalities (ACAs) may be present in some CML patients, including:

• Major-route ACAs, such as +Ph, +8, i(17q), +19, which are associated with a poorer prognosis, as noted by 1
• High-risk ACAs, such as +21, +17, -7/7q-, 3q26.2, 11q23 rearrangements, and complex karyotypes, which are also associated with a poorer prognosis, as reported by 1
• Clonal chromosome abnormalities in Ph-negative cells, which may be associated with hematological toxicity of TKI therapy, but do not have a significant impact on overall prognosis, as described by 1

Molecular Abnormalities

The BCR-ABL fusion gene is the primary molecular abnormality associated with CML, and is the target for treatment with tyrosine kinase inhibitors, as noted by 1. The BCR-ABL mutation is not just diagnostic but also the primary target for treatment with tyrosine kinase inhibitors like imatinib, nilotinib, and dasatinib, which have dramatically improved outcomes for CML patients, as reported by 1.

From the FDA Drug Label

Myelosuppression was commonly reported in all patient populations. The frequency of Grade 3 or 4 neutropenia, thrombocytopenia, and anemia was higher in patients with advanced phase CML than in chronic phase CML Cytopenias, and particularly neutropenia and thrombocytopenia, were a consistent finding in all studies, with a higher frequency at doses greater than or equal to 750 mg (Phase 1 study). The occurrence of cytopenias in CML patients was also dependent on the stage of the disease In patients with newly diagnosed CML, cytopenias were less frequent than in the other CML patients

The abnormalities characteristic of Chronic Myelogenous Leukemia (CML) include:

• Myelosuppression:
  • Neutropenia: a lower than normal number of neutrophils, a type of white blood cell
  • Thrombocytopenia: a lower than normal number of platelets
  • Anemia: a lower than normal number of red blood cells or the amount of hemoglobin in the blood
• Cytopenias: a reduction in the number of blood cells, including neutropenia, thrombocytopenia, and anemia These abnormalities are more frequent in advanced phase CML than in chronic phase CML 2 3.

From the Research

Characteristic Abnormalities of Chronic Myelogenous Leukemia

• The presence of the Philadelphia (Ph) chromosome, which results from the translocation of the ABL1 gene from chromosome 9 to the BCR gene located in chromosome 22, forming the BCR-ABL gene on chromosome number 22, accounts for approximately 95% of CML cases 4.
• Complex translocation involving other chromosomes can occur, such as a translocation (16;22) (q24,q11.2), which is a rare case of CML with a variant Ph chromosome 4.
• The BCR-ABL fusion oncogene generates a BCR-ABL oncoprotein, which is the molecular consequence of the translocation t (9;22) (q34;q11.2) 5.
• Approximately 90% of people with CML present with an indolent chronic phase of CML, defined as blasts of less than 10% in the blood or bone marrow, absence of extramedullary evidence of leukemia, basophils of less than 20%, and platelet counts of 100 to 1000 × 10^9/L 6.
• The most advanced stage is CML blastic phase (CML-BP), characterized by the World Health Organization as 20% or more blasts/immature cells and by the MD Anderson Cancer Center and European LeukemiaNet as 30% or more 6.

Cytogenetic Abnormalities

• The Philadelphia chromosome is defined by the BCR::ABL1 oncogene that develops after fusion of the ABL1 proto-oncogene to the constitutively active BCR gene 6.
• The t(9;22)(q34;q11) translocation can be found in chronic myeloid leukemia (CML) as well as in a subset of acute lymphoblastic leukemias (ALL) 7.
• Next-generation sequencing is likely to become a precious tool for mutation testing because of the greater sensitivity and the possibility to discriminate between compound and polyclonal mutations 7.

Molecular Abnormalities

• The deregulated BCR-ABL1 tyrosine kinase encoded by the fusion gene resulting from the translocation is considered the pathogenetic driver and can be therapeutically targeted 7.
• The BCR/ABL1 chimeric protein is a constitutively active tyrosine kinase that activates multiple signaling pathways, which collectively lead to malignant transformation 8.
• Testing for BCR-ABL1 transcript levels by real-time quantitative polymerase chain reaction (RQ-PCR) has become the gold standard to monitor patient response, anticipate relapse, and guide therapeutic decisions 7.