What is the pathophysiology of Chronic Myelogenous Leukemia (CML) and its management?

Chronic Myelogenous Leukemia: Pathophysiology Pearls

Molecular Basis and Chromosomal Abnormality

CML arises from a balanced translocation t(9;22)(q34;q11.2) between chromosomes 9 and 22, creating the Philadelphia chromosome (Ph), which was the first recurrent chromosomal abnormality identified in human malignancy in 1960. 1, 2

• The translocation fuses the ABL1 gene from chromosome 9q34 with the BCR gene on chromosome 22q11.2, generating the BCR-ABL1 fusion oncogene 1, 3, 4
• In most patients (>95%), chromosomal breakpoints occur in intron 13 or 14 of the BCR gene (major breakpoint cluster region; M-BCR), while ABL1 breaks occur between exons Ib and Ia, or between exons 1 and 2 1
• Splicing almost invariably fuses ABL1 exon 2 with BCR exons 13 or 14, producing e13a2 and e14a2 transcripts 1

The BCR-ABL1 Oncoprotein

The BCR-ABL1 fusion gene encodes a chimeric protein (p210BCR-ABL) with constitutively active, deregulated tyrosine kinase activity that drives CML pathogenesis. 1, 5

• The p210 protein contains NH2-terminal domains of BCR and COOH-terminal domains of ABL 1
• Three critical functional changes occur: (1) ABL becomes constitutively active as a tyrosine kinase enzyme, (2) DNA-protein binding activity is attenuated, and (3) binding to cytoskeletal actin microfilaments is enhanced 1
• These molecular changes increase proliferation, impair differentiation, and block apoptosis in hematopoietic stem cells 1, 6

Variant BCR-ABL1 Transcripts

• Unusual transcripts include e1a2 encoding p190 (typically seen in Ph-positive acute lymphoblastic leukemia, involving minor BCR; m-BCR) and e19a2 encoding p230 (associated with enhanced neutrophil differentiation, involving micro BCR; μ-BCR) 1
• Atypical transcripts (e13a3, e14a3, e6a2) occur in approximately 1-2% of CML patients 1

Disease Phases and Natural History

CML occurs in three distinct phases—chronic phase (CP), accelerated phase (AP), and blast phase (BP)—with most patients (90-95%) diagnosed in chronic phase in developed countries. 1, 2, 7

Chronic Phase Characteristics

• Defined by <15% blasts in blood and bone marrow 7
• Peripheral blood shows excessive granulocytosis with left shift, including immature forms (myelocytes, metamyelocytes), plus basophilia and eosinophilia 2, 7
• White blood cell count often exceeds 100 × 10⁹/L at presentation 7

Disease Progression Timeline

• Untreated CP-CML progresses to AP-CML or BP-CML in 3-5 years on average 1, 6, 8
• With modern tyrosine kinase inhibitor (TKI) therapy, annual progression rate has decreased dramatically to 1-1.5% from the historical >20% 5
• Gene expression profiling demonstrates that the bulk of genetic changes occur during the transition from CP to AP, with AP and BP showing similar expression patterns 1, 5

Accelerated Phase

• Defined by 15-29% blasts in peripheral blood or bone marrow 7
• Progression bridges a continuum of clinical features including fever, bone pain, increasing spleen size, and cytogenetic changes 1

Blast Phase

• Defined by ≥30% blasts (European LeukemiaNet criteria) or ≥20% blasts (WHO criteria) in blood or bone marrow, or extramedullary blast involvement 5, 7
• 70-80% of blast phase cases are myeloid phenotype, resembling acute myeloid leukemia 5
• Blast phase CML remains BCR-ABL1 positive (Philadelphia chromosome positive), distinguishing it from de novo AML which is BCR-ABL1 negative 5
• Survival at blast phase is less than 1 year without effective treatment 6

Mechanisms of Disease Progression

BCR-ABL1 positive cells are genetically unstable and prone to develop additional genomic abnormalities (clonal evolution), leading to disease progression. 2

• Additional chromosomal abnormalities in Ph-positive cells (ACA/Ph+) represent clonal cytogenetic evolution 1
• Activation of the beta-catenin signaling pathway in CML granulocyte-macrophage progenitors enhances self-renewal activity and leukemic potential, representing a key pathobiologic event in evolution to blast phase 1
• During progression, mutations accumulate and the Philadelphia chromosome persists through clonal evolution 6

Diagnostic Confirmation

Diagnosis requires demonstration of the Philadelphia chromosome or BCR-ABL1 fusion gene in a patient with characteristic peripheral blood findings showing excessive granulocytosis with left shift. 2, 7

• Bone marrow cytogenetics detects the t(9;22)(q34;q11) translocation and identifies additional chromosomal abnormalities 1, 7
• Fluorescence in situ hybridization (FISH) with dual probes for BCR and ABL1 genes is acceptable when bone marrow evaluation is not feasible, though interphase FISH has a false-positive rate of 1-5% 1
• Quantitative RT-PCR establishes baseline BCR-ABL1 transcript levels and is the most sensitive assay for measuring BCR-ABL1 mRNA, detecting one CML cell in a background of 100,000 normal cells 1, 7