What is Chronic Myeloid Leukemia (CML)?

Chronic Myeloid Leukemia (CML): Definition and Overview

Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of the Philadelphia chromosome, resulting from a reciprocal translocation between chromosomes 9 and 22 that creates the BCR-ABL1 fusion gene, producing a protein with high tyrosine kinase activity that drives abnormal cell proliferation. 1

Pathophysiology

• CML originates from hematopoietic stem cells with the t(9;22)(q34;q11) translocation, which creates the Philadelphia chromosome (22q-) 1
• The translocation juxtaposes the ABL1 gene from chromosome 9 with the BCR gene from chromosome 22, forming the BCR-ABL1 fusion gene 1
• This fusion gene codes for BCR-ABL1 transcripts and fusion proteins with deregulated tyrosine kinase activity, which is the primary driver of the disease 1
• The most common transcript types are e13a2 and e14a2 (also known as b2a2 and b3a2), which encode the p210 protein 1
• Less common variants include p190 (usually associated with Ph+ acute lymphoblastic leukemia) and p230 (associated with enhanced neutrophil differentiation) 1

Epidemiology

• The incidence of CML ranges between 10-15 cases per million people per year without major geographic or ethnic differences 1
• Median age at diagnosis is 60-67 years in Europe and the US, though CML can occur in all age groups 1
• CML accounts for approximately 15% of adult leukemias 1
• The prevalence is steadily increasing due to improved survival with targeted therapies 1

Disease Phases

CML progresses through three distinct phases:

1. Chronic Phase (CP):

   • 90-95% of patients are diagnosed in this phase 1
   • Characterized by <15% blasts in blood and bone marrow 1
   • Most indolent phase, can last 3-5 years if untreated 1, 2

2. Accelerated Phase (AP):

   • Defined by 15-29% blasts in blood or bone marrow, >20% basophils, or clonal cytogenetic evolution 1
   • Represents a transitional phase between chronic and blast phases 1

3. Blast Phase (BP):

   • Defined by ≥30% blasts in blood or bone marrow or extramedullary blast infiltration 1
   • Resembles acute leukemia with poor prognosis 1
   • Can be myeloid (70-80%) or lymphoid (20-30%) 1

Clinical Presentation

• About 50% of patients diagnosed in Europe are asymptomatic, with the disease often discovered incidentally through routine blood tests 1
• Common symptoms when present include:
  • Fatigue, weight loss, and malaise (due to anemia) 1
  • Left upper quadrant fullness or pain (due to splenomegaly) 1
• Less common manifestations include:
  • Bleeding (from thrombocytopenia or platelet dysfunction) 1
  • Thrombosis (from thrombocytosis or marked leukocytosis) 1
  • Gouty arthritis (from elevated uric acid) 1
  • Retinal hemorrhages and gastrointestinal ulceration (from basophilia) 1
• Physical findings:
  • Splenomegaly is the most consistent sign, present in 40-50% of cases 1
  • Hepatomegaly is less common 1

Diagnostic Evaluation

• Diagnosis is typically based on characteristic blood count findings:

  • Excessive granulocytosis with left shift (immature granulocytes at all stages of maturation) 1
  • Thrombocytosis 1
  • Basophilia and eosinophilia 1

• Confirmation requires:

  • Identification of Philadelphia chromosome by cytogenetics 1
  • Detection of BCR-ABL1 transcripts by RT-PCR 1
  • In 5% of cases where Ph chromosome is not detectable, FISH or RT-PCR can confirm BCR-ABL1 fusion 1

• Bone marrow evaluation shows:

  • Increased cellularity with proliferation of myelopoiesis 1
  • Predominance of mature forms 1
  • Smaller than normal megakaryocytes with hypolobulated nuclei 1
  • Moderate to marked reticulin fibrosis in 30% of cases 1

Treatment Overview

• Tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 are the standard first-line treatment 3
• Five TKIs are approved for first-line treatment: imatinib, dasatinib, bosutinib, nilotinib, and asciminib 3
• TKI therapy has dramatically improved survival, with mortality decreasing from 10-20% per year to 1-2% per year 3
• Allogeneic stem cell transplantation is reserved for patients who fail multiple TKIs or those with advanced disease 3

Prognosis

• With modern TKI therapy, patients with CML have survival rates similar to those of age-matched general population 3
• Without treatment, CML would progress from chronic phase to accelerated or blast phase in 3-5 years on average 1
• The progression rate has significantly decreased with TKI therapy, with annual progression rates of about 1-2% 1

Monitoring

• Regular monitoring includes:
  • Complete blood counts every 15 days until complete hematologic response is achieved 1
  • Bone marrow karyotype at 3 and 6 months 1
  • Quantitative RT-PCR every 3 months to monitor molecular response 1
  • Mutational analysis in case of treatment failure 1

Common Pitfalls and Caveats

• CML must be distinguished from atypical CML, which is Philadelphia-negative and BCR-ABL1 negative 1
• Medication adherence is crucial for maintaining treatment response and preventing disease progression 3
• Each TKI has specific adverse effects that should be considered when selecting therapy 3
• Progression to advanced phases can occur despite treatment, particularly with poor adherence or development of resistance mutations 1