What are the key features and prognosis of Chronic Myeloid Leukemia (CML)?

Chronic Myeloid Leukemia: Key Features and Prognosis

Chronic Myeloid Leukemia (CML) is characterized by the Philadelphia chromosome t(9;22)(q34;q11) resulting in the BCR-ABL1 fusion gene, with excellent long-term prognosis in the tyrosine kinase inhibitor era, where most patients can achieve survival rates similar to age-matched controls when treated appropriately. 1

Pathophysiology

CML is a hematopoietic stem cell disorder arising from a balanced genetic translocation between chromosomes 9 and 22, creating the Philadelphia chromosome. This translocation results in:

• Formation of the BCR-ABL1 fusion gene
• Production of BCR-ABL1 oncoprotein with constitutively activated tyrosine kinase activity
• Genetic instability leading to potential disease progression 1

Key Clinical Features

Presentation

• Often asymptomatic (40% of cases diagnosed incidentally) 1
• When symptomatic: weight loss, asthenia, low-grade fever, sweats, malaise 1
• Physical examination: splenomegaly in >50% of patients 1

Laboratory Findings

• Leukocytosis with characteristic left shift in granulopoiesis
• Basophilia (hallmark finding)
• Presence of immature granulocytes (metamyelocytes, myelocytes, promyelocytes)
• Few or occasional myeloblasts (<5% in chronic phase)
• Thrombocytosis (frequent)
• Anemia (rarely severe) 1

Diagnostic Criteria

Diagnosis requires:

1. Characteristic blood count and differential
2. Confirmation by either:
   • Cytogenetics showing t(9;22)(q34;q11.1) Philadelphia chromosome
   • RT-PCR showing BCR-ABL1 transcripts 1

Additional testing includes:

• Chromosome banding analysis (CBA) of marrow cell metaphases
• FISH may be used when CBA cannot be performed
• Qualitative RT-PCR to identify transcript type (e14a2, e13a2, rarely e19a2 or e1a2) 1

Disease Phases and Progression

CML progresses through three distinct phases:

1. Chronic Phase (CP)

   • <5% blasts in bone marrow
   • Most patients diagnosed in this phase
   • Best prognosis

2. Accelerated Phase (AP)

   • 15-29% blasts in blood or bone marrow

   • 20% basophils in blood

   • Thrombocytosis or thrombocytopenia unrelated to therapy
   • Clonal chromosome abnormalities in Ph+ cells

3. Blast Phase (BP)/Blast Crisis (BC)

   • ≥30% blasts in blood or bone marrow
   • Extramedullary blastic infiltration
   • Myeloid blast crisis (70-80%) or lymphoid blast crisis (20-30%)
   • Poor prognosis 1

Bone Marrow Findings

• Increased cellularity with granulocytic proliferation
• Predominance of myelocytes and segmented forms
• No substantial dysplasia
• Prominent eosinophils
• "Dwarf megakaryocytes" (smaller than normal with hypolobulated nuclei)
• Moderate to marked reticulin fibrosis in ~30% of cases
• Pseudo-Gaucher cells and sea-blue histiocytes 1

Prognosis

Risk Stratification

Prognostic scores based on:

• Age
• Spleen size
• Blood cell counts
• Differential count 1

These scores help predict:

• Response rates to therapy
• Progression-free survival
• Overall survival 1

Treatment Outcomes

With modern tyrosine kinase inhibitor (TKI) therapy:

• Excellent long-term prognosis in chronic phase
• 6-year progression-free survival of 84%
• 6-year overall survival of 88% 1
• Survival approaching that of age-matched controls 2

Factors Affecting Prognosis

• Disease phase at diagnosis (CP has best prognosis)
• Response to TKI therapy
• Development of BCR-ABL1 kinase domain mutations (especially T315I)
• Additional chromosomal abnormalities 1

Treatment Considerations

• Four TKIs approved for first-line treatment: imatinib, dasatinib, bosutinib, and nilotinib 3, 4
• Treatment choice should consider:
  • Efficacy
  • Response durability
  • Tolerability
  • Quality of life impact
  • Avoidance of serious toxicities
  • Ease of administration
  • Cost 2

Common Pitfalls and Caveats

1. Misdiagnosis: Ensure confirmation with cytogenetics or molecular testing, as other myeloproliferative disorders can present similarly.

2. Inadequate monitoring: Regular monitoring of BCR-ABL1 transcript levels is essential for assessing treatment response.

3. Missing disease progression: Watch for signs of progression to accelerated or blast phase, which requires prompt treatment modification.

4. Overlooking mutations: BCR-ABL1 kinase domain mutations, especially T315I, can cause treatment resistance and require specific TKI selection.

5. Atypical CML: Some patients may present with CML-like features but lack the Philadelphia chromosome (Ph-negative, BCR-ABL1 negative), representing a different disease entity with different treatment approaches 1.