Pathology · Year 2 · from Pathology

Case 2: Philadelphia Chromosome-Positive Chronic Myeloid Leukemia

Patient Demographics

• Age: 45 years old
• Sex: Female
• Occupation: Accountant

Chief Complaint

"Abdominal fullness and fatigue for 2 months"

History of Present Illness

A 45-year-old female presents with progressive fatigue and a sensation of fullness in the left upper abdomen for the past 2 months. She reports early satiety and occasional left shoulder discomfort after eating. She has experienced night sweats and has lost 5 kg unintentionally. She denies fever, bleeding, or bruising. She has no significant past medical history.

Physical Examination

• Vital Signs: BP 118/74 mmHg, HR 82 bpm, RR 14/min, Temp 37.0C
• General: Mild pallor, no acute distress
• Abdomen: Massive splenomegaly with spleen palpable 12 cm below left costal margin, crossing midline; mild hepatomegaly
• Lymph nodes: No significant lymphadenopathy
• Skin: No petechiae or ecchymoses

Diagnostic Workup

Laboratory Studies:

Peripheral Blood Smear:

• Marked leukocytosis with full spectrum of myeloid maturation
• Increased basophils and eosinophils
• Myelocytes and metamyelocytes present
• No significant dysplasia

Bone Marrow Biopsy:

• Hypercellular (95%) with myeloid predominance
• M:E ratio 15:1
• Increased megakaryocytes, some small hypolobated forms

Cytogenetics:

• t(9;22)(q34;q11) - Philadelphia chromosome present in 100% of metaphases

Molecular Testing:

• BCR-ABL1 fusion gene positive (p210 transcript)
• BCR-ABL1/ABL1 ratio: 85%

Pathology Correlation

This case demonstrates oncogene activation through chromosomal translocation:

The Philadelphia Chromosome:

• Translocation t(9;22) creates fusion of BCR gene (chromosome 22) with ABL1 gene (chromosome 9)
• BCR-ABL1 fusion protein is a constitutively active tyrosine kinase
• Unlike normal ABL, which cycles between active and inactive states, BCR-ABL is "always on"

Oncogenic Mechanisms:

1. Constitutive tyrosine kinase activity - drives continuous cell proliferation
2. Activation of RAS/MAPK pathway - promotes growth signals
3. Activation of PI3K/AKT pathway - promotes cell survival
4. Inhibition of apoptosis - prevents normal cell death

Disease Phases:

• Chronic phase: Excessive but functional granulocyte production
• Accelerated phase: Increasing blasts, genomic instability
• Blast crisis: Acute leukemia (additional mutations, often TP53)

Targeted Therapy Revolution: Imatinib (Gleevec) specifically inhibits BCR-ABL tyrosine kinase activity - the paradigm for targeted therapy based on understanding molecular pathogenesis.

Clinical Image

Diagram illustrating the Philadelphia chromosome translocation t(9;22) creating the BCR-ABL fusion gene, which encodes a constitutively active tyrosine kinase driving uncontrolled proliferation in CML.

Image Source: Wikimedia Commons - "Philadelphia chromosome" License: Public Domain URL: https://commons.wikimedia.org/wiki/File:Philadelphia_chromosome.svg

Diagnosis

Chronic Myeloid Leukemia, BCR-ABL1 positive, Chronic Phase

Treatment

1. Tyrosine kinase inhibitor (TKI) therapy:

• First-line: Imatinib 400 mg daily, OR
• Second-generation TKI (dasatinib, nilotinib) for faster/deeper response

1. Monitor BCR-ABL1 transcript levels by quantitative PCR
2. Milestone assessments:

• 3 months: BCR-ABL <10% (Early Molecular Response)
• 12 months: BCR-ABL <0.1% (Major Molecular Response)

1. Consider TKI discontinuation if sustained deep molecular response

Teaching Points

1. Chromosomal translocations can activate oncogenes by creating fusion proteins or dysregulating gene expression
2. The Philadelphia chromosome represents the paradigm of targeted therapy development
3. BCR-ABL is a classic example of an oncogene encoding a constitutively active signaling molecule
4. Understanding molecular pathogenesis enables development of precision medicine
5. TKIs have transformed CML from a fatal disease to a manageable chronic condition
6. Drug resistance can develop through ABL kinase domain mutations, requiring alternative TKIs

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