A 58-year-old man presents with fatigue and splenomegaly. Peripheral blood shows WBC 85,000/µL with left shift, and bone marrow biopsy confirms chronic myeloid leukemia (CML) in chronic phase with BCR-ABL1 positivity. What is the drug of choice for first-line treatment?

Question

Accepted Answer

D. Imatinib mesylate. ## First-Line Treatment of CML in Chronic Phase

**Key Point:** Imatinib mesylate is the standard first-line tyrosine kinase inhibitor (TKI) for BCR-ABL1-positive CML in chronic phase, achieving complete cytogenetic response in >80% of patients.

### Mechanism of Action
Imatinib is a selective BCR-ABL1 tyrosine kinase inhibitor that blocks the constitutive kinase activity driving myeloid proliferation in CML.

### Dosing and Response
- Standard dose: 400 mg daily for chronic phase CML
- Leads to complete hematologic response in 95% and complete cytogenetic response in 80–90% at 12 months
- Monitoring: BCR-ABL1 transcript levels by qPCR at 3, 6, and 12 months

### Why Imatinib Over Other Agents

| Feature | Imatinib | Hydroxyurea | Busulfan | IFN-α |
|---------|----------|-------------|----------|-------|
| Mechanism | BCR-ABL1 TKI | Ribonucleotide reductase inhibitor | Alkylating agent | Immune modulation |
| Cytogenetic response | 80–90% | <10% | <5% | 20–30% |
| Survival benefit | Yes (landmark) | Cytoreduction only | Cytoreduction only | Modest |
| Tolerability | Excellent | Moderate | Poor (cumulative toxicity) | Poor (flu-like) |
| Current role | First-line | Cytoreduction in TKI-intolerant | Rarely used | Historical |

**High-Yield:** Imatinib revolutionized CML management post-2001 and is the gold standard; second-generation TKIs (dasatinib, nilotinib, bosutinib) are reserved for imatinib resistance or intolerance.

**Clinical Pearl:** Patients with imatinib-resistant CML (defined as failure to achieve milestones: CHR by 3 months, minor CyR by 6 months, complete CyR by 12 months) should be screened for BCR-ABL1 kinase domain mutations and switched to second-generation TKI.

**Mnemonic:** **TKI-CML** = Tyrosine Kinase Inhibitor is the gold standard for CML.

Answer

A. Busulfan

Answer

B. Interferon-alpha

Answer

C. Hydroxyurea

A 58-year-old man presents with fatigue and splenomegaly. Peripheral blood shows WBC 85,000/µL with left shift, and bone marrow biopsy confirms chronic myeloid leukemia (CML) in chronic phase with BCR-ABL1 positivity. What is the drug of choice for first-line treatment?

Explanation

First-Line Treatment of CML in Chronic Phase

Mechanism of Action

Dosing and Response

Why Imatinib Over Other Agents

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Feature	Imatinib	Hydroxyurea	Busulfan	IFN-α
Mechanism	BCR-ABL1 TKI	Ribonucleotide reductase inhibitor	Alkylating agent	Immune modulation
Cytogenetic response	80–90%	<10%	<5%	20–30%
Survival benefit	Yes (landmark)	Cytoreduction only	Cytoreduction only	Modest
Tolerability	Excellent	Moderate	Poor (cumulative toxicity)	Poor (flu-like)
Current role	First-line	Cytoreduction in TKI-intolerant	Rarely used	Historical