A 62-year-old man with chronic myeloid leukemia (CML) in chronic phase is found to have the Philadelphia chromosome t(9;22) with BCR-ABL fusion gene. What is the drug of choice for first-line treatment?

Question

Accepted Answer

A. Imatinib mesylate. ## BCR-ABL Tyrosine Kinase Inhibition in CML

**Key Point:** Imatinib mesylate is the gold-standard first-line tyrosine kinase inhibitor (TKI) for Philadelphia chromosome-positive CML in all phases.

### Mechanism of Action
Imatinib selectively inhibits the constitutively active BCR-ABL tyrosine kinase, which results from the t(9;22) translocation. This fusion protein drives uncontrolled proliferation in CML.

### Clinical Evidence
- Induces complete hematologic response in >95% of chronic phase CML patients
- Achieves major molecular response in ~80% of patients
- Significantly improved overall survival compared to historical interferon-based regimens
- Standard starting dose: 400 mg daily for chronic phase

**High-Yield:** Imatinib revolutionized CML treatment and is the prototype of targeted cancer therapy against a specific oncogenic driver.

### Comparison with Alternatives

| Agent | Role in CML | Limitation |
|-------|-------------|------------|
| Imatinib | First-line TKI | Resistance in ~20% (BCR-ABL mutations) |
| Daunorubicin | Chemotherapy (pre-TKI era) | Non-selective; inferior outcomes |
| Hydroxyurea | Cytoreductive agent | Temporary control; not curative |
| Interferon-alpha | Historical first-line | Poorly tolerated; inferior to TKIs |

**Clinical Pearl:** Resistance to imatinib may develop through BCR-ABL point mutations (especially T315I) or gene amplification, necessitating second-generation TKIs (dasatinib, nilotinib, ponatinib).

Answer

B. Hydroxyurea

Answer

C. Daunorubicin

Answer

D. Interferon-alpha

A 62-year-old man with chronic myeloid leukemia (CML) in chronic phase is found to have the Philadelphia chromosome t(9;22) with BCR-ABL fusion gene. What is the drug of choice for first-line treatment?

Explanation

BCR-ABL Tyrosine Kinase Inhibition in CML

Mechanism of Action

Clinical Evidence

Comparison with Alternatives

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Agent	Role in CML	Limitation
Imatinib	First-line TKI	Resistance in ~20% (BCR-ABL mutations)
Daunorubicin	Chemotherapy (pre-TKI era)	Non-selective; inferior outcomes
Hydroxyurea	Cytoreductive agent	Temporary control; not curative
Interferon-alpha	Historical first-line	Poorly tolerated; inferior to TKIs