A 28-year-old woman with newly diagnosed B-cell acute lymphoblastic leukemia (B-ALL) with Philadelphia chromosome is being counseled on induction therapy. Which drug is the preferred first-line tyrosine kinase inhibitor to combine with chemotherapy?

Question

Accepted Answer

B. Imatinib mesylate. ## Philadelphia Chromosome–Positive B-ALL: TKI Selection

**Key Point:** Ph+ B-ALL (t(9;22) with BCR-ABL1 fusion) requires dual therapy: chemotherapy + tyrosine kinase inhibitor (TKI). First-generation TKI imatinib remains the standard induction choice.

### BCR-ABL1 Pathophysiology
The Philadelphia chromosome produces a constitutively active tyrosine kinase that drives uncontrolled proliferation. TKIs block this kinase activity and restore apoptosis.

### TKI Comparison in Ph+ B-ALL

| TKI | Generation | CNS Penetration | Potency | Resistance Profile | Role in B-ALL |
|-----|-----------|-----------------|---------|-------------------|---------------|
| **Imatinib** | 1st | Moderate | Standard | BCR-ABL1 WT sensitive | **First-line induction** |
| Nilotinib | 2nd | Poor | Higher | Resistant mutants | Salvage/relapse |
| Dasatinib | 2nd | Excellent | Higher | Resistant mutants | CNS-positive disease |
| Ponatinib | 3rd | Moderate | Highest | Pan-resistant | T315I mutants only |

**High-Yield:** Imatinib + chemotherapy (e.g., hyper-CVAD or similar) achieves **85–90% complete remission** in newly diagnosed Ph+ B-ALL. Addition of imatinib to chemotherapy has transformed Ph+ B-ALL from a dismal prognosis to one with long-term survival rates >50%.

### Clinical Pearl
- Imatinib is preferred in induction because it has the longest clinical track record, lowest toxicity, and proven efficacy in combination with chemotherapy.
- Second-generation TKIs (nilotinib, dasatinib) are reserved for:
  - Imatinib resistance or intolerance.
  - CNS involvement (dasatinib preferred for superior CNS penetration).
  - Relapsed/refractory disease.
- Ponatinib is reserved exclusively for T315I-mutant BCR-ABL1, which confers resistance to all other TKIs.

### Monitoring During Therapy
- BCR-ABL1 transcript levels (RT-PCR) at 3, 6, and 12 months.
- Mutational analysis if loss of response occurs.

[cite:Harrison 21e Ch 110]

Answer

A. Dasatinib

Answer

C. Nilotinib

Answer

D. Ponatinib

A 28-year-old woman with newly diagnosed B-cell acute lymphoblastic leukemia (B-ALL) with Philadelphia chromosome is being counseled on induction therapy. Which drug is the preferred first-line tyrosine kinase inhibitor to combine with chemotherapy?

Explanation

Philadelphia Chromosome–Positive B-ALL: TKI Selection

BCR-ABL1 Pathophysiology

TKI Comparison in Ph+ B-ALL

Clinical Pearl

Monitoring During Therapy

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TKI	Generation	CNS Penetration	Potency	Resistance Profile	Role in B-ALL
Imatinib	1st	Moderate	Standard	BCR-ABL1 WT sensitive	First-line induction
Nilotinib	2nd	Poor	Higher	Resistant mutants	Salvage/relapse
Dasatinib	2nd	Excellent	Higher	Resistant mutants	CNS-positive disease
Ponatinib	3rd	Moderate	Highest	Pan-resistant	T315I mutants only