A 4-year-old boy from rural India presents with a 2-week history of fever, pallor, petechiae, and hepatosplenomegaly. Bone marrow examination shows 80% blasts with morphology consistent with acute myeloid leukemia (AML). Regarding the management and prognostic factors of pediatric AML, all of the following statements are true EXCEPT:

Question

A 4-year-old boy from rural India presents with a 2-week history of fever, pallor, petechiae, and hepatosplenomegaly. Bone marrow examination shows >80% blasts with morphology consistent with acute myeloid leukemia (AML). Regarding the management and prognostic factors of pediatric AML, all of the following statements are true EXCEPT:

Accepted Answer

C. FLT3-ITD (internal tandem duplication) mutation is associated with favorable prognosis and lower relapse risk. ## Prognostic Markers and Cytogenetics in Pediatric AML

### AML Risk Stratification Framework

**Key Point:** Cytogenetic and molecular features are the primary determinants of prognosis in pediatric AML. Favorable-risk AML includes core binding factor (CBF) AML and APL; unfavorable-risk includes FLT3-ITD, TP53 mutations, and complex karyotype.

### Favorable vs. Unfavorable Prognostic Markers

| Marker | Type | Prognosis | Mechanism |
|--------|------|-----------|----------|
| t(8;21) RUNX1-RUNX1T1 | Cytogenetic | **Favorable** | CBF AML; chemotherapy-sensitive |
| inv(16) CBFB-MYH11 | Cytogenetic | **Favorable** | CBF AML; good response to high-dose cytarabine |
| t(15;17) PML-RARA | Cytogenetic | **Favorable** | APL; ATRA/ATO highly effective |
| FLT3-ITD | Molecular | **UNFAVORABLE** | Constitutive kinase; high relapse, poor EFS |
| TP53 mutation | Molecular | **UNFAVORABLE** | Genomic instability; therapy resistance |
| Complex karyotype | Cytogenetic | **UNFAVORABLE** | Multiple abnormalities; poor response |

### Why FLT3-ITD is Unfavorable

1. **Constitutive FLT3 activation:** Internal tandem duplication in the juxtamembrane domain leads to ligand-independent receptor activation and uncontrolled proliferation.
2. **High relapse risk:** FLT3-ITD is the most common molecular abnormality in pediatric AML (~25–30% of cases) and is strongly associated with higher cumulative incidence of relapse (CIR) and lower event-free survival (EFS).
3. **Requires FLT3 inhibitor escalation:** Modern protocols incorporate FLT3 inhibitors (sorafenib, midostaurin) in addition to standard chemotherapy for FLT3-ITD AML.
4. **Inverse prognostic significance:** Unlike favorable markers (CBF, APL), FLT3-ITD independently predicts worse outcome even after adjusting for other risk factors.

**High-Yield:** FLT3-ITD is one of the most important **unfavorable** prognostic markers in pediatric AML — the opposite of what the stem claims in option 3.

### Favorable Markers (Options 1, 3, 4 — all correct)

- **t(15;17) APL:** ATRA + ATO achieves >90% complete remission and excellent long-term survival; revolutionized APL management.
- **t(8;21) and inv(16) CBF-AML:** Both respond well to high-dose cytarabine consolidation; 5-year EFS ~60–70%.

**Clinical Pearl:** In pediatric AML, FLT3-ITD detection triggers intensified therapy (higher chemotherapy doses, FLT3 inhibitors, consideration of allogeneic HSCT in first remission), whereas CBF-AML and APL can often be managed with chemotherapy alone.

[cite:Harrison 21e Ch 110; Robbins 10e Ch 7]

Answer

A. t(15;17) (q24;q21) PML-RARA (acute promyelocytic leukemia) requires all-trans retinoic acid (ATRA) and arsenic trioxide as cornerstone therapy

Answer

B. inv(16)(p13q22) or t(16;16) CBFB-MYH11 is classified as core binding factor (CBF) AML with relatively good prognosis

Answer

D. t(8;21) (q22;q22) RUNX1-RUNX1T1 is associated with favorable prognosis and better response to high-dose cytarabine

Explanation

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