What is the efficacy and safety of different treatment regimens, including chemotherapy and hematopoietic stem cell transplantation (HSCT), in pediatric patients (children and adolescents under 18) with acute myeloid leukemia (AML)?

Novel High-Level Topics for Systematic Review and Meta-Analysis in Pediatric Hematology

Based on the evidence gaps identified in current pediatric AML guidelines and research, the most impactful systematic review would examine the optimal conditioning regimen for allogeneic HSCT in pediatric AML, comparing myeloablative chemotherapy-based protocols versus reduced-intensity approaches across different risk groups, with primary outcomes of overall survival, disease-free survival, and treatment-related mortality. 1

High-Priority Topics with Clinical Equipoise

1. Optimal Conditioning Regimens for Pediatric AML HSCT

• Current guidelines acknowledge that "the optimal conditioning regimen remains to be identified and standardized" despite consensus that myeloablative chemotherapy is preferred over total body irradiation 1
• This represents a critical knowledge gap affecting mortality and quality of life through late effects and secondary malignancies 1
• A meta-analysis could stratify by risk group, donor type, and specific conditioning protocols to identify optimal approaches 1

2. Role of Allogeneic HSCT in Intermediate-Risk Pediatric AML in First Complete Remission

• Guidelines explicitly state that results for intermediate-risk patients are "controversial, showing either no benefit in first CR or some benefit" 1
• Recent meta-analysis showed improved overall survival (RR 1.15,95% CI 1.06-1.24) and disease-free survival (RR 1.31,95% CI 1.17-1.47) with allo-HSCT in high-risk patients 2
• A systematic review incorporating molecular stratification and MRD monitoring could refine indications for intermediate-risk patients 2
• This directly impacts the "at least 10 children must be transplanted to avoid 1 relapse" calculation mentioned in guidelines 1

3. Optimal Number and Composition of Intrathecal Treatments for CNS Prophylaxis

• Guidelines acknowledge "the optimal number of intrathecal treatments (range 4-12) remains unknown" 1
• Evidence shows changing from triple intrathecal therapy to cytarabine alone increased CNS relapse rates, but optimal regimen is undefined 1
• This affects both efficacy and quality of life through neurotoxicity 1

4. Anthracycline Dose Optimization and Cardioprotection Strategies

• Guidelines note cumulative doses >300 mg/m² cause significant cardiotoxicity but optimal dosing remains unclear 1, 3
• Liposomal daunorubicin allows dose escalation to 80 mg/m² × 3 days without increased cardiotoxicity, but comparative effectiveness is understudied 1
• Alternative agents like homoharringtonine show promise with lower anthracycline exposure (cumulative HHT 165 mg/m², daunorubicin only 120 mg/m²) achieving 65% 5-year OS 4
• A meta-analysis comparing anthracycline dosing strategies, formulations, and cardioprotection approaches would directly impact long-term quality of life 3, 5

5. Optimal Salvage Therapy for Relapsed/Refractory Pediatric AML

• Survival after relapse improved dramatically from 19% (1987-1992) to 45% (2005-2010), primarily through better salvage therapy and HSCT allocation 6
• Multiple regimens exist (fludarabine/cytarabine/G-CSF with or without liposomal daunorubicin, clofarabine-based) with second CR rates of 59-69% 1, 3
• A network meta-analysis comparing salvage regimens stratified by relapse timing (early vs. late) and prior therapy would guide treatment selection 1

6. Role of Minimal Residual Disease Monitoring in Treatment Allocation

• Guidelines note "high levels of MRD before HSCT have been associated with poorer outcome" but specific thresholds for treatment decisions are undefined 1
• MRD is identified as crucial for risk stratification but optimal timing, methodology, and response-adapted strategies lack standardization 3, 2
• A systematic review of MRD-guided treatment algorithms could refine HSCT indications 2

7. Haploidentical HSCT versus Matched Unrelated Donor HSCT in Pediatric AML

• Guidelines acknowledge "recently improved outcome with HSCT using unrelated matched donors" but comparative effectiveness with haploidentical donors is unclear 1
• Haploidentical HSCT shows promising results even in IC1st-resistant patients (76.3% 3-year OS) 7
• A meta-analysis comparing donor types stratified by risk group and MRD status would inform donor selection algorithms 7

Methodological Considerations for High-Impact Reviews

Why These Topics Are Ideal for Systematic Review:

• Clinical equipoise exists - guidelines explicitly acknowledge uncertainty 1
• Multiple studies available - sufficient literature exists for meta-analysis 2, 6
• Direct impact on mortality and quality of life - not surrogate endpoints 1, 3
• Actionable results - findings would immediately inform treatment protocols 1

Common Pitfalls to Avoid:

• Do not select topics where guidelines already provide clear recommendations (e.g., auto-HSCT in first CR - clearly not beneficial) 1
• Avoid topics with insufficient published data (e.g., novel targeted therapies with limited pediatric experience) 8
• Do not choose topics addressing only surrogate endpoints without survival or quality of life data 1

The conditioning regimen topic represents the single most impactful opportunity because it affects every transplanted patient, has explicit guideline acknowledgment of uncertainty, and directly impacts both mortality through treatment-related complications and quality of life through late effects. 1