What is the role of high dose cytarabine (HDAC) in the consolidation phase of acute myeloid leukemia (AML) treatment?

Role of High-Dose Cytarabine (HDAC) in AML Consolidation

High-dose cytarabine (HDAC) is the standard of care for consolidation therapy in favorable-risk AML patients, while its use should be risk-stratified for intermediate and poor-risk patients based on cytogenetic and molecular profiles. 1

Risk-Stratified Approach to HDAC Consolidation

Favorable-Risk AML

• Recommended regimen: 3-4 cycles of HDAC (3 g/m² over 3 hours every 12 hours on days 1,3,5) 1
• Evidence strength: Category 1 recommendation (highest level of evidence) 1
• Alternative option: Intermediate-dose cytarabine (1,000 mg/m²) plus daunorubicin and gemtuzumab ozogamicin for CD33-positive AML (Category 2A) 1

Intermediate-Risk AML

• Recommended options:
  1. Matched sibling or alternative donor hematopoietic cell transplantation (HCT) 1
  2. HDAC 2-3 g/m² over 3 hours every 12 hours on days 1,3,5 for 3-4 cycles 1
  3. For FLT3-mutation positive: HDAC with midostaurin 50 mg every 12 hours on days 8-21 1

Poor-Risk/Treatment-Related AML

• Primary recommendation: Clinical trial or allogeneic HCT 1
• If transplant not available: HDAC consolidation (with midostaurin for FLT3-positive cases) 1

Dosing Considerations

Important evidence has emerged regarding optimal cytarabine dosing:

• No clear advantage of 3 g/m² over intermediate doses (1.5 g/m²) in intermediate-risk AML 1
• The Dutch-Belgian HOVON/SAKK study demonstrated no significant differences between intermediate-dose (1 g/m²) and high-dose (2 g/m²) cytarabine in terms of:
  • Complete remission rates (80% vs 82%)
  • 5-year event-free survival (34% vs 35%)
  • 5-year overall survival (40% vs 42%) 2
• Higher doses result in increased toxicity without therapeutic benefit, suggesting a plateau in dose-response relationship 2

Toxicity Profile

HDAC consolidation is associated with significant toxicities:

• Common toxicities: Febrile neutropenia (56.7%), nausea/vomiting (23.9%), mucositis (14.9%), diarrhea (11.9%) 3
• Serious complications: Bacteremia (34.2%), typhlitis, invasive fungal disease 3
• Treatment-related mortality: Approximately 1.8-14.3% 3, 4
• Age-related toxicity: Particularly concerning in patients >60 years (cerebellar toxicity, prolonged cytopenias) 1

Special Considerations

• Age adaptation: Consider dose reduction to 1.5-2 g/m² for patients who are less fit or older 1
• Transplant bridge: Patients awaiting donor identification may require at least one cycle of HDAC to maintain remission 1
• FLT3-positive AML: Addition of midostaurin to HDAC consolidation improves outcomes 1
• CD34+ stem cell support: Limited autologous stem cell support may reduce toxicity while maintaining efficacy 4

Practical Implementation

For optimal implementation of HDAC consolidation:

1. Assess risk category based on cytogenetics and molecular markers
2. Evaluate patient fitness for HDAC (age, comorbidities, performance status)
3. Select appropriate dose based on risk profile and patient characteristics
4. Monitor closely for toxicities, particularly cerebellar dysfunction, myelosuppression, and infections
5. Consider stem cell collection after first consolidation if autologous transplant is planned

HDAC consolidation remains a cornerstone of AML treatment, but its application must be tailored according to disease risk factors and patient characteristics, with careful attention to toxicity management.