What is HDAC (Histone Deacetylase) consolidation in cancer treatment?

HiDAC Consolidation in Acute Myeloid Leukemia

For younger patients with AML (<50 years), HiDAC consolidation at 3 g/m² every 12 hours on days 1,3, and 5 for 3-4 cycles achieves a 4-year disease-free survival of 44% and represents the standard consolidation approach for favorable and intermediate-risk disease. 1

Definition and Dosing

HiDAC (High-Dose Cytarabine) consolidation refers to post-remission therapy using cytarabine at doses of 1.5-3 g/m² administered every 12 hours, typically for 3-4 cycles. 1 This differs fundamentally from standard-dose cytarabine (100-200 mg/m²) and serves to prevent relapse after achieving complete remission. 1

Evidence-Based Dosing by Age and Risk Group

Patients <50 Years Old

• Optimal regimen: 3 g/m² every 12 hours on days 1,3, and 5 per course for 4 cycles achieved 4-year DFS of 44% in the CALGB trial. 1
• Alternative regimen: 2 g/m² every 12 hours for 6 days for 2 cycles achieved comparable 4-year OS of 52% in the SWOG trial. 1
• The SWOG data demonstrates that patients receiving both HiDAC induction and consolidation had superior outcomes (52% OS, 34% DFS at 4 years) compared to standard-dose approaches. 1

Patients 50-60 Years Old

• Preferred dose: 2 g/m² is recommended over 3 g/m² due to toxicity concerns. 1
• The original 3 g/m² dose was reduced to 2 g/m² in the SWOG trial after excessive treatment-related mortality (14% vs 5%) and neurologic toxicity (8% vs 2%) were observed. 1

Patients >60 Years Old

• HiDAC consolidation at 2-3 g/m² can be used, but intermediate-dose cytarabine (1.5 g/m²) may be more appropriate for less fit patients. 1
• No evidence supports superiority of HiDAC (2-3 g/m²) over intermediate-dose (1.5 g/m²) cytarabine in intermediate-risk AML for this age group. 1

Risk-Stratified Recommendations

Favorable-Risk Cytogenetics (CBF without KIT mutation)

• First-line: 3-4 cycles of HiDAC (Category 1 recommendation). 1
• Alternative: Intermediate-dose cytarabine (1,000 mg/m²) plus daunorubicin and gemtuzumab ozogamicin for CD33-positive disease. 1
• Allogeneic transplant is NOT recommended in first remission for favorable-risk disease outside clinical trials. 1

Intermediate-Risk Cytogenetics

• Preferred: Matched sibling or alternate donor allogeneic HCT provides lower relapse risk. 1
• Alternative: 3-4 cycles of HiDAC at 2 g/m² (preferred dose) or 2-3 g/m² for less fit patients. 1
• For FLT3-mutation-positive AML: HiDAC (1.5-3 g/m²) with midostaurin should be considered. 1
• Autologous HCT is NOT recommended outside clinical trials due to improvements in allogeneic transplant options. 1

Critical Toxicity Monitoring

Neurologic Toxicity

• Consolidation at 3 g/m²: 16% grade ≥3 neurologic toxicity vs 0% with standard dose in patients <50 years. 1
• Consolidation at 2 g/m²: 2% grade ≥3 neurologic toxicity vs 0% with standard dose. 1
• Neurologic function must be closely monitored throughout treatment, with dose reduction or discontinuation for significant toxicity. 1

Treatment-Related Mortality

• Consolidation at 3 g/m²: 4% treatment-related deaths vs 0% with standard dose. 1
• Consolidation at 2 g/m²: 2% treatment-related deaths vs 0% with standard dose. 1
• Overall treatment-related mortality with HiDAC consolidation ranges from 5-12% across trials. 1

Renal Insufficiency

• Renal function requires close monitoring as risk increases with HiDAC. 1
• Dose adjustments should be made for declining renal function during treatment. 1

Number of Cycles

• Standard approach: 4 cycles of HiDAC consolidation per CALGB trial. 1
• Alternative approach: 2 cycles may be sufficient if HiDAC was used during induction or if early autologous HCT is planned. 1
• The decision on cycle number should account for whether high-dose therapy was used during induction, as fewer consolidation cycles may be needed. 1

Common Pitfalls to Avoid

• Do not use 3 g/m² in patients ≥50 years: This dose was abandoned in the SWOG trial due to excessive toxicity (10% treatment-related deaths, 16% grade ≥3 neurotoxicity). 1
• Do not proceed with consolidation without assessing fitness: Twice as many patients in the HiDAC induction arm failed to proceed to consolidation compared to standard-dose arms. 1
• Do not ignore cytogenetic risk stratification: Response rates vary dramatically by risk group (87% CR for favorable-risk vs 62% for poor-risk). 1
• Do not use HiDAC consolidation for poor-risk cytogenetics: These patients should proceed directly to allogeneic HCT rather than receive multiple cycles of chemotherapy. 1