Background
Phase III RCT (CALGB 8525); 1088 patients with newly diagnosed AML received 7+3 induction (5+2 if day-14 marrow ≥5% blasts), and the 596 who achieved CR were randomized to one of three cytarabine dose levels for consolidation, then 4 monthly maintenance courses.
Interventions and follow up
Arm A: Cytarabine 100 mg/m2/d CIV days 1-5
Arm B: Cytarabine 400 mg/m2/d CIV days 1-5
Arm C: Cytarabine 3 g/m2 BID days 1, 3, 5 (HiDAC)
Post-consolidation: all received 4 monthly courses cytarabine 100 mg/m2 SQ BID x5d + daunorubicin 45 mg/m2 x1d
Primary endpoint: OS / DFS
Median follow-up: 52 mo
Arm B: Cytarabine 400 mg/m2/d CIV days 1-5
Arm C: Cytarabine 3 g/m2 BID days 1, 3, 5 (HiDAC)
Post-consolidation: all received 4 monthly courses cytarabine 100 mg/m2 SQ BID x5d + daunorubicin 45 mg/m2 x1d
Primary endpoint: OS / DFS
Median follow-up: 52 mo
Results
Induction CR: 64% overall (75% if <40y, 68% if 40-60y, 47% if >60y); 68% with one induction course
4-yr DFS (all): 21% vs 25% vs 39% (A vs B vs C); A vs C HR 0.67, 95%CI 0.53-0.86; A vs B HR 0.75, 95%CI 0.60-0.94
4-yr DFS (≤60y): 24% vs 29% vs 44%, P=.002
4-yr DFS (>60y): ≤16% in each group
4-yr OS (all): 31% vs 35% vs 46%; A vs C HR 0.74, 95%CI 0.57-0.96; A vs B HR 0.78, 95%CI 0.61-1.00
4-yr OS (≤60y): 35% vs 40% vs 52%, P=.02
4-yr DFS (all): 21% vs 25% vs 39% (A vs B vs C); A vs C HR 0.67, 95%CI 0.53-0.86; A vs B HR 0.75, 95%CI 0.60-0.94
4-yr DFS (≤60y): 24% vs 29% vs 44%, P=.002
4-yr DFS (>60y): ≤16% in each group
4-yr OS (all): 31% vs 35% vs 46%; A vs C HR 0.74, 95%CI 0.57-0.96; A vs B HR 0.78, 95%CI 0.61-1.00
4-yr OS (≤60y): 35% vs 40% vs 52%, P=.02
Adverse events
Hematologic/cytopenias: Severe myelosuppression universal across all dose groups; HiDAC produced the most prolonged cytopenias.
Neurologic: Serious CNS (cerebellar) toxicity occurred only with HiDAC (Arm C, 12%).
Tolerability: Courses requiring hospitalization 16% vs 59% vs 71%; post-remission cytarabine delivered to 76% vs 74% vs 56%; only 29% of patients >60y tolerated HiDAC.
Neurologic: Serious CNS (cerebellar) toxicity occurred only with HiDAC (Arm C, 12%).
Tolerability: Courses requiring hospitalization 16% vs 59% vs 71%; post-remission cytarabine delivered to 76% vs 74% vs 56%; only 29% of patients >60y tolerated HiDAC.
Conclusions
A significant cytarabine dose-response was demonstrated for post-remission therapy in AML; high-dose cytarabine (3 g/m2) improved DFS and OS versus lower doses, particularly in patients ≤60 years, establishing HiDAC consolidation as standard.
Key Limitations
Benefit confined to younger patients; HiDAC poorly tolerated and not beneficial in those >60y. Predates molecular/cytogenetic risk stratification; cytogenetic subgroups not prospectively defined. No allogeneic HCT comparison.
Clinical Context
Landmark trial establishing HiDAC consolidation as standard post-remission therapy for younger adults with AML, particularly favorable-risk (e.g., core-binding factor) disease, per ELN/ASCO frameworks. Predates targeted-agent and MRD-guided approaches.
7+3: cytarabine 200 mg/m2 x7d + daunorubicin 45 mg/m2 days 1-3 (30 mg/m2 if >60y). 5+2: 5 days cytarabine + 2 days daunorubicin.
7+3: cytarabine 200 mg/m2 x7d + daunorubicin 45 mg/m2 days 1-3 (30 mg/m2 if >60y). 5+2: 5 days cytarabine + 2 days daunorubicin.
References