Table 1.
Summary of randomized trials comparing cytarabine dose during induction in acute myeloid leukemia
| Authors | Study Subjects | Eligibility Criteria | Induction Cycles | Induction Regimens | Cumulative Cytarabine Dose in Planned Induction(s) | Consolidation | Outcomes |
|---|---|---|---|---|---|---|---|
| Bishop et al 1996 | 301 | de novo AML, ages 15–60 | 1 cycle if CR, up to 3 identical induction cycles | DNR 50mg/m2 D1–3 + VP16 75mg/m2 D1–7 + cytarabine 100mg/m2 D1–7 DNR 50mg/m2 D1–3 + VP16 75mg/m2 D1–7 + cytarabine 3g/m2 q12h D1,3,5,7 | 700mg/m2 24g/m2 | 2 cycles of DNR 50mg/m2 D1–2 + VP16 75mg/m2 D1–5 + cytarabine 100mg/m2 D1–5 | Improved CIR, RFS |
| Weick et al, 1996 * | 723 | de novo or secondary AML, ages 15–64 | 1 cycle | DNR 45mg/m2 D5–7 + cytarabine 200mg/m2 × D1–7 DNR 45mg/m2 D7–9 + cytarabine 2g/m2 q12h D1–6 | 1.4mg/m2 24g/m2 | CR: Randomized to 2 cycles of DNR 45mg/m2 D6–7 + cytarabine 200mg/m2 D1–7 vs 1 cycle of DNR 45mg/m2 D6–7+ cytarabine 2g/m2 q12h D1–5 CR: Nonrandomly assigned to DNR 45mg/m2 D6–7 + cytarabine 2g/m2 D1–5 | Improved CIR, RFS |
| Buchner et al, 2006 ** | 1770 | de novo or secondary AML, ages 16–85 (median 60) | 2 cycles | C1: DNR 60mg/m2 D3–5 + TG 100mg/m2 q12h D3–9 + cytarabine 100mg/m2 D1–8; C2: MTZ 10mg/m2 D3–5 + cytarabine 3g/m2 q12h D1–3 C1: MTZ 10mg/m2 D3–5 + cytarabine 3g/m2 q12h D1–3; C2: MTZ 10mg/m2 D3–5 + cytarabine 3g/m2 q12h D1–3 Note: For patients ≥60, higher dose cytarabine was dosed at 1g/m2 q12h D1–3 | 18.8g/m2 36g/m2 | CR: 1 course of DNR 60mg/m2 D3–5 + TG 100mg/m2 q12h D3–9 + cytarabine 100mg/m2 D1–8 After consolidation chemotherapy, randomized to maintenance or autoSCT | No significant difference |
| Buchner et al, 1999 ** | 725 | de novo AML, ages 16–60 (median 44) | 2 cycles | C1: DNR 60mg/m2 D3–5 + TG 100mg/m2 q12h D3–9 + cytarabine 100mg/m2 D1–8; C2: C1: DNR 60mg/m2 D3–5 + TG 100mg/m2 q12h D3–9 + cytarabine 100mg/m2 D1–8 C1: DNR 60mg/m2 D3–5 + TG 100mg/m2 q12h D3–9 + cytarabine 100mg/m2 D1–8; C2: MTZ 10mg/m2 D3–5 + cytarabine 3g/m2 q12h D1–3 | 1.6g/m2 18.8g/m2 | CR: 1 course of DNR 60mg/m2 D3–5 + TG 100mg/m2 q12h D3–9 + cytarabine 100mg/m2 D1–8 Consolidation followed by maintenance AlloSCT if <50 w/ sibling donor | No significant difference Subgroup analysis poor-risk (>40% residual blasts, adverse cytogenetics, elevated LDH): Improved CR, EFS, and OS |
| Buchner et al, 2009 | 1284 | de novo AML, ages 16–85 | 2 cycles | C1: DNR 60mg/m2 D3–5 + TG 100mg/m2 q12h D3–9 + cytarabine 100mg/m2 D1–8; C2: MTZ 10mg/m2 D3–5 + cytarabine 3g/m2 q12h D1–3 C1: MTZ 10mg/m2 D3–5 + cytarabine 3g/m2 q12h D1–3; C2: MTZ 10mg/m2 D3–5 + cytarabine 3g/m2 q12h D1–3 Note: For patients ≥60, higher dose cytarabine was dosed at 1g/m2 q12h D1–3 | 18.8g/m2 36g/m2 | CR: 1 course of DNR 60mg/m2 D3–5 + TG 100mg/m2 q12h D3–9 + cytarabine 100mg/m2 D1–8 Random assignment to autoSCT or maintenance | No significant difference |
| Lowenberg et al, 2011 | 858 | de novo AML or RAEB (IPSS≥1.5), ages 18–60 (median 49) | 2 cycles | C1: IDA 12mg/m2 D5–7 + cytarabine 200mg/m2 D1–7; C2:amsacrine 120mg/m2 D3,5,7 + cytarabine 1g/m2 q12h D1–6 C1: IDA 12mg/m2 D5–7 + cytarabine 1g/m2 q12h D1–5; C2: amsacrine 120mg/m2 D3,5,7 + cytarabine 2g/m2 q12h D1,2,4,6 | 13.4g/m2 26g/m2 | If CR after 2nd induction, risk adapted strategy of HiDAC vs alloSCT vs autoSCT | No significant difference |
| Willemze et al, 2013 | 1942 | de novo or secondary AML, ages 15–60 (median 45) | 1 cycle if CR, 2nd identical induction if PR | DNR 50mg/m2 D1,3,5 + VP16 50mg/m2 D1–5 + cytarabine 100mg/m2 D1–10 DNR 50mg/m2 D1,3,5 + VP16 50mg/m2 D1–5 + cytarabine 3g/m2 q12h D1,3,5 | 1g/m2 18g/m2 | If CR, one cycle of DNR 50mg/m2 D4–6 + cytarabine 500mg/m2 q12h D1–5 AlloSCT if suitable donor, otherwise autoSCT | Improved CR, EFS, and OS (ages <46) |
| Wei et al, 2020 | 591 | de novo AML, ages 15–55 (median 36) | Up to 2 induction cycles in conventional cytarabine arm if CR not accomplished after C1 | DNR 40mg/m2 D1–3 + omacetaxine 2mg/m2 D1–7 + cytarabine 100mg/m2 D1–7 DNR 40mg/m2 D1–3 + omacetaxine 2mg/m2 D1–7 + cytarabine 1g/m2 q12h D5–7 | 700mg/m2 6g/m2 | If CR, randomized to 1st consolidation with DNR 40mg/m2 D1–3 + cytarabine 3g/m2 q12h D1–3 vs DNR 40mg/m2 D1–3 + cytarabine 1.5mg/m2 q12h D1–3 C2: MTZ 6mg/m2 D1–3 | Improved CR, DFS, EFS, OS |
*
Initially HiDAC was dosed 3g/m2 in induction and consolidation for pts<50, however this was reduced to 2g/m2 In 1988 (DMC). In all consolidation arms, DNR was reduced to 30mg/m2 for ages 50–64.
**
Maintenance therapy after consolidation consisting of monthly cytarabine 100mg/m2 q12h SQ D1–5 paired with alternating DNR 45mg/m2 D3–4, TG 100mg/m2 q12h D1–5, and cyclophosphamide 1g/m2 D3 for 3 year duration