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Survival Benefit With High-Dose Cytarabine Induction in AML Patients Aged < 46 Years

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Key Points

  • High-dose vs standard-dose cytarabine induction was associated with borderline significant greater survival in all patients.
  • Results became significant on multivariate analysis adjusting for cytogenetic features, age, disease type, white blood cell count at diagnosis, and performance status.
  • High-dose cytarabine was associated with significantly greater survival among patients aged < 46 years.

In a European Organisation for Research and Treatment of Cancer (EORTC) and Gruppo Italiano Malattie Ematologiche dell’ Adulto (GIMEMA) phase III trial (AML-12) reported in Journal of Clinical Oncology, Willemze et al compared induction regimens containing high-dose or standard-dose cytarabine in patients with newly diagnosed acute myeloid leukemia (AML). They found that the high-dose regimen was associated with improved overall survival, particularly among patients aged < 46 years.

Study Details

In the trial, 1,942 patients with newly diagnosed AML aged 15 to 60 years received induction therapy with daunorubicin, etoposide, and either standard-dose cytarabine (n = 969; 100 mg/m2 per day by continuous infusion for 10 days) or high-dose cytarabine (n = 973; 3,000 mg/m2 every 12 hours by 3-hour infusion on days 1, 3, 5, and 7). Patients in complete remission received a single consolidation cycle containing daunorubicin and intermediate-dose cytarabine (500 mg/m2 every 12 hours for 6 days). Stem cell transplantation was planned. The primary endpoint was overall survival.

Median age was 45 years in both groups, and 52% of both groups were male. The high-dose and standard-dose groups were balanced for World Health Organization performance status (0-1 in 90% of both), de novo AML (94.5% and 93.5%), presence of FLT3-ITD mutation (14% and 13%), white blood cell counts at diagnosis, cytogenetics (intermediate risk in 27% and 30%), and donor availability in those achieving complete remission.

Overall Survival

Median follow-up was 6 years. Six-year overall survival rates were 42.5% in the high-dose group vs 38.7% in the standard-dose group (hazard ratio [HR] = 0.89, P = .06). In multivariate analysis adjusting for cytogenetic features, age, disease type, white blood cell counts at diagnosis, and performance status, the high-dose group had significantly better overall survival (HR = 0.86, P < .009). Among the 490 high-dose patients and 490 standard-dose patients aged < 46 years, 6-year survival was 51.9% vs 43.3% (HR = 0.79, P = .009; multivariate analysis P = .003). Among the 483 and 479 patients aged 46 to 60 years, 6-year survival was 32.9% vs 33.9% (HR = 0.99, P = .91). Complete remission rates were 78.7% vs 72.0% (P = .009), including 82.4% vs 75.6% in patients aged < 46 years (P = .01) and 74.8% vs 68.3% in patients aged ≥ 46 years (P = .03).

Toxicities

Grade 3 and 4 nonhematologic toxicities were similar in the two groups during induction and consolidation; grade 2 or 3 conjunctivitis was more common during induction in the high-dose group (12.4% vs 0.5%). Grade 3 or 4 infectious complications occurred in 66.2% of high-dose patients and 67.6% of standard-dose patients. Median time to neutrophil recovery after the start of induction was 25 and 27 days, and median time to platelet recovery was 27 and 29 days. After consolidation, median time to neutrophil recovery was 22 days in both groups and median time to platelet recovery was 22 and 20 days.

The investigators concluded: “[High-dose] cytarabine produces higher remission and survival rates than [standard-dose] cytarabine, especially in patients younger than age 46 years.”

Roelof Willemze, MD, PhD, of Leiden University Medical Center, is the corresponding author for the Journal of Clinical Oncology article.

The study was supported by the EORTC Charitable Trust. Study author Theo de Witte, MD, PhD, has served in a consultant or advisory role for Novartis and has received research funding from Novartis.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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