High-Dose Cytarabine in Induction Treatment Improves the Outcome of Adult Patients Younger Than Age 46 Years With Acute Myeloid Leukemia: Results of the EORTC-GIMEMA AML-12 Trial

Abstract

Purpose Cytarabine plays a pivotal role in the treatment of patients with acute myeloid leukemia (AML). Most centers use 7 to 10 days of cytarabine at a daily dose of 100 to 200 mg/m2 for remission induction. Consensus has not been reached on the benefit of higher dosages of cytarabine. Patients and Methods The European Organisation for Research and Treatment of Cancer (EORTC) and Gruppo Italiano Malattie Ematologiche dell' Adulto (GIMEMA) Leukemia Groups conducted a randomized trial (AML-12; Combination Chemotherapy, Stem Cell Transplant and Interleukin-2 in Treating Patients With Acute Myeloid Leukemia) in 1,942 newly diagnosed patients with AML, age 15 to 60 years, comparing remission induction treatment containing daunorubicin, etoposide, and either standard-dose (SD) cytarabine (100 mg/m2 per day by continuous infusion for 10 days) or high-dose (HD) cytarabine (3,000 mg/m2 every 12 hours by 3-hour infusion on days 1, 3, 5, and 7). Patients in complete remission (CR) received a single consolidation cycle containing daunorubicin and intermediate-dose cytarabine (500 mg/m2 every 12 hours for 6 days). Subsequently, a stem-cell transplantation was planned. The primary end point was survival. Results At a median follow-up of 6 years, overall survival was 38.7% for patients randomly assigned to SD cytarabine and 42.5% for those randomly assigned to HD cytarabine (log-rank test P = .06; multivariable analysis P = .009). For patients younger than age 46 years, survival was 43.3% and 51.9%, respectively (P = .009; multivariable analysis P = .003), and for patients age 46 to 60 years, survival was 33.9% and 32.9%, respectively (P = .91). CR rates were 72.0% and 78.7%, respectively (P < .001) and were 75.6% and 82.4% for patients younger than age 46 years (P = .01) and 68.3% and 74.8% for patients age 46 years and older (P = .03). Patients of all ages with very-bad-risk cytogenetic abnormalities and/or FLT3-ITD (internal tandem duplication) mutation, or with secondary AML benefitted from HD cytarabine. Conclusion HD cytarabine produces higher remission and survival rates than SD cytarabine, especially in patients younger than age 46 years.

Acute myeloid leukemia—Major progress over four decades and glimpses into the future

“…Among patients 45 years or younger, the high-dose cytarabine was associated with significantly higher CR rates (82% versus 76%; p 5 0.01), 6-year event-free survival rates (44% versus 35%; p 5 0.003), and 6-year survival rates (52% versus 43%; p 5 0.009). Among patients of 45-60 years, high-dose cytarabine was also associated with significant improvements in CR and 6-year eventfree survival rates, as well as a trend for better survival among patients with FLT3-ITD AML or poor prognosis karyotypes [77].…”

Minimal residual disease as biomarker for optimal biologic dosing of ARA‐C in patients with acute myeloid leukemia

“…Between January 1998 and January 2008, 163 consecutive adult patients <60 years old with de novo non-M3 AML were enrolled into the European Organization for Research and Treatment of Cancer (EORTC)/Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) protocols AML-10 [5] and AML-12 [14], at Tor Vergata University and St Eugenio Hospital. Of the initial enrollees, 144 (88%) expressed a leukemia-associated immunophenotype (LAIP) at the time of diagnosis, and 130 (80%) achieved m-CR after induction, thus qualifying for the present analysis.…”

“…In the AML-12 trial, patients were randomly assigned to HDAC (3 g/m 2 /12 hr for 4 days) plus daunorubicin (50 mg/m 2 /day on Days 1,3, and 5) and etoposide (100 mg/m 2 /day on Days 1-5) or agents of the AML-10 DCE arm. The consolidation regimen for patients achieving m-CR received was the same as that of the AML-10 trial, followed by ASCT or AuSCT based on donor availability [14]. The present analysis was confined to all AML-12 subjects and the AML-10 DCE patient subset for full comparability.…”

“…1B). According to a recent EORTC/GIMEMA publication [14], patients <46 years old are likely to benefit most from an HDAC regimen. On this basis, the distribution of MRD status was further analyzed by age.…”

“…Whereas no clear prognostic advantage for HDAC over intermediate/SDAC was shown by the first study [13], HDAC was associated with a higher CR rate and survival advantage in the second trial, albeit in patients <46 years old and those with secondary AML or adverse-risk genetic/cytogenetic profiles [14]. Hence, the superiority of HDAC over SDAC is still in contention, fueled only by the oncologic premise that "more is better."…”