The Intermediate Dose Verse Conventional Dose Cytarabine in Induction Therapy in Adult Acute Myeloid Leukemia: A Phase Ⅲ Randomized Controlled Trial

Purpose: A daily dose of 100 to 200 mg/m² cytarabine for induction therapy in adult acute myeloid leukemia (AML) has been widely used. There is no consensus whether higher dosages of cytarabine can improve outcomes of adult AML.

Patients and Methods: A phase Ⅲ randomized parallel controlled trial was conducted. The patients were randomly assigned to receive either intermediate-dose cytarabine, 100 mg/m² per day as a 12-hour IV infusion on days 1 through 4 and 1,000 mg/m² every 12 hours as a 3-hour IV infusion on days 5, 6, and 7, or conventional dose cytarabine, 100 mg/m² per day as a 12-hour IV infusion for 7 days, combined with homoharringtonine 2mg/m² for 7 days and daunorubicin 40mg/m² for 3 days for induction therapy in adult AML. All patients who achieved CR were randomly assigned to receive either high dose of cytarabine (3,000 mg/m²every 12 hours as a 3-hour IV infusion on days 1, 2, and 3) or intermediate dose of cytarabine (1,500 mg/m²every 12 hours as a 3-hour IV infusion on days 1, 2, and 3) combined with anthracycline (daunorubicin or mitoxane). Allogeneic stem-cell transplantation was based on genetic risk and patients' intention. The study was approved by the ethical committee of Blood Disease Hospital, CAMS and was conducted in accordance with the Declaration of Helsinki. All patients signed the informed consent. The primary endpoint is disease-free survival (DFS). The duration of neutropenia and thrombocytopenia was analyzed in patients who achieved CR and defined as the time from start of induction treatment to the last day on which neutrophil count was less than 0.5 × 10⁹ neutrophils per L and platelet count was less than 25 × 10⁹ platelets per L. The trial is registered at www.chictr.org.cn (identifier: ChiCTR-TRC-10001202)

Results: Five hundred and ninety-six newly diagnosed patients with de novo AML were enrolled. Five patients were excluded for misdiagnosis (3 patients), withdrawal of consent (1 patent), and not meeting inclusion criteria (1 patent). Overall, the median age of eligible 591 randomized patients was 36 (15 to 55) years. Two hundred and twenty-nine of 296 patients (77.4%) in the conventional dose group, and 256 of 295 (86.8%) in the intermediate dose group, achieved CR (P=0.003). Early death within 30 days was 2.4% and 1.4% in intermediate and conventional dose group, respectively, and without significant difference (P=0.355). There was no significant difference in the duration of neutropenia between intermediate and conventional dose group (21 vs 20 days, respectively, P=0.520). But patients receiving intermediate dose required a slightly but significantly longer time to recover from thrombocytopenia. Median duration with a platelet count less than 25 × 109/L was 20 days for the conventional dose group and 22 days for the intermediate dose group (P=0.020). There was a trend toward more bacteria sepsis and RBC transfusion in intermediate dose group compared with conventional dose group (P=0.092 and P=0.093, respectively).

The median follow-up of survivors is 30.4(5.1-74.4) months. The probability of 3-year DFS patients were 66.7% for the intermediate dose group (95% CI 60.4% to 72.9%) and 55.4% for the conventional dose group (95% CI 48.3% to 62.4%), respectively (P=0.013). And the probability of 3-year overall survival (OS) were 67.7% for the intermediate dose group (95% CI 61.8% to 73.7%) and 59.3% for the convention al dose group (95% CI 53.1% to 65.5%), respectively (P=0.0604). Subgroup analysis was performed to reveal whether different risk groups benefited from dose escalation of cytarabine. For patients in non-adverse risk subgroup, the 3-year DFS were 69.7% in the intermediate dose group and 56.1% in the conventional dose group (P= 0.004). The 3-year OS were 72.0% in the intermediate dose group and 60.8% in the conventional group (P= 0.017).

Conclusion: Induction regimen with dose escalation of cytarabine in adult AML is well tolerated and superior to conventional dose for DFS, especially for patients in non-adverse risk patients.

Acknowledgments: This study was supported, in part, by State Key Program of National Natural Science of China (81430004),Foundation for Innovative Research Groups of the NaturalScience Foundation of China (81421002)