Abstract
Introduction: Until now, the standard induction therapy for acute myeloid leukemia (AML) has been a continuous infusion of cytarabine at 100 to 200 mg/m² per day for 7 days, combined with either idarubicin at 12 mg/m² per day or daunorubicin at 45 to 90 mg/m² per day for 3 days. In a phase 1 clinical trial using the traditional 3+3 design, the maximal tolerated dose (MTD) of idarubicin was not reached when starting at 12 mg/m² per day, with dose escalations of 3 mg/m² up to 18 mg/m². Based on the results of this phase 1 study, we conducted a phase 2 clinical study to investigate the safety and efficacy of an intensified dose of idarubicin in treating acute myeloid leukemia.
Methods: Patients aged 20 to 65 years with previously untreated de novo or secondary acute myeloid leukemia, including biphenotypic leukemia, and with adequate organ function, were treated with idarubicin at 18 mg/m² per day for 3 days, along with a continuous infusion of cytarabine at 100 mg/m² per day for 7 days in this phase 2 clinical study. Survival analyses were conducted using the Kaplan-Meier method, with comparisons evaluated through the log-rank test.
Results: Thirty-eight patients were enrolled in the study between February 2014 and August 2023. One patient was excluded due to death from bacterial pneumonia on day 7 of induction therapy, resulting in a total of 37 patients analyzed for outcomes. The median age of the evaluable patients was 51 years (range: 21 to 64). Males represented 22 of the study population (59.5%). Thirty-two cases were identified as de novo AML (86.5%). The majority of patients had an ECOG performance status of 1 (83.8%). According to the European LeukemiaNet (ELN) risk stratification, ten, fifteen, and twelve patients were categorized as having favorable risk, intermediate risk, and adverse risk, respectively (27.0% vs. 40.5% vs. 32.4%).
The median times to recovery for neutrophils (ANC ≥ 500/µL) and platelets (platelet count ≥ 20,000/µL) following the start of induction therapy were day 24 (range: 16 to 61) and day 20 (range: 10 to 101), respectively. The duration of neutropenia (ANC < 500/µL) was 19 days (range: 6 to 49). Grade 4 hematologic toxicities were observed in all patients, as anticipated with this AML induction therapy. Three grade 4 adverse events were reported according to NCI CTCAE (one case of mucositis, one case of nausea, and one case of fever). At 4 weeks post-induction therapy, the morphology-based complete remission (CR) rate was 70.3%, with 48.6% achieving cytogenetic CR and 8.1% achieving molecular CR. The 5-year event-free survival (EFS) was 38.1%, with a median EFS of 24.0 months. The 5-year overall survival (OS) was 52.3%, and the median OS had not been reached by the final data cutoff (July 11, 2025).
EFS curves showed significant differences between the CR group and the non-CR group (P < 0.0001), with median EFS being “not reached” in the CR group versus 6 months in the non-CR group. Similarly, the OS curves differed significantly between the two groups (P = 0.0092), with median OS being “not reached” versus 12 months. EFS curves significantly varied among the ELN risk categories (median EFS: favorable “not reached” vs. intermediate 47 months vs. poor 6.5 months, P = 0.022), though the OS curves did not differ significantly (median OS: “not reached” vs. “not reached” vs. 14 months, P = 0.21). Among patients who underwent allogeneic stem cell transplantation at either CR or non-CR status, EFS and OS curves showed significant differences (EFS, P = 0.001; OS, P = 0.017). The median OS was higher in the de novo AML group compared to the secondary AML group (90 months vs. 10 months, P = 0.037).
Conclusions: Intensifying the dose of idarubicin was effective and safe for remission induction therapy in adult AML patients. A phase 3 trial is warranted, and we propose an induction therapy regimen consisting of idarubicin at 18 mg/m² per day for 3 days alongside cytarabine at 100 mg/m² per day as a continuous infusion for 7 days in adult AML patients without mutated FLT3. This trial was registered at www.clinicaltrials.gov under #NCT01518556.
