Idarubicin dose escalation during consolidation therapy in adult AML patients - phase III ALLG M12 study

Increased doses of daunorubicin, an anthracycline, during induction therapy have been shown to improve remission rates and survival in Acute Myeloid Leukemia (AML) patients.¹

In order to further improve the outcomes of AML patients by increased anthracycline dose, Kenneth F. Bradstock from the Westhead Hospital, University of Sydney, and colleagues, on behalf of the Australasian Leukaemia & Lymphoma Group (ALLG), conducted a phase III study (ALLG M12, Australian New Zealand Clinical Trials Registry [ANZCTR] number – 12605000095662) in which standard consolidation was compared to increased idarubicin dose during consolidation therapy after high-dose cytarabine-based induction. The results of the study were published ahead of print in the Journal of Clinical Oncology on 3^rd April 2017.²

A total of 293 AML patients (median age = 45 years) in complete remission after induction therapy were randomly assigned to receive two cycles of standard (cytarabine 100 mg/m² daily for 5 days and etoposide 75 mg/m² daily for 5 days, n = 146) or intensive (idarubicin 9 mg/m² daily for either 2 or 3 days, n = 147) consolidation treatment.

The key results of the study were:

• 3-year Leukemia Free Survival (LFS) in patients in the intensive and standard arm; 47% vs 35%, HR = 0.74, P = 0.045
• 3-year Overall Survival (OS) in patients in the intensive and standard arm; 61% vs 50%, HR = 0.75, P = 0.092
• Duration of grade 3–4 neutropenia and thrombocytopenia was significantly longer in the intensive arm than the standard arm
• Grade 3–4 non-hematological toxicities were similar in both the intensive and standard arms
• There was no benefit for intensive consolidation in specific cytogenetics and FLT3 and NPM1 gene mutation subgroups

The authors concluded by stating that “increased dose intensity of idarubicin during consolidation therapy for adult AML results in improved LFS, without increased non-hematologic toxicity”. They further suggested that increased idarubicin intensity should be explored in order to improve outcomes of patients with AML.

Abstract

Purpose

Higher doses of the anthracycline daunorubicin during induction therapy for acute myeloid leukemia (AML) have been shown to improve remission rates and survival. We hypothesized that improvements in outcomes in adult AML may be further achieved by increased anthracycline dose during consolidation therapy.

Patients and Methods

Patients with AML in complete remission after induction therapy were randomly assigned to receive two cycles of consolidation therapy with cytarabine 100 mg/m2 daily for 5 days, etoposide 75 mg/m2 daily for 5 days, and idarubicin 9 mg/m2 daily for either 2 or 3 days (standard and intensive arms, respectively). The primary end point was leukemia-free survival (LFS).

Results

Two hundred ninety-three patients 16 to 60 years of age, excluding those with core binding factor AML and acute promyelocytic leukemia, were randomly assigned to treatment groups (146 to the standard arm and 147 to the intensive arm). Both groups were balanced for age, karyotypic risk, and FLT3–internal tandem duplication and NPM1 gene mutations. One hundred twenty patients in the standard arm (82%) and 95 patients in the intensive arm (65%) completed planned consolidation (P < .001). Durations of severe neutropenia and thrombocytopenia were prolonged in the intensive arm, but there were no differences in serious nonhematological toxicities. With a median follow-up of 5.3 years (range, 0.6 to 9.9 years), there was a statistically significant improvement in LFS in the intensive arm compared with the standard arm (3-year LFS, 47% [95% CI, 40% to 56%] v 35% [95% CI, 28% to 44%]; P = .045). At 5 years, the overall survival rate was 57% in the intensive arm and 47% in the standard arm (P = .092). There was no evidence of selective benefit of intensive consolidation within the cytogenetic or FLT3–internal tandem duplication and NPM1 gene mutation subgroups.

Conclusion

An increased cumulative dose of idarubicin during consolidation therapy for adult AML resulted in improved LFS, without increased nonhematologic toxicity.