Anthracycline Dose Intensification in Acute Myeloid Leukemia

Abstract

BACKGROUND In young adults with acute myeloid leukemia (AML), intensification of the anthracycline dose during induction therapy has improved the rate of complete remission but not of overall survival. We evaluated the use of cytarabine plus either standard-dose or high-dose daunorubicin as induction therapy, followed by intensive consolidation therapy, in inducing complete remission to improve overall survival. METHODS In this phase 3 randomized trial, we assigned 657 patients between the ages of 17 and 60 years who had untreated AML to receive three once-daily doses of daunorubicin at either the standard dose (45 mg per square meter of body-surface area) or a high dose (90 mg per square meter), combined with seven daily doses of cytarabine (100 mg per square meter) by continuous intravenous infusion. Patients who had a complete remission were offered either allogeneic hematopoietic stem-cell transplantation or high-dose cytarabine, with or without a single dose of the monoclonal antibody gemtuzumab ozogamicin, followed by autologous stem-cell transplantation. The primary end point was overall survival. RESULTS In the intention-to-treat analysis, high-dose daunorubicin, as compared with a standard dose of the drug, resulted in a higher rate of complete remission (70.6% vs. 57.3%, P<0.001) and improved overall survival (median, 23.7 vs. 15.7 months; P = 0.003). The rates of serious adverse events were similar in the two groups. Median follow-up was 25.2 months. CONCLUSIONS In young adults with AML, intensifying induction therapy with a high daily dose of daunorubicin improved the rate of complete remission and the duration of overall survival, as compared with the standard dose.

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

“…In the study involving younger patients, high-dose daunorubicin was associated with a significantly higher CR rate (71% versus 57%; p < 0.001) and longer survival (median 24 versus 16 months; p 5 0.003). But the benefit was observed only in patients younger than 50 years and those with normal karyotypes [72]. In the study of older patients, high-dose daunorubicin was associated with a higher CR rate (64% versus 54%; p 5 0.002) but not with improved survival, although a survival benefit was observed in the subset of patients 60-65 years old [94].…”

“…High-dose cytarabine consolidations were followed by 4 additional courses of 2 1 5 chemotherapy [71]. The latter addition has been omitted from the subsequent comparative trials, an important consideration since later studies using this regimen as the standard of care reported five-year survival rates of 20-30% rather than 40% [72]. Following the findings of this pivotal trial, high-dose cytarabine for 4 consolidations became the consolidation standard of care in AML.…”

“…Traditionally, daunorubicin 45-60 mg/m 2 daily 3 3 is used for induction therapy. Two studies compared higher dose daunorubicin 90 mg/m 2 daily 3 3 to daunorubicin 45 mg/m 2 daily 3 3, both in combination with cytarabine 100-200 mg/m 2 daily 3 7 in younger (age less than 60 years) and older patients (age 601 years) [72,94]. In the study involving younger patients, high-dose daunorubicin was associated with a significantly higher CR rate (71% versus 57%; p < 0.001) and longer survival (median 24 versus 16 months; p 5 0.003).…”

Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia

“…31 These findings were subsequently confirmed in numerous other trials. [33][34][35][36][37] In general, patients with FLT3-ITD AML achieve complete remission rates comparable to those of patients with wild-type disease, but have significantly higher rates of relapse and shorter durations of disease-free and overall survival (OS). 31,[33][34][35] In the Medical Research Council studies, patients with FLT3-ITD AML had a 74% relapse rate vs 48% for patients with FLT3-wild-type AML.…”

Comparison of 60 or 90 mg/m2 of daunorubicin in induction therapy for acute myeloid leukemia with intermediate or unfavorable cytogenetics

“…Recently, the use of high dose 90 mg/ m 2 daunorubicin (DNR) was reported in several phase III clinical trials to improve both complete remission (CR) rate and overall survival (OS) as compared with low dose DNR (45 mg/m 2 ) and is now considered as a standard of care [1,2]. However, the dose of 45 mg/m 2 is not used worldwide and several groups use intermediate dose of 60 mg/m 2 and reported OS of approximately 40%-45% at 5 years in younger AML patients [3,4].…”