A randomized trial of high-versus conventional-dose cytarabine in consolidation chemotherapy for adult de novo acute myeloid leukemia in first remission after induction therapy containing high-dose cytarabine

Abstract

The value of administering sequential courses of chemotherapy containing highdose cytarabine in both induction and consolidation therapy for acute myeloid leukemia (AML) has not been assessed in a prospective randomized trial. Two hundred ninety-two AML patients aged 15 to 60 years were enrolled in the Australasian Leukaemia and Lymphoma Group (ALLG) AML trial number 7 (M7) protocol to evaluate this question. All received induction therapy with the ICE protocol (idarubicin 9 mg/ m 2 ؋ 3; cytarabine 3 g/m 2 twice a day on days 1, 3, 5, 7; etoposide 75 mg/m 2 ؋ 7). Complete remission was achieved in 234 (80%) patients. Two hundred two patients in remission were then randomized to either a further identical cycle of ICE or 2 attenuated courses (cytarabine 100 mg/m 2 daily ؋ 5, idarubicin ؋ 2, etoposide ؋ 5 [IcE]). ICE consolidation therapy was more toxic than IcE, however, the treatment-related death rate was not significantly different. There was no difference between the 2 consolidation arms for relapse-free survival at 3 years (49% for ICE vs 46% for IcE; P ‫؍‬ .66), survival following randomization (61% vs 62%; P ‫؍‬ .91), or the cumulative incidence of relapse (43% vs 51%; P ‫؍‬ .31), and there was no difference within cytogenetic risk groups. Intensive induction chemotherapy incorporating high-dose cytarabine results in high complete remission rates, but further intensive consolidation treatment does not appear to confer additional benefit. (Blood. 2005;105:481-488)

Risk factors for early death after high-dose cytosine arabinoside (HiDAC)-based chemotherapy for adult AML

“…This dose was revised to 9 mg/m 2 for 3 days for the remainder of the study by the ALLG safety and data monitoring committee, based on excessive early morbidity associated with this regimen. 3 A comparison of early death rates revealed no excess 42-day mortality from 12 mg/m 2 idarubicin (11.4%), compared with the subsequent 248 patients receiving the revised 9 mg/m 2 idarubicin dose (13.7%, P-value ¼ 0.67).…”

“…Randomized comparisons have consistently shown that HiDAC-based induction chemotherapy results in a higher complete remission rate after the first cycle of therapy, compared with standard dose ara-C induction. Complete remission rates of 77% after a single induction cycle can be achieved using HiDAC in combination with idarubicin and etoposide, compared with 41-66% with standard dose ara-C. [1][2][3] Although HiDAC-based induction achieves good early disease control, the benefits are offset by excessive induction-related toxicity and an increased risk of early death compared with standard dose ara-C. The definition of induction-related death varies widely between reports, making cross-study comparisons difficult.…”

“…3 In brief, 292 patients aged between 15-60 years, inclusive with de novo AML (excluding acute promyelocytic leukemia), received induction therapy with 'ICE', comprising idarubicin (9 mg/m 2 on days 1, 2 and 3), HiDAC (3 g/m 2 12-hourly on days 1, 3, 5 and 7), and etoposide (75 mg/m 2 daily on days 1 to 7 inclusive). Prophylactic anti-fungal therapy was with oral fluconazole 200 mg daily.…”

“…[4][5][6] Early mortality after HiDAC induction ranges between 7-18%. 3,4,[6][7][8] Identification of baseline risk factors predictive of early treatment-related mortality in adult AML after HiDAC-based induction therapy in a cooperative group setting has not been reported. A risk-stratified approach limiting HiDAC induction regimens to AML patients with a lower risk of early treatmentrelated mortality may be helpful in limiting factors that may contribute to iatrogenic death.…”

The DLK1-MEG3 locus in malignant cells of proposed primordial germ cell origins.

“…A sevenday induction therapy following the DAC schedule was used to treat patients: seven consecutive days of 200 mg/m 2 cytarabine via continuous IV infusion, three consecutive days of 50 mg/m 2 anthracycline via IV push; five days of 5 mg/m 2 cladribine via IV push [83]. Following evaluation of the induction response, non-responding patients were given re-induction protocol therapy of cytarabine, cladribine, filgrastim, and mitoxantrone (CLAG-M) and/or idarubicin, cytarabine, and etoposide (ICE) [84][85][86]. Consolidation therapies for patients who achieved complete remission consisted of cytarabine and mitoxantrone first, then a high dose of cytarabine, and finally either allogenic HSC transplantation or maintenance therapy.…”