A randomized study of high-dose cytarabine in induction in acute myeloid leukemia [see comments]

Abstract

High-dose cytarabine (ara-c) may overcome cytarabine resistance in leukemic blasts. It has been used as a successful salvage and in postremission therapy but not as initial induction treatment. Patients aged 15 to 60 years, presenting with newly diagnosed acute myeloid leukemia (AML) were randomized to receive either high-dose cytarabine, 3 g/m2 12 hourly on days 1, 3, 5, and 7 for 8 doses, daunorubicin 50 mg/m2 days 1 to 3, etoposide 75 mg/m2 days 1 to 7, (HIDAC-3–7) or standard dose cytarabine 100 mg/m2 continuous intravenous infusion for 7 days with daunorubicin and etoposide at the same dose and schedule as above (7–3–7). Patients could receive a second or third induction course if complete remission (CR) was not achieved. All patients received the same postinduction consolidation therapy (5–2–5) for 2 courses. Eligible patients had no prior chemotherapy or myelodysplastic disease. Patients have been followed for a median of 4.5 years. Of 301 patients treated, complete response (CR) was achieved in 71% with HIDAC- 3–7 and 74% with 7–3–7. For patients in CR, the estimated median remission duration was 45 months with HIDAC-3–7 and 12 months with 7–3– 7 (P = .0005 univariate analysis, P = .0004 multivariate analysis). The estimated percentage of patients relapse free 5 years after achieving a CR was 49% on HIDAC-3–7 and 24% on 7–3–7. Patients in CR tended to survive longer with HIDAC-3–7 but there were no overall survival differences between the two arms. HIDAC-3–7 was associated with significantly more toxicity in induction with more leukopenia, thrombocytopenia, nausea, and vomiting and eye toxicity (all P < .001) but a similar incidence of severe central nervous system and cerebellar toxicity compared to 7–3–7. The consolidation treatment was the same in both arms but caused significantly more leukopenia and thrombocytopenia in patients previously treated with HIDAC-3–7 induction (P < .0001). We conclude that a dose-effect exists for cytarabine in AML and that HIDAC- 3–7 prolongs remission duration and disease-free survival and is tolerable when used as initial induction therapy in patients with de novo AML.

No impact of high‐dose cytarabine on the outcome of patients transplanted for acute myeloblastic leukaemia in first remission

“…The LFS was better in patients treated with HD Ara-C, but was associated with significantly more lethal toxicities. Similar findings were reported by the Australian Leukaemia Study Group (Bishop et al, 1996) in a study that compared HD Ara-C plus daunorubicin and etoposide with SD Ara-C plus daunorubicin and etoposide. Patients in CR tended to survive longer with HD Ara-C, but there was no statistical difference between the two arms in terms of overall survival.…”

MDR 1 expression is an independent prognostic factor for response and survival in de novo acute myeloid leukaemia

“…In contrast, the effect of Ara-C is not affected by MDR 1 expression. High-dose Ara-C administered during induction or consolidation therapy significantly improves the disease-free and overall survival of AML patients (Mayer et al, 1994;Bishop et al, 1996). A significant improvement of survival may also be accomplished by intensification with alkylating agents or radiation therapy followed by marrow transplantation.…”

Incidence of bacterial and fungal infections in newly diagnosed acute myeloid leukaemia patients younger than 65 yr treated with induction regimens including fludarabine: retrospective analysis of 224 cases

“…Addition of a third drug to the standard combination of anthracycline and arabinosyl cytosine (Ara-C) or the use of high-dose Ara-C (HD-AC) are the most common approaches to intensify induction (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). We attempted to improve induction's efficacy with a non-conventional induction regimen of fludarabine in combination with intermediate-dose Ara-C and standard dose idarubicin (FLAI) (23)(24)(25)(26)(27).…”