Increasing Anthracycline Dose during Induction Chemotherapy Leads to Higher Remission Rates in Acute Myelogenous Leukaemia (AML).

Introduction: The optimal schedule for the treatment of AML remains to be defined. No systematic analysis of the dose intensity of anthracycline agents during induction chemotherapy has been published. We have compared the outcome of 2 consecutive protocols where daunorubicin was given at two different dose intensities.

Methods and patients: Consecutive patients with AML younger than 60 years and who had adequate organ function and were HIV non reactive were entered into a prospective study. Induction therapy included etoposide 100 mg/m² (for 7 days), cytarabine 100 mg/m² (as infusion for 7 days) and daunorubicin 75 mg/m² (for 3 days) followed by one similar consolidation course where daunorubicin was reduced to 60 mg/ (for 3 days) (Group 1). Patients remaining in CR were offered autologous or allogeneic stem cell transplantation (if HLA donor available). They were compared to a previous cohort (Group 2; 1993–1998) who had received similar combination therapy but Daunorubicin was given at 45 mg/m² and was followed by 2 consolidation courses. Group 2 patients achieving CR were also offered high dose therapy and stem cell grafts.

Results: Seventy one individuals (Group 1) with AML with median age of 36 years (14–60) were studied. Fourteen had favourable cytogenetics but had other adverse prognostic factors; 22 had intermediate risk while 16 had adverse karyotypes and no results were available in 20 cases. Three patients had biphenotypic leukaemia. Circulating blast count greater than 50x10⁹/L was present in 17 individuals. Remission was achieved in 80% (57 patients; 8 after 2 courses). Four patients did not receive consolidation because they had persistent fungal infection (n=2), cardiotoxicity (n=1) or refusal. Reduction in cardiac ejection fraction was seen in 3 individuals. Thirty nine patients underwent autologous (n=17) or allogeneic stem cell transplantation (n=22). At median follow up of 338 days, 39% survive disease free. Only two individuals of 19 who achieved CR but did not receive high dose therapy is alive (p < 0.05). Unfavourable cytogenetics but not older age (above median) was associated with adverse outcome. Kaplan and Meier analysis showed superior survival was associated with Allogeneic SCT (73%) than autologous (58%; p= 0.08). Patients in the historical control fraction, (Group 2) had no significant pre-treatment differences with Group 1. Remission in Group 2 was achieved in 59% (p= 0.03). CR occurred with a single course in 86% vs. 64% (p= 0.02) respectively. There were no differences in the toxicity profile between these two combinations. Disease recurred in 28% and 50% (p= 0.07) patients. For the 142 individuals, median follow up is 254 (range 19–4451) and 453 (12–1702; p= 0.01) days. Survival is 23% and 39% respectively, favouring patients treated in Group 1 (Log Rank; p= 0.03).

Conclusions: We conclude that increasing daunorubicin during induction chemotherapy was not associated with excessive toxicity, while remission rates were of 80% and 58%. However, a particularly favourable outcome was seen in patients receiving allogeneic stem cell transplantation.