Increasing dose intensity of anthracycline antibiotics improves outcome in patients with acute myelogenous leukemia

Abstract

To understand the effect of dose concentration in the overall survival of AML, we conducted a study on the efficacy and toxicity of a drug combination where the dose of daunorubicin was intensified. For this analysis, the outcome of patients entered into two consecutive prospective trials was compared. Inclusion criteria in both arms were identical and consisted of primary AML in adults. Treatment protocol for Cape Town Regimen 4 (CTR-IV) comprised of cytarabine infusion (100 mg/m(2)) and etoposide (100 mg/m(2)), injection daily for 7 days in combination with daunorubicin (45 mg/m(2)) on days 1, 2, and 3. Patients achieving remission were given two further courses of the same chemotherapy and received allogeneic or autologous transplantation. CTR-V was a similar treatment program, except that daunorubicin was escalated on days 1, 2, and 3 to 75 mg/m(2) during induction and to 60 mg/m(2) during a single consolidation. Patients were also offered stem cell transplantation. Between 1990 and 1997, 78 patients (median age 33; range 13-67 years) fulfilled entry criteria and received CTR-IV. From 1998 onwards, 35 patients (median age 36; range 15-66 years) were prospectively enlisted into the CTR-V trial. The patient population in CTR-V had fewer Caucasian individuals (P = 0.02) and had significantly lower presentation hemoglobin (P = 0.0002). Following initiation of induction chemotherapy, 40 patients failed to respond. Among these, 10 patients demised before day 28. Another 30 (25/69 CTR-IV and 5/32 in CTR-V groups; P = 0.01) had leukemia that was resistant to chemotherapy, and all died. Remission was achieved in 59% of patients treated with CTR-IV and 77% of those receiving CTR-V (P = 0.03). CR occurred with a single course in 64% versus 88% (P = 0.02), respectively. There were no differences in the toxicity profile between these two combinations. Disease recurred in 50% and 28% (P = 0.07) of patients. For the 113 individuals, median follow up is 254 (range 19-4,451) and 304 (12-1,702; P = 0.03) days. Survival is 23% and 40%, respectively, favoring patients treated with CTR-V (log rank; P = 0.03). Cox regression analysis showed that treatment group (P < 0.001), FAB type, hemoglobin level, and platelet count were independent factors for response to chemotherapy. Older age and not undergoing myeloablative therapy were the only adverse factors for survival. We conclude that increase in the treatment dose of daunorubicin in patients with AML led to a higher remission rate, particularly with a single course of chemotherapy and had an equivalent toxicity profile. This therapeutic modification is also likely to result in substantial reduction in patient stay in hospital and in the overall expenditure.