Post-remission therapy of adult acute myeloid leukaemia: One cycle of high-dose versus standard-dose cytarabine

Background: Intensification of post-remission therapy improves thecure rate of acute myeloid leukemia (AML) but is often accompanied byunacceptable toxicity. From 1985 to 1992 the Swiss Group for Clinical CancerResearch (SAKK) performed a randomized phase III trial to evaluate theeffectiveness of one single postremission course of high-dose cytarabine(HDAC) in terms of leukaemia-free and overall survival in adults with de novoAML.Patients and methods: Adult (15–65 years) AML patients inremission after two induction courses were randomly assigned to oneconsolidation course either with standard (SDAC: 100 mg/sqm 24 hours infusionover seven days) or with high-dose cytarabine (HDAC: 3000 mg/sqm every 12hours as one-hour-infusion for six days). In addition, both arms includeddaunorubicin (45 mg/sqm daily on days 1 to 3). Thereafter, patients wereobserved without maintenance until relapse.Results: After two induction courses 208/276 eligible patientsachieved remission (CR: 169, 61%, PR: 39, 14%), 41 wereresistant (15%) and 20 died early (7%). Seventy-one patients inremission were not randomized. One hundred thirty-seven were randomized inCR/PR (67 SDAC, 70 HDAC). 4/70 patients randomized to HDAC did not receive it.Treatment-related mortality in HDAC was 1.4% (1/66). WHO grade3–4 toxicities occurred in 14/67 SDAC and in 38/66 HDAC patients (P <0.0001). The median event free survival was 10.8 (SDAC) vs. 12.2months (HDAC; P = 0.18). The median overall survival was 24.6 (SDAC) vs.32.6 months (HDAC; P = 0.07). Although statistically uncertain, HDACreduced the hazard of progression (hazard ratio: 0.69, P = 0.08) and ofdeath (hazard ratio: 0.70, P = 0.13). For 112 patients stratified as CRthe estimated four-year disease-free survival was 25%(±6%) withSDAC and 37% (±6%) with HDAC (P = 0.09). Theoverallsurvival rates at four years were 38% (+7%) and 48%(+7%), respectively (P = 0.10). In multivariate analysis HDACsignificantly reduced the hazard of relapse by 39% compared to SDAC(hazard ratio = 0.61, 95% CI: 0.37–0.99; P = 0.049).Conclusions: We conclude that early consolidation of adult AML in CRwith a single course of HDAC is superior in terms of outcome to one cycle ofSDAC. The results of our intensive, single course HDAC group comparefavourably with less intensive, repetitive HDAC cycles, suggesting that Ara-Cdose intensity may be more important than total dosage. In addition, ourtreatment strategy is much less toxic and less expensive.