Addition of Liposomal Daunorubicin (DaunoXome®) to FLAG Significantly Improves Treatment Response in Pediatric Relapsed AML: Final Results From the International Randomised Phase III Study Relapsed AML 2001/01.

Long-term survival in pediatric relapsed AML is only 20-30%. Optimal reinduction therapy is unknown, and there is a concern about cardiotoxicity with repeated anthracycline use at relapse. Preclinical in vitro and animal studies, and limited clinical data suggest that liposomal daunorubicin (DaunoXome^®, DNX) is less cardiotoxic. These considerations lead to a phase III study, in the setting of the International BFM Study Group.

FLAG was randomised against FLAG/DNX in the 1^st reinduction course. The conventional 5-days FLAG only was recommended as the 2^nd course. DNX was dosed at 60 mg/m2/day on days 1, 3 and 5. After induction, allogeneic stem cell transplantation was generally recommended, but time-to-transplant could be bridged by high- or low-intensive consolidation therapy. Primary endpoint of the study was early treatment response, based on bone marrow examination shortly before reinduction course 2, and defined as either good (≤20% leukemic blasts) or poor (>20% leukemic blasts). This endpoint was chosen because of its prognostic value in earlier relapsed AML BFM-trials, and because compliance with an extended protocol guideline was likely to be suboptimal within the context of a highly multinational and multicenter AML Relapse protocol. However, secondary endpoints were defined, including the CR2 rate determined after 2 courses, long-term survival, and toxicity. Patients with AML M3 and those >18 years of age at initial diagnosis were ineligible. The study opened in most countries in 2002/2003. The study closed for accrual on April 1, 2009 when the required 360 fully eligible and evaluable patients had been randomized. Early and late relapsed AML was defined as a relapse within or after 1 year from initial diagnosis, but this only influenced treatment in that early relapsed AML patients were eligible for haploidentical SCT, while late relapsed AML patients were eligible for autologous SCT, if a matched or partly mismatched transplant was not possible. Thirteen groups from 20 countries and >100 centers have enrolled patients, with informed consent and after approval of the study by regulatory authorities. Data are presented according to intention-to-treat, with a median follow-up of 2.7 years for patients at risk.

Overall 4-year probability of survival (pOS) was 35% SE 2%, the overall CR2 rate 62%. The good early responders had a 4-year pOS of 45% SE 3% versus 10% SE 3% for poor responders (p<0.0001). Similar differences were seen in the subgroups early relapse (pOS 36% SE 5% vs 5% SE3%) and late relapse (53% SE 4% vs 17% SE7%). For the main endpoint, patients randomized to FLAG/DNX had a 12% higher early good response rate than patients randomized to FLAG, 81% vs 69% (p= 0.009). Within early relapsed AML (52% of all patients), this difference was 17% in favor of DNX (p=0.025), in late relapsed AML it was 8% in favor of DNX (p=0.12). In terms of secondary endpoints, CR2 rate was 10% higher with DNX (68% vs 58%, p=0.047). Overall survival was also higher with DNX, but not significantly: 4-years pOS FLAG 35% SE 4% vs. 40% SE 4% for FLAG/DNX. Toxicity was similar in both groups and was significantly different only for skin eruptions (FLAG 1%, FLAG/DNX 5%, p=0.04). Grade III/IV cardiotoxicity was seen in 5 (3.2%) patients treated with FLAG/DNX (1 grade IV, 4 grade III), and in 2 (1.4%) patients treated with FLAG (1 grade IV, 1 grade III), often coinciding with severe infections and was treatable.

adding DNX to FLAG improves treatment response in pediatric relapsed AML, both in terms of BM status after the 1^st reinduction course and the CR2 rate after 2 courses. The 5% improved pOS with DNX and FLAG was not statistically significant, but the study was not powered to detect small differences in survival. Furthermore, short-term toxicity of FLAG/DNX was similar to FLAG. Analysis of long-term toxicity will require longer follow-up. In view of these data, standard reinduction chemotherapy for pediatric relapsed AML according to I-BFM-SG protocols should consist of high-dose ara-C plus DNX, but the cumulative dose of anthracyclines should always be taken into account. In addition, pediatric relapsed AML is curable in a subgroup of patients, particularly those with a good early treatment response, irrespective of whether the relapse of AML was early or late. Finally, international collaboration proved to be feasible in the treatment of pediatric relapsed AML, and resulted in the best outcome reported sofar with pOS of 35%.

Off Label Use: Liposomal daunorubicin (DaunoXome®) in pediatric relapsed acute myeloid leukemia.