Relapsed Acute Myeloid Leukemia in Children and Adolescents: Interim Results of the International Randomised Phase III Study “Relapsed AML 2001/01”.

Relapse occurs in 30–40% of newly diagnosed AML patients, with long-term survival in 20% of them. We initiated a study for relapsed AML excluding AML M3 and those >18 years of age. As backbone, FLAG is being used for 2 consecutive courses: fludarabine 30 mg/m²/day x 5, cytarabine 2 g/m²/day x 5, G-CSF 200 μg/m²/dose for 6 days, starting day −1. Liposomal daunorubicin (DaunoXome®, DNX) is a “new” anthracycline with potentially less cardiotoxicity, applicable in the total group of patients, and with the perspective to be useful at initial treatment as well. Therefore, DNX at 60 mg/m²/day on days 1, 3 and 5 was added or not in a 1:1 randomised fashion to the first course of FLAG. The ongoing prospective study must determine the efficacy and toxicity of DNX when added to FLAG, and the long-term outcome in a large group of relapsed AML patients. 13 groups worldwide are enrolling patients. 303 patients were registered as per April 2005. This planned interim analysis with blinded efficacy data concerns 226 eligible and evaluable patients with first relapsed AML, 140 (62%) being male. Median age at relapse was 9.7 (range, 0.7–18) years. 50% of patients relapsed within 1 year from initial diagnosis. The majority concerned isolated bone marrow relapse (85%), with 1% isolated and 5% combined central nervous system involvement. Median WBC at relapse was 4.0 (range, 0.4–293) x 10⁹/l. Dominating FAB types are M2 with auer rods, M4 without eosinophils and M5. The randomisation was actually performed in 81% of patients. A total of 63% of patients was transplanted, the majority with a matched unrelated donor. Poor response to the 1^st course of therapy (>20% of blasts in the BM shortly before the 2^nd course), was seen in 23% of patients. Early death occurred in 6% of patients. Complete remission (CR) was achieved in 62% of patients, and they have a probability of survival at 2 years (2-yr pSurv.) of 47±6% (compared to 33±5% for the total group), 38±9% for early relapses and 54±7% for late relapses. Patients not achieving CR had a 2-yr pSurv. of 5±4%. Compared to early relapses, patients with late relapse had higher CR rates (74 vs 51%), and higher 2-yr pSurv.: 42±6% vs 21±5%. There was significant grade III/IV toxicity, but no unexpected toxicity, and no clinically relevant differences between the arms with and without DNX, especially not in cardiotoxicity. In conclusion, it is feasible to perform a large randomised study in a very international setting. DNX added to FLAG does not result in major additional toxicity, but follow-up of cardiotoxicity should be extended as planned in this protocol. Late relapses do better in terms of CR and overall survival, but early relapses achieving CR have a realistic chance of survival as well. The study is ongoing until 360 patients have been randomised, to answer the question whether liposomal daunorubicin improves outcome in pediatric relapsed AML. Meanwhile, overall outcome is encouraging, with CR achieved in 62% of patients of whom 47% are survivors at 2 years.