Intensification of Chemotherapy Does Not Improve Prognosis of Standard Risk Patients Undergoing Therapy for Acute Myelogenous Leukemia: Results of the Pediatric Clinical Trial AML-BFM 98.
Authors: Creutzig Ursula , Reinhardt Dirk , Ritter Joerg , Henze Guenter , Hermann Johannes , Klingebiel Thomas , Lehrnbecher Thomas , Niemeyer Charlotte M. , Reiter Alfred , Gadner Helmut , Stary Jan , Zimmermann Martin 
Published: October 2019

Abstract
In order to further improve survival of children undergoing therapy for acute myeloid leukemia (AML), the multicenter clinical trial AML-BFM 98 intensified chemotherapy for standard risk (SR) patients (pts.). In addition, this randomized trial prospectively evaluated whether 2 short cycles of chemotherapy resulted in better prognosis than a 6-week consolidation.
Patients and Methods: Between July 1998 and June 2003, 461 pts. < 18 years with de novo AML were enrolled in the trial AML-BFM 98. The SR group consisted of 170 (37%) pts. (FABM1/M2 with Auer rods or M4eo with ≤ 5 % blasts in the day 15 bone marrow; all pts. with FAB M3). All other pts. (n=291) were considered as high-risk (HR) pts.. In contrast to trial AML-BFM 93, a 2nd induction (HAM) was included in the treatment strategy for SR pts. (excluding FAB M3) which consisted of high-dose cytarabine (3g/m/12h x3 days) and mitoxantrone (10mg/m/d x2 days). Both SR and HR pts. were then randomly assigned to receive a 6-week consolidation or two short cycles of therapy. Compared to the 6-week consolidation, the short cycles contained higher doses of cytarabine, but the same cumulative dose of anthracylines. All other therapy elements [first induction (AIE; cytarabine, idarubicin and etoposide), intensification (HAE; high dose cytarabine, etoposide), and maintenance therapy] were identical in studies 93 and 98.
Results: Overall, 407 out of 461 (88%) pts. achieved remission (CR). Five-year survival, event-free survival (EFS) and disease-free survival (DFS) were 59%±3%, 49%±3% and 55%±3%, respectively. Estimated survival and pEFS were similar to those of study 93 (58%±2% and 50%±2%, p logrank .09 and .80). Analysis of SR pts. (FAB M3 excluded) showed that the additional application of HAM did not improve the prognosis of SR pts. compared to AML-BFM 93 [CR rate 92% vs. 91%, p(chi)=.78; 5-year pEFS 58%±5% vs. 66%±4%; p logrank =.24]. However, when comparing HAM in study 98 and the 2nd chemotherapy cycle in study 93, significantly more severe infections (grade 3/4) occurred with HAM. Overall treatment related mortality in CR was 4% in both HR and SR pts., which was similar to trial AML-BFM 93. In addition, the outcome of pts. randomized for the 6-week consolidation was similar to that of the short cycles (p logrank .81). However, morbidity was lower in the short cycle arm (6 vs. 11 deaths in CCR, 2 vs. 4 in SR pts.).
Conclusion: Our results indicate that in SR pts. with AML, a more intensive chemotherapy consisting of HAM does not result in improved survival. Therefore, new treatment options should be considered in this patient group. At the same time, optimizing treatment using the less toxic therapy with short cycles and improvement of supportive care strategies might help to reduce treatment related mortality and improve outcome in children with AML.