Long-Term Results in Patients with Acute Myeloid Leukemia (AML): The Influence of High-Dose AraC, G-CSF Priming, Autologous Transplantation, Prolonged Maintenance, Age, History, Cytogenetics, and Mutation Status. Data of the AMLCG 1999 Trial.
Authors: Buchner Thomas , Berdel Wolfgang E. , Haferlach Claudia , Schnittger Susanne , Haferlach Torsten , Serve Hubert , Müller-Tidow Carsten , Braess Jan , Spiekermann Karsten , Kienast Joachim , Mesters Rolf , Volpert Sarah , Staib Peter , Grüneisen Andreas , Kern Wolfgang , Reichle Albrecht , Ludwig Wolf-Dieter , Maschmeyer Georg , Balleisen Leopold , Eimermacher Hartmut , Aul Carlo , Giagounidis Aristoteles , Rasche Herbert , Hehlmann Rüdiger , Lengfelder Eva , Köpcke Wolfgang , Krug Utz O. , Sauerland Maria Cristina , Heinecke Achim , Woermann Bernhard J , Hiddemann Wolfgang 
Published: October 2019

Abstract
Abstract 485
In order to assess the relative value of major treatment variables for AML and subgroups in a representative setting 2693 patients were treated in a multicenter trial. To avoid a selection during treatment and to provide intention-to-treat conditions in a factorial design patients were randomized up-front in one step to receive TAD-HAM versus HAM-HAM induction, G-CSF priming with all chemotherapy courses during the 1st year versus no G-CSF, and for postremission therapy TAD consolidation followed by monthly myelosuppressive maintenance versus autologous stem cell transplantation instead of maintenance (TAD, thioguanine, araC standard dose and daunorubicin; HAM, araC 3 (age <60) or 1 (age 60+) g/m2 × 6 with mitoxantrone; G-CSF 150μg/m2/day from 48h before until the end of the chemotherapy course; maintenance, 5-day standard dose araC with daunorubicin or with thioguanine or with cyclophosphamide alternatingly). The median age was 61 (range 16-85) years with 55% of patients 60 years or older, 27% patients had AML secondary to cytotoxic treatment or myelodysplasia. Favorable, intermediate, and unfavorable cytogenetics were found in 7.5%, 67% and 25.5% of patients, respectively. Among 956 patients with normal cytogenetics the mutation status was availabel with NPM1 mut/ FLT3-ITD neg in 33% and other combinations in 67%. The median observation time for the entire patients was 4.4 years . In the patients <60 years the overall survival (OS) at 5 years is 40%. 65% went into complete remission (CR). Their relapse rate (RR) at 5 years is 52%. Patients of 60+years show an OS of 13% at 5 years, a CR rate of 54%, and a RR of 81% at 5 years. There were no significant differences in these parameters with respect to randomizations between TAD-HAM versus HAM-HAM, G-CSF priming versus no G-CSF, maintenance versus autologous stem cell transplantation. In a multivariate analysis including all patients and ages the main determinants of OS were age 60+y (HR 2.00; 95% CI 1.82-2.21), de-novo AML (0.79; 0.71-0.88), unfavorable karyotype (2.05; 1.84-2.28), favorable karyotype (0.47; 0.37-0.60), day 16 b.m. blast clearance (0.66; 0.61-0.74), and LDH (1.36; 1.19-1.54). Corresponding factors for the RR were age 60+ (1.90; 1.65-2.18), unfavorable karyotype (1.83; 1.54-2.17), favorable karyotype (0.41; 0.30-0.55), LDH (1.33; 1.11-1.59), and day 16 b.m. blast clearance (0.79; 0.68-0.93). In patients with normal karyotype the main determinants of OS were age 60+ (2.12; 1.77-2.54), NPM1mut/ FLT3-ITD neg (0.45; 0.36-0.56), and for the RR age 60+ (1.87; 1.49-2.35), and NPM1mut/ FLT3-ITD neg (0.37; 0.29-0.48). Even in patients <60 years age older than the median (47y) is a major risk factor for OS (1.56; 1.33-1.82) and RR (1.35; 1.10-1.66).

Conclusion:
In a prospective analysis of representative and unselected patients with AML the outcome of therapy is mainly determined by chromosomal and molecular abnormalities and by older age as an own risk factor. The influence of treatment variables such as substantial increase in high-dose araC, G-CSF priming, or autologous SCT is neglectable. Present data may contribute a basis for novel molecular and immunologic approaches.

Disclosures:
No relevant conflicts of interest to declare.