Risk-Adapted Therapy in Younger Adults with Acute Myeloid Leukemia: Results of the AMLHD98A Trial of the AMLSG.
Authors: Schlenk Richard F. , Dohner Konstanze , Pralle Hans , Götze Katharina , Pfreundschuh Michael , Kneba Michael , Gastl Günther , Germing Udo , Haase Detlef , Dohner Hartmut 
Published: April 2020

Abstract
Objective: To evaluate outcome of younger adult patients with acute myeloid leukemia (AML) allocated to different treatment strategies according to the risk factors “karyotype” and “response to first induction cycle”.
Methods: Between 1998 and 2004, 871 patients (age 16–60 yrs) were enrolled. 77% of pts had de novo AML, 16% s-AML, and 7% t-AML. Risk stratification was based on cytogenetics and response to first induction therapy: i) low-risk: t(8;21); ii) intermediate-risk: normal karyotype, inv(16), t(11q23) or other rare aberrations; iii) high-risk: abn(3q), −5/5q-, −7/7q-, abn(12p), abn(17p) or complex karyotype and/or all pts having refractory disease (RD) after the 1st or not achieving complete remission (CR) after the 2nd induction. All pts received first induction with ICE (idarubicin, cytarabine, etoposide) followed by a second cycle ICE in case of CR/PR; pts with RD after first induction were assigned to high-dose cytarabine based salvage therapy. Pts achieving CR after response-adapted induction received first consolidation therapy with HAM. Second consolidation therapy was stratified according to the risk definition: i) low-risk pts were assigned to a second course of HAM; ii) intermediate-risk pts with an MRD were assigned to a HLA-matched related donor (MRD) stem cell transplantation (SCT), whereas the remaining pts were either randomized between autologous SCT and a second course of HAM in case of normal karyotype or assigned to autologous SCT if cytogenetic aberrations were present; iii) all high-risk pts were assigned to allogeneic SCT from a MRD or unrelated donor (MUD).
Results: Response after response-adapted double induction therapy was as follows: CR 70%, RD 18%, death 12%. In 69 pts risk assessment could not be performed due to unsuccessful cytogenetics; 701 (91%) were assigned to a specific risk: i) high-risk n=255 (36%); ii) intermediate-risk: 408 (58%) pts, comprising 254 pts with normal karyotype and 154 with aberrations; iii) low-risk: 38 pts. (5%) with t(8;21). The median follow-up time was 47 months. Overall survival (OS) for the whole study population at 4 years was 40% (95%-CI 37-42%). All 38 low-risk pts received intensive chemotherapy translating in an OS of 75% (95%-CI 61%-92%). Intention to treat-analysis for intermediate-risk patients exhibiting a normal karyotype revealed a relapse free survival (RFS) of 63%, 38% and 46% for patients assigned to MRD-SCT, autologous SCT and HAM, respectively (p=0.01). However, this difference in RFS did not translate into a difference (p=0.36) in OS due to effective salvage treatment, i.e. mainly MUD-SCT. Within the intermediate-risk group defined by cytogenetic abnormalities no difference in RFS (p=0.16) and OS (p=0.61) was evident between the intended MRD-SCT and autologous SCT. High-risk: 93 pts received MUD-SCT, 57 MRD-SCT, and 93 no allogeneic SCT, resulting in a feasibility of 58% and an OS of 28%, 29% and 5%, respectively (p&lt;0.0001). Conclusions: In this prospective study, allogeneic SCT from MRD or MUD improved outcome of patients with high-risk features. In addition, pts with normal karyotype had a significant better RFS after allogeneic SCT.