Improved Outcome in High Risk and Very High Risk ALL by Risk Adapted SCT and in Standard Risk ALL by Intensive Chemotherapy in 713 Adult ALL Patients Treated According to the Prospective GMALL Study 07/2003.
Authors: Gökbuget Nicola , Arnold Renate , Böhme Angelika , Fietkau Rainer , Freund Mathias , Ganser Arnold , Kneba Michael , Lipp Thomas , Ludwig Wolf-Dieter , Maschmeyer Georg , Messerer Dorle , Rieder Harald , Thiel Eckard , Hoelzer Dieter 
Published: October 2019

Abstract
In 2003 the German Multicenter ALL Study Group (GMALL) initiated the trial GMALL 07/2003. Major aims were improvement of outcome by shortened, intensified induction, intensified consolidation, risk adapted and extended SCT indication and minimal residual disease (MRD) based treatment stratification. 8drug-induction was followed by uniform 1st consolidation based on HDARAC and HDMTX. Further treatment was stratified according to the following risk factors (RF): WBC > 30.000 in B-prec. ALL, late CR (>3wks), proB-, earlyT and mature T-ALL, Ph/BCR-ABL and t(4;11)/ALL1-AF4. The risk groups were defined as follows: standard risk (SR, no RF), high risk (HR,>= 1RF) and very high risk (VHR,Ph/BCR-ABL). HR and VHR pts were scheduled for SCT in CR1 with the following priorities: allo sibling, allo matched unrelated and autologous. VHR pts mostly received Imatinib according to different schedules. SR pts received 5 consolidation cycles (HDMTX/ASPx3, VP16/ARAC, CYCLO/ARAC) and reinduction. SR pts with high MRD after consolidation I were allocated to SCT. In the remaining SR pts decision on maintenance therapy was based on MRD. Between 04/03-12/06 713 evaluable (15–55 yrs) pts were included. The median age was 34 yrs. The CR rate after induction was 89% with 5% early death and 6% failure. 50%, 33% and 17% were allocated to SR (N=353), HR (N=235) and VHR (N=117) with similar CR rates of 92%, 88% and 85%. CR rate was not different in pts < vs > 35 yrs (90% vs 89%). 5 year overall survival (OS) was 54% and survival of CR (S-CR) pts was 59%. HR and VHR pts obtained 55% and 49% S-CR at 3 yrs resp. HR subgroups showed different S-CR for early T (58%), mature T (70%), pro B (66%) and other B-lineage ALL (37%). 68% and 71% of HR and VHR pts received SCT in CR1 as scheduled which thus contributed substantially to improved outcome. In SR- ALL S-CR was 69% (68% c/preB, 66% thymicT). The CCR probability was 52% at 3 yrs. CNS prophylaxis was very effective since only 2% of the CR pts had CNS involvement at relapse. Univariate analysis confirmed a significant prognostic impact of immunphenotype, WBC in B-lin ALL, time to CR and Ph/BCR-ABL. WBC was no prognostic factor in T-lin-ALL. Age was highly significant for survival with 64% survival < 35 yrs vs 48% above 35 yrs. In adolescents below 25 years the most favourable survival of 67% was achieved. In standard risk pts below 35 yrs the survival was 73% without SCT in CR1. Overall the study yielded improved CR rates (89%) and survival (54%). Risk adapted SCT indication was feasible (realised in 70% of HR/VHR pts) and lead to improved survival particularly in early/mature T-ALL and pro B-ALL. In standard risk (SR) the survival is favourable, even above 70% in young pts; however, the relapse rate is still high. Further intensification of therapy during the first year seems required. By definition of new risk factors additional SR patients could be allocated to SCT in CR1. There is however no intention to transfer all SR patients to SCT. Future improvement will be attempted by further inclusion of subtype specific and targeted therapies.