Dexamethasone Dose and Schedule Significantly Influences Remission Rate and Toxicity of Induction Therapy in Adult Acute Lymphoblastic Leukemia (ALL): Results of the GMALL Pilot Trial 06/99.
Authors: Goekbuget Nicola , Baur Karl-Heinz , Beck Joachim , Diedrich Helmut , Lamprecht Monika , Leimer Lothar , Lipp Thomas , Neteler Jutta , Reutzel Regina , Rutjes Jan , Schmid Mathias , Staib Peter , Stelljes Matthias , Hoelzer Dieter 
Published: April 2020

Abstract
In 1999 the German Multicenter Study Group for Adult ALL (GMALL) activated a pilot study (GMALL 06/99). One major aim was to develop a new, shortened and intensified induction regimen based on the following new principles compared to previous GMALL trials: 1) Dexamethasone (DEXA) instead of prednisone to improve antileukemic activity and prophylaxis of CNS relapse 2) prephase with cyclophosphamide (CYCLO) 3) G-CSF parallel to chemo 4) intensified daunorubicin with two 2day cycles (DNR) vs 4 wkly applications 5)1 dose PEG-L-Asparaginase (ASP) instead of 14 d conventional ASP Induction I was followed by GMALL induction phase II as previously reported and a uniform consolidation I. Remission control took place on d24 and d44. Thereafter treatment was risk adapted.
Induction I consisted of DEXA, CYCLO and G-CSF. In addition pts received PEG-ASP 1000 U/m2 (d13), vincristin 2 mg (d4,11,18) and DNR 45 mg/m2 (d4+5,11+12). The regimen was modified by 3 amendments which separated the study to 4 pilot phases. The major modifications referred to reduction of DEXA/CYCLO and earlier application of G-CSF.
Table 1: Major modifications of induction phase I Drug Pilot 1 Pilot 2 Pilot 3 DEXA 40 mg/m2 (d1–3) 10 mg/m2 (d4–17) 10 mg/m2 (d 1–6,11–16) 10 mg/m2 (d 1–5,11–14) CYCLO 200 mg/m2 (d1–3) none none G-CSF from d13 from d4 from d4
Overall 843 pts were included between 4/99 and 10/03. The median age was 36 (15–65) yrs. Subtypes distribution was c-/pre B 65%, pro B 8%, early T 8%, thymic 14%, mature T 6%. 23% had Ph/BCR-ABL+ ALL. The overall CR rate was 83%, with 12% failure/PR and 7% early death (ED). Significant differences were detected for the pilot phases (p=.0008). The high mortality in pilot I was mainly due to infections. With lower doses of DEXA the rate of ED (p=.0002) and severe infections decreased significantly whereas the failure rate increased slightly. The earlier application of G-CSF contributed to a significant decrease of grade III/IV granulocytopenias and probably also mucositis.
Table 2: Results and major toxicities (grade III/IV) of induction therapy Pilot 1 Pilot 2 Pilot3 P Evaluable 103 100 605 CR 76% 83% 82% .0008 PR/Failure 9% 9% 14% ED 16% 8% 5% Survival (3y) 45% 47% 47% &gt;.05 Granulopenia 84% 72% 69% .008 Median duration 17d 15d 12d &lt;.0001 Infections 30% 33% 14% &lt;.0001 Mucositis 23% 14% 6% &lt;.0001
We conclude that dose and schedule of DEXA in induction of ALL has a significant effect on rate of infections and ED. A dose reduced schedule with interruption to allow for early detection of infections led to a favourable CR rate of 82% with ED of 5% after only 6 wks of induction therapy. The parallel application of chemo and G-CSF rendered the regimen more feasible and contributed to the lower rate of infections and mucositis. The optimised regimen which includes again prephase with CYCLO is now used as induction therapy of the ongoing GMALL study 07/2003. Interim results confirmed the high antileukemic activity with CR rates of 89% and the feasibility with 4% ED. Beside the optimised induction the use of Imatinib in Ph+ ALL parallel to induction contributed to the improvement. Further progress is now attempted by additional use of rituximab in CD20 positive pts.