PEG-Asparaginase in Adult Acute Lymphoblastic Leukemia (ALL): Efficacy and Feasibility Analysis with Increasing Dose Levels
Authors: Goekbuget Nicola , Baumann Anja , Beck Joachim , Boos Joachim , Brueggemann Monika , Diedrich Helmut , Hüttmann Andreas , Leimer Lothar , Lipp Thomas , Naumann Ralph , Mohren Martin , Reichle Albrecht , Schäfer-Eckart Kerstin , Schmalzing Marc , Schmid Mathias , Schmitz Norbert , Therwey Theis , Hoelzer Dieter 
Published: April 2020

Abstract
Asparaginase (ASP) has a unique role in the treatment of ALL, and several pediatric studies have demonstrated that modifications of schedule, preparation and dose of ASP may have an impact on overall outcome. The optimisation of ASP treatment is therefore an important aim of the German Multicenter Study Group for Adult ALL (GMALL). In 1999 a pilot trial for adult ALL was started (GMALL 06/99), followed by the ongoing main trial 07/2003. Induction comprised dexamethasone, vincristine, daunorubicine and i.th. methotrexate. One dose of pegylated ASP (PEG-ASP) 1000 U/m2 (500 U/m² if &gt; 55yrs) was given instead of 7 doses of 5000 U/m2 native E.coli asparaginase (ASP) given over 14 days in previous GMALL studies. In consolidation one dose PEG-ASP (500 U/m2) replaced one dose of E.coli ASP (10000 U/m2) in combination with high-dose methotrexate (1500 U/m²) and mercaptopurine. ASP activity was above 100 U/l at day 10 in 80% of the pts after 1000U/m2 and in only 42% after 500 U/m2. Based on this correlation between dose and duration of activity in study 07/2003 (amendment II in 12/2006) the dose for PEG-ASP was increased to 2000 U/m2 in induction and consolidation for pts &lt; 55 yrs and to 1000 U/m2 for pts &gt; 55 yrs in order to improve treatment efficacy. Details of the protocol have been reported (Brüggemann, Blood2006: 107;1116).
Patients: 959 pts with a median age of 36 yrs are evaluable. 8% (N=82) were older than 55 yrs. Clinical characteristics were representative for adult ALL and similar in the cohorts. 766 pts were treated before the amendment with 1000 U/m2 (cohort 1) and 117 pts after the amendment with 2000 U/m2 (cohort 2), with the respective reductions for pts &gt; 55yrs. 76 pts did not receive ASP in induction due to various reasons (cohort 3).
Efficacy: In cohort 1 and 2 91% and 90% achieved CR after induction (80% in cohort 3). Data on molecular response, defined as MRD below 10 −4,after induction are available in a subset of both cohorts. There is a trend towards earlier and higher molecular CR rate in cohort 2 (82% after induction) compared to cohort 1 (70%). Survival after 1 yr is similar in cohort 1 (79%) compared to cohort 2 (77%) and inferior in cohort 3 (66%). Probability of continuous CR after 1 year shows a trend to improvement with 87% in cohort 2 vs 77% in cohort 1.
Toxicity in induction: Toxicity reported here is focused on potentially ASP related oIII–IV (WHO scale) events. 676 pts are evaluable for cohort 1 and 107 pts for cohort 2. Incidences for both cohorts are as follows: GOT or GPT (30%/27%), bilirubine (12%/14%), thrombosis (5%/2%), bleeding (2%/0%) and hypersensitivity (1%/1%). Details on adverse events of all degrees are available in a subset of pts showing an increase of any WHO grade in 81% for bilirubine, 80% for GPT, 52% for amylase, 29% for lipase and 51% for glucose. Data on substitution of clotting factors were available in 84 and 61 pts: 73% vs 93% required substitution (25%/12% FFP, 37%/46% ATIII concentrate and 37%/42% both).
Conclusions: This is the largest cohort of adult ALL pts treated with PEG-ASP so far. Overall intensified PEG-ASP was feasible in the context of intensive multidrug induction. Coagulation disturbances occurred frequently and substitution was extensive, but bleeding or thrombosis were rare events. Although substitution of clotting factors was clinically effective it remains open whether it is clinically necessary. The rate of severe hepatotoxicity was stable after dose escalation however lead to significant treatment delays in individual pts. Lab value changes e.g. liver occured in a large proportion of pts; it remains open to what extent they are clinically relevant and require interruption of further chemotherapy. It would be an important goal to identify parameters to predict severe ASP related toxicities e.g. by pharmacogenomics. The molecular CR rates after dose escalation are promising and will hopefully turn out into an improved overall survival.
Supported by supported by Deutsche Krebshilfe 70-2657-Ho2 and partly BMBF 01GI 9971 and Medac GmbH