Page 135 - 2019_09-HaematologicaMondo-web

Effects of PEG-asparaginase on CSF asparagine levels
respectively. In this study cerebrospinal fluid asparagine levels were reduced during pegylated-asparaginase treatment, but complete depletion was only observed in a minority of patients. No clear threshold of serum pegylated-asparaginase activity level resulting in complete cerebrospinal fluid asparagine depletion was iden- tified. The consistency of the results found in the two independent data sets strengthen the observations of this study. Details of the treatment are available in the European Clinical Trials Database at https://www.clin- icaltrialsregister.eu/ctr-search/trial/2007-004270-43/IT.
Introduction
Asparaginase is one of the major anticancer drugs used in the treatment of acute lymphoblastic leukemia (ALL). The enzyme reduces the levels of asparagine in serum by hydrolyzing it to aspartic acid and ammonia. Currently there are three commercially available asparaginase prod- ucts.1 The oldest one is the purified native enzyme extract- ed from Escherichia coli, subsequently also available in a polyethylene glycol conjugated form (PEG-asparaginase) commonly used as the first-line preparation in the treat- ment of children with ALL throughout Europe and USA. A third asparaginase product derived from Erwinia chrysanthe- mi (ERW-asparaginase) exists and, due to its structural dif- ferences with respect to the E. coli asparaginase products, has been primarily used as a second-line treatment in chil- dren with hypersensitivity reactions to the E. coli products.2 Since leukemic cells need exogenous asparagine for their survival much more than the normal host cells do, the depletion of asparagine in serum serves as a surrogate for the anti-leukemic action of asparaginase, no matter which type of product is used. Due to this mechanism of action and to the pharmacodynamic ability of asparaginase prod- ucts to reduce asparagine pools also in the cerebrospinal fluid (CSF), it has been questioned whether profound and prolonged asparagine depletion, as that determined in the serum, could be of relevance in preventing central nervous system (CNS) relapses.3 Of course, it is exceedingly diffi- cult to ascertain the role of a single drug in the prevention of ALL relapses, especially in an extramedullary compart- ment such as the CNS where relapses are quite rare. However, in a previous study, patients with higher CSF asparagine levels (>1 μmol/L) during asparaginase treat- ment were more likely to have isolated CNS relapse.4
Available studies reporting data on CSF asparagine depletion during asparaginase treatment have been mostly performed in limited cohorts of patients and using differ- ent asparaginase products, schedules and assays. In the past it has been consistently reported that profound and prolonged CSF asparagine depletion in children treated with standard induction chemotherapy treatment sched- ules5–9 is achieved when native forms of asparaginase are used. To this end the conceptual question on how asparaginase products may determine asparagine deple- tion in the CSF remains unanswered. One possible expla- nation for the asparagine depletion observed in the CSF could lie in a continuous balance between the serum and CSF asparagine pools.10,11 Another possible explanation is that, at peak levels, very small amounts of asparaginase products could cross the blood-brain barrier;12 however, activity levels have never been directly measured in the CSF during the administration of native forms of asparag- inase. Given that PEG-asparaginase has a far greater molecular weight than that of the native forms of asparag- inase, it is conceivable that it is even more difficult for the pegylated form to cross the blood-brain barrier. Different
results have been reported in patients treated with PEG- asparaginase wherein detectable CSF asparagine levels have been almost invariably reported thus suggesting that pharmacodynamic differences exist between the different asparaginase products.4,13–15 We very recently demonstrat- ed, even with the limitations of the experimental preclini- cal model adopted, that in the CSF of rats asparaginase activity levels could be measured, consistently even if transiently, only for non-pegylated formulations.16
In the international AIEOP-BFM ALL 2009 trial protocol (https://www.clinicaltrialsregister.eu/ctr-search/trial/2007- 004270-43/IT), conducted by members of the Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP) and Berlin-Frankfurt-Münster (BFM) group, children with newly diagnosed ALL have been treated with multiple antileukemic agents, including PEG-asparaginase as the first-line preparation. Since PEG-asparaginase has been used in the AIEOP-BFM ALL 2009 study protocol for the first time as a front-line asparaginase agent instead of the previously used native E. coli asparaginase product and since two different randomized studies, consisting of PEG-asparaginase-intensified schedules, are the most rele- vant treatment questions of the AIEOP-BFM ALL 2009 study, a tight therapeutic drug monitoring study of PEG- asparaginase treatment has been implemented to better understand the pharmacological phenomena underlying asparaginase treatment in this therapeutic context.
The main findings of the above-mentioned therapeutic drug monitoring specifically related to CSF asparagine lev- els and asparaginase serum activity, analyzed in parallel after the administration of PEG-asparaginase in the induc- tion phase of the AIEOP-BFM ALL 2009 study, are the focus of the present report.
Methods
haematologica | 2019; 104(9)
Patients’ eligibility and treatment schedule
Children ≥1 year and <18 years old diagnosed with ALL and eli- gible for the AIEOP-BFM ALL 2009 protocol were investigated in this study. PEG-asparaginase (Oncaspar®, Shire) was given during the induction phase (namely protocol IA) to children diagnosed and treated in the participating centers. The drug was given intra- venously as a 2 h infusion at the dosage of 2,500 IU/m2 with a maximum dose of 3,750 IU/m2 on days 12 and 26. Details of the treatment are available in the European Clinical Trials Database at https://www.clinicaltrialsregister.eu/ctr-search/trial/2007-004270-43/IT. CSF asparagine levels were evaluated when lumbar punctures rel- evant for this part of the PEG-asparaginase study were scheduled in protocols IA and the subsequent consolidation phase protocol IB, i.e., on protocol days +33 and +45, respectively, which corre- spond to days 7 and 19 after the second PEG-asparaginase dose of protocol IA. Serum asparaginase activity levels were measured at the same two time points. Mainly because of the long half-life of PEG-asparaginase and the slow decay of the related activity levels, and in order to have a larger set of samples to be analyzed, data
1813