Five‐year single‐center study of asparaginase therapy within the ALL‐BFM 2000 trial

Abstract

BackgroundTherapeutic drug monitoring (TDM) of asparaginase (ASNase), a fundamental element of acute lymphoblastic leukemia treatment, was integrated in the ALL‐BFM 2000 protocol on a voluntary basis.MethodsOver a 5‐year period, 127 patients (1,355 samples) were monitored for asparaginase activity in a single‐center setting. We report monitoring data from throughout the ASNase containing treatment elements. Additional information obtained on risk stratification, minimal residual disease (MRD), steroid randomization and relapse is discussed in relation to ASNase activity.ResultsAt completion of the induction phase 93% (115/124) of patients showed sufficient ASNase activity (5,000 U/m2 Escherichia coli ASNase), 77 of 86 (90%) monitored patients finished the first re‐intensification element without requiring Erwinia ASNase. MRD, risk stratification and steroid randomization were not associated with significant differences in ASNase activity. Of patients who relapsed, only 25% (3/12) were able to maintain sufficient ASNase activity after E. coli ASNase.ConclusionThis single‐center data set gives a true and unbiased insight into clinical reality of ASNase therapy. It shows no significant relationship between MRD positivity or risk stratification and ASNase treatment intensity. Overall, within the ALL‐BFM 2000 trial, 90% of patients completed first re‐intensification without requiring third‐line Erwinia ASNase. Pediatr Blood Cancer 2011; 57: 378–384. © 2011 Wiley‐Liss, Inc.

Anti–Escherichia coli asparaginase antibody levels determine the activity of second-line treatment with pegylated E coli asparaginase: a retrospective analysis within the ALL-BFM trials

“…[8][9][10]18 Direct monitoring of anti-E coli ASE Abs, to confirm immunologic reactions, has not been performed within the ALL-BFM trials so far. With ASE monitoring provided on an optional basis, the serum samples available for this study originated from a subset of all patients and all ASE administrations in the ALL-BFM 2000 and the ALL-REZ BFM 2002 trials.…”

“…In consequence, the proportion of patients in this retrospective study who received pegylated E coli ASE as a second-line and E Chrysanthemi as a third-line treatment were not supposed to match studies that monitored all the ASE administrations of all patients. 10 The detection of Abs against E coli ASE was significantly associated with clinically manifest allergic reactions to E coli ASE, although not all of the patients who demonstrated symptoms of allergic reactions to native E coli ASE tested positive for Abs against E coli ASE. In addition, several samples collected after patients were switched to pegylated E coli ASE, when allergic reactions to front-line native E coli ASE had occurred or were anticipated, were Ab negative.…”

“…A review of the cases included in the drug monitoring program also revealed, however, a considerable number of patients with insufficient ASE activity who were subsequently switched to third-line treatment with Erwinia ASE. 8,10 Also in this retrospective study sufficient ASE activity Ͼ 100 U/L was found in approximately 65.9% (295/448) of the samples taken within 14 days after the administration of 1000 U/m 2 pegylated E coli ASE (69.0% with ASE activity Ͼ 50 U/L [309/448 samples]). By monitoring ASE activity and anti-E coli Ab levels, however, we were for the first time able to relate the efficacy of second-line treatment with pegylated E coli ASE to Ab levels against E coli ASE.…”

“…6,7 Thus, good tolerability was reported for pegylated E coli ASE applied after allergic reactions to native E coli ASE. [8][9][10] Because E chrysanthemi and E coli ASE share only 70% amino acid homology, crossreactivity with native E coli-derived ASE is low. 11 In the case of allergic reactions to ASE, the treatment can usually be continued by switching to another ASE preparation.…”

Current and Emerging Therapies in T-cell Acute Lymphoblastic Leukemia

“…Table 1 lists the commonly used chemotherapeutic drugs for the current treatment of ALL and their biological effects on leukemic cells. These drugs include DNA damaging agents (anthracyclines, 36 alkylating agents, 37 and epipodophyllotoxins 38,39 ), anti-metabolites (nucleotides analogues such as 6-mercaptopurine 40 and methotrexate 41,42 ), mitotic inhibitors (vincristine 43,44 ), protein synthesis inhibitors (specifically, asparaginase and its more potent derivatives, PEG-asparaginase or Oncaspar ® , [45][46][47][48][49] etc.) and corticosteroids (glucocorticoid analogues, prednisone and dexamethasone).…”