Abstract
PurposeFavorable outcomes were achieved for children with acute lymphoblastic leukemia (ALL) with the first Russian multicenter trial Moscow–Berlin (ALL-MB) 91. One major component of this regimen included a total of 18 doses of weekly intramuscular (IM) native Escherichia coli-derived asparaginase (E. coli-ASP) at 10000 U/m2 during three consolidation courses. ASP was initially available from Latvia, but had to be purchased from abroad at substantial costs after the collapse of Soviet Union. Therefore, the subsequent trial ALL-MB 2002 aimed at limiting costs to a reasonable extent and also at reducing toxicity by lowering the dose for standard risk (SR−) patients to 5000 U/m2 without jeopardizing efficacy.MethodsBetween April 2002 and November 2006, 774 SR patients were registered in 34 centers across Russia and Belarus, 688 of whom were randomized. In arm ASP-5000 (n = 334), patients received 5000 U/m2 and in arm ASP-10000 (n = 354) 10 000 U/m2 IM.ResultsProbabilities of disease-free survival, overall survival and cumulative incidence of relapse at 10 years were comparable: 79 ± 2%, 86 ± 2% and 17.4 ± 2.1% (ASP-5000) vs. 75 ± 2% and 82 ± 2%, and 17.9 ± 2.0% (ASP-10000), while death in complete remission was significantly lower in arm ASP-5000 (2.7% vs. 6.5%; p = 0.029).ConclusionOur findings suggest that weekly 5000 U/m2E. coli-ASP IM during consolidation therapy are equally effective, more cost-efficient and less toxic than 10000 U/m2 for SR patients with childhood ALL.
Highlights
Since Oettgen et al have first described the antileukemic effects of L-asparaginase (ASP) in 1967, the bacterial enzyme has become a mainstay in both remission induction and post-induction consolidation (Oettgen et al 1967)
disease-free survival (DFS) was significantly superior in boys, and overall survival (OS) higher in boys and young children in arm ASP-5000
Death in complete remission (CR) was mainly caused by infections and occurred significantly less frequently in arm ASP-5000 (n = 9, 2.7%) than arm ASP-10000 (n = 23, 6.5%) (p = 0.029) (Table 5)
Summary
Since Oettgen et al have first described the antileukemic effects of L-asparaginase (ASP) in 1967, the bacterial enzyme has become a mainstay in both remission induction and post-induction consolidation (Oettgen et al 1967). Journal of Cancer Research and Clinical Oncology (2019) 145:1001–1012 pegylated E. coli-ASP [PEG-ASP] or recombinant ASP), dosing, and route of administration (intramuscular, IM vs intravenous, IV), ASP is regularly associated with adverse effects. Life-threatening side effects may be thrombosis, necrotizing pancreatitis, and hypersensitivity reactions (HSR) due to antibodies directed against ASP, the latter especially after prolonged and IV administration (Schmiegelow et al 2016; Ko et al 2015). ASP-related myelosuppression requiring dose reductions of other antineoplastic agents during consolidation has been reported (Oehlers et al 1969; Kolarz and Pietschmann 1971; Johnston et al 1974; Merryman et al 2012)
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