Postinduction Dexamethasone and Individualized Dosing of Escherichia Coli L-Asparaginase Each Improve Outcome of Children and Adolescents With Newly Diagnosed Acute Lymphoblastic Leukemia: Results From a Randomized Study—Dana-Farber Cancer Institute ALL Consortium Protocol 00-01

Abstract

There was no overall difference in skeletal toxicity by corticosteroid type; dexamethasone was associated with more infections and, in older children, increased incidence of osteonecrosis and fracture. There was no difference in asparaginase-related toxicity by EC-Asnase dosing method. Dexamethasone and ID EC-Asnase were each associated with superior EFS. Monitoring NSAA during treatment with EC-Asnase may be an effective strategy to improve outcome in pediatric ALL.

The toxicity of very prolonged courses of PEGasparaginase or Erwinia asparaginase in relation to asparaginase activity, with a special focus on dyslipidemia

“…Recently, the Dana Farber Consortium Institute group reported a comparable incidence of pancreatitis (5%) and thrombosis (8%) with the same schedule. 9 We demonstrate that high levels of asparaginase activity are related to hypertriglyceridemia and hypercholesterolemia (dyslipidemia). It should be noted that PEGasparaginase activity levels were much higher than Erwinia asparaginase activity levels.…”

Consensus expert recommendations for identification and management of asparaginase hypersensitivity and silent inactivation

“…Also demonstrated has been the phenomenon of "silent inactivation," with the formation of neutralizing antibodies and reduced asparaginase activity in the absence of a clinically evident allergic reaction. 2,3,[10][11][12] The risk of development of clinical allergy and silent inactivation may be influenced by several factors including the formulation preparation of asparaginase, the route of administration, the schedule of administration (such as in schedules with intermittent dosing with gaps in asparaginase exposure followed by reintroduction of asparaginase), the line of treatment (i.e. relapse protocols) and the concurrent use of other chemotherapeutic agents including corticosteroids.…”

“…Recent data suggest that the development of silent inactivation is clinically important in the context of leukemiadirected therapy, and that acting upon silent inactivation may improve outcome. 2,3 The results of the DFCI ALL Consortium Protocol 00-01 suggested that the evaluation of nadir serum asparaginase levels in patients receiving native E. coli asparaginase, and changing asparaginase preparation in the setting of silent inactivation (as defined by persistently low nadir serum asparaginase activity, with or without antibody positivity), was associated with improved outcome in children with ALL. 2 These results highlight the importance of switching asparaginase preparation in the setting of silent inactivation.…”

“…2,12 Some patients may have developed antibodies to PEG before the start of pegaspargase treatment, presumably due to previous exposure to PEG (for example in creams). 33 We recommend the testing of serum asparaginase activity level after the first dose of E. coli-derived asparaginase.…”

“…Children and adolescents with ALL who receive an inadequate course of planned asparaginase therapy due to either intolerable side effects or silent inactivation have been shown to have inferior outcomes compared with those who receive the majority of intended doses of asparaginase, highlighting the importance of maximizing the delivery of planned asparaginase therapy. [1][2][3] L-asparaginase preparations are bacterial enzymes derived from either Escherichia coli (E. coli) or Erwinia chrysanthemi (Erwinia). E. coli-derived preparations include native E. coli-asparaginase, no longer available in the United States, and pegylated formulations (pegaspargase), in which the E. coli-derived enzyme is modified by the covalent attachment of polyethylene glycol.…”