Safety, efficacy, and clinical utility of asparaginase in the treatment of adult patients with acute lymphoblastic leukemia

Figures & data

Table 1 Asparaginase formulations and their characteristics

Product	Trade name	Source	Elimination half-life	Dosage
Native E. coli asparaginase	Elspar	Merck & Co, Inc.	26–30 hours	6,000 IU/m^2 three times per week
Erwinia asparaginase	Erwinase	Speywood Pharmaceuticals, Inc.	5.5–7 days	6,000 IU/m^2 daily × ten doses, then three doses weekly, or 30,000 IU/m^2 daily × ten doses in induction
PEG-asparaginase	Oncospar	Enzon Pharmaceuticals	16 hours	2,000–2,500 IU/m^2 every 2 or 4 weeks
l-Asparaginase-loaded RBCs	GRASPA	Erytech Pharma	40 days	100 IU/kg every 4 weeks

Abbreviation: RBCs, red blood cells.

Table 2 Recommended management of common asparaginase toxicities

Toxicity	Grade 2	Grade 3	Grade 4
Non-CNS thrombosis	Continue unless clinical signs or symptoms present	Withhold therapy until acute toxicity resolved and patient stabilized on anticoagulation	Withhold therapy until acute toxicity resolved and patient stabilized on anticoagulation
Non-CNS hemorrhage	Withhold therapy until bleeding is ≤ grade 1; do not withhold for hypofibrinogenemia in the absence of clinical findings	Withhold therapy until bleeding is ≤ grade 1 and factor replacement therapy is completed	Withhold therapy until bleeding is ≤ grade 1 and factor replacement therapy is completed
CNS thrombosis	Continue therapy assuming no clinical signs or symptoms (abnormal laboratory findings only)	Discontinue therapy until full resolution; may resume ASNase therapy at decreased dose or increased dosing interval	Permanent discontinuation of therapy
CNS hemorrhage	Continue therapy assuming no clinical signs or symptoms (abnormal laboratory findings only)	Discontinue therapy until full resolution; may resume ASNase therapy at decreased dose or increased dosing interval	Permanent discontinuation of therapy
Hepatic transaminitis	Continue as long as elevations remain < 3–5 times the ULN	For elevation >5–20 times the ULN, delay dose until < grade 2	For elevation >20 times the ULN, discontinue if toxicity reduction to < grade 2 takes longer than 1 week
Hyperbilirubinemia	Continue if direct bilirubin is <3.0 mg/dL	If direct bilirubin is 3.1–5.0 mg/dL, hold until direct bilirubin is <2.0 mg/dL	If direct bilirubin is >5.0 mg/dL, discontinue. Do not make up for missed doses
Hypertriglyceridemia	If serum triglycerides <1,000 mg/dL, monitor closely for development of pancreatitis	If triglycerides >1,000 mg/dL, hold therapy and resume at a lower dose when triglycerides are at baseline	If triglycerides >1,000 mg/dL, hold therapy and resume at a lower dose when triglycerides are at baseline
Pancreatitis	Continue for asymptomatic elevations in amylase and lipase <3 times the ULN or only for radiologic findings	Hold therapy for elevations in amylase or lipase >3 times the ULN until stabilized or declining	Permanently discontinue for clinical pancreatitis
Hypersensitivity	Continue for urticaria without bronchospasm, hypotension, or edema	For bronchospasm, angioedema, or hypotension, discontinue. If Erwinia asparaginase is available, replace PEG-asparaginase dose with 6 doses of Erwinia asparaginase 25,000 IU/m^2 IM every other day	For life-threatening reactions, discontinue. If Erwinia asparaginase available, replace PEG-asparaginase dose with 6 doses of Erwinia asparaginase 25,000 IU/m^2 IM every other day

Abbreviations: ASNase, asparaginase; CNS, central nervous system; IM, intramuscular; ULN, upper limit of normal; PEG, polyethylene glycol.

Table 3 Frontline trials of asparaginase in adults with ALL

Study	Number of patients	Patient age range (years)	Asparaginase dose	Asparaginase preparation	CR rate	Survival
Hoelzer et al^Citation31	162	15–65	5,000 IU/m^2 ×14 doses during induction	E. coli l-asparaginase	78%	Median OS =26 months Median remission duration =20 months
DeAngelo et al^Citation32	92	18–50	Starting dose of 12,500 IU/m^2 IM pharmacokinetically dose-adjusted given weekly for 30 weeks	E. coli l-asparaginase	85%	DFS =69%, OS =67% at 4 years
Douer et al^Citation34	51	18–57	2,000 IU/m^2 for a total of six doses	Pegaspargase	96%	DFS =58%, OS =51% at 7 years
Rijneveld et al^Citation35 (for the Dutch- Belgian HOVON study group)	54	17–40	6,000 IU/m^2 for a total of 21 doses	E. coli l-asparaginase	91%	EFS =66%, OS =72% at 32 months
Huguet et al^Citation36 (for the GRAALL)	225	15–60	6,000 IU/m^2 for a total of eight doses	E. coli l-asparaginase	93.5%	EFS =55%, OS =60% at 42 months

Abbreviations: CR, complete remission; DFS, disease-free survival; EFS, event-free survival; IM, intramuscular; OS, overall survival; ALL, acute lymphoblastic leukemia.

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