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Table 3-4

Dosing, Monitoring, and Management of Asparaginase-Related Adverse Events

ASPARAGINASE-RELATED ISSUEDOSING/MONITORING/MANAGEMENT
Dosing strategies
  • Pegaspargase (2,500 IU/m2 IV) capped at one vial (3,750 IU) for all nonstudy adult patients
Hypersensitivity reactions
  • IV administration and premedication with acetaminophen, hydrocortisone, and diphenhydramine to prevent hypersensitivity reactions
  • Permanent discontinuation of pegaspargase and switching to Erwinase (asparaginase Erwinia chrysanthemi) for patients who experience a ≥grade 3 severe hypersensitivity reaction
Hepatotoxicity
  • Monitor aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, and direct bilirubin at baseline and weekly for at least 4 weeks after each pegaspargase dose
  • If direct bilirubin >3 mg/dL or liver function tests (LFTs) >3× the upper limit of normal (ULN), administer vitamin B complex one tablet by mouth (PO) twice daily and L-carnitine 50 mg/kg/day IV in six divided doses
  • Patients with pegaspargase-induced hyperbilirubinemia or transaminitis may receive pegaspargase in subsequent cycles of treatment if the bilirubin/AST/ALT return to normal range and potential clinical benefit outweighs risk
Pancreatitis
  • Monitor amylase and lipase at baseline, 2–3 days after administration of pegaspargase, then weekly for at least 4 weeks after each pegaspargase dose
  • Permanently discontinue pegaspargase in patients who develop clinical pancreatitis (e.g., vomiting or severe abdominal pain) with amylase/lipase elevation >3× ULN for >3 days and /or develop pancreatic pseudocyst. These patients should not receive any other asparaginase products
Hemorrhage
  • Monitor fibrinogen at baseline and three times per week for at least 4 weeks after the initial dose of pegaspargase and up to three times per week as needed for at least 4 weeks for each subsequent dose. If fibrinogen <80 mg/dL, replete with 1 unit of cryoprecipitate and ensure adequate repletion by measuring postrepletion level within 24 hours. If fibrinogen 80–150 mg/dL and thrombin time (TT) >1.5 × ULN, replete with 1 unit of cryoprecipitate
  • Withhold subsequent pegaspargase doses for >grade 2 hemorrhage in conjunction with hypofibrinogenemia until toxicity <grade 1 as defined by Common Terminology Criteria for Adverse Events (CTCAE)
Thromboprophylaxis
  • Administration of enoxaparin to all patients for at least 4 weeks after each pegaspargase dose-enoxaparin 40 mg subcutaneously (SQ) daily for patients <80 kg; enoxaparin 60 mg SQ daily for patients >80 kg. Patients must meet the following criteria: not already receiving therapeutic anticoagulation; platelet count >30 K/μL; absence of significant bleeding; creatinine clearance >30 mL/min
  • Monitor antithrombin III level at baseline and twice weekly for at least 4 weeks after each pegaspargase dose (or until two sequential levels normalize to >50%). Replete antithrombin III when level is ≤50%
  • Antithrombin III dose = ([80% − current antithrombin III level %] × body weight in kg)/1.4