The toxicity profile of asparaginase products presents significant challenges in clinical management. The following eviQ guidelines are based on recommendations from an expert panel.r See Table II (below) for further information.
Hypersensitivity reactions are due to anti-asparaginase antibody production. The incidence of clinically significant hypersensitivity ranges from 10-15%.r Reactions range from mild to life threatening and include; pruritus, rash, erythema, pain, oedema, and anaphylaxis. Clinical hypersensitivity occurs frequently in post induction regimens when asparaginase has not been given for weeks or months, but reactions have been reported after the first dose.
Neutralizing anti-asparaginase antibody can occur without clinical allergic reaction, called silent hypersensitivity. These antibodies may cause rapid inactivation of the asparaginase resulting in suboptimal asparagine depletion. PegASNase appears to have a lower rate of inducing neutralising antibody than E. coli asparaginase.r
An anaphylaxis kit and facilities for resuscitation should be available at the bedside and the patient observed for 1 hour after treatment.
Pre-medication with steroids, paracetamol and antihistamines is generally considered effective.
Asparaginase (colaspase) - In patients on corticosteroids in a treatment phase consider a delay in treatment for 3 to 4 days after the start of steroid therapy to reduce the risk of serious hypersensitivity.r
Pegasparaginase - If not on concurrent corticosteroids, premedication with hydrocortisone 100 mg IV is recommended.r
Steroids, antihistamines, oxygen and epinephrine should be administered as clinically indicated.
Switching formulations - For any potentially life threatening reaction with E. coli ASNase or pegASNase, further treatment with either is contraindicated. Antibodies to E. coli ASNase can cross react with pegASNase.r Erwinia has no cross reactivity with E. coli ASNase,r therefore patients who develop hypersensitivity can continue treatment with Erwinia if the appropriate premedications and precautions are taken.
Hepatotoxicity and abnormal liver function
Elevation of transaminases is common and usually resolves however hyperbilirubinaemia can delay the delivery of chemotherapy agents such as vinca alkaloids and anthracyclines. Evaluate hepatic enzymes and bilirubin before each dose of asparaginase and before any dose of a drug scheduled for administration after ASNase that is cleared or metabolised by the liver, such as a vinca alkaloid, anthracycline or azole antifungal.
Avoid the concurrent use of alcohol and hepatoxic drugs including azole antifungal antibiotics. Consider avoiding ASNase therapy in patients with underlying chronic hepatic dysfunction, especially due to alcoholism and viral hepatitis.r
Stock et alr have suggested a management strategy as provided in Table II. This recommends withholding ASNase treatment when grade 3-4 hepatotoxicity develops and then rechallenging with careful monitoring if the toxicity resolves to grade 1. Currently there is no data to suggest the need for dose reduction after recovering from hepatotoxicity.r
Thrombosis and bleeding (coagulation abnormalities)
Coagulation abnormalities may lead to haemorrhagic or more commonly, thrombotic events. This is due to impaired synthesis of proteins involved in coagulation and fibrinolysis, with greatest reduction in levels of plasma antithrombin (AT) and fibrinogen, and decreased levels of protein C, protein S and plasminogen.r Thrombotic and haemorrhagic events occur most commonly in the CNS (e.g. cerebral venous thrombosis), while PE and DVT have also been reported. Cerebral venous sinus thrombosis is primarily as a consequence of antithrombin depletion.r The incidence of thrombotic events associated with asparaginase administration in adults with ALL, has been reported at 4.2 to 9.3%.r
Haemostatic function should be monitored and replacement therapy initiated depending on absolute levels and clinical condition. (See Monitoring section below ) Patients presenting with neurologic symptoms should be investigated promptly.
Prevention of thrombosis and bleeding
It is not possible to provide firm recommendations regarding thromboprophylaxis and factor replacement for patients on asparaginase, owing to the lack of high quality trial data addressing this specific question. It is recommended that individual units develop a strategy of blood factor monitoring (AT, fibrinogen, INR) and a thromboprophylaxis/factor replacement regimen for patients on asparaginase. The exact strategy for each unit will be influenced by the available laboratory resources.
The majority of thrombotic events take place during induction therapy, therefore prophylaxis is likely to be most beneficial during this period. Low antithrombin should be replenished, though the replacement threshold needs to be selected (see below). Antithrombin dose is 50 Units/kg.
For treatment of low fibrinogen during asparaginase therapy, it needs to be recalled that fresh frozen plasma contains asparagine which may counteract the antileukemic effect of asparaginase. Therefore several groups avoid FFP for this reason. Conversely, cryoprecipitate contains high concentrations of Factor 8 which is thrombogenic and therefore should be used conservatively. These issues should influence the threshold selected for fibrinogen replacement. The French GRAALL recommends cryoprecipitate therapy for fibrinogen less than 0.5 g/L while the Mayo Clinic threshold is 1.0 g/L. Others replace fibrinogen only in bleeding patients. If cryopreciptate is to be used prophylactically concurrent anticoagulant thromboprophylaxis should be strongly considered.r
The current ALL6 protocol (V2 16/06/2014) recommends the following (in units with access to ATIII monitoring):
- Check coagulation studies including fibrinogen twice weekly during asparaginase therapy.
- If fibrinogen is less than 1.0 g/L, assess ATIII activity.
- If ATIII activity is less than 50%, give FFP 20 mL/kg over 4 hours and ATIII concentrate 50 Units/kg. Cryoprecipitate at 1 Unit/10kg could also be used.
- Prophylactic enoxaparin is recommended for all patients receiving asparaginase therapy during induction, unless contraindicated.
Treatment of thrombohaemorrhagic complications
AT concentrates and cryoprecipitate infusions should be used to treat thrombohaemorrhagic events due to AT and fibrinogen deficiency respectively. For non-urgent thrombohaemorrhagic episodes, FFP should be avoided since it contains asparagine.
For a clinically significant DVT the patient should be anticoagulated with or without antithrombin supplementation, whether or not it is associated with a central line. ASNase is discontinued for all clinically significant bleeding or thrombosis. Whether it is restarted depends on the nature and resolution of the thrombotic event as shown in Table II. Rechallenge after a CNS thrombohaemorrhagic event has resolved may be considered, but is in general not recommended.r
Pancreatitis can occur during or after therapy and can generally be managed without long-term sequelae.r The incidence of pancreatitis in the adult population given pegASNase has been low.r
Patients should be educated to report abdominal pain. Observe for abdominal tenderness and mid epigastric pain with vomiting. Serum amylase and lipase levels should be obtained prior to each cycle of therapy.
Avoidance of alcohol is a key preventative measure.r Treatment of hypertriglycerideaemia greater than 1000 mg/dL with gemfibrozil may prevent acute pancreatitis.r
Permanently discontinue asparaginase in the presence of grade 3 or 4 pancreatitis. In the case of grade 2 pancreatitis (enzyme elevation or radiographic findings only) asparaginase should be held until these findings normalise and then resume. Treatment of clinically significant pancreatitis includes hospitalisation, consultation with gastroenterology and/or surgical teams, nil by mouth status (NBM), IV hydration, analgesia, octreotide, antibiotics, consider nasogastric (NG) decompression and alimentation if necessary.
Asparaginase may cause a marked increase in plasma triglycerides and total cholesterol levels. In the case of grade 4 hypertriglyceridaemia, withhold asparaginase until normalised, then resume. Monitor closely for pancreatitis if hypertriglyceridaemia is present.r
The concomitant use of corticosteroids and asparaginase increases the occurrence of hyperglycaemia.r Transient diabetes mellitus may develop and usually responds to discontinuation of asparaginase. Insulin may be required for severe hyperglycaemia.
Central nervous system (other than thrombosis or haemorrhage)
Symptoms may include depression, drowsiness, confusion, hallucinations, personality changes, headache and more rarely a Parkinson-like syndrome.r ASNase therapy may cause hyperammonaemia with a diffuse encephalopathy or reversible posterior leukoencephalopathy syndrome. The latter is associated with T2 and FLAIR hyperintense signals in MR studies in occipital parenchyma. There is no preventative strategy. Serum ammonia should be obtained in patients with altered mental status, unexplained fatigue, somnolence or seizures. Discontinuation of ASNase and supportive care should be sufficient for recovery from this form of toxicity.r
In patients with CNS toxicity and hyperammonaemia, the use of lactulose to reduce intestinal production of ammonia is indicated. No active treatment is available for patients with reversible posterior leukoencephalopathy.r
Table II from Stock et al.r
© Leukemia & Lymphoma 2011