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, urticaria, rash, erythema, bronchospasm, hypotension, 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.
Neutralising anti-asparaginase antibodies can develop without a clinical allergic reaction and is known as silent hypersensitivity. These antibodies may cause rapid inactivation of asparaginase resulting in suboptimal asparagine depletion. Pegasparaginase appears to have a lower rate of inducing the development of neutralising antibodies than asparaginase (colaspase).r
An anaphylaxis kit and facilities for resuscitation should be available at the bedside and the patient observed for one hour after treatment.
Pre-medication with steroids, paracetamol and antihistamines is generally considered effective.
Asparaginase (colaspase): for 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: for patients not on concurrent corticosteroids, premedication with hydrocortisone 100 mg IV is recommended.r
If a severe hypersensitivity or anaphylactic-type reaction occurs treatment should be discontinued immediately. Steroids, antihistamines, oxygen and epinephrine should be administered as clinically indicated.
Switching formulations: patients receiving treatment with asparaginase (colaspase), and who develop hypersensitivity to that enzyme may be able to continue treatment with Erwinia asparaginase as the enzymes are immunologically distinct.
There is cross reactivity between patient antibodies raised against asparaginase (colaspase) and pegasparaginase, but not Erwinia asparaginase.r
Hepatotoxicity and abnormal liver function
Elevation of bilirubin, ALT, AST, alkaline phosphatase and cholesterol levels are common and usually resolve. However hyperbilirubinaemia can delay the delivery of chemotherapy agents such as vinca alkaloids and anthracyclines. Liver function tests must be monitored before each dose of asparaginase and before the administration of a hepatically metabolised or cleared drug which is scheduled for administration after the asparaginase e.g. vinca alkaloid, anthracycline or azole antifungal.
Avoid the concurrent use of alcohol and hepatotoxic drugs including azole antifungal antibiotics. Consider avoiding the use of asparaginase 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 asparaginase treatment when grade 3-4 hepatotoxicity develops and then re-challenging 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 the impaired synthesis of proteins involved in coagulation and fibrinolysis, with the 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
Due to the lack of high quality trial data, recommendations on thromboprophylaxis and factor replacement for patients on asparaginase cannot be made in this document.
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/Lr while the Mayo Clinic threshold is 1.0 g/L. Some centres replace fibrinogen only in bleeding patients. If cryopreciptate is to be used prophylactically, concurrent anticoagulant thromboprophylaxis should be strongly considered.r
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. Asparaginase 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 Acute pancreatitis occurs in <10% of cases. There have been isolated reports of pseudocyst formation up to four months after last treatment, so appropriate testing (e.g. ultrasound) may need to be considered beyond last treatment.r In very rare cases, haemorrhagic or necrotising pancreatitis occurs, with fatal consequences.r
Serum amylase, lipase and/or insulin levels should be monitored to exclude hyperglycaemia and severe pancreatitis
Patients should be educated to report any clinical symptoms of pancreatic abnormality such as abdominal pain. Observe for abdominal tenderness and mid epigastric pain with vomiting.
Avoidance of alcohol is a key preventative measure. Treatment of hypertriglycerideaemia greater than 1000 mg/dL with gemfibrozil may prevent acute pancreatitis.r
Grade 3 or 4 pancreatitis: permanently discontinue asparaginase.r
Grade 2 pancreatitis: based on enzyme elevation or radiographic findings, withhold asparaginase until these findings normalise and then resume treatment.r
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.r
Asparaginase may cause a marked increase in plasma triglycerides and total cholesterol levels.
Grade 4 hypertriglyceridaemia: withhold asparaginase until levels are normalised, then resume treatment. 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 Asparaginase 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 asparaginase 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