Canterbury DHB

L-Asparaginase Administration and Toxicity

Pegylated Asparaginase has now replaced Asparaginase, because it gives more prolonged and intensive Asparaginase depletion. All preparations of Asparaginase can cause significant risk of major complications particularly involving thrombosis and/or bleeding. Cerebral venous sinus thrombosis complicated by CNS bleeding is a rare but well recognised complication. It is essential that you familiarise yourself with the details of Asparaginase treatment, its complications, and their management. Refer to Asparaginase Data Sheets on Medsafe. See also Aldoss, I. and D. Douer (2020). "How I treat the toxicities of pegasparaginase in adults with acute lymphoblastic leukemia." Blood 135(13): 987-995.

Subsequent peg Asparaginase doses may have to be withheld or the drug discontinued in the presence of pancreatitis (identified by raised amylase or low serum insulin), severe liver dysfunction, life-threatening allergic reactions, and significant thrombosis. Previous experience suggests that 4-5% of patients will have asparaginase-related toxicity with hyperglycaemia being the commonest problem. Since hyperglycaemia may be due to prednisone rather than L-asparaginase, serum insulin and amylase measurements should be performed before withdrawal of L-asparaginase.

Note: The recommendations given below for monitoring coagulation factor levels and any subsequent replacement treatment must be followed. They differ from the full UKALL 14 protocol. Coagulation factors and liver function tests need to be monitored during L-asparaginase treatment. See the next sections.

Management of Anaphylaxis

The risk of a hypersensitivity reaction is increased after repeated courses of therapy. Signs and symptoms can include hypotension, respiratory distress (dyspnea and/or bronchospasm), tachycardia, urticaria and angioedema. If a reaction occurs it must be documented in the patient’s notes.

Occasional patients who have had anaphylaxis with pegylated asparaginase have been successfully treated with asparaginase derived from Erwinia.

L-asparaginase – bleeding and thrombosis

A rare but devastating side effect is the development of serious thrombotic problems, particularly within the central nervous system. There may also be an increased bleeding risk with reduction of clotting factors. The following advice regarding management of asparaginase-induced thrombophilia must be followed:

• Levels of anti–thrombin III (ATIII), fibrinogen, APTT, INR, amylase, glucose, Na, K, creatinine and LFTs should be monitored while the patient is receiving L-asparaginase. These should be done before start of L-asparaginase, to get a baseline, and then three times a week until the AT3 has recovered.
• If the level of fibrinogen is below 0.8 g/litre or the APTT is >70 seconds at any time during L–asparaginase treatment, replacement therapy with fresh frozen plasma (FFP) will be given at a dose of 15 mL/kg.
• If antithrombin level is <70% replace with antithrombin concentrate at 1000 IU. Discuss with the Consultant whether L-asparaginase should be stopped. If the patient has a low body weight, the dose will need to be calculated as per dosing instructions. See the Medsafe data sheet for information on dosing and administration.
• Coag. lab needs adequate warning of samples for testing to allow results to be processed in time to administer dose. Notify Coag. lab on the Friday if there will be weekend samples.

Topic Code: 4743