Management of asparaginase therapy

Class and mode of action

Asparaginase catalyses the conversion of L-asparagine to aspartic acid and ammonia. This reduces serum L-asparagine and starves the leukaemic cells of the L-asparagine necessary for DNA, RNA and protein synthesis resulting in cell death. Leukaemic cells are unable to synthesise adequate amounts of L-asparagine and are dependant on extracellular sources.^r

Formulations

Note: the term asparaginase refers to all three formulations

* Kyowa units (KU) are used to express the strength of asparaginase (Leunase®) used in Australia.^r 

Indications^rrr

• Acute lymphoblastic leukaemia (ALL)
• Myeloid leukaemia, malignant lymphoma

Contraindications

Erwinia asparaginase should not be used in patients who have:^r

• hypersensitivity reactions to erwinia asparaginase, including anaphylaxis
• existing pancreatitis
• serious pancreatitis with prior L-asparaginase therapy
• serious thrombosis or haemorrhagic events

Pegaspargase should not be used in patients who have:^r

• previous anaphylaxis or severe hypersensitivity to asparaginase formulations
• severe hepatic impairment
• existing or a history of pancreatitis
• previous haemorrhagic or severe thrombotic events

Cautions/exclusions:

• Pegaspargase should be used with caution in patients over 40 years of age and those with a body mass index (BMI) greater than 30 due to an increase risk of side effects.^r  

Pegaspargase protocols and dosing

There is limited evidence on the dose and frequency of pegaspargase in the adult population, however there are some trials in the paediatric and adolescent and young adult setting.

It is the consensus of the eviQ Haematology Reference Committee that pegaspargase should not be substituted into protocols where the trial used L-asparaginase. The recommended protocol/s currently in use in Australia for young adult (15 - 40 years) acute lymphoblastic leukaemia (ALL) patients requiring an asparaginase protocol is the ALL06 protocol. For the older adult population (>40 years) asparaginase containing regimens should be used with caution and protocol specifics closely followed. For lymphoma patients with natural killer T-cell lymphoma there is some limited evidence for the use of modified SMILE (mSMILE) and DDGP.

Pegaspargase seems more toxic in the older population and some toxicities have a higher incidence if patients have the following risk factors:^r 

• higher BMI (greater than 30) or obesity (higher incidence of hyperbilirubinaemia, hypertriglyceridaemia, hypofibrinogenaemia and thrombosis) 
• receive no pre-medication (higher incidence of hypersensitivity) 
• administration during induction compared with later cycles (higher incidence of hyperbilirubinaemia, thrombosis and hypofibrinogenaemia

Please refer to the monitoring section for further information on toxicities.

Administration advice​

Erwinia asparaginase (crisantaspase)^rr

• Erwinia asparaginase is serologically and biochemically distinct from E. coli derived asparaginase. When switching to Erwinia asparaginase following hypersensitivity reaction to asparaginase (colaspase), a higher dose and increased dosing frequency are required to ensure optimal asparagine depletion.^r 
• Patients who have had a previous hypersensitivity reaction to asparaginase (colaspase) are more likely react to this formulation.
• Serious allergic reactions may occur and facilities for resuscitation should be close at hand during administration.
• For intramuscular (IM) use, limit the volume of reconstituted Erwinia asparaginase at a single injection site to 2 mL. For doses greater than 2 mL, administer via multiple injection sites.
• For intravenous (IV) use, infuse Erwinia asparaginase in 100 mL sodium chloride 0.9% over 1 to 2 hours. Do not administer other intravenous drugs through the same intravenous line.
• It is not known whether the IV or IM route of administration of Erwinia asparaginase is optimal.^r IM administration results in a longer half-life (15.6 hours) in comparison to IV administration (7.51 hours).
• When administering Erwinia asparaginase intravenously, consider monitoring nadir (pre-dose) serum asparaginase activity (NSAA) levels and switching to intramuscular administration if desired NSAA levels are not achieved.
• Consider changing to intramuscular administration if patient experiences severe nausea and vomiting with intravenous administration.

Pegaspargase (pegylated asparaginase)^r

• For smaller volumes, the preferred route of administration is IM. IM administration is preferred over IV administration due to a lower incidence of hepatotoxicity, coagulopathy, gastrointestinal and renal disorders^r
• For doses greater than 2 mL, the dose may be administered between two sites. Rotate site of injection.
• Pegaspargase has a longer half-life and decreased toxicity compared to the other asparaginase formulations.
• While pegaspargase is reported to be the least immunogenic formulation, serious hypersensitivity or anaphylactic-type reactions may occur and facilities for resuscitation should be close at hand during administration.

Dose modifications

Dose modifications should be at the clinician's discretion. Use with caution in patients with renal or hepatic impairment.

The toxicity profile of asparaginase products presents significant challenges in clinical management. The following eviQ guidelines are based on published references and recommendations from an expert panel.^r See Table II (below) for further information.

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 pulmonary embolism (PE) and deep vein thrombosis (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 The reported rate of > grade 3 thrombosis associated with pegaspargase administration is 11 to 27%.^r

Haemostatic function should be closely monitored and replacement therapy considered depending on suggested blood parameters defined below as well as the clinical condition and bleeding phenotype of the patient (which can change over the course of therapy) (see Monitoring section below). Patients presenting with neurological symptoms should be investigated promptly for central sinus vein thrombosis.

Prevention of thrombosis and bleeding

It is recommended that all patients on pegaspargase should receive thromboembolic prophylaxis (unless contraindicated - see below) with low molecular weight heparin (LMWH).^rr

It is recommended that individual units develop local strategies for blood factor monitoring (AT, fibrinogen, INR) and a thromboprophylaxis/factor replacement regimen for patients on pegaspargase. The exact strategy for each unit will be influenced by factors including available laboratory resources.

The majority of thrombotic events take place during induction therapy, therefore prophylaxis is likely to be most beneficial during this period. It may be appropriate to consider administration of antithrombin concentrate to patients with low antithrombin levels (e.g. ≤ 60%)^r. However, recent evidence suggests there is little or no impact on the incidence of asparaginase-induced venous thromboembolism (VTE).^r

For treatment of hypofibrinogenaemia during asparaginase therapy, it is important to consider that:

• fresh frozen plasma (FFP) contains asparagine which may counteract the antileukaemic effect of asparaginase - several groups avoid FFP for this reason 
• cryoprecipitate contains high concentrations of Factor 8 which is thrombogenic and therefore should be used conservatively. Some groups have observed a correlation between cryoprecipitate replacement for severe hypofibrinogenaemia and onset of VTE during pegaspargase therapy.^r

These issues should influence the threshold selected for fibrinogen replacement. The French GRAALL recommends cryoprecipitate therapy for fibrinogen less than 0.5 g/L^r while the Mayo Clinic threshold is 1.0 g/L. Many centres now replace fibrinogen only in bleeding patients with hypofibrinogenaemia. 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 VTE (e.g. DVT or PE) the patient should be anticoagulated with standard therapeutic LMWH with or without antithrombin supplementation, whether or not it is associated with a central line. Asparaginase is discontinued for all clinically significant active bleeding or thrombosis events. Whether it is restarted depends on the nature and resolution of the thrombotic event as shown in Table II but for non-CNS thrombohaemorrhagic events, pegaspargase can generally be safely restarted without reoccurrence assuming appropriate management strategies are maintained.^r 

Pancreatic disorders

Pancreatitis can occur during or after therapy and can generally be managed without long-term sequelae.^r Clinical pancreatitis occurs in 5 to 14% of adults treated with pegaspargase, with chemical increase in pancreatic enzymes (amylase, lipase) occurring more frequently (24%).^r 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.^rr In very rare cases, haemorrhagic or necrotising pancreatitis occurs, with fatal consequences.^r 

Development of asparaginase-induced pancreatitis is a clear contraindication for ongoing pegaspargase therapy as the recurrence rate with re-challenging doses is 46% to 63%, with half of cases being severe. Switching asparaginase formulation (e.g. pegaspargase to Erwinia asparaginase) in patients who develop clinical pancreatitis should be avoided due to high likelihood of recurrence.^r

Serum amylase, lipase and/or insulin levels should be monitored routinely to exclude hyperglycaemia and severe pancreatitis (see Monitoring below).^r

Patients should be educated to report any clinical symptoms of pancreatic abnormality such as abdominal pain (especially radiating to the back). Observe for abdominal tenderness and mid epigastric pain with vomiting. 

Prevention

Avoidance of alcohol is a key preventative measure. Treatment of hypertriglycerideaemia greater than 1000 mg/dL with gemfibrozil may prevent acute pancreatitis.^r

Management

Clinical/symptomatic pancreatitis: permanently discontinue all asparaginase formulations (do not switch).^rTreatment 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

Chemical pancreatitis (elevated amylase and/or lipase up to 3 x ULN, without symptoms or radiological findings): continue asparaginase, ensure continued frequent monitoring of levels and observe patient closely for development of clinical pancreatitis requiring early and aggressive intervention. Asparaginase therapy should be permanently discontinued for clinical pancreatitis with amylase or lipase elevation >3 x ULN for >3 days and/or development of pancreatic pseudocyst.^r 

Hepatotoxicity and abnormal liver function

Hepatotoxicity is the most common adverse effect of pegaspargase treatment in adults with a high incidence of both hyperbilirubinaemia and transaminitis. The toxicity is reversible, almost always not associated with clinical liver disease and rarely results in liver failure. Pegaspargase-induced hyperbilirubinaemia occurs most commonly during induction therapy with the incidence usually declining or not recurring in subsequent cycles.^r However hyperbilirubinaemia can delay the delivery of chemotherapy agents such as vinca alkaloids and anthracyclines. Liver function tests (LFT) 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. LFT monitoring should be continued for at least 4 weeks after each pegaspargase dose.

Prevention

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

Management

Stock et al^r have suggested a management strategy as provided in Table II. This recommends continuing asparaginase therapy if direct bilirubin < 3.0 mg/dL (< 50 micromol/L) and /or ALT/AST up to 5 x ULN and withholding asparaginase treatment when grade 3-4 hepatotoxicity develops and then re-challenging with careful monitoring when the toxicity resolves to grade 1. Currently there is no data to suggest the need for dose reduction after recovering from hepatotoxicity.^r

Single case observations and small case series report success with the use of L-carnitine and/or vitamin B complex in reducing asparaginase-induced hyperbilirubinaemia.^rr

Hypersensitivity

Hypersensitivity reactions occur due to anti-asparaginase antibody production. The incidence of clinically significant hypersensitivity ranges from 10-15% and varies with prior exposure, concomitant or prior immunosuppressive therapy and the individual patient.^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 and only rarely occurs with 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. Pegaspargase appears to have a lower rate of inducing the development of neutralising antibodies than asparaginase (colaspase).^r

Clinical infusion reactions most often occur with the first pegaspargase dose and are not anti-asparaginase antibody mediated reactions, therefore do not result in enzyme inactivation. They may occur as a result of pre-existing anti-PEG (polyethylene glycol) antibodies which may be present (e.g. as a result of exposure to cosmetics) as well as elevated ammonia levels resulting from increased extracellular asparagine catabolism. There is no indication to switch to Erwinia asparaginase due to a clinical infusion reaction (as opposed to true hypersensitivity/anaphylaxis or silent inactivation – see Management below).^r

Prevention

An anaphylaxis kit and facilities for resuscitation should be available at the bedside and the patient observed for one hour after treatment.

Pre-medication: standard Australian practice (e.g. ALLG ALL trials) is currently to not pre-medicate with any drugs prior to pegaspargase administration, due to the possibility of masking signs of clinical allergy resulting from enzymatic inactivation by anti-asparaginase antibodies. This will render the drug ineffective and may result in loss of treatment effect. Pre-medication may be considered if a centre is able to measure serum asparaginase enzymatic activity (typically a serum level approximately 3-7 days after the dose and aiming for a level > 0.1 IU/mL) to determine if enzymatic inactivation has occurred. The use of pre-medications have been shown to reduce the incidence of clinical hypersensitivity by 60% in one study.^rr 

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

Therapeutic drug monitoring of asparaginase

Therapeutic drug monitoring (TDM) is available for patients who receive asparaginase therapy.^r 

There are three laboratories in Australia which perform asparaginase activity assays:

• Children's Hospital Westmead, NSW: Contact Dr Christa Nath, christa.nath@health.nsw.gov.au
• Royal Brisbane and Women's Hospital, QLD: Contact Dr Carel Pretorius, Carel.Pretorius@health.qld.gov.au
• Alfred Hospital Melbourne, VIC: Contact Heather Aumann, h.aumann@alfred.org.au

For further information on sample requirements please refer to the ANZCHOG Guideline: Serum asparaginase activity monitoring in children and adolescents

Management

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. TDM can be considered for subsequent doses.

It is possible to reduce the risk of a pegaspargase related infusion reaction by increasing the duration of the IV infusion, with 10% of pegaspargase infused over the first hour and remaining 90% infused over the second hour.^r

Switching formulations: patients receiving treatment with pegaspargase (Oncaspar^®), and who develop hypersensitivity to that enzyme or where silent inactivation has been proven by TDM, should continue treatment with Erwinia asparaginase as the enzymes are immunologically distinct and cross-reactivity is limited.^r

Pegaspargase desensitisation: with the continued limited availability and high cost of Erwinia asparaginase and the discontinuation of the native E.coli asparaginase (colaspase) product the use of a pegaspargase desensitisation regimen may be an appropriate alternative approach in patients with a prior hypersensitivity to pegaspargase or who develop a hypersensitivity during pegaspargase treatment.^r One suggested desensitisation regimen is published in Verma et al.^r

Hyperlipidaemia

Asparaginase may cause a marked increase in plasma triglycerides and total cholesterol levels. This usually occurs after the first induction cycle and is more frequent during consolidation therapy.^r

Grade 4 hypertriglyceridaemia: withhold asparaginase until levels are normalised, then resume treatment. Monitor closely for pancreatitis if hypertriglyceridaemia is present.^r

Hyperglycaemia

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 levels 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

Management

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

Documented interactions with asparaginase are limited. However, a range of clinical effects can occur due to the mechanism of action of asparaginase.

The following are routine measurements and assessments that should be scheduled with this treatment.

Patient education should include:

• asparaginase drug regimen education
• information about potential complications and side effects
• how to report signs and symptoms of infection or other side effects, or any worsening of symptoms or other health problems.

It is also important to inform the patient's carer/s about the side effects of asparaginase.

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