Crisantaspase

Asparaginases are enzymes that convert the amino acid L-asparagine into L-aspartic acid and ammonia. Crisantaspase is recombinant Erwinia chrysanthemi L-asparaginase, produced by recombinant DNA technology in Pseudomonas fluorescens; its amino acid sequence is identical to that of the native enzyme. In an in-vitro activity assay, 1 mg of the recombinant enzyme corresponds to about 1,000 U of native crisantaspase, and in healthy subjects 25 mg/m² of the recombinant product gave serum asparaginase activity comparable to 25,000 U/m² of the native product, intravenously or intramuscularly. Enrylaze is dosed in mg/m², not in units/m² as other asparaginase preparations are.

Mechanism of Action

• Asparagine depletion: the enzyme removes L-asparagine from the plasma, and the killing of leukaemic cells follows from this depletion.
• Why leukaemic cells are sensitive: leukaemic cells with low expression of asparagine synthetase can hardly make their own asparagine and depend on an outside supply to survive.
• Structure (DrugBank): a tetramer of four identical subunits of about 35 kDa each; it also deaminates glutamine to a lesser extent.
• Use after E. coli asparaginase: there is little or no cross-reactivity between crisantaspase and E. coli-derived asparaginases, which is why it can be used in patients who reacted to the latter. Silent inactivation means that the E. coli enzyme is neutralised without an obvious allergic reaction.
• Efficacy marker: efficacy was judged by whether a nadir serum asparaginase activity (NSAA) of at least 0.1 U/mL was reached and maintained, in an open-label study of 228 adult and paediatric patients (median age 10 years, range 1 to 25) with ALL or LBL who had developed hypersensitivity to a long-acting E. coli-derived asparaginase.

Pharmacokinetics

• Basis: pharmacokinetics are described by serum asparaginase activity (SAA). Peak activity (Cmax) and area under the curve rise roughly in proportion to dose between 12.5 and 50 mg/m².
• Absorption: after intramuscular injection the median time to peak is 16 hours and mean absolute bioavailability is 38%.
• Distribution: after intravenous dosing the volume of distribution is 1.75 L/m².
• Metabolism: expected to be broken down into small peptides by ordinary catabolic pathways.
• Elimination: clearance after intravenous dosing is 0.14 L/h/m². The half-life is 8.6 hours after intravenous dosing and 18.8 hours after intramuscular dosing.
• Trough activity (after the last 25/25/50 mg/m² Monday/Wednesday/Friday dose of cycle 1): intramuscular, 0.66 U/mL at 48 hours and 0.47 U/mL at 72 hours; intravenous, 0.25 U/mL at 48 hours and 0.10 U/mL at 72 hours. SAA varies substantially between patients, which is why it is monitored.
• Special populations: there was no dedicated study in renal or hepatic impairment. Dose adjustment is not needed for total bilirubin up to 3 times the upper limit of normal (ULN) during treatment, nor for pre-existing mild or moderate hepatic impairment; data are limited for bilirubin above 3 and up to 10 times ULN.

• Acute lymphoblastic leukaemia (ALL) and lymphoblastic lymphoma (LBL): as a component of a multi-agent chemotherapeutic regimen, in adult and paediatric patients (1 month and older) who developed hypersensitivity or silent inactivation to E. coli-derived asparaginase.

• History of severe hypersensitivity reactions to the active substance.
• Hypersensitivity to any of the excipients.
• Severe pancreatitis.
• History of severe pancreatitis during previous asparaginase therapy.
• Severe thrombosis during previous asparaginase therapy.
• Severe haemorrhagic events during previous asparaginase therapy.

In the clinical trial 59% of patients had serious adverse reactions, most often febrile neutropenia (29%), pyrexia (10%), vomiting (8%), sepsis (7%), medicinal product hypersensitivity (6%), nausea (6%) and pancreatitis (5%). The most common reactions were anaemia (52%), vomiting (49%), thrombocytopenia (42%), neutropenia (41%), nausea (38%), febrile neutropenia (32%), fatigue (32%), pyrexia (32%), decreased appetite (29%), increased transaminases (29%), abdominal pain (27%), decreased white blood cell count (27%), headache (25%), diarrhoea (22%) and decreased lymphocyte count (20%). The frequencies below come from 228 patients who received 6 doses of Enrylaze together with multi-agent chemotherapy; effects of bone marrow suppression and infections are known with such regimens, so the part played by Enrylaze is not always clear.

Very common (≥1/10): anaemia, thrombocytopenia, neutropenia, febrile neutropenia; drug hypersensitivity; decreased appetite, hyperglycaemia, hypoalbuminaemia; anxiety; headache; vomiting, nausea, abdominal pain, diarrhoea; pain in a limb; fatigue, pyrexia; increased transaminases, decreased white blood cell and lymphocyte counts, weight decreased, increased blood bilirubin; contusion.

Common (≥1/100 to <1/10): sepsis; anaphylactic reaction, hypersensitivity; hypertriglyceridaemia, hypoglycaemia, hyperammonaemia; irritability; dizziness; hypotension; pulmonary embolism; pancreatitis; maculo-papular rash, pruritus, rash, urticaria, erythematous rash; injection site pain, injection site reaction; increased blood creatinine, prolonged activated partial thromboplastin time, decreased blood fibrinogen, decreased antithrombin III; infusion-related reaction.

Uncommon (≥1/1,000 to <1/100): superior sagittal sinus thrombosis, jugular vein thrombosis, deep vein thrombosis.

Selected reactions:

• Hypersensitivity: drug hypersensitivity occurred in 11% of patients (severe in 8%) and anaphylactic reaction in 2% (severe in all). Reactions were more frequent with intravenous than with intramuscular dosing, and led to discontinuation in 10%.
• Pancreatitis: 7% overall, 5% serious and 1% life-threatening; one patient developed a pancreatic pseudocyst that resolved without sequelae. Pancreatitis led to discontinuation in 5%.
• Antibodies: 116 of 228 patients (51%) had confirmed anti-drug antibodies. Their presence did not appear to correlate with hypersensitivity, and SAA stayed at or above 0.1 U/mL at all available 48- and 72-hour time points in cycle 1 in these patients.
• Age groups: 86% of patients were under 18 years, so frequencies cannot be compared across age groups. Hepatotoxicity, thrombosis and pancreatitis have been reported more often in adults than in children with ALL given other asparaginases; the safety profile in adults over 25 years has not been studied.

No interaction studies have been performed. Asparaginase can raise the toxicity of other medicines through its effect on liver function and plasma protein levels.

• Vincristine: given at the same time as, or just before, asparaginase it may be more toxic, because asparaginase inhibits the hepatic clearance of vincristine.
• Methotrexate and cytarabine: non-clinical data show that L-asparaginase given before or with them weakens their effect, while given after them it acts synergistically. The clinical effect of this sequence is unknown.
• Glucocorticoids (for example prednisone): given with or just before asparaginase they may change coagulation parameters, such as lowering fibrinogen and antithrombin III levels.
• Oral contraceptives: an indirect interaction cannot be ruled out, so effective non-hormonal contraception is advised during treatment.

Enrylaze must be prescribed and administered by physicians and healthcare staff experienced in the use of antineoplastic medicines. Appropriate resuscitation equipment and the agents needed to treat anaphylaxis must be available at administration. Enrylaze is not interchangeable with other crisantaspase products to complete a cycle of treatment.

Recommended Dose

• Every 48 hours: 25 mg/m² intramuscularly or intravenously.
• Monday/Wednesday/Friday schedule (one of three options):
  • 25 mg/m² intramuscularly on Monday and Wednesday and 50 mg/m² intramuscularly on Friday; or
  • 25 mg/m² intravenously on Monday and Wednesday and 50 mg/m² intramuscularly on Friday; or
  • 25 mg/m² intravenously on Monday and Wednesday and 50 mg/m² intravenously on Friday.
• Therapy can be further adjusted according to local treatment protocols.

Premedication

Consider premedicating with paracetamol, an H1 receptor blocker and an H2 receptor blocker 30–60 minutes before an intravenous dose, to lower the risk and severity of infusion-related and hypersensitivity reactions.

Monitoring of Asparaginase Activity

SAA varies between individuals, so trough SAA is monitored. With dosing every 48 hours the trough is measured 48 hours after a dose. On the Monday/Wednesday/Friday schedule it is measured 72 hours after the Friday dose, before the next Monday dose. The optimal level is at least 0.1 U/mL; if it is not reached, the schedule or route is adapted individually, for example by giving the dose intramuscularly or changing to a 48-hour interval.

Method of Administration

• Intramuscular: limit the volume at one injection site to 2 mL when body surface area (BSA) is above 0.5 m², and to 1 mL when BSA is below 0.5 m²; use several sites for larger volumes.
• Intravenous: infuse the dose over 2 hours. Section 6.6 of the SmPC gives dilution instructions.

Special Populations

• Hepatic impairment: no adjustment if total bilirubin stays up to 3 × ULN during treatment. Withhold if it rises above 3 and up to 10 × ULN, and continue once resolved. If it exceeds 10 × ULN, stop treatment and do not rechallenge. No adjustment for pre-existing mild or moderate hepatic impairment (bilirubin above 1 and up to 3 × ULN, or AST above ULN); data are insufficient for pre-existing severe impairment.
• Renal impairment: data are insufficient to support a dose recommendation.
• Children: no dose adjustment is needed in paediatric patients aged 1 month and older; safety and efficacy below 1 month of age have not been established.
• Elderly: no dose adjustment.

Traceability

As a biological medicinal product, the name and batch number of the administered product must be clearly recorded.

Hypersensitivity Reactions

Grade 3 and 4 hypersensitivity reactions occurred in the trials, and may be more frequent with intravenous administration. Enrylaze is given where resuscitation equipment and the agents needed to treat anaphylaxis are available, and is discontinued in patients with severe hypersensitivity reactions.

Pancreatitis

Patients with symptoms of pancreatitis are evaluated. Enrylaze is discontinued for necrotising or haemorrhagic pancreatitis. If lipase or amylase rise above 2 × ULN, or pancreatitis is symptomatic, it is withheld until values and symptoms subside, and may be resumed after resolution.

Glucose Intolerance

Glucose intolerance has been reported. Glucose is monitored at baseline and periodically, and insulin is given as needed for hyperglycaemia.

Coagulation Disorders

Thrombotic and bleeding events, including sagittal sinus thrombosis and pulmonary embolism, have been reported with L-asparaginase therapy. Treatment is held for a thrombotic or haemorrhagic event until symptoms resolve and may then be resumed.

Hepatotoxicity

Therapy including Enrylaze can cause hepatotoxicity. Bilirubin and transaminases are monitored before treatment and as clinically required; in severe liver toxicity treatment must be discontinued and supportive care given.

Neurotoxicity

Central nervous system toxicity, including encephalopathy, seizures and CNS depression, and posterior reversible encephalopathy syndrome (PRES) may occur with any asparaginase. PRES shows on MRI as reversible lesions or oedema, mainly in the posterior brain; symptoms include raised blood pressure, seizures, headaches, changed mental state and acute visual impairment. It is treated symptomatically, and dose reduction or discontinuation of concomitant immunosuppressive medicines may be needed. Expert advice should be sought.

Pregnancy, Breastfeeding and Fertility

• Contraception: men and women should use contraception during treatment with Enrylaze-containing chemotherapy and, because the safe interval is unknown, effective contraception for at least 3 months after stopping. Patients of childbearing potential should use effective non-hormonal methods during treatment, as an indirect interaction with oral contraceptives cannot be ruled out. A pregnancy test is done before treatment starts.
• Pregnancy: there are no data in pregnant women. Studies with Erwinia chrysanthemi L-asparaginase in pregnant animals suggest embryonic and foetal harm. Enrylaze should not be used in pregnancy unless the woman’s condition requires treatment and justifies the potential risk to the foetus; a patient who becomes pregnant is informed of the hazard.
• Breastfeeding: it is not known whether recombinant crisantaspase passes into human milk; mothers are advised not to breastfeed during therapy and for two weeks after the last dose.
• Fertility: no human data are available.

Sodium Content

Enrylaze contains less than 1 mmol (23 mg) sodium per dose, so it is essentially sodium-free.

Effect on Driving

Enrylaze has a minor influence on the ability to drive and use machines, based on the adverse reactions that may occur.

Store in a refrigerator at 2–8 °C, with the vial upright and kept in the outer carton to protect it from light. Do not freeze. Cold-chain handling applies: the vials stay at 2–8 °C from dispatch until use. Storage after dilution is described under Shelf Life. The solution is supplied in 2 mL Type I clear borosilicate glass vials with a halobutyl rubber stopper, aluminium overseal and violet plastic cap; each pack contains 3 vials.

Unopened vial: 4 years. From a microbiological point of view the product should be used immediately, unless the method of opening or dilution rules out the risk of microbial contamination; otherwise in-use times and conditions are the user’s responsibility. Chemical and physical in-use stability has been shown for the intramuscular preparation in a polypropylene syringe for up to 8 hours at room temperature (15–25 °C) or 24 hours refrigerated (2–8 °C), and for the intravenous preparation for up to 12 hours at room temperature (15–25 °C) or 24 hours refrigerated (2–8 °C).

Prescription only (Rx): a medicinal product subject to restricted medical prescription (Annex II B), prescribed and administered by physicians and healthcare staff experienced in the use of antineoplastic medicines. It is given by intramuscular injection or intravenous infusion in a setting with resuscitation equipment, so it is supplied to the hospital or clinic that administers it, with cold-chain delivery at 2–8 °C.