PEG-Asparaginase in the Treatment of Childhood Acute Lymphoblastic Leukaemia

Pharmacotherapy

PEG-asparaginase in the treatment of childhood acute lymphoblastic leukaemia

V. Mondelaers, MD1, T. Bauters, PharmD, PhD2, B. De Moerloose, MD, PhD1, Y. Benoit, MD, PhD1

Asparaginase is an essential compound of combination chemotherapy in acute lymphoblastic leukaemia in children and adults. Essentially, three preparations of asparaginase are used in childhood acute lymphoblastic leukaemia: native Escherichia coli asparaginase, Erwinia chrysanthemi asparaginase and PEG- asparaginase. Although PEG-asparaginase seems to have some advantages over the other asparaginase preparations, its clinical use in Europe is limited to second-line therapy after allergic reactions to native asparaginase. This is in contrast to the United States, where PEG-asparaginase has been approved as first-line treatment of children with acute lymphoblastic leukaemia. This report describes the properties, clinical benefits and side effects of PEG-asparaginase. (Belg J Hematol 2013;4(4):138-143)

Introduction Asparaginase is a potent antitumor agent used in the proval for first- or second-line treatment differs in the treatment of childhood acute lymphoblastic leukaemia United States and Europe.4 This review focuses on the (ALL) for over 40 years. Asparaginase, a high molecular use of PEG-asparaginase (Oncaspar®) in childhood ALL. weight enzyme, depletes plasma asparagine by hydro- lysing asparagine in aspartic acid and ammonia. Expo- Chemistry sure of lymphoblasts to asparaginase results in inhibition PEG-asparaginase (polyethylene glycol-L-asparaginase, of protein synthesis and subsequent cell death by the Oncaspar®, Medac, Germany), a modified version of E. incapacity to produce intracellular asparagine.1 coli asparaginase, is produced by covalent conjugation Combination chemotherapy to induce remission in of monomethoxy polyethylene glycol (PEG) to E. coli childhood ALL patients usually consists of asparaginase asparaginase, more specifically to enzyme sites that are together with corticosteroids, vincristine and anthracy- not active. Pegylation blocks potentially immunogenic clines, resulting in remission induction rates of 90 to epitopes and reduces the dose limiting hypersensitivity 100%.2,3 The main drawbacks for the use of asparaginase reactions that are associated with native E. coli aspara- are the adverse effects on normal protein synthesis and ginase. In addition, it delays the elimination of the en- the frequent hypersensitivity reactions. zyme by prolonging the half-life of the drug (5.5 versus Currently, three preparations of asparaginase are used 1.2 days).5 The prolonged half-life of PEG-asparaginase to treat frontline and relapsed ALL in children: native allows for dosing once every fourteen days, which Escherichia coli (E. coli) asparaginase, Erwinia chrysan- obviates the need for long hospitalisations or multiple themi asparaginase and PEG-asparaginase, a form of visits to day-clinics. native E. coli asparaginase linked to a polyethylene glycol In patients who were previously treated with E. coli as- monomethyl ether. These preparations differ in activity, paraginase with documented hypersensitivity reactions, pharmacokinetics and immunising capacity. The ap- pharmacokinetics of PEG-asparaginase can be adversely

1Department of Paediatric Hemato-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium 2Department of Pharmacy, Ghent University Hospital, Ghent, Belgium. Please send all correspondence to: V. Mondelaers, MD, Ghent University Hospital, Department of Paediatric Hemato-Oncology and Stem Cell Transplantation, 3K12D, De Pintelaan 185, 9000 Ghent, Belgium, tel: +32 9 332 64 63, fax: +32 9 332 38 75, email: [email protected]. Conflict of interest: The authors have nothing to disclose and indicate no potential conflict of interest. Key words: acute lymphoblastic leukaemia, efficacy, paediatrics, PEG-asparaginase, side effects.

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Table 1. Incidence of grade 3-4 toxicities apparently* related to PEG-asparaginase in paediatric and adult patients with ALL

Paediatric Patients Adult Patients

Patients / No. Doses 1274 / 6670 76 / 192

Age (y) 1-18 14-68 (mean=30)

Toxicity (%)

allergy/hypersensitivity 10 1

bleeding 2 0

thrombosis 3 8

CNS ischemia 3 3

neuropathy 7 3

nausea/vomiting 3 7

hyperglycemia 7 25

pancreatitis 2 5

elevated liver enzymes 20 36

hyperbilirubinemia 3 14

hypofibrinogenemia 2 16

elevated PT/INR 0 0

*Apparent refers to the difficulty in determining whether the observed toxicity was due to PEG-asparaginase or to another agent in the multidrug regimen of ALL therapy, or to a combination of drugs that would not have occurred with PEG-asparaginase alone. Adapted from Stock et al.19

affected by the development of antibodies to the aspar- of hypersensitivity reactions to native asparaginase.8,9 aginase portion, associated with diminished half-life.6 A phase II, open-label multicentre study (ASP-201A) involved 21 relapse ALL patients under 21 years of age, Route of administration who were pre-treated with native E. coli asparaginase. PEG-asparaginase is not absorbed from the gastro-in- On day one, all patients received PEG-asparaginase testinal tract and therefore requires parenteral admin- 2000 IU/m² as a single-agent; at day fourteen a second istration (intramuscularly (IM) or intravenously (IV)). dose of PEG-asparaginase was given and the treatment It is distributed mainly in the intravascular space and was intensified with addition of prednisolone, vincristine has minimal blood-brain barrier penetration.7 Specific and doxorubicin for the continuation of the induction guidelines for dosage adjustments in hepatic or renal phase. Of the patients, 17% were in complete remission impairment are not available; however, these patients (CR) after the single dose of PEG-asparaginase and a may be at increased risk for toxicity. total of 67% achieved CR at the end of induction.10 Two prospective randomised phase III clinical trials Efficacy of PEG-asparaginase in child- comparing PEG-asparaginase to conventional native hood ALL E. coli asparaginase have been carried out in front-line At first, favourable effect of PEG-asparaginase was dem- childhood ALL. In the DFCI ALL protocol 91-01, stan- onstrated in phase I studies which were conducted on dard and high risk paediatric patients were randomised patients with solid tumours and refractory or relapsed to receive either native E. coli asparaginase 25.000 IU/m² patients with leukaemia or lymphoma who had a history IM weekly for 30 doses or PEG-asparaginase 2.500IU/

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m² IM bi-weekly for fifteen doses in combination with ALL for PEG-asparaginase at a dose of 2.500 IU/m² IM multi-drug chemotherapy. Patients treated with PEG- either weekly or biweekly during remission induction asparaginase had a five-year (5-y) event-free survival (EFS) in combination with vincristine, prednisolone and of 78%, which was not significantly different from the doxorubicin. The CR rate was significantly higher in patients in the native E. coli arm (5-y EFS: 84%; p: 0.29). the weekly (97%) compared to the biweekly (82%) However, the survival rates were significantly influenced PEG-asparaginase (p=0.003) regimen. This study sug- by the duration of the treatment with any of these aspara- gests that weekly administration of PEG-asparaginase ginases. Patients who were treated with asparaginase should be favoured especially in patients with prior for at least 26 weeks had a 5-y EFS of 90% compared hypersensitivity to E. coli asparaginase.15 to 73% in the patients who were treated for less than Twenty newly diagnosed ALL patients who were treated 25 weeks (p<0.01).11 with an induction according to the AIEOP ALL 2000 A phase III paediatric Children’s Cancer Group (CCG)- protocol (in which all patients received PEG-asparagi- 1962 trial randomised 118 newly diagnosed ALL pa- nase as first-line asparaginase preparation in induction tients to either one dose of PEG-asparaginase (2.500 IU/ (2 doses of PEG-asparaginase 1.000 IU/m² at day twelve m² IV) or to nine doses of E. coli asparaginase (6.000 IU/ and 27) and in reinduction (1x 1.000 IU/m²)) were stud- m² IV 3x/week for 3 weeks) in induction and in both ied by Rizzari et al. Asparaginase activity of ≥100 U/L delayed intensification phases. This study did not only was achieved in induction at almost every sample point demonstrate a prolonged half-life and an adequate and (except for samples in three patients on day 27, 39 and lasting depletion of asparagine by PEG-asparaginase, 45). All samples, including those with lower asparagi- but also a more rapid clearance of lymphoblasts in the nase activity, had undetectable asparagine levels (≤0.2 bone marrow on day fourteen (96% compared to 83% in µM). In reinduction, asparaginase activity levels of ≥100 the native asparaginase receiving patients). Both treat- U/L were achieved for at least two weeks in almost all ment arms were equivalent in terms of EFS (~82%).12 patients. One patient displayed silent inactivation from The report of Dinndorf et al. led to the Food and Drug day eleven. Except for this patient, all other patients Administration (FDA) approval for PEG-asparaginase had asparagine levels below the detection limit during in first-line treatment for children with ALL in the US. reinduction. No patient had a clinically relevant hyper- They demonstrated a similar pattern and degree of aspara- sensitivity reaction. The authors state that second expo- gine depletion with less injections compared to native E. sure to PEG-asparaginase after a previous exposure to coli asparaginase and without loss of clinical activity in the same product almost completely prevents the onset terms of EFS, which was the main endpoint for the FDA.4 of the silent inactivation, while this is expected in 30% of the patients who are previously treated with native Several pharmacokinetic and pharmacodynamic stud- E. coli asparaginase.16 ies have been conducted in the paediatric population, More recently, Silverman et al. demonstrated prolonged mostly during reinduction or in relapsed patients, which asparagine depletion after IV administration of a single means that patients were previously exposed to E. coli dose of PEG-asparaginase (2.500 IU/m²) in induction in asparaginase. Müller et al. showed that two-thirds of 197 paediatric patients enrolled on Dana-Farber Cancer 66 non-allergic patients receiving one dose of PEG- Institute ALL Consortium Protocol 05-01. Adequate asparaginase (1.000 IU/m² IV) in reinduction had an asparaginase activity of more than 100 IU/L was detected adequate asparaginase activity for two weeks. A total of in 95% of the patients at eleven days and in 88% at eigh- 22 patients showed a rapid decline in activity, silent teen days after administration. However, at 25 days only inactivation, which is probably a result of circulating 7% of the patients had sufficient asparaginase activity. antibodies against E. coli asparaginase that cross-react This study concludes that therapeutic asparaginase with PEG-asparaginase.13 In a second study in reinduc- activity is maintained for at least two weeks with the tion of relapsed patients, he showed no prolongation of conventional dosing of 2.500 IU/m².17 effective asparaginase activity by increasing the dose to 2.500 IU/m² and concluded that, in this specific popu- Safety and tolerability of PEG-asparaginase lation, a longer duration of therapeutic activity can PEG-asparaginase is usually well tolerated and severe only be achieved by increasing the number of adminis- toxicity is infrequent in the majority of patients. An over- trations.14 This observation is supported by the study of view of adverse reactions can be found in the summary Abshire et al. who randomised 148 children with relapse of the product characteristics.18

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Table 2. ALL study groups with PEG-asparaginase in first-line

Study group

Pediatric studies

UKALL UK

COG United States, Australia, Canada, New Zealand, Puerto Rico, Switzerland

Dana Farber Cancer Institute United States, Canada, Puerto Rico

St. Jude Children's Research Hospital United States

NOPHO Denmark, Finland, Iceland, Norway, Sweden

AIEOP-BFM Australia, Austria, Czech Republic, Germany, Israel, Italy, Switzerland

COALL Germany

Studies in Adolescents and Young Adults

MD Anderson Cancer Center United States

CALGB United States

NOPHO Denmark, Finland, Iceland, Norway, Sweden

Studies in Adults

GMALL Germany, protocol also used in other countries, ex. Belgium

SWOG United States

Dana Farber Cancer Institute United States, Canada

CALGB United States

HOVON / EORTC Netherlands, Belgium, France, Croatia

UCL-UKALL UK, Ireland

As in native asparaginase, adverse events are generally ity, the toxic profile of PEG-asparaginase is comparable related to inhibition of the normal protein synthesis, with that of native E. coli asparaginase or Erwinia as- mainly in the liver and pancreas, or are related to hyper- paraginase and side effects are similar after intravenous sensitivity. Comparable to other asparaginases, the effect or intramuscular administration of PEG-asparaginase. of PEG-asparaginase on the protein synthesis in the liver Table 1 summarises the most frequent side effects of results in hypoalbuminemia and a depletion of pro- and PEG-asparaginase in children compared to adults.19 anticoagulant factors, making the patients prone to bleed- In contrast to E. coli asparaginase, formation of anti-as- ing and thrombosis. The risk of thrombosis and pancre- paraginase antibodies is remarkably reduced with PEG- atitis in adults seems to be equivalent to that in children. asparaginase, and seems to be lower in adult patients Hyperglycemia and liver toxicity, reflected by transami- compared to children. The primary endpoint of the CCG- nase elevation and hyperbilirubinemia is more promi- 1962 study was to demonstrate in the PEG-arm a more nent in adults, but is generally transient. The excess in than 50% reduction in antibody formation in first delayed liver toxicity is partially explained by the fact that adult intensification phase compared to the native asparaginase patients have more comorbidities and frequently take arm. Forty-two percent of the native asparaginase pa- more concomitant medications or alcohol.19,20 tients developed antibody titres of 1.5 (sample/control), Mucositis and myelosuppression are rare after admin- compared to 11% of the PEG-asparaginase patients. In istration of PEG-asparaginase. Except for immunogenic- the native asparaginase arm, the antibodies were as-

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Key messages for clinical practice

• PEG-asparaginase (Oncaspar®, Medac, Germany) is produced by covalent conjugation of monomethoxy polyethylene glycol to E. coli asparaginase, which results in distinct pharmacokinetics. • PEG-asparaginase can be administered intravenously or intramuscularly. • The use of PEG-asparaginase in combination chemotherapy for childhood and adult ALL is safe, well tolerated and has comparable efficacy as native asparaginases. • Compared to native asparaginases, PEG-asparaginase has an equivalent non-allergic toxicity profile and its use results in a significant reduction of allergic reactions (around 10%). • Compared to children, serious allergic reactions and pancreatitis do not appear to be increased in adult patients. Hyperglycemia and transient liver toxicity is more frequent in adult patients, especially in patients with comorbidity and concomitant hepatotoxic medication. • The prolonged half-life of PEG-asparaginase (5.5 days) allows for dosing once every fourteen days, which obviates the need for long hospitalisations or multiple visits to day-clinics. • Substitution of PEG-asparaginase for native asparaginases has important socio-economic advantages. • Since January 2013 Oncaspar® is reimbursed in first-line treatment of acute lymphoblastic leukaemia in children and adults in Belgium.

sociated with low asparaginase activity in half of the Asparaginase in the treatment of patients, whereas in the PEG-asparaginase arm aspara- childhood ALL in Belgium and worldwide ginase activity remained adequate for all patients. Only In the US, the FDA approved PEG-asparaginase by in- two of the 118 patients had a clinical allergic reaction, tramuscular injections for patients with ALL and hyper- both in the PEG-asparaginase arm. The low incidence sensitivity to native asparaginases in 1994 and by in- of clinical hypersensitivity is possibly due to the high- travenous administration in 2005. The CCG study-1962 dose prednisone started three days before asparagi- resulted in an FDA approval for PEG-asparaginase in nase administration. The high incidence of circulating the front-line treatment of ALL patients in the US.4,12 antibodies with inactivation of asparaginase activity Until December 2012, only native E. coli asparaginase highlights the major concern of silent inactivation after (Paronal®) was licensed for front-line ALL therapy in exposure to native asparaginase. Other adverse events, Belgium while E. chrysanthemi asparaginase (Erwinia®) infections and hospitalisations were equal in both groups. was licensed for patients with a hypersensitivity to The event free survival (EFS) at three years was 82% in Paronal®. In Belgium, as in most European countries, both groups.12 Four years later Avramis et al. published PEG-asparaginase (Oncaspar®) was merely reimbursed follow-up data of these patients and showed that there as a component of multi-drug chemotherapy in ALL in was a statistical trend in favour of the PEG-arm with nine children and adult patients with known hypersensitivity relapses of 58, compared to sixteen of 58 in the native to native asparaginases. arm. They presume that this reduction in events is a result of the sum of advantages of PEG-asparaginase This review on PEG-asparaginase together with the over native asparaginase.21,22 cost-minimisation performed by our group (also in this issue of BJH) led to the recent approval by the National As mentioned before, an increased incidence of anti- Institute for Health and Disability Insurance (NIHDI, bodies after exposure to PEG- asparaginase is observed RIZIV, INAMI) for reimbursement of Oncaspar® in in relapse ALL patients previously treated with native first-line treatment of acute lymphoblastic leukaemia E. coli asparaginase or in newly diagnosed patients who in children and adults in Belgium. received PEG-asparaginase in delayed intensification As PEG-asparaginase results in sustained asparagine after an induction with native E. coli asparaginase. depletion and less hypersensitivity reactions, it is increas-

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ingly used in clinical trials for front-line therapy of child- Expert Opin Biol Ther 2009;9(1):111-9. hood ALL worldwide. Also protocols for adults with ALL 7. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc. increasingly incorporate PEG-asparaginase in paediatric- 2012. URL: http://www.clinicalpharmacology.com. Updated June 2012. based regimens. Some examples of ALL study groups 8. Taylor CW, Dorr RT, Fanta P, et al. A phase I and pharmacodynamic evaluation with PEG-asparaginase in first-line can be seen inTable 2 of polyethylene glycol-conjugated L-asparaginase in patients with advanced (see www.clinicaltrials.gov for more details). solid tumors. Cancer Chemother Pharmacol 2001;47(1):83-8. 9. Kawashima K, Takeshima H, Higashi Y, et al. High efficacy of monometh- Conclusion oxypolyethylene glycol-conjugated L-asparaginase (PEG2-ASP) in two patient As supported by many others and based on several with hematological malignancies. 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A randomized comparison of native reduced with PEG-asparaginase compared to other as- Escherichia coli asparaginase and polyethylene glycol conjugated asparaginase paraginase preparations. Because of a longer half-life and for treatment of children with newly diagnosed standard-risk acute lymphoblastic sustained asparagine depletion, PEG-asparaginase can leukaemia: a Children's Cancer Group study. Blood 2002;99(6):1986-94. be given bi-weekly and will replace four to six native E. coli 13. Müller HJ, Löning L, Horn A, et al. Pegylated asparaginase (Oncaspar) in asparaginases. Introduction of PEG-asparaginase in first- children with ALL: drug monitoring in reinduction according to the ALL/NHL- line ALL therapy leads to a more convenient regimen for BFM 95 protocols. Br J Haematol 2000;110(2):379-84. the patients with a reduction of intravenous administra- 14. Müller HJ, Beier R, da Palma JC, et al. PEG-asparaginase (Oncaspar) 2500 tions and hospitalisations. 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