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Asparaginase Toxicity

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Asparaginase toxicity
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  LEUKEMIA & LYMPHOMA, 2016VOL. 57, NO. 4, 748–757http://dx.doi.org/10.3109/10428194.2015.1101098 REVIEW Asparaginase-associated toxicity in children with acute lymphoblasticleukemia Nobuko Hijiya a and Inge M. van der Sluis b a Division of Hematology/Oncology/Stem Cell Transplant, Ann & Robert H. Lurie Children’s Hospital of Chicago and Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA;  b Department of Pediatric Oncology/Hematology,Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands ABSTRACT Asparaginase is an integral component of multiagent chemotherapy regimens for the treatment of children with acute lymphoblastic leukemia. Positive outcomes are seen in patients who are able tocomplete their entire prescribed course of asparaginase therapy. Toxicities associated withasparaginase use include hypersensitivity (clinical and subclinical), pancreatitis, thrombosis,encephalopathy, and liver dysfunction. Depending on the nature and severity of the toxicity,asparaginase therapy may be altered or discontinued in some patients. Clinical hypersensitivity isthe most common asparaginase-associated toxicity requiring treatment discontinuation, occurringin up to 30% of patients receiving  Escherichia coli  –derived asparaginase. The ability to rapidlyidentify and manage asparaginase-associated toxicity will help ensure patients receive the maximalbenefit from asparaginase therapy. This review will provide an overview of the common toxicitiesassociated with asparaginase use and recommendations for treatment management. ARTICLE HISTORY Received 25 June 2015Revised 16 September 2015Accepted 21 September 2015 KEYWORDS acute lymphoblasticleukemia, asparaginase,hypersensitivity, toxicity Introduction With current multiagent chemotherapy regimens,long-term outcomes for children with acute lympho-blastic leukemia (ALL) have greatly improved, withreported overall survival rates  4 90% compared with 5 30% in the 1960s [1,2]. These substantial gains in survival are due, at least in part, to the increased use of intense and prolonged asparaginase therapy [3–5].However, asparaginase use is associated with anumber of toxicities. Failure to receive the full courseof asparaginase therapy due to treatment-emergenttoxicity has been associated with poor outcomes inchildren with ALL [3,6–8]. This review provides a concise overview of common toxicities associated with aspar-aginase therapy and recommendations formanagement. Mechanism of action of asparaginase The administration of asparaginase reduces plasmaasparagine concentrations by catalyzing thedeamination of asparagine into aspartic acid andammonia [8]. At sufficient enzyme activity levels,asparaginase therapy results in the complete depletionof serum asparagine concentrations, depriving leukemicblasts of this amino acid [9], resulting in reduced proteinsynthesis and ultimately leukemic cell death.Three different asparaginase preparations are cur-rently used for the treatment of patients with ALL. Twopreparations, native  Escherichia coli   ( E. coli  ) asparaginaseand polyethylene glycolated (PEG)-asparaginase, arederived from the bacterium  E. coli   [10]. Native  E. coli  asparaginase has been widely used as a first-linetreatment in ALL; however, the supply of this prepar-ation has recently ceased in the United States and haslargely been replaced with PEG-asparaginase [11]. Thethird preparation,  Erwinia  asparaginase, is derived fromthe bacterium  Erwinia chrysanthemi   [12]. The distinctbacterial srcins of   Erwinia  asparaginase give it a uniqueimmunogenic profile, showing no cross-reactivity withnative  E. coli   asparaginase or PEG-asparaginase [13]. Erwinia  asparaginase is indicated as a component of amultiagent chemotherapy regimen for the treatment of  CONTACT  Nobuko Hijiya, MD nhijiya@luriechildrens.org Division of Hematology/Oncology/Stem Cell Transplant, Ann & Robert H. Lurie Children’sHospital of Chicago, Box #30, 225 E. Chicago Avenue, Chicago, IL 60611, USA orInge M. van der Sluis, MD, PhD i.vandersluis@erasmusmc.nl Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children’s Hospital, Na1607 Wytemaweg, 3015 CN, Rotterdam, The Netherlands   2015 The Author(s). Published by Taylor & FrancisThis is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the srcinal work is properly cited, and is not altered, transformed, or builtupon in any way.  patients with ALL who have developed hypersensitivityto  E. coli  –derived asparaginases [14]. Each of the threeasparaginase preparations displays markedly differentpharmacokinetics that must be accounted for whendetermining dosing schedules [15]. The half-life of PEG-asparaginase has been estimated at 4.8–7.0 daysand is longer than that reported with native  E. coli  asparaginase and  Erwinia  asparaginase [16–19]. In com-parison, the half-life of native  E. coli   asparaginase and Erwinia  asparaginase are 1.28 days and 15.6 hours,respectively [14,19]. Due to the shorter half-life of  Erwinia  asparaginase, patients who switch to thisformulation should receive a higher dose at a greaterfrequency in order to maintain therapeutic levels of asparagine depletion [20]. Asparaginase toxicity Hypersensitivity  The asparaginases used in ALL treatment protocols arelarge molecules of bacterial srcin, and thus have theability to elicit an immune response in patients [8].Immune reactions to asparaginase are classified as eitherclinical or subclinical hypersensitivity (also referred to as‘‘silent inactivation’’). Clinical hypersensitivity is one of the most common reasons for the discontinuation of asparaginase therapy.Rates of clinical hypersensitivity reactions in theliterature vary. Clinical hypersensitivity to native  E. coli  asparaginase has been reported in up to 75% of patientswith ALL [21], although rates generally range from10–30% [7,22–26]. Clinical hypersensitivity reactions appear to be less prevalent with PEG-asparaginase,with rates from 3–24% reported in clinical trials[3,7,24,26]. Hypersensitivity reactions to PEG-asparagi- nase are more common when patients have beenpreviously exposed to native  E. coli   asparaginase,owing to their common bacterial source [27].Rates of clinical hypersensitivity in patients receiving Erwinia  asparaginase, which is derived from an alterna-tive bacterial source, have been reported in 3–37% of patients in clinical trials [7,14,20,26,28–34]. Patients who develop clinical hypersensitivity to asparaginase haveshown increased antibody formation and decreasedasparaginase activity levels compared with patients whodo not develop hypersensitivity [32,35,36]. Tong and colleagues [32] reported clinical hypersensitivity (grades1–4) in 20 of 89 patients (22%) administeredPEG-asparaginase during the intensification phase afterreceiving native  E. coli   asparaginase during the inductionphase of the Dutch Childhood Oncology Group (DCOG)ALL-10 protocol. All 20 patients with hypersensitivityshowed PEG-asparaginase activity levels of 0IU/L, and E. coli   antibodies were found in all patients withhypersensitivity during intensification.The likelihood of asparaginase eliciting an immuneresponse in patients may be influenced by a number of factors, including the asparaginase preparation, treat-ment intensity, and use of concomitant medications[23,24,29,36,48]. The risk of antibody formation for patients increases with repeated exposure to asparagi-nase; consolidation and reinduction phases of treatmentshow the greatest incidence of hypersensitivity reactionsand antibody formation [30,49]. However, prolonged exposure to asparaginase, without gaps in treatment,has been associated with decreased antibody levels[36,50]. Due to this, hypersensitivity reactions are most common within the first few doses of asparaginase aftera break in treatment [32]. Additionally, the concomitantadministration of corticosteroids has been associatedwith reduced signs of clinical hypersensitivity [24,25]. However, as clinical hypersensitivity is often the onlyobservable symptom of antibody formation, suppressionof these symptoms may only mask signs of hypersen-sitivity and result in prolonged periods of suboptimalasparaginase activity levels in patients. Whenever pos-sible, therapeutic dose monitoring of asparaginaseactivity levels should be utilized to identify patientswith suboptimal activity levels to adjust treatment inthese patients accordingly [32].Patients who display a hypersensitivity reaction to an E. coli  –derived asparaginase should immediately discon-tinue their current therapy and be switched to  Erwinia asparaginase (Table I) [33, 37]. Patients with hypersen- sitivity switched to  Erwinia  asparaginase show thera-peutic levels of asparaginase activity, and the majority of patients with hypersensitivity are able to complete theirprescribed course of treatment [33]. The FDA-approveddose substitution of   Erwinia  asparaginase for eachplanned dose of PEG-asparaginase is 25,000IU/m 2 administered intramuscularly (IM) or intravenously (IV)3 times a week (Monday/Wednesday/Friday) for sixdoses [14]. No established guidelines exist for whentreatment with the new preparation should be initiatedin patients who switch asparaginase preparationsbecause of clinical hypersensitivity. In practice, manypatients with hypersensitivity begin treatment with thenew preparation at the time of their next scheduleddose. Given the strong association between clinicalhypersensitivity and reduced asparaginase activity [32],this practice may result in suboptimal asparaginedepletion in the patients between doses. To avoid aprolonged gap in asparagine depletion, patients withhypersensitivity to asparaginase should begin treatmentwith an alternative asparaginase as early as possible,preferably within 48–72 hours after the hypersensitivity ASPARAGINASE-ASSOCIATED TOXICITY 749  event if symptoms are fully resolved [51,52]. Patients who develop hypersensitivity to both  E. coli  – and Erwinia chrysanthemi– derived formulations are forcedto discontinue asparaginase treatment [32].Subclinical hypersensitivity is characterized by thedevelopment of antiasparaginase antibodies and sig-nificantly reduced asparaginase activity levels [19,37]. Although difficult to identify because of the lack of clinical symptoms, subclinical hypersensitivity hasbeen reported in 8–29% of patients receiving  E.coli  –derived asparaginases [25,32,37]. Subclinical hypersensitivity is strongly associated with poor clin-ical outcomes if not readily identified and addressed[25,37]. The ability to prospectively identify patients with subclinical hypersensitivity and switch thesepatients to an alternate asparaginase formulation hasbeen associated with improved outcomes in a clinicaltrial [37].Following the IV administration of asparaginase,localized non-antibody-mediated infusion reactionsmay occur in patients [53]. Unlike true clinical hyper-sensitivity reactions, patients who display an infusionreaction to asparaginase do not show antiasparaginaseantibodies and infusion reactions are not associatedwith a decrease in asparaginase activity levels. Patientswith a non-antibody-mediated infusion reaction toasparaginase may be rechallenged with a longerinfusion duration and appropriate premedication.Differentiating between clinical hypersensitivity, sub-clinical hypersensitivity, and non-antibody-mediatedinfusion reactions can be difficult in practice. Butmeasurement of asparaginase activity levels mighthelp to differentiate between these reactions. Hyperglycemia The use of asparaginase is associated with reducedinsulin production and possibly a decrease in theexpression of insulin receptors [38,54]. Corticosteroid use is associated with greater insulin resistance and anincrease in hepatic gluconeogenesis [55,56]. Hyperglycemia is more common during phases of therapy when asparaginase and corticosteroids areadministered together and in relatively higher doses[38,57]. Asparaginase-associated hyperglycemia has beenreported in 4–20% of pediatric patients receiving  E. coli  asparaginase for ALL [57–60] and in 4–17% of patientsreceiving  Erwinia  asparaginase [14,33,34]. The aspar- aginase preparation and the type of corticosteroid(prednisone or dexamethasone) used in treatment donot seem to influence the risk of hyperglycemia[24,58,60]. Insulin therapy may be required in severe      T    a     b     l    e     I .     A    s    p    a    r    a    g     i    n    a    s    e  -    a    s    s    o    c     i    a    t    e     d    t    o   x     i    c     i    t     i    e    s    a    n     d    r    e    c    o    m    m    e    n     d    a    t     i    o    n    s     f    o    r    m    a    n    a    g    e    m    e    n    t    o     f    a    s    p    a    r    a    g     i    n    a    s    e    t     h    e    r    a    p   y     [     3     3 ,     3    7  –    4    7     ] . 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     F    o    c   u    s    e     d    o    n    a     d   u     l    t    p    a    t     i    e    n    t    s   w     i    t     h    a    c   u    t    e     l   y    m    p     h    o     b     l    a    s    t     i    c     l    e   u     k    e    m     i    a . 750 N. HIJIYA & I. M. VAN DER SLUIS  cases; however, asparaginase therapy can continue if thepatient shows normal glucose levels ( 5 200mg/dL or11mmol/L) with insulin [Table I] [8,38,40]. The final decision regarding the continuation of asparagainseshould be made by the treating physician based on thepatient’s general status. Pancreatitis While the precise pathogenesis of pancreatitis isunknown, the reduction in protein synthesis resultingfrom asparaginase-induced depletion of asparagine hasbeen implicated [61]. In clinical trials, pancreatitis hasbeen reported in 2–18% of patients undergoingasparaginase therapy for ALL, with grade 3/4 pancreatitisoccurring in 5–10% of patients [39,61–65]. The formula- tion of asparaginase does not influence the incidence of pancreatitis in patients [61].Diagnosis of pancreatitis is based on a combination of clinical, biochemical (amylase, lipase), and radiologicalevidence. Asparaginase therapy can be continued withmildly elevated amylase or lipase levels if clinical signsare absent; however, asparaginase treatment is generallydiscontinued in the case of severe pancreatitis [Table I][39,40]. Patients with mild pancreatitis may be rechal- lenged with asparaginase if within 48 hours the patientdisplays no clinical symptoms, amylase and lipase levelsare below 3 times the upper limit of normal (ULN), andthere are no signs of pseudocysts or necrosis on imaging[61]. Caution should be exercised, as recurrence of pancreatitis has been reported in up to 63% of patientsfollowing re-exposure to asparaginase [62]. Thrombosis Asparaginase is associated with a decrease in theproduction of a number of proteins involved in coagu-lation and fibrinolysis, and may increase the risk of thrombosis or bleeding [66–70]. The majority of asparaginase-associated thrombotic events occurduring induction and are likely attributable to multiplefactors, including indwelling central venous catheter,treatment with corticosteroids, treatment with asparagi-nase, and leukemia itself [41,71]. The incidence of  symptomatic thrombosis ranges from 2–7% in clinicaltrials and has been reported with both  E. coli  – and Erwinia -derived asparaginase [14,33,34,41,71–73]. A meta-analysis of 17 studies focused on thromboticcomplications in children with ALL found that the overallincidence of thrombosis is 5.2% [71]. The authors reportthat the majority of events (53.8%) occurred in thecentral nervous system (CNS), and 28.6% of the totalevents were classified as central venous thrombosis. Of the non-CNS events, the greatest incidence was seen inthe upper limbs and was categorized as deep venousthrombosis and central venous catheter–related [71].Patients with deep venous thrombosis should bemanaged with anticoagulation therapy, preferably withlow-molecular-weight heparin (LMWH) [42].Asparaginase use should be temporarily discontinuedin the case of clinically significant bleeding or throm-botic events; however, reports suggest that re-exposureto asparaginase with LMWH is safe and feasible inpatients who develop thrombosis once clinical symp-toms have resolved [Table I] [43,73]. Screening patients for prothrombotic risk factors has been suggested insome reports [71]; however, the evidence linkingthrombophilia and other risk factors to the incidenceof thrombotic events is mixed [74–78]. Encephalopathy  Encephalopathy has been reported in patients receivingasparaginase treatment for ALL, although the preciserelationship between asparaginase and neurotoxicity isunclear [40,44,79,80]. Posterior reversible encephalop- athy is one of the encephalopathies sometimes seen inpatients with ALL. The majority of reported cases of posterior reversible encephalopathy in patients with ALLoccur during induction treatment, which could also berelated to hypertension caused by glucocorticoids, andresolve without serious complications in most cases.[80–83].Elevated plasma ammonia levels, due to the aspar-aginase-driven breakdown of asparagine into asparticacid and ammonia, are sometimes associated withencephalopathy in patients undergoing asparaginasetherapy [79,80,84]; however, hyperammonemia alone does not typically result in symptoms, and reducedexpression of the glutamine transporter proteins mayalso play a role [85]. Patients with existing liver diseasemay be at an increased risk for developing symptoms of hyperammonemia. There is no standard therapy forpatients with asparaginase-induced hyperammonemia.Treatments with decreased protein intake, lactulosetreatment, benzoic acid, and arginine and sodiumphenylbutyrate have been reported; however, there issparse evidence for these treatments and their efficacy isunclear [84,86,87]. Myelosuppression Although a number of early studies described anassociation between asparaginase use and myelosup-pression [88,89], asparaginase itself is not typically considered a myelosuppressive agent. Asparaginase ASPARAGINASE-ASSOCIATED TOXICITY 751
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