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Keywords:

  • acute lymphoblastic leukemia;
  • asparagine depletion;
  • asparaginase;
  • Erwinia asparaginase;
  • Erwinase;
  • ALL

Abstract

  1. Top of page
  2. Abstract
  3. ASPARAGINASE THERAPY IN ALL
  4. ERWINIA ASPARAGINASE IN ALL
  5. CURRENT STATUS OF AND RECOMMENDATIONS FOR THE USE OF ERWINIA ASPARAGINASE
  6. CONCLUSIONS
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Asparaginases are a cornerstone of treatment protocols for acute lymphoblastic leukemia (ALL) and are used for remission induction and intensification treatment in all pediatric regimens and in the majority of adult treatment protocols. Extensive clinical data have shown that intensive asparaginase treatment improves clinical outcomes in childhood ALL. Three asparaginase preparations are available: the native asparaginase derived from Escherichia coli (E. coli asparaginase), a pegylated form of this enzyme (PEG-asparaginase), and a product isolated from Erwinia chrysanthemi, ie, Erwinia asparaginase. Clinical hypersensitivity reactions and silent inactivation due to antibodies against E. coli asparaginase, lead to inactivation of E. coli asparaginase in up to 60% of cases. Current treatment protocols include E. coli asparaginase or PEG-asparaginase for first-line treatment of ALL. Typically, patients exhibiting sensitivity to one formulation of asparaginase are switched to another to ensure they receive the most efficacious treatment regimen possible. Erwinia asparaginase is used as a second- or third-line treatment in European and US protocols. Despite the universal inclusion of asparaginase in such treatment protocols, debate on the optimal formulation and dosage of these agents continues. This article provides an overview of available evidence for optimal use of Erwinia asparaginase in the treatment of ALL. Cancer 2011. © 2010 American Cancer Society.

The long-term outcome of acute lymphoblastic leukemia (ALL) has improved dramatically during the last few decades because of the development of effective treatments and well-designed treatment protocols. Long-term, event-free, survival rates in children are currently around 80%,1-6 and overall survival rates are close to or exceeding 90%.4 Although overall survival rates in adults have improved in recent years, only 38% to 50% achieve long-term survival.7, 8 Compared with adult ALL patients, who have a poorer tolerance to some chemotherapy regimens,9-11 childhood ALL patients achieve a superior outcome, attributed to a higher proportion of favorable genetic subtypes, more effective treatment options, and better compliance with treatment by patients, parents, and physicians. Although the majority of recent regimens for adult ALL patients are based on pediatric treatment schedules, there is room for further treatment refinement in these patients.9, 10, 12-17

Among the drugs used in the treatment of ALL are bacteria-derived enzymes, referred to as asparaginases.6, 18 Three main types of asparaginase have been used so far: 1) native asparaginase derived from Escherichia coli (E. coli asparaginase: Kidrolase, EUSA Pharma, Oxford, UK; Elspar, Ovation Pharmaceuticals, Deerfield, Illinois; Crasnitin, Bayer AG, Leverkusen, Germany; Leunase, Sanofi-Aventis, Paris, France; Asparaginase Medac, Kyowa Hakko, Tokyo, Japan), 2) a pegylated form of the native E. coli asparaginase (polyethylene glycol [PEG]-asparaginase: Oncaspar, Sigma-Tau Pharmaceuticals, Inc., Gaithersburg, MD),19 and 3) an enzyme isolated from Erwinia chrysanthemi, referred to as Erwinia asparaginase (Erwinase, EUSA Pharma, Oxford, UK).18 It is important to note that some of these preparations are no longer available in all countries. A fourth, new, recombinant E. coli asparaginase preparation is currently undergoing clinical evaluation; it is engineered to have an amino acid sequence identical to that of Asparaginase Medac, with initial data showing a efficacy and toxicity profile comparable to those of the other E. coli-asparaginases.20 An asparaginase encapsulated into homologous red blood cells has recently been proposed as a new approach to maintain enzyme activity, while reducing formation of antiasparaginase antibodies.21 In addition, a pegylated form of recombinant Erwinia asparaginase is under preclinical study.22

The parenteral administration of asparaginase results in rapid and complete deamination of the amino acid asparagine and, to a lesser extent, glutamine,23-26 leading to depletion of asparagine, especially in the plasma23, 27-31 and, in part, the cerebrospinal fluid (CSF).32, 33 Differences in biological activity among available E. coli asparaginase preparations have been suggested.32 The tolerated dose has varied among trials,4, 25, 34 which is also suggestive of differences in the relative potency of the available asparaginase products.

Despite its use as an essential drug used in all treatment protocols for ALL, asparaginase's optimal formulation and dosage are still being debated. We provide an overview of available data on the use of asparaginases with a focus on Erwinia asparaginase, which has been less well studied compared with other forms.

ASPARAGINASE THERAPY IN ALL

  1. Top of page
  2. Abstract
  3. ASPARAGINASE THERAPY IN ALL
  4. ERWINIA ASPARAGINASE IN ALL
  5. CURRENT STATUS OF AND RECOMMENDATIONS FOR THE USE OF ERWINIA ASPARAGINASE
  6. CONCLUSIONS
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Efficacy Data for Asparaginases

Extensive clinical data support the use of asparaginase therapy in pediatric ALL,2, 4, 6, 35-38 and the benefit of intensive asparaginase treatment compared with less intensive regimens has been demonstrated (Fig. 1).2, 38-41 In a study conducted by the Dana-Faber Cancer Institute (DFCI) ALL Consortium and designed to improve outcomes and minimize toxicities in pediatric patients with standard-risk or high-risk ALL, 377 children were enrolled to receive a high-dose native E. coli asparaginase (25 000 IU/m2 weekly) or PEG-asparaginase (2 500 IU/m2 every other week) for 30 weeks during intensification therapy. The estimated 5-year, event-free survival rate was significantly higher than that of a previously conducted DFCI ALL Consortium study (83% ± 2% vs 74% ± 3%; P < .01), a finding that was attributed to the prolonged asparaginase intensification.2 In addition, in this study, children who tolerated more than 25 weekly doses of asparaginase had a better event-free survival than those who received 25 or fewer doses.2 Furthermore, a randomized study carried out by the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) determined the efficacy of a BFM-type modified chemotherapy regimen with or without prolonged use of high-dose native E. coli asparaginase (25 000 IU/m2 weekly for 20 weeks) during continuation therapy in 355 children with standard-risk ALL.41 Children given asparaginase had a significantly increased 10-year disease-free survival (87.5% vs 78.7%) and an overall survival (93.7% vs 88.6%), with a 40% reduction in the relative risk of failure compared with patients who were not treated with asparaginase.41 This finding supports previous data from Amylon et al38 showing that high-dose native E. coli asparaginase (25 000 IU/m2 weekly for 20 weeks) during consolidation significantly improved complete continuous remission in pediatric patients with T-cell ALL and lymphoblastic lymphoma compared with patients treated with a lower-dose asparaginase regimen (71.3% vs 57.8%, respectively). The randomized studies conducted by Moghrabi et al40 and Duval et al39 made clear that asparaginase preparations with a shorter half-life result in a poorer event-free survival, albeit less toxicity, compared with the use of asparaginase preparation with a longer half-life given at the same dose and frequency (Fig. 1). It is also noteworthy that in a study carried out by Rizzari et al,42 no significant difference in disease-free survival was observed between patients who received standard treatment (10 000 IU/m2 asparaginase for 4 doses during reinduction) and those who received high-dose treatment (25 000 IU/m2 asparaginase weekly for 20 weeks during reinduction and early continuation).

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Figure 1. The effect of intensification with asparaginases on event-free survival is shown. EFS indicates event-free survival; Study 1, Silverman2; Studies 2 and 3, Amylon38; Study 4, Rizzari42; Study 5, Pession41; Study 6, Moghrabi40; Study 7, Duval.39

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As a result of these trials, asparaginases are now a universal component of ALL therapy and are used for remission induction and intensification treatment in every pediatric regimen for ALL. However, much debate remains regarding the optimal formulation and dosage of asparaginase in the treatment of ALL. Therapy aims to achieve serum asparagine depletion, but no crucial minimum value for efficacy has yet been established.24, 25, 43 A serum level of asparaginase >100 IU/L corresponds to depletion of asparagine (ie, below the level of quantification)27 and, therefore, is often considered the target trough asparaginase level; complete asparagine depletion is observed less frequently with enzyme concentrations below this level.43, 44 However, there is some evidence to suggest that trough asparaginase levels of below 50 IU/L can also result in serum and CSF asparagine depletion.44

Toxicity of Asparaginases: Hypersensitivity

Asparaginases are associated with a unique set of side effects. Hypersensitivity reactions, due to antiasparaginase antibody production, have been observed in up to 60% of patients at some time during E. coli asparaginase therapy.45 The development of these antibodies appears to be more commonly observed with native E. coli asparaginase28, 46, 47 compared with the pegylated enzyme.28, 48 (Table 1) Symptoms of clinical hypersensitivity include anaphylaxis, pain, edema, Quincke edema, urticaria, erythema, rash, and pruritis.46 The route of administration determines the clinical symptoms with a greater incidence of major skin reactions observed with intramuscular (IM) administration compared with intravenous (IV) administration.52 Clinical hypersensitivity occurs almost exclusively in postinduction regimens (ie, intensification, reinduction)50, 53 when asparaginase has not been given for weeks or months. There are several possible explanations for the rarity of allergic reactions during remission induction. For example, there is a delay in an effective immune response due to the time taken for complement activation and the subsequent production of antibodies,18 the symptoms associated with allergy might be masked by intensive corticosteroids treatment that occurs during induction,18 and the frequency of dosing during induction may have a desensitizing effect, as allergic reactions are rarely observed in this phase despite measurable antibody production. Some studies have shown that the incidence of hypersensitivity to asparaginase is similar between age groups,2, 54 although others have suggested that infants and younger patients develop antibody and hypersensitivity reactions less frequently than teenagers and adult patients.18

Table 1. Incidence of Specific Antibodies Induced by the Three Main Asparaginase Types
Asparaginase TypeDoseConcomitant Steroid MedicationsAntibody- Positive PatientsCitation
  1. E. coli indicates Escherichia coli; IM, intramuscular; SC, subcutaneous; PEG, polyethylene glycol; IV, intravenous.

E. coli10 000 IU/m2 IM 3x/wk for 9 doses during induction and 9 during reinductionPrednisolone35.5%Woo 200046
6000 IU/m2 IM 3x/wk for 9 (induction) and 6 (intensification) dosesPrednisolone/dexamethasone26-42%Avramis 200228
6000 IU/m2 SC 2x/wk for 14 doses (induction/intensification)Prednisolone20%Larson 199847
PEG2500 IU/m2 IM for a total of 4 doses (induction) and 1 dose (intensification)Dexamethasone11%Hawkins 200448
2500 IU/m2 IM for 1 dose (induction) and 1 dose (delayed intensification)Prednisolone/dexamethasone2-11%Avramis 200228
Erwinia10 000 IU/m2 IM 3x/wk for a total of 9 doses (induction/reinduction)33%Wang 200349
30 000 IU/m2 IV or IM daily for a total of 10 doses (induction), 2x/wk for a total of 4 doses (reinduction)Prednisolone21%Albertsen 200250
30 000 IU/m2 IV or IM daily for a total of 10 doses (induction),2x/wk for a total of 4 doses (reinduction)Prednisolone/dexamethasone8-10%Albertsen 200253

Antibodies produced in response to asparaginases do not always lead to clinical hypersensitivity but may instead cause rapid inactivation of the asparaginase, resulting in suboptimal asparagine depletion. This is commonly referred to as “silent hypersensitivity” or “silent inactivation”45, 55, 56 and may occur in approximately 30% of the patients.45 Development of antiasparaginase antibodies can, thus, confer resistance to asparaginase therapy and is associated with higher plasma levels of asparagine57 and reduced therapeutic efficacy in some,55, 58 but not all, studies.46, 47 This inconsistency of antiasparaginase antibodies as a prognostic indicator may be explained by the efficacy of the overall treatment regimens and the use of alternative asparaginase preparations after allergic reactions, which may mitigate the adverse effects of silent hypersensitivity.

Typically, patients exhibiting clinical allergy symptoms to one formulation of asparaginase are switched to another product to ensure they receive the most efficacious treatment regimen possible.45, 56 However, because patients with silent hypersensitivity lack clinical symptoms and routine antibody monitoring is often not implemented, asparaginase switching does not usually occur in this setting.45 PEG-asparaginase has a relatively lower immunogenicity due to the covalent conjugation to monomethoxy polyethylene glycol59 and often replaces E. coli asparaginase in patients who develop allergic reaction. This switch may not be optimal because antibodies against E. coli asparaginase can cross-react with PEG-asparaginase.49, 60 Moreover, PEG-asparaginase may also induce silent inactivation56 with antibodies, resulting in a fast decline in asparaginase activity.61 Switching from PEG-asparaginase after an allergic reaction to E. coli asparaginase is not considered a viable treatment option.62

Other Toxicities Associated With Asparaginases

Pancreatitis occurs in 4% to 18% of pediatric patients, depending upon the definition used in the study, and can cause significant morbidity.54, 63, 64 Adolescents appear to be at higher risk for developing this condition than younger children.54 Pancreatitis tends to occur after the first few weeks of asparaginase, suggesting a predisposition to this complication rather than a cumulative drug effect.64 Retreatment with asparaginase after an episode of pancreatitis is associated with a high risk of recurrence,64 and so further doses of asparaginase are often omitted, which may negatively impact event-free survival.2 Other asparaginase-related toxicities include abnormalities of hemostasis (including central nervous system [CNS] thromboses and hemorrhage, and peripheral deep venous thromboses in 2% to 4% of patients), hyperglycemia, and abnormalities of lipid metabolism.59, 65 As with pancreatitis, thrombotic complications are more common in adolescents and adults than in younger children.54 In adult patients, liver toxicity with elevated liver enzymes or increased bilirubin is a frequent clinical problem.8

ERWINIA ASPARAGINASE IN ALL

  1. Top of page
  2. Abstract
  3. ASPARAGINASE THERAPY IN ALL
  4. ERWINIA ASPARAGINASE IN ALL
  5. CURRENT STATUS OF AND RECOMMENDATIONS FOR THE USE OF ERWINIA ASPARAGINASE
  6. CONCLUSIONS
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Currently, there are no widely accepted guidelines for the use of asparaginases, especially Erwinia asparaginase. Several comparative studies have been conducted with Erwinia asparaginase and native E. coli preparations; the dose and schedules of asparaginase in these studies have been inconsistent, and outcomes have been variable.39, 40, 66, 67 However, the efficacy of Erwinia asparaginase after hypersensitivity to E. coli asparaginase preparations has been demonstrated.45, 68 The differences in these results highlight the need for recommendations to provide guidance for the optimal use of Erwinia asparaginase in the treatment of ALL.

Efficacy Data for Erwinia Asparaginase

Eden et al66 carried out a nonrandomized study (UKALL VIII) comparing the toxicity of IM administration of Erwinia asparaginase with E. coli asparaginase (6000 IU/m2 3 times weekly for 3 weeks) in 758 unselected children with ALL. No apparent difference in event-free survival was observed after 4.5 years of follow-up, but the incidence of neurotoxicity, pancreatitis, and life-threatening sepsis was significantly lower in children treated with Erwinia asparaginase compared with those who received E. coli asparaginase (neurotoxicity, 2% vs 4%; pancreatitis, 0% vs 2%; sepsis, 18% vs 20%).66 Results from this early trial led to the first randomized study (European Organisation for Research and Treatment of Cancer-Children's Leukemia Group [EORTC-CLG] 58881) comparing Erwinia asparaginase with E. coli asparaginase39 and included 700 children (aged <18 years) with ALL (93%) or lymphoblastic non-Hodgkin lymphoma (7%). Patients were randomized to receive the same dosage of either asparaginase (10 000 IU/m2 IV twice-weekly for a total of 8 doses in the induction phase and 4 doses in the reinduction phase). Significantly more patients administered Erwinia asparaginase failed to achieve complete remission compared with those who received E. coli asparaginase (4.9% vs 2%), and the relapse rate was higher, resulting in reduced event-free survival. Overall 6-year survival was also significantly superior, but coagulopathy was more common in patients administered E. coli asparaginase compared with the Erwinia asparaginase group (83.9% vs 75.1%).39

A subsequent randomized study, DFCI-ALL-95-01, compared administration of Erwinia asparaginase (25 000 IU/m2 once in induction followed by once-weekly doses for 20 weeks during intensification) with the same doses of E. coli asparaginase in 286 ALL patients (aged 0-18 years).40 The 139 children given Erwinia asparaginase had significantly reduced toxicity (10% vs 24%; P < .01) and fewer allergic reactions (6% vs 14%; P = .03) compared with 147 patients treated with E. coli asparaginase but had significantly lower 5-year event-free survival (78% ± 4% vs 89% ± 3%).40 There were also significantly more relapses involving the CNS in children receiving Erwinia asparaginase compared with those receiving E. coli asparaginase (6% vs 1%).40

Another study by Kwok et al67 compared the efficacy of Erwinia asparaginase and E. coli asparaginase in 116 children with ALL. Erwinia asparaginase was administered at a dose of 10,000 IU/m2 IM and E. coli asparaginase at 7500 to 10,000 IU/m2 IM twice-weekly for 8 doses during remission induction. Patients treated with Erwinia asparaginase were 6.7 times more likely to have residual leukemia levels ≥10−2 in bone marrow compared with patients treated with E. coli asparaginase.67

Due to the shorter half-life of Erwinia asparaginase compared with E. coli-derived preparations,55 a higher dose and increased frequency of treatment is required to ensure adequate serum enzyme activity and complete serum asparagine depletion. It is, therefore, possible that the inferior outcome of patients treated with Erwinia asparaginase in these trials (with parallel decreases in adverse reactions) is a result of insufficient dose and frequency of this preparation.11, 40, 62, 69 Indeed, Boos et al25 reported that only 26% of samples from ALL patients had complete depletion of asparagine (ie, ≤0.1 μmol/L) 3 days after administration of Erwinia asparaginase (10,000 IU/m2 at 3-day intervals). In addition, physiological asparagine levels recovered faster after Erwinia asparaginase than E. coli preparations.25

In one study, Erwinia asparaginase (30,000 IU/m2 IV or IM) was given daily during induction therapy and twice a week for 2 weeks during reinduction phase. The trough levels (measured immediately before the next administration) were below 100 IU/L in approximately two-thirds of samples during reinduction.43 Consequently, the majority of patients failed to achieve complete depletion of asparagine during reinduction. Similarly, in a DFCI ALL Consortium trial, in which patients switched to Erwinia asparaginase (25,000 IU/m2 twice-weekly) after allergy to E. coli asparaginase, 83% of patients had serum enzyme activity levels at or above 100 IU/L 3 days after administration, but only 42% of patients maintained that level 4 days postdosing.68 These data highlight that even with relatively high Erwinia asparaginase doses (25,000-30,000 IU/m2), a twice-weekly regimen was still associated with inadequate enzyme levels in most patients.43, 68 Despite these findings, treatment with twice-weekly Erwinia asparaginase after E. coli asparaginase allergy did not adversely impact rates of event-free survival in the DFCI ALL Consortium trial.68

Evidence from Viera Pinheiro et al26 suggests increased dosing frequency enhances Erwinia asparaginase activity. In this study, patients with ALL and non-Hodgkin lymphoma were administered Erwinia asparaginase (20 000 IU/m2 3-times weekly) and trough asparagine levels and asparaginase activity were assessed 2 and 3 days after therapy.26 Mean serum asparaginase trough levels were above the target level of 100 IU/L 2 days after administration of Erwinia asparaginase (mean asparaginase level, 156 IU/L), although the activity fell after 3 days (mean asparaginase activity, 50 IU/L). Finally, Erwinia asparaginase administered at 10,000 U/m2 IV every second day resulted in a median trough activity of 115 U/L 2 days after administration, but asparaginase activities were below 100 U/L in 45% of samples.70 Taken together, these data show that even a regimen of 3-times weekly dosing (with a 2-day interval at weekends) yields inadequate asparaginase trough activity for at least part of the treatment schedule (typically at the weekend). In this regard, all the comparative studies in which Erwinia asparaginase yielded “inferior” outcomes included less frequent and/or lower absolute doses than those used by Viera Pinheiro et al,26 and, therefore, serum asparagine levels may not have been sufficiently depleted.

Second-Line Treatment With Erwinia Asparaginase

Despite the apparently inferior outcomes of comparative studies of Erwinia asparaginase with E. coli-derived preparations, a study of 1001 high-risk pediatric ALL patients treated with 9 doses of native E. coli asparaginase during induction (6000 IU/m2 3-times weekly for 3 weeks) demonstrated the efficacy of switching products after clinical hypersensitivity.45 Results from an interim analysis of 280 patients, who were evaluated for at least 30 months after induction, showed that 41% developed clinical allergic reactions with positive antibody formation and were switched to Erwinia asparaginase. The antibody-positive patients with allergic symptoms were switched to Erwinia asparaginase, resulting in a reduction in their hazard ratio for treatment failure from 3.2 to 0.6. In contrast, 29% of patients had silent hypersensitivity and continued to receive E. coli asparaginase; these children had poorer outcomes.45 This demonstrates that awareness of the presence of asparaginase antibodies (in the absence of allergy) and subsequent switching to Erwinia asparaginase might mitigate the adverse effects of silent hypersensitivity.

Studies have shown cross-reactivity between patients' antibodies against E. coli asparaginase and PEG-asparaginase, but not between those against E. coli asparaginase and Erwinia asparaginase.49, 60 Moreover, asparagine concentrations were less depleted by PEG-asparaginase than by Erwinia asparaginase in a small study of patients with antibodies against E. coli asparaginase.57 Interestingly, one study showed that patients may also develop antibodies to the nonprotein PEG moiety of PEG-asparaginase.71 This was associated with rapid clearance of PEG-asparaginase in a subgroup of pediatric patients who otherwise did not present a clinical manifestation of hypersensitivity or allergy. Furthermore, a population pharmacokinetic model demonstrated a fast decline in asparaginase activity in a group of patients, most likely related to the development of antibodies against PEG-asparaginase.61 It has, therefore, been suggested that anti-PEG level monitoring/screening or asparaginase activity measurements could allow for modification in PEG-asparaginase dosing or the use of an alternative asparaginase.61, 71 So far, the presence of anti-PEG antibodies has not been confirmed by others. Routine antibody assessment or measurement of asparaginase levels has been proposed to predict future allergic reaction or to alert physicians to the possibility of silent hypersensitivity.18, 26, 46

As yet, there are no data from large well-designed studies to demonstrate a preference for Erwinia asparaginase over PEG-asparaginase in patients developing hypersensitivity to E. coli asparaginase, and there is no consensus opinion on this. After allergic reactions to E. coli preparations, substitution with an alternative asparaginase should be based on drug monitoring.25Erwinia asparaginase appears to be well tolerated in children with previous allergy to E. coli asparaginase.68 Allergic reactions to Erwinia asparaginase have also been reported in up to 33% of patients switching to Erwinia asparaginase after clinical hypersensitivity to native E. coli asparaginase.68, 72

CURRENT STATUS OF AND RECOMMENDATIONS FOR THE USE OF ERWINIA ASPARAGINASE

  1. Top of page
  2. Abstract
  3. ASPARAGINASE THERAPY IN ALL
  4. ERWINIA ASPARAGINASE IN ALL
  5. CURRENT STATUS OF AND RECOMMENDATIONS FOR THE USE OF ERWINIA ASPARAGINASE
  6. CONCLUSIONS
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Both E. coli asparaginase and PEG-asparaginase can be used as first-line treatment in pediatric ALL protocols, depending upon country. Before a temporary interruption in 2002 that resulted from manufacturing issues related to vial stoppers, Erwinia asparaginase was considered the best alternative in cases of clinical hypersensitivity to these enzymes.62Erwinia asparaginase production was reinstated in 2006, and previous European licenses are planned for reinstatement, together with a process of mutual recognition in other European countries and full approval in the United States.

Which Patients Should Receive Erwinia Asparaginase?

Patients developing allergic reactions to a particular asparaginase should be switched to an alternative product, to ensure maximum clinical benefit in terms of survival. Second-line asparaginase therapy should be dictated by protocols or regulatory and availability factors, and the type of asparaginase used in front-line therapy; some protocols advise Erwinia asparaginase as a preferable preparation after allergic reaction to native E. coli asparaginase, whereas others prescribe PEG-asparaginase as replacement for native E. coli asparaginase and Erwinia asparaginase as third-line drugs.

Several clinical trial groups in Europe and the United States allow the use of Erwinia asparaginase as a second-line agent (eg, Nordic Society of Pediatric Hematology and Oncology [NOPHO], German Multicenter Acute Lymphoblastic Leukemia Study Group [GMALL], EORTC-58951, French Acute Lymphoblastic Leukemia group [FRALLE], Children's Oncology Group [COG]), DFCI ALL Consortium and, for others, as a third-line treatment (AIEOP, ALL-BFM-2000, Dutch Childhood Oncology Group [DCOG-ALL-10], Czech Republic protocols). Selection of the individual asparaginase is determined by availability, treatment protocol, and treatment status of the patients (ie, asparaginase-naive or relapsed), and various Erwinia asparaginase dosing regimens are in use (Table 2; Table 3).

Table 2. Current Regional Use of Asparaginases (Source: EUSA Pharma)
  North America, UK, Australia, New ZealandEurope (BFM Zone)Rest of World
  1. BFM indicates Berlin-Frankfurt-Munster; PEG, polyethylene glycol; E. coli, Escherichia coli.

ChildrenNaive patientsFirst-line: PEG-asparaginaseFirst-line: E. coli-asparaginaseFirst-line: E. coli-asparaginase
  Second-line: Erwinia asparaginaseSecond-line: Erwinia asparaginase or PEG-asparaginaseSecond-line: Erwinia asparaginase or PEG-asparaginase
 Relapsed patientsFirst-line: PEG-asparaginaseFirst-line: PEG-asparaginaseFirst-line: E. coli-asparaginase
  Second-line: Erwinia asparaginaseSecond-line: Erwinia asparaginaseSecond-line: Erwinia asparaginase or PEG-asparaginase
AdultsNaive patientsFirst-line: E. coli-asparaginase or PEG-asparaginaseFirst-line: E. coli-asparaginase or PEG-asparaginaseFirst-line: E. coli-asparaginase
  Second-line: Erwinia asparaginase or PEG-asparaginaseSecond-line: Erwinia asparaginaseSecond-line: Erwinia asparaginase or PEG-asparaginase
Table 3. ALL Protocols Currently Used for Erwinia asparaginase (Second-Line or Third-Line Treatment)
ProtocolTreatment
  1. NOPHO indicates Nordic Society of Pediatric Hematology and Oncology; AIEOP, Associazione Italiana Ematologia Oncologia Pediatrica; GMALL, German Multileft Acute Lymphoblastic Leukemia Study Group; COG, Children's Oncology Group; COALL, Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia; DCOG, Dutch Childhood Oncology Group; BFM, Berlin-Frankfurt-Münster; EORTC, European Organization for Research and Treatment of Cancer; FRALLE, French Acute Lymphoblastic Leukemia group; DFCI, Dana-Faber Cancer Institute; IV, intravenous; IM, intramuscular; HR, high risk.

NOPHOErwinia asparaginase 20 000 IU/m2 2-3x/wk (x6)
Second-line
AIEOPErwinia asparaginase 20 000 IU/m2 every other day
Third-line
GMALL 07/2003 and 01/2003Erwinia asparaginase 20 000 IU/m2 3x/wk (x5); IV(10 000 IU/m2 in patients aged >55 y)
Second-line
COGErwinia asparaginase 25 000 IU/m2 3x/wk (x6); IM
Second-line
COALL-07-03Erwinia asparaginase 45 000 IU/m2 (x2)
Czech RepublicInduction and late intensification:
Third-lineErwinia asparaginase 10 000 IU/m2 2x/wk
HR blocks:
Erwinia asparaginase 10 000 IU/m2 2x/wk
First relapse:
Erwinia asparaginase 10 000 IU/m2 2x/wk
DCOG ALL-10Induction:
Third-lineErwinia asparaginase 10 000 IU/m2 2-3x/wk
Intensification (standard or medium risk):
Erwinia asparaginase 10 000 IU/m2 2-3x/wk
HR blocks:
Erwinia asparaginase 10 000 IU/m2, 2-3x/wk
BFM-2000Protocol 1:
Second-lineErwinia asparaginase 10 000 IU/m2 every 2 days IM/IV
Protocol II:
Erwinia asparaginase 10 000 IU/m2 every 2 days IM/IV
Block HR-1:
Erwinia asparaginase 10 000 IU/m2 every 2 days IM/IV
EORTC-58951Erwinia asparaginase 20 000 IU/m2 2-3x/wk; IM
Second-line
FRALLE- 2000Induction, delayed intensification(s): Erwinia asparaginase 12 000 IU/m2 3x/wk; IM, ie double dose compared with E .coli asparaginase
Second-Line
St JudeInduction:
Second-lineErwinia asparaginase 20 000 IU/m2 3x/wk (x6) IM;
Post-remission: 30 000 or 42 000 IU/m2 2x/wk IM for 30 wks (standard/high-risk patients), 2x/wk for 4 wks during first and second reinduction (low-risk patients)
DFCI ALL ConsortiumPostinduction consolidation:
Second-lineErwinia asparaginase 25 000 IU/m2 2x/wk IM for 30 wks
Recommendations
  • Erwinia asparaginase should be used for the second- or third-line treatment of ALL, depending upon regulatory requirements, in patients developing hypersensitivity to E. coli asparaginase preparations.

  • Erwinia asparaginase should be prescribed when switching from PEG-asparaginase is required (ie, second-line use of native E. coli asparaginase is not justified).

Erwinia Asparaginase Dosing and Schedule

Due to the short half-life of Erwinia asparaginase,55 a higher dose and increased dosing frequency are required to ensure optimal asparagine depletion. Current evidence suggests that Erwinia asparaginase should be administered at dosages of at least 20,000 IU/m2 3-times weekly, ie, every second day with a 3-day interval at the weekend.26 Twice-weekly dosing at higher doses (25,000-30,000 IU/m2) has been associated with suboptimal trough serum enzyme activity but not consistently with inferior event-free survival,43, 68 and, as a result, this dosing regimen is still used by some groups.

As Erwinia asparaginase requires frequent dosing to maintain asparagine depletion, therapeutic drug monitoring data (specifically for serum asparaginase levels) could assist in determining whether increasing the interval between doses is possible and could, therefore, help to minimize inconvenience to both patients and physicians. Furthermore, the development of pegylated Erwinia asparaginase with a longer half-life would make the dosing schedule more convenient for patients.

Recommendations
  • Erwinia asparaginase should be administered at dosages of at least 20,000 IU/m2 multiple times per week (eg, 3 times weekly).

Duration of Treatment

The optimal duration of Erwinia asparaginase treatment has yet to be established, although it has been suggested that prolonged intensification results in improved survival. This was demonstrated in a study by Silverman et al,2 where the 5-year, event-free, survival rate of patients who received at least 26 weeks of asparaginase therapy was significantly better than those who tolerated 25 weeks or fewer of therapy (90% vs 73%). This study, together with the studies presented above and summarized in Figure 1, suggests that prolonged and intensified therapy with asparaginase improves outcome of children with ALL.

When Erwinia asparaginase is used as second-line treatment to replace native E. coli asparaginase or PEG-asparaginase, the duration of treatment depends on the protocol and the yielded duration of asparagine depletion. Also, the duration of asparaginase treatment will depend on the backbone of combination chemotherapy that is given.

Recommendations
  • Use prolonged intensification with asparaginase to optimize survival benefits.

Route of Administration of Erwinia Asparaginase

Intravenous (IV) administration results in higher peak plasma concentrations, whereas IM administration results in a concurrent slower increase of asparaginase activity due to the depot effect. Accordingly, administration of 10,000 U/m2Erwinia asparaginase applied every second day results in median trough activities of 115 U/L (determined from 58 samples of 15 patients) when applied intravenously and of 151 U/L (determined from 39 samples of 14 patients) when applied intramuscularly. After IM administration, only 15% of analyzed samples showed asparaginase activities below the desired activity of 100 U/L, whereas 45% of samples were below 100 U/L when Erwinia asparaginase was administered intravenously.70

However, Rizzari et al44 found no significant differences in mean enzyme activity or frequency of samples showing complete asparagine depletion after IV or IM administration of Erwinia asparaginase 10,000 IU/m2 every 3 days (8 doses) administered in the induction phase.44 Similarly, Albertsen et al43 found comparable complete asparagine depletion in patients given a more intense regimen of IV or IM administration at 30,000 IU/m2 daily for 10 days in the induction phase.43 In this study, however, Erwinia asparaginase administered by the IM route produced trough asparaginase plasma levels significantly lower (by approximately 28%) than IV administration. During the subsequent reinduction phase (30,000 IU/m2 twice-weekly for 2 weeks), no differences were observed between the 2 routes in terms of trough asparaginase activities or in the proportion of patients who failed to achieve complete asparagine depletion.43 Finally, no significant differences have been observed between 2 routes of administration of Erwinia asparaginase 30,000 IU/m2 twice-weekly for 2 weeks as a reinduction regimen in terms of neutralizing asparaginase antibody formation.50

The results of studies investigating the optimal route for the administration of asparaginase are inconsistent and, therefore, further studies are required to determine whether IV or IM administration of Erwinia asparaginase is associated with any meaningful clinical differences.24

Recommendations
  • No recommendations are made for the route of administration as more data are required to define the optimal route. However, most groups in Europe currently use IV asparaginases, whereas North American groups more often administer this agent by intramuscularly.

Monitoring of Asparaginase Trough Levels and/or Depletion of Asparagine

Initially, the US Food and Drug Administration required that asparagine levels be used as the primary outcome measure in clinical trials. Asparaginase therapy aims to achieve serum asparagine depletion, but no critical minimal value for efficacy has yet been established,24, 25, 43 and asparagine levels are difficult to measure accurately when asparaginase is present in blood because the enzyme can continue to breakdown asparagine ex vivo if the sample is not immediately processed and stored on ice. Therefore, monitoring of asparaginase levels is more reliable than measurement of asparagine itself. A serum level of asparaginase >100 IU/L, and possibly >50 IU/L, corresponds to depletion of asparagine (ie, below the level of quantification)44, 73; complete asparagine depletion is observed less frequently with enzyme concentrations below this level.43, 44 However, clinical testing to measure asparaginase levels or asparagine depletion is not routinely carried out, although therapeutic drug monitoring is offered in Europe to guide therapeutic decisions (Boos et al, personal communication).

Recommendations
  • Because of technical difficulties in measuring serum asparagine levels, monitoring asparaginase levels is more reliable and, therefore, recommended for adaptation of asparaginase dosing in individual cases and for trials in which regulatory authorities ask for pharmacokinetic and pharmacodynamic endpoints.

Monitoring of Erwinia Asparaginase Antibody Levels

Although it has been advocated previously to determine antiasparaginase antibody levels to discover whether alterations in dosing regimen should be used to overcome the risk of silent hypersensitivity, monitoring of asparaginase levels should be sufficient to identify silent hypersensitivity because not all antibodies lead to asparaginase inactivation.

Recommendations
  • No recommendations are made for monitoring antibody status.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. ASPARAGINASE THERAPY IN ALL
  4. ERWINIA ASPARAGINASE IN ALL
  5. CURRENT STATUS OF AND RECOMMENDATIONS FOR THE USE OF ERWINIA ASPARAGINASE
  6. CONCLUSIONS
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Advances in therapies for ALL have led to improved long-term survival rates for pediatric and adult patients. Asparaginases form a cornerstone of ALL treatment protocols with 3 main preparations for use in treatment protocols: the native E. coli asparaginase, a pegylated form (PEG-asparaginase), and an alternative enzyme isolated from Erwinia chrysanthemi, referred to as Erwinia asparaginase. Despite the availability of these agents, much debate remains on the optimal formulation and dose for the treatment of pediatric and adult ALL patients. This article aims to provide recommendations, based on data available in the literature, to ensure optimal use of Erwinia asparaginase. Patients who receive an asparaginase as first-line treatment for ALL and develop antiasparaginase antibodies should be switched to another asparaginase preparation to ensure maximal survival benefit. Monitoring of asparaginase levels is preferable to assess the extent of serum asparagine depletion and to identify cases of silent inactivation. Erwinia asparaginase is a valid second- or third-line therapy, depending upon protocols, regulatory factors, and availability. Evidence from published studies suggests that Erwinia asparaginase should be administered at a dose of at least 20,000 IU/m2 3-times weekly, by either the IV or IM route. Further clinical and pharmacokinetic studies of Erwinia asparaginase will help optimize the use of this agent.

CONFLICT OF INTEREST DISCLOSURES

  1. Top of page
  2. Abstract
  3. ASPARAGINASE THERAPY IN ALL
  4. ERWINIA ASPARAGINASE IN ALL
  5. CURRENT STATUS OF AND RECOMMENDATIONS FOR THE USE OF ERWINIA ASPARAGINASE
  6. CONCLUSIONS
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

This work was supported in part by grant CA-21,765 from the US National Institutes of Health, by the American Lebanese Syrian Associated Charities, and by EUSA Pharma. Pieters is involved in scientific collaborations with different companies producing and developing asparaginases. Hunger is the Ergen Family Chair in Pediatric Cancer. Boos served personally as consultant and participated in advisory boards for different asparaginase-selling companies, including EUSA Pharma and former license holders. In addition, Boos is also involved in scientific collaborations with different companies producing and developing asparaginase. Rizzari is involved in scientific researches supported by different companies producing and/or marketing asparaginase products. Silverman served on an advisory board for EUSA Pharma and as a consultant for Enzon Pharmaceuticals. Baruchel received an honorarium from OPI for a lecture. Goekbuget is involved in scientific collaborations with different companies producing and developing asparaginases. Schrappe is involved in scientific collaborations with different companies producing and developing asparaginases. Pui received an honorarium from EUSA Pharma for a lecture.

REFERENCES

  1. Top of page
  2. Abstract
  3. ASPARAGINASE THERAPY IN ALL
  4. ERWINIA ASPARAGINASE IN ALL
  5. CURRENT STATUS OF AND RECOMMENDATIONS FOR THE USE OF ERWINIA ASPARAGINASE
  6. CONCLUSIONS
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES
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