Open access journal of the Ferrata-Storti Foundation, a non-profit organization
Spotlight Review

Back to the future: the amazing journey of the therapeutic anti-leukemia enzyme asparaginase Erwinia chrysanthemi

Department of Public Health and Primary Care (PHEG), Leiden University Medical Center, Leiden, The Netherlands; Argos Zorggroep “DrieMaasStede”, Center for Specialized Geriatric Care, Schiedam
Department of Pediatrics, Foundation IRCCS San Gerardo dei Tintori, Monza, Italy; Department of Medicine and Surgery, University of Milano-Bicocca
Vol. 108 No. 10 (2023): October, 2023 https://doi.org/10.3324/haematol.2022.282324

Abstract

For several decades, asparaginase has been considered world-wide as an essential component of combination chemotherapy for the treatment of childhood acute lymphoblastic leukemia (ALL). Discovered over 60 years ago, two main unmanipulated asparaginase products originated from primary bacteria sources, namely Escherichia coli and Erwinia chrysanthemi, have been available for clinical use. A pegylated product of the Escherichia coli asparaginase was subsequently developed and is now the main product used by several international co-operative groups. The various asparaginase products all display the same mechanism of action (hydrolysis of circulating asparagine) and are associated with similar efficacy and toxicity patterns. However, their different pharmacokinetics, pharmacodynamics and immunological properties require distinctive modalities of application and monitoring. Erwinia chrysanthemi asparaginase was initially used as a first-line product, but subsequently became a preferred second-line product for children who experienced immunological reactions to the Escherichia coli asparaginase products. An asparaginase product displaying the same characteristics of the Erwinia chrysanthemi asparaginase has recently been produced by use of recombinant technology, thus securing a preparation available for use as an alternative, or as a back-up in case of shortages, for the non-recombinant product. The long journey of the Erwinia chrysanthemi asparaginase product as it has developed throughout the last several decades has made it possible for almost every child and adult with ALL to complete the asparaginase-based protocol treatment when an immunological reaction has occurred to any Escherichia coli asparaginase product.

The various asparaginase products: mechanism of action and pharmacological properties

Asparaginase (ASNase) is a therapeutic enzyme used now for over 50 years as a component of multi-agent chemotherapy for children with ALL.1-8 ASNase preparations available in the market mainly derive from the Escherichia coli (E. coli) and from the Erwinia chrysanthemi (Erwinia c.) strains,9-14 display the same mechanism of action, have different pharmacokinetic (PK) and pharmacodynamic (PD) properties, and are available for clinical use in different forms: native E. coli and Erwinia c. products and the PEGylated E. coli product (PEG-ASNase) (Figure 1). ASNase mediates the breakdown of asparagine into aspartic acid and ammonia thus depleting the patient's bloodstream of the amino acid asparagine, which is indispensable for the leukemic blast metabolism, thus exploiting the metabolic weakness of leukemic blasts to autonomously produce asparagine, an amino acid important for the synthesis of several proteins.15,16 In addition to asparagine (ASN) depletion, each ASNase product also results in a variable degree of glutaminase activity, whose significance remains partially unexplained and somewhat controversial. As an example, while Panosyan et al. found that deamination of glutamine (GLN) is a prerequisite for optimal ASN deamination by ASNases in vivo,17 Chan et al. suggested, in contrast, that glutaminase-negative variants of ASNase would provide larger therapeutic indices than wild-type ASNase for asparagine synthetase (ASNS)-negative cancers.18 Since GLN is the most abundant amino acid in the blood, its depletion under ASNase treatment is limited; however, a substantial reduction of blood GLN levels leads to extensive ammonia production and has been associated with ASNase-induced liver dysfunction and neurotoxicity. Since the glutaminase activity of the Erwinia c. ASNase is approximately five times higher than that of the E. coli ASNase products, it is important to consider such differences when investigating infusion-related and toxic side effects of the Erwinia c. ASNase products.19,20 Also, it has been suggested that, although GLN is broken down to glutamic acid by ASNase, this may not necessarily lead to a high GLN depletion, as this amino acid can be supplemented from other organs in vivo.21

Figure 1.Different asparaginase preparations used from 1970s onwards. Each preparation is accompanied by the following information: initial FDA approval, half-life (days), recommended dosing and interval, recommended interval and seminal EU/US trials. Adapted from Maese et al. Front Pediatr 2022.62 IM; intramuscular; IV; intravenous; IU; international units; M/W/F: Monday, Wednesday, Friday schedule of dosing. The original NCT trials are available at: https://clinicaltrials.gov/.

Native E. coli ASNase has a half-life of 1.24 days following an initial dose of 25,000 IU/m2 (high dose ASNase, intramuscular [IM]), therefore multiple doses are necessary to attain prolonged and profound asparagine depletion.22 In 1978, this preparation was authorized by the US Food and Drug Administration (FDA), but is currently no longer available in the United States for use in children under 18 years of age. Another paper reported that the half-life of native E. coli ASNase after an intravenous (IV) dose of 6,000 IU/m2 is 17.3-19 hours.23 In the 1970s, Erwinia c. ASNase was found to have PK characteristics similar to that of native E. coli ASNase, but with a shorter half-life of 0.65 days after IM administration.22 In 2011, Erwinia c. ASNase (dosed at 25,000 IU/m2) was approved by the FDA as a treatment option for ALL patients who experienced a hypersensitivity reaction (HSR) to E. coli-derived ASNase preparations.13

PEG-ASNase, a native E. coli ASNase product linked to polyethylene glycol (PEG), results in substantially prolonging the native E. coli ASNase half-life and reducing the associated hypersensitivity phenomena. PK and PD studies of PEG-ASNase began in the 1980s, and were usually conducted in patients who had HSR to native E. coli ASNase.24-26 The half-life of PEG-ASNase given at 2,000 and 2,500 IU/m2 was 357 +/- 243 hours (IV).24 In 2006, based on a toxicity profile similar to that of the native E. coli ASNase and on a decreased incidence of antibody formation, the FDA approved PEG-ASNase for first-line use in patients with ALL.27,28

In 2008, the results of a study conducted in ALL children on a recombinant variant of native E. coli ASNase were reported by Pieters et al. They concluded that the recombinant and the native E. coli ASNase products were bioequivalent and had the same PD and toxicity profile.29 This recombinant E. coli ASNase product is currently not available in the United States.

In 2018, the FDA approved a long-acting product similar to PEG-ASNase, namely calaspargase pegol-mknl (Cal-PEG).30 This formulation used a different linker to E. coli ASNase, resulting in a longer half-life and shelf life. Patients treated with Cal-PEG every three weeks had a similar safety profile and event-free survival (EFS) to those treated with the traditional PEG-ASNase product.30

In 2021, based on the interim results of the COG AALL1931 trial study on the use of a recombinant Erwinia c. ASNase derived from a novel expression platform, the FDA approved its IM use at the dosage of 25 mg/m2. In 2023, Maese et al. reported that this recombinant Erwinia c. ASNase was efficacious at 25/25/50 mg/m2 when given IM on a MondayWednesday-Friday (MWF) schedule.31 The use of this preparation resulted in a safety profile consistent with other ASNases that had earlier been approved by the FDA.

An interesting paper by Brigitha et al. recently evaluated how much ASNase is needed for optimal outcome in childhood ALL.32 The authors concluded that: i) the level and duration of exposure have usually been based on the PK profile of the drug and on the assumption that a trough ASNase activity level of 100 U/L or greater is necessary to obtain a complete ASN depletion; ii) the level of exposure has not yet been associated with the outcome as long as the therapeutic level was reached. Authors also concluded that no clear cut-off for optimal exposure duration could be determined and that the achievement of this goal can also depend on immunophenotype, (cyto)genetic subgroups, risk group stratification, and backbone therapy.32

Clearly, the various ASNase products are not readily interchangeable and need to be used at specific schedules and doses. This is especially true for the Erwinia c. ASNase when it is used as second-line agent to replace the E. coli ASNase products when a clinically overt HSR or silent inactivation (SI) phenomena occurs.2 Since several clinical studies have established the efficacy of Erwinia c. ASNase as a first- or second-line product, this specific aspect will be addressed later on in this Spotlight Review. Given that the incidence of E. coli ASNase and PEG-ASNase-associated HSR and SI are overall reported to be up to 60-70%, the importance of the availability of Erwinia c. ASNase is readily apparent.33-39

Erwinia c. asparaginase as first-line therapy: the journey starts

The benefits derived from an intensive use of any ASNase products, including the Erwinia c. ASNase, have been extensively reported. Table 1 shows all relevant clinical trials (including their main characteristics and relative results) where the Erwinia c. ASNase has been used as first-line product. Beginning in the 1990s, the UK Medical Research Council ALL consortium conducted a non-randomized trial comparing the toxicity of the E. coli and of the Erwinia c. ASNases given IM to a large cohort of ALL patients as first-line therapy.40 Patients treated with E. coli ASNase had a significantly higher incidence of neurotoxicity, pancreatitis, and life-threatening sepsis than those receiving Erwinia c. ASNase. With a minimum follow-up of 4.5 years, the cohort of patients treated with the Erwinia c. ASNase had an outcome similar to that of patients treated with the native E. coli ASNase. This was the first study showing the efficacy of Erwinia c. ASNase when used as first-line therapy.40

Albertsen et al. studied the different patterns of ASN depletion between the IV and the IM administration route with the Erwinia c. ASNase given daily at 30,000 IU/m2 for ten days during induction and twice weekly doses for two weeks during the re-induction phase of the NOPHO-92 ALL-protocol.41 Over 92% of the treated patients had trough activity levels > 500 U/L42,43 for both administration routes. Conversely, when the ASNase activity levels were evaluated during the re-induction, lower percentages of patients achieved the target level of > 100 U/L (almost 65% for the IV-treated children vs. 73% for the IM-treated children). The authors concluded that the Erwinia c. ASNase schedule adopted in the induction phase was unnecessarily intense, whereas it was insufficient for both administration routes in the re-induction phase.

In a national randomized study enrolling newly diagnosed patients in the AIEOP ALL-91 study, Rizzari et al. evaluated the therapeutic effects of the Erwinia c. ASNase product given IM to the subjects enrolled in the intermediate risk (IR) group of ALL either at weekly high doses, i.e., 25,000 IU/m2, for a total of 20 doses over 20 weeks (experimental arm) during the reinduction and the early phase of maintenance or at standard doses, i.e., 10,000 IU/m2, every 3-4 days for a total of four doses over two weeks, during the reinduction phase only (standard arm).44 In this study, the results concerning outcome between the two arms were superimposable, thus proving that the Erwinia c. ASNase product given at standard doses and within a standard treatment schedule was capable of maintaining the outcomes expected from previous Berlin-Frankfurt-Münster (BFM)-based clinical trials using native E. coli ASNase.

A similar randomized study embedded in the same AIEOP ALL-91 study but designed for standard risk (SR) ALL patients was conducted in the frame of the IDH international co-operative effort named which included patients from Italy, Hungary and The Netherlands.45 That study aimed to determine the efficacy of a BFM-type modified (i.e., less intensive) chemotherapy regimen including (experimental arm) or not (standard arm) a prolonged use of ASNase given at high doses (i.e., 25,000 IU/m2, for a total of 20 doses over 20 weeks) at the beginning of the continuation phase. In contrast to the previously described study conducted in IR patients, this randomized clinical trial, conducted in 355 SR ALL children, showed that, compared to the group receiving the standard treatment, the group receiving high-dose ASNase (Erwinia c.) for a protracted period of time (experimental arm) had a significantly increased 10-year disease-free survival (DFS) (87.5% vs. 78.7%) and a higher overall survival (OS) (93.7% vs. 88.6%). Of note, a 40% relative reduction (RR) in the risk of failure was achieved in the group of patients receiving the protracted high-dose ASNase (Erwinia c.) product, thus proving the beneficial effects of that product and schedule, in that chemotherapy context and in that subgroup of patients.45

Table 1.Main findings reported in the studies featuring Erwinia c. ASNase given as first- or second-Line product.

Notwithstanding, two randomized clinical trials carried out in the same period (early-mid 1990s) in Europe by the European Organisation for Research and Treatment of Cancer (EORTC)46 and in the US by the Dana-Farber Cancer Institute (DFCI) Consortium (Table 1)47 showed that among ALL children (belonging to any risk group) randomly assigned to receive throughout the whole treatment schedule either the native E. coli ASNase or the Erwinia c. ASNase products (same dosage, administration route and treatment schedule), those treated with the Erwinia c. ASNase had consistently lower toxic effects but poorer EFS. These findings were mainly interpreted as secondary to an inadequate timing and dosage adopted for the Erwinia c. ASNase and therefore to a consequently inadequate asparagine depletion.

In 2006, Kwok et al. reported the results of their investigations on minimal residual disease (MRD) to compare the efficacy of Erwinia c. ASNase and native E. coli ASNase given IM at similar dosage and intervals during a classical four-drug induction therapy. They found that patients treated with the Erwinia c. ASNase were 6.7 times more likely to have higher MRD levels (≥ 10-2) thus reflecting slower lymphoblast clearance, presumably due to insufficient ASNase activity.48

Both the therapeutic and toxic effects associated with the Erwinia c. ASNase used as front-line product may be either very similar or very different from those associated with the native E. coli ASNase products, greatly depending on the dosage and the schedule adopted.

Erwinia c. asparaginase as second-line therapy: the journey continues

After the first decade of its use, when Erwinia c. ASNase had mainly been used as a first-line ASNase with the findings previously reported, the efficacy of a switch to the Erwinia c. ASNase preparation after HSR to a native E. coli ASNase product became more evident and its use as second-line product became widespread.1 Table 1 summarizes the most relevant details of the various clinical trials in which the Erwinia c. ASNase product has been used as second-line product. (See also below.)

The ASNase activity reduction found among the 280 high-risk pediatric ALL patients treated with Erwinia c. ASNase after HSR to a native E. coli ASNase had an impact on the outcome of the treated patients; in fact, Panosyan et al. found an increased rate of events among patients with Ab-positive titers detected during the interim maintenance-1 and the delayed intensification.35 Also, Vrooman et al. showed that patients with SI occurring during treatment with native E. coli ASNase had a worse outcome when not switched to another ASNase product, whilst those with a HSR and switched to Erwinia c. ASNase fully maintained the expected outcome.49

In two further clinical studies conducted by the Dutch Childhood Oncology Group (DCOG), Erwinia c. ASNase was used as a second-line preparation. In the first study, Tong et al. studied ALL children presenting with either HSR or SI to PEG-ASNase during the intensification phase of ALL therapy and who were switched to Erwinia c. ASNase. Such a switch led to effective ASNase activity levels in most patients.21 In the second study, Kloos et al. studied the role of therapeutic drug monitoring (TDM) within the DCOG ALL-11 protocol.50 After a HSR, 37 patients were started on Erwinia c. ASNase at 20,000 IU/m2 (IV) three times a week for two weeks. During the two weeks, 76% had trough activity levels at 48 hours > 100 U/L but only 24% at 72 hours. Thereafter, the Erwinia c. ASNase product dose varied between 15,000 and 40,000 IU/m2.50 The main finding of that study was that, besides SI, also allergiclike reactions could be identified by using TDM.

Finally, the Children’s Oncology Group (COG AALL0232) studied more than 3,000 patients with high-risk ALL comparing the outcome of patients receiving all the planned PEG-ASNase doses (group 1) with that of patients switched to receive the Erwinia c. ASNase to complete the planned ASNase treatment (group 2), and with that of patients who completely missed a variable number of ASNase doses, mainly, but not only, due to HSR (group 3). The authors found that the DFS was similar between groups 1 and 2, whilst in group 3, the DFS was inferior compared to group 1, with a HR of 1.5 (P=0.002).51 The data showed that children with either HSR and/or SI occurring during the administration of E. coli ASNase consistently had a poorer outcome compared to those without such an immunological reactivity; when the Erwinia c. ASNase product was substituted for the E. coli ASNase, outcomes were maintained without unexpected additional toxicities.

Recombinant Erwinia c. ASNase product: is the future already here?

Despite the approval of the Erwinia c. ASNase as a second-line ASNase since 2011, important difficulties in the manufacturing process of Erwinia c. ASNase have occurred over the last two decades and this has led to global supply shortages of Erwinia c. ASNase.52,53 For this reason, a recombinant Erwinia c. ASNase (namely JZP-458) utilizing a novel Pseudomonas fluorescent technology expression platform has recently been developed;52 it has the same amino acid sequence as Erwinia c. ASNase and results in no immunologic cross-reactivity to E. coli-derived ASNase products. The recombinant technology-based production allows a stable and enhanced production process thus avoiding the supply problems with the non-recombinant Erwinia c. ASNase.

In 2021, in a phase I study conducted in healthy adult volunteers,54 JZP-458 was used at a starting dose of 25 mg/m2 (IM). Previously, it had been demonstrated that this formulation and dosage was similar in achieving sufficient ASNase activity when compared to the non-recombinant Erwinia c. ASNase (based on the dosage of 25,000 IU/m2).55 Lin et al. concluded that a single IM dose of JZP-458 (25 mg/m2) resulted in similar ASNase activity levels compared to 25,000 IU/m2 of the non-recombinant Erwinia c. ASNase.54 In 2021, based on the clinical and pharmacological data derived from the studies described, the FDA granted the approval of JZP-458.31

In 2022, the results of a phase II/III study conducted within the AALL1931 protocol of the COG were published.31 This study focused on the efficacy and safety of the recombinant Erwinia c. ASNase. Each scheduled dose of PEG-ASNase remaining after an HSR had occurred was replaced by six doses of JZP-458 given IM on a Mon/Wed/Fri basis. Maese et al. thoroughly studied three dosing regimens and concluded that JZP-458 given IM at 25/25/50 mg/m2 on a Mon/Wed/Fri schedule was effective in ALL patients, thus supporting the conclusion that this product with such a dosage, schedule and administration route has an efficacy and a toxicity profile similar to that of the non-recombinant Erwinia c. ASNase, and also of the other ASNase preparations available for clinical use and applied at equivalent dosages. The IM use of the recombinant Erwinia c. ASNase is currently approved by the FDA but additional data deriving from the IV use are under evaluation.

As far as the preferred use of administration route is concerned, ASNase products should be given IV. In fact, the study by Place et al. showed that IV administration of PEG-ASNase was associated with similar outcomes and toxicity pattern but with decreased anxiety compared with IM native E. coli ASNase doses.56 When focusing on the route of the native form of Erwinia c. ASNase, Tong et al. showed that the administration route might explain the higher median ASNase activity levels found by Salzer et al.21,57 Of note, previous studies have shown that no differences in mean ASNase activity levels, ASN depletion, and ASNase antibodies were found after IV or IM administration of Erwinia c. ASNase.41,43,58

How best to choose and administer Erwinia c. ASNase products in the modern protocols?

Currently, the use of Erwinia c. ASNase is limited to the second-line setting and not to the first-line setting because of: i) the results of the previous (old) clinical trials; and ii) its PK characteristics which mandate the drug administration every 48 hour to maintain therapeutic ASNase activity levels ≥ 100 U/L, making it very difficult, if not impossible, to deliver the drug to cover the often several weeks-long ASN depletion needed to exploit its therapeutic efficacy. For example, a huge number of doses would be needed during the induction phase of the AIEOP-BFM ALL protocols (and of many others protocols) to achieve the 4 weeks-long ASN depletion needed.

Furthermore, when one considers also the current costs of Erwinia c. ASNase, its use in the first-line setting would be very expensive.59 Therefore, the very few doses needed when PEG ASNase or the calaspargase products are used in the first-line setting make the use of these products the preferred option to be pursued.

Because of the recent frequent global shortages of the Erwinia c. ASNase, the recombinant form of Erwinia c. ASNase represents an opportunity to complement the market availability of the non-recombinant Erwinia c. ASNase preparation. This reassures physicians and parents on being able to complete any E. coli ASNase treatment in case of HSR or SI, and secures adequate opportunities of cure to ALL patients presenting with HSR or SI to the E. coli ASNase products.60

In the wider scenario of childhood ALL treatment, the currently available Erwinia c. ASNase products remain important drugs for the treatment of childhood ALL.8 Even if a number of promising (and also quite expensive) new biological agents (such as blinatumomab and inotuzumab) are currently under investigation to show their efficacy and to deepen their acute and mid-/long-term toxicity profile, it seems quite difficult at the present time to foresee a time when ASNase products will be substituted by such targeted drugs in the short-medium term. Furthermore, some innovative Erwinia c. ASNase formulations aiming to improve its characteristics appear on the horizon, making it even more interesting to look towards the future of this important antileukemia agent.

Future directions

In this Spotlight Review, we have retraced the journey taken over the last six decades by the Erwinia c. ASNase, a chemotherapy agent particularly important for successfully replacing native or pegylated E. coli ASNase products when they were associated with clinically relevant HSR or SI.

The journey started by the Erwinia c. ASNase product in the 1970s has been characterized by the pioneering experiences conducted as a first-line ASNase preparation and, in more recent decades, as a second-line product after HSR and SI to E. coli ASNase products. Across the subsequent decades, the journey has also been characterized by a lack of continuity in its availability caused by flaws in the production process which, for the moment, seem to have been overcome. In any case, the new recombinant Erwinia c. ASNase product, currently available on the market, secures the continuous availability of this important drug.

The scientific knowledge accumulated over the decades on the pharmacology, biological characteristics and clinical use of the Erwinia c. ASNase today represents a very important asset to ensure that all children with ALL can be treated with the best dosage and schedule, and that they can attain the expected full benefit from any planned ASNase-based treatment programs.

Concluding reflections

The title of this Spotlight Review was intuitively derived from the 1985 American film directed by Robert Zemeckis “Back to the Future” starring Michael J. Fox and Christopher Lloyd, considered one of the greatest science-fiction films ever made. When both of us, as co-authors, were working on this scientific review of the Erwinia c. ASNase product, we came to realize even more, and even better, its long journey, marked by different events as far as its use (first- and second-line), schedules (including administration routes and dosages), manufacturing technologies (traditional and recombinant), and availability (shortages) have been concerned. And it somewhat resembled to us the “imaginary” journey made in that famous movie by the two leading actors with their time machine flying from the present to the past and then back to the future. But certainly, the “real” story of Erwinia c. ASNase is not yet over, and there is surely still more to come, just like all the sequels and adaptations made to the original movie after its first appearance in the cinemas.

Footnotes

  • Received March 14, 2023
  • Accepted July 10, 2023

Correspondence

°Current address: Evean "Oostergouw", Center for Specialized Geriatric Care, Zaandam, The Netherlands

W.H. Tong w.h.tong@lumc.nl

Disclosures

CR has received reimbursement for travelling expenses and personal fees for scientific talks at scientific meetings sponsored by Servier, Jazz Pharmaceuticals, and Clinigen, companies involved in the production and marketing of different asparaginase products.

Contributions

WHT and CR performed the literature research and wrote the manuscript. CR supervised this Spotlight Review.

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Vol. 108 No. 10 (2023): October, 2023 : Spotlight Review
 
DOI
https://doi.org/10.3324/haematol.2022.282324
Pubmed
37470157
 
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2023-07-20
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0390-6078
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1592-8721
 
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