A Meta-Analysis of Hypersensitivity to Pegylated Escherichia coli Asparaginase Used As First-Line Treatment in Contemporary Pediatric Acute Lymphoblastic Leukemia Protocols

PURPOSE Asparaginase is a key component of acute lymphoblastic leukemia (ALL) therapy. Hypersensitivity reactions challenge its use and occur frequently (30-75%) after native Escherichia. Coli (E.coli) asparaginase (Appel et al., 2008; Muller et al., 2001; Panosyan et al., 2004; Silverman et al., 2001). The international ALL Ponte di Legno Toxicity Work Group (PTWG) classifies hypersensitivity to asparaginase as (i) allergy in case of symptoms of allergy (always associated with undetectable asparaginase activity levels), (ii) allergic-like reactions in case of symptoms without inactivation, and (iii) silent inactivation (SI) with inactivation of asparaginase activity, but without hypersensitivity symptoms (Schmiegelow et al., 2016). Allergic-like reactions and SI can only be diagnosed with monitoring of asparaginase activity levels. A meta-analysis was performed based on data from the PTWG to estimate the incidence of hypersensitivity and risk factors for hypersensitivity to asparaginase in ALL protocols using pegylated E.coli asparaginase (PEGasparaginase) as first line of treatment. PATIENTS AND METHODS Questionnaires were sent to all members of the PTWG. Information on protocol level regarding PEGasparaginase dose, dosing regimen (e.g. dosing frequency, total number of doses, PEGasparaginase-free intervals(s)), administration route, total induction and post-induction hypersensitivity rates per protocol and per risk group and use of therapeutic drug monitoring (TDM). To facilitate comparison between protocols with and without TDM, we defined allergic reactions as the sum of allergies and allergic-like reactions. Silent inactivation was analyzed separately. RESULTS A total of 5880 patients with newly diagnosed ALL, aged 1 to 24 years old, were enrolled in seven different upfront ALL protocols using PEGasparaginase as first-line treatment. The overall incidence of allergic reactions along with 95% confidence interval (CI) were 9% [6%; 13%], 2% [1%; 3%] and 8% [5%; 11%] in the overall protocol, induction and post-induction, respectively (Figure 1). Severity of allergic reactions were described, according to the CTCAE version 3.0 or 4.03, per protocol. 47% of the reactions were classified as grade 3/4. Univariate meta-regression analysis showed a positive association between the incidence of allergic reactions and number of PEGasparaginase-free intervals (P=0.005). High risk group stratification (P<0.001), post-induction treatment phase (P<0.001) and start of PEGasparaginase treatment in post-induction (P=0.006) were also associated with a higher incidence of allergic reactions. Route of administration (IV (8.9%, range 8.6-10.5%) versus IM (6.5%, range 5.5-14.8%)) did not significantly influence risk of hypersensitivity. Number of doses, duration of first PEGasparaginase-free interval and dosage did not significantly influence risk of hypersensitivity. Multivariate meta-regression analysis showed a positive association between the incidence of allergic reactions and the number of PEGasparaginase-free intervals (P=0.006) and start of PEGasparaginase in the post-induction treatment phase (P=0.02). Two out of seven study groups reported an incidence of allergic reactions of 1.6-2.0%, which was 9-16% of all hypersensitivity. Three out of seven study groups reported an incidence of SI of 3.7-4.1%, which was 23-29% of all hypersensitivity reactions. All protocols prescribed a switch to Erwinia asparaginase in case of clinical hypersensitivity and/or SI. 308 out of 348 (89%) of the patients with hypersensitivity to PEGasparaginase received Erwinia asparaginase. 19 out of these 308 (6%) exposed patients had an allergic reaction to Erwinia asparaginase, of which 7 out of 19 (37%) were grade 3/4. CONCLUSION The incidence of allergic reactions is lower in protocols using PEGasparaginase as first-line treatment compared to that reported for native E.coli asparaginase or PEGasparaginase after native E.coli asparaginase. Post-induction phase, a higher number of PEGasparaginase-free intervals, and initiation of PEGasparaginase in post-induction phase are risk factors for allergic reactions. These results are important for planning of PEGasparaginase administrations in future frontline therapy. Figure 1 Figure 1. Disclosures Albertsen: Erytech: Honoraria, Speakers Bureau; Servier: Speakers Bureau; BKA: Other: Sponsor of the investigator-initiated trial NOR-GRASPALL2016.

Initial Results from a Phase 2/3 Study of Recombinant Erwinia Asparaginase (JZP458) in Patients with Acute Lymphoblastic Leukemia (ALL)/Lymphoblastic Lymphoma (LBL) Who Are Allergic/Hypersensitive to E. coli-Derived Asparaginases

Background: In patients with ALL, inability to receive L-asparaginase therapy due to hypersensitivity is associated with higher relapse risk (Gupta S, et al. J Clin Oncol. 2020). JZP458 is a recombinant Erwinia asparaginase derived from a novel Pseudomonas fluorescens expression platform to produce a reliable supply of enzyme with minimal immunologic cross-reactivity to E. coli-derived asparaginases. It has an amino acid sequence identical to that of native Erwinia asparaginase and its activity on asparagine is comparable based on in vitro measurements. This report includes initial analyses from the phase 2/3 open-label, multicenter, confirmatory pharmacokinetic (PK) and safety study (NCT04145531) of JZP458 in patients with ALL/LBL who developed hypersensitivity or silent inactivation to a long-acting E. coli-derived asparaginase. Methods: For eligible patients, each remaining course of long-acting E. coli-derived asparaginase was substituted by six doses of intramuscular (IM) JZP458 on a Monday/Wednesday/Friday (M/W/F) schedule. The primary efficacy endpoint of the trial was evaluated by the proportion of patients with the last 72-hr (primary endpoint) and last 48-hr (key secondary endpoint) nadir serum asparaginase activity (NSAA) level ≥0.1 IU/mL during the first treatment course. Cohort 1a started with 25 mg/m 2 IM JZP458 (M/W/F) and Cohort 1b explored a higher dose of 37.5 mg/m 2 IM M/W/F. A preliminary population pharmacokinetic (PPK) model using Cohort 1a and 1b data predicted that a regimen of 25 mg/m 2 (M/W) and 50 mg/m 2 (F) would be optimal to support M/W/F dosing and Cohort 1c was initiated using this regimen. Results: This initial report (data cutoff of Jan 11, 2021) provides data from 102 study patients enrolled in Cohort 1a (n=33, 51.5% male), 1b (n=53, out of 87 patients enrolled, 62.3% male), and 1c (n=16, out of 52 patients enrolled, 50.0 % male). The median (range) number of courses received in Cohorts 1a, 1b, and 1c as of the data cutoff was 4 (1, 14), 3 (1, 12), and 1 (1, 2), respectively, and 53% of patients were ongoing in treatment. The mean serum asparaginase activity (SAA) levels (95% confidence intervals [CIs]) for evaluable patients in Cohorts 1a, 1b, and 1c at 48 hrs were 0.4489 IU/mL (0.3720, 0.5258), 0.8376 IU/mL (0.6813, 0.9939), and 0.5085 IU/mL (0.3261, 0.6908); and at 72 hrs were 0.1543 IU/mL (0.1162, 0.1924), 0.3000IU/mL (0.2269, 0.3730), and 0.3579 IU/mL (0.2184, 0.4974). The proportion of patients achieving NSAA ≥0.1 IU/mL at 48 and 72 hr time points are presented in Table 1. PPK modeling and simulation analysis suggested that JZP458 given IM as 25 mg/m 2 on M/W and 50 mg/m 2 on F was expected to achieve NSAA levels ≥0.1 IU/mL in 99.8% of patients (95% CI: 99.6%, 100%) at 48 hours and 97.3% of patients (95% CI: 96.5%, 98.0%) at 72 hours. Grade 3 or higher treatment-emergent adverse events, regardless of causality, occurred in 73/102 (72%) patients. Adverse drug reactions (ADRs) are shown in Table 2. These ADRs are consistent with the safety profile observed with other asparaginases. Conclusions: The JZP458 IM dosing regimen of 25 mg/m 2 M and W, and 50 mg/m 2 F demonstrates a positive benefit:risk profile, achieving SAA levels ≥0.1 IU/mL in >90% of patients studied at both 48- and 72-hrs and a safety profile that is consistent with what has been observed in published literature on asparaginases. Figure 1 Figure 1. Disclosures Maese: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Loh: MediSix therapeutics: Membership on an entity's Board of Directors or advisory committees. Lin: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Aoki: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Zanette: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Agarwal: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Silverman: Jazz Pharmaceuticals: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Choi: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Silverman: Takeda, Servier, Syndax, Jazz Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Raetz: Pfizer: Research Funding; Celgene: Other: DSMB member. Rau: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Servier Pharmaceuticals: Consultancy; AbbVie Pharmaceuticals: Other: Spouse is employee and stock holder.

Pegaspargase Re-Challenge after Grade 2 Hypersensitivity Reaction in Childhood Acute Lymphoblastic Leukemia: Results from DFCI 16-001

Introduction: Hypersensitivity reactions with asparaginase occur frequently in pediatric patients (pts) with acute lymphoblastic leukemia (ALL). The standard approach for pts with reaction to E.coli-derived asparaginase is to switch to Erwinia asparaginase, given concern that clinical reactions reflect presence of neutralizing antibodies; however, Erwinia requires more frequent dosing and is often unavailable. Therapeutic drug monitoring allows for discrimination between pts with pegaspargase hypersensitivity who have sub-therapeutic asparaginase activity and those still able to derive therapeutic benefit from pegaspargase. We prospectively piloted re-challenging pts with pegaspargase after initial Grade 2 hypersensitivity to this agent, with premedication at re-challenge and assessment of serum asparaginase activity (SAA). Methods: Pts aged 1 to < 22 years with newly diagnosed ALL were eligible for DFCI 16-001. Pts received 1 dose of intravenous pegaspargase during Induction, and every 2 weeks for 15 total doses in Post-Induction phases, without routine premedication. Pts were monitored during/after pegaspargase for allergy, with CTCAE version 4.0 event grading. Those with ≥Grade 3 allergy discontinued pegaspargase and were switched to Erwinia. Those with Grade 2 allergic reaction were eligible for pegaspargase re-challenge with pre-medication (acetaminophen, diphenhydramine, and hydrocortisone, or per institutional standard) and slower infusion rate. If < 50% of the intended dose had been administered when reaction occurred, re-challenge was within 1-7 days of initial reaction. If ≥ 50% of the intended dose had been given, re-challenge was at next planned pegaspargase dose. SAA was measured 1-hour, 7-days, and 14-days after the re-challenge infusion (if dose completed). If 1-hour or 7-day level ≥ 0.1 IU/mL, and 14-day level ≥ 0.025 IU/mL, SAA was considered adequate, and the pt continued to receive pegaspargase with premedication. Pts with an inadequate SAA level, or with new ≥ Grade 2 allergic reaction with the re-challenge dose were considered to have failed re-challenge and were changed to Erwinia (or enrolled on a clinical trial of recombinant crisantaspase, an alternative Erwinia preparation). Results: Between 3/2017- 7/2020, 317 eligible pts enrolled. Overall, 81 of 299 (27%) total evaluable pts experienced a first allergic reaction to pegaspargase, 68 pts with Grade 2 reaction, 13 with Grade ≥3. During Induction, 17 of 299 (6%) evaluable pts had allergic reaction to pegaspargase; all Grade 2. Of the 17 Grade 2 reactions, 13 pts (76%) underwent re-challenge in Induction, 9 (69%) re-challenges successful and 4 failed. Post-Induction, 64 of 241 evaluable pts (27%) had a first allergic reaction; 51 Grade 2 and 13 Grade ≥3. Thirty-six of 51 (71%) pts with Grade 2 allergy during Post-Induction underwent re-challenge, as did 1 additional pt with allergy during Induction who was re-challenged with first Post-Induction pegaspargase dose (per protocol guideline, due to receiving ≥50% of Induction dose). Among these re-challenges, 16 were successful, 21 failed. Overall, 25 of 50 (50%) pts who were re-challenged after Grade 2 reaction had a successful challenge and were able to continue pegaspargase. Among the 25 pts with failed re-challenge, 6 pts (24%) had inadequate SAA alone as cause of failure, 17 pts (68%) had an allergic reaction with the re-challenge dose, and 2 (8%) additional patients had both allergic reaction and documented inadequate SAA. Three pts who were successfully re-challenged had a subsequent allergic reaction to pegaspargase. Among the 22 pts who experienced another allergic reaction with pegaspargase (at re-challenge or subsequent dose), 19 pts (86%) experienced Grade 2, and 3 pts experienced Grade 3 reaction. Conclusion: Fifty percent of pts with a Grade 2 reaction to pegaspargase were able to tolerate and achieve adequate SAA when re-challenged with premedication. For those who did react with or after re-challenge, reactions were not more severe. The re-challenge approach limits premedication exposure only to a minority of pts with a history of prior reaction and substantially decreases the number of pts needing to switch to Erwinia asparaginase, which can be challenging to deliver due to administration schedule and drug shortage. Disclosures Place: Novartis: Consultancy, Other: Institutional Research Funding; AbbVie: Consultancy. Silverman:Takeda: Other: advisory board; Servier: Other: advisory board; Syndax: Other: advisory board.

Individualized Asparaginase Dosing in Childhood Acute Lymphoblastic Leukemia

PURPOSE In the DCOG ALL-11 protocol, polyethylene glycol–conjugated Escherichia coli asparaginase (PEGasparaginase) and Erwinia asparaginase treatment of pediatric acute lymphoblastic leukemia are individualized with therapeutic drug monitoring (TDM). The efficacy of TDM and its effect on asparaginase-associated toxicity are reported. PATIENTS AND METHODS After induction with 3 fixed intravenous doses of 1,500 IU/m2 PEGasparaginase, medium-risk patients (n = 243) received 14 individualized doses that targeted trough levels of 100-250 IU/L, standard-risk patients (n = 108) received 1 individualized dose, and high-risk patients (n = 18) received 2-5 fixed administrations (1,500 IU/m2). After a neutralizing hypersensitivity reaction, patients were started with 20,000 IU/m2 Erwinia asparaginase 3 times per week, and l-asparagine was measured to monitor asparaginase efficacy. Several asparaginase-associated toxicities were studied. RESULTS The final median PEGasparaginase dose was lowered to 450 IU/m2. Overall, 97% of all trough levels of nonallergic patients were > 100 IU/L. Asparagine was < 0.5 μM in 96% and 67% of the PEGasparaginase and Erwinia asparaginase levels > 100 IU/L, respectively. Ten percent developed a neutralizing hypersensitivity reaction to PEGasparaginase, of which 40% were silent inactivations. The cumulative incidence of grade 3-4 pancreatitis, central neurotoxicity, and thromboses was 12%, 4%, and 6%, respectively, and not associated with asparaginase activity levels. During medium-risk intensification, 50% had increased ALT and 3% hyperbilirubinemia (both grade 3/4 and correlated with asparaginase activity levels), and 37% had grade 3/4 hypertriglyceridemia. Hypertriglyceridemia occurred less in intensification compared with ALL-10 (37% v 47%), which is similar to ALL-11 but with higher asparaginase levels during intensification. CONCLUSION TDM of asparaginase results in a significant reduction of the PEGasparaginase dose with adequate asparaginase activity levels and sufficient asparagine depletion. In addition, with TDM, silent inactivation and allergic-like reactions were identified. However, the effect of reduced asparaginase activity levels on toxicity is limited.

The cost-effectiveness of pegaspargase versus native asparaginase for first-line treatment of acute lymphoblastic leukaemia: a UK-based cost-utility analysis

Background L-asparaginase is a key component of treatment for patients with acute lymphoblastic leukaemia (ALL) in the UK. Commonly used forms of asparaginase are native E. coli-derived asparaginase (native asparaginase) and pegaspargase in first-line combination therapy, and native Erwinia chrysanthemi-derived asparaginase (Erwinia asparaginase) as second-line treatment. The objective of this study was to evaluate the cost-effectiveness of pegaspargase versus native asparaginase in first-line combination therapy for patients with newly diagnosed ALL. A combined decision tree and health-state transition Markov cost-effectiveness model was developed to assess the relative costs and health outcomes of pegaspargase versus native asparaginase in the UK setting. Results In base case analyses, first-line pegaspargase (followed by Erwinia asparaginase in cases of hypersensitivity) dominated first-line native asparaginase followed by Erwinia asparaginase; i.e. resulted in lower costs and more quality-adjusted life year gain. The favourable hypersensitivity rates and administration profile of pegaspargase led to lifetime cost savings of £4741 versus native asparaginase. Pegaspargase remained cost-effective versus all treatment strategies in all scenario analyses, including use of the 2500 IU/m2 dose, recommended for patients ≤21 years of age. Conclusions Pegaspargase, as part of multi-drug chemotherapy, is a cost-effective option for the treatment of newly diagnosed ALL. Based on this study, The National Institute for Health and Care Excellence Technology Appraisal Committee concluded that it could recommend pegaspargase as a cost-effective use of National Health Service resources in England & Wales for treating ALL in children, young people and adults with untreated, newly diagnosed disease. Trial registration UKALL 2011, EudraCT number 2010-020924-22; UKALL 2003, EudraCT number 2007-004013-34; UKALL14, EudraCT number 2009-012717-22.