Asparaginase therapy in patients with acute lymphoblastic leukemia: expert opinion on use and toxicity management

Abstract

The addition of asparaginase to acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) treatment regimens provides significant patient benefits. Asparaginase therapies vary in origin (Escherichia coli– or Erwinia-derived) and preparation (native or pegylated), conferring distinct pharmacokinetic and immunogenic profiles. Clinical hypersensitivity reactions (HSRs) are commonly reported in patients and range from localized erythema to systemic anaphylaxis. Due to its favorable pharmacokinetic profile and reduced immunogenicity compared to native E. coli preparations, pegaspargase is the first-line asparaginase therapeutic option. Switching to an Erwinia-derived asparaginase is recommended for patients who experience HSRs or antibody-mediated inactivation to achieve the significant clinical benefit observed in patients who complete asparaginase treatment. Previous global shortages of asparaginase Erwinia chrysanthemi necessitated conversion mitigation strategies such as premedication protocols, desensitization, and asparaginase activity level monitoring. Here, we discuss the efficacy, safety, pharmacokinetics, current use, and administration of asparaginase therapies for pediatric and adolescent patients with ALL/LBL.

Keywords:

• Allergy and hypersensitivity
• lymphoid leukemia
• chemotherapeutic approaches
• pharmacotherapeutics

Introduction

Asparaginase therapies are an integral treatment component for patients with acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) [1]. Unlike healthy cells, which are able to synthesize asparagine via asparagine synthetase, malignant hematopoietic cells lack this capacity and rely on exogenous asparagine for continued growth [2]. Hydrolysis of extracellular asparagine by asparaginase depletes circulating asparagine, selectively targeting leukemic cells, ultimately resulting in cell death [3,4].

Five therapeutic asparaginase products have been US Food and Drug Administration (FDA) approved; three are currently available in the United States. The two native preparations of asparaginase—no longer marketed—are derived from the bacteria Escherichia coli and Erwinia chrysanthemi [5,6]. The nonnative formulations are pegaspargase, calaspargase pegol, and recombinant Erwinia asparaginase. The manufacturer of pegaspargase and calaspargase plans to phase out use of pegaspargase in favor of calaspargase for all patients ≥1 month and <21.5 years of age as of December 1, 2022. Patients <1 month and ≥21.5 years of age will still be eligible to receive pegaspargase. All preparations have the same mechanism of action; however, pharmacokinetic and immunogenic profiles differ between asparaginase products [4,7].

Erwinia asparaginase, first described in 1969, is typically reserved for patients who have developed hypersensitivity to E. coli–derived asparaginase and has been used in patients exhibiting allergic reactions to E. coli–derived asparaginase since the early 1970s [8–10]. However, manufacturing issues in the modern era have led to repeated global shortages of native Erwinia asparaginase. These shortages required institutions and providers to develop alternative strategies, such as universal premedication, desensitization, and rechallenge, in an effort to allow patients to complete their full treatment regimen. In 2021, the FDA approval of recombinant Erwinia asparaginase eased prior supply shortages [11–14]. Here, we review the literature regarding the efficacy, safety, pharmacokinetics, and administration considerations of asparaginase products in pediatric patients with ALL or LBL, as well as specific considerations for young adult or adult patients.

Efficacy and safety of asparaginase in ALL

Efficacy

The clinical benefit derived from the inclusion of asparaginase therapies in ALL and LBL treatment regimens is well established. A study of 484 pediatric patients found that patients who received 20 weeks of asparaginase (25,000 IU/m²) in consolidation achieved a higher rate of continuous complete remission at 4 years (71.3%) versus patients who did not receive asparaginase in consolidation (57.8%) [15]. In one study of 355 children with ALL, the addition of 20 weekly doses of L-asparaginase to the early continuation phase of a Berlin-Frankfurt-Münster backbone resulted in a disease-free survival (DFS) probability of 88.1% at 5 years and 87.5% at 10 years compared to 82.5% and 78.7%, respectively, for patients who did not receive L-asparaginase (one-sided p = 0.03) [16].

Several studies have directly compared different types of asparaginase therapy. In the Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 87-01 trial, including 263 children with newly diagnosed ALL who were randomized to asparaginase therapy, there were no significant differences in 9-year event-free survival (EFS; 77% vs 73% vs 67%) or overall survival (OS; 88% vs 83% vs 80%) for native E. coli asparaginase, pegaspargase, and native Erwinia asparaginase, respectively [17]. However, the study was not statistically powered to detect differences in these outcomes. In a separate pediatric Dana-Farber study (DFCI 05-001), 463 patients were randomized to receive either intravenous (IV) pegaspargase or intramuscular (IM) native E. coli asparaginase. Rates of 5-year DFS (90% vs 89%) and 5-year OS (96% vs 94%) were similarly high in both groups [18]. In a recent phase 3 study of 239 children and adolescents with ALL (DFCI 11-001), 5-year EFS (84.9% vs 88.1%) and 5-year OS (95.8% vs 94.0%) were similar for pegaspargase and calaspargase pegol [19].

Completion of the planned asparaginase treatment course is vital to achieving optimal outcomes. In the DFCI 91-01 study of 386 children with ALL, eligible patients were randomized to receive IM pegaspargase every other week for 15 doses or native E. coli asparaginase every week for 30 weeks during the intensification phase [20]. Five-year EFS was significantly worse for patients receiving <25 weeks of asparaginase therapy versus ≥26 weeks of asparaginase therapy (73% vs 90%; p < 0.01).

In a study conducted in seven European countries on the Nordic Society of Paediatric Haematology and Oncology ALL2008 protocol, 1401 children with ALL received IM pegaspargase, five doses at 2-week intervals during treatment consolidation. Patients were then randomized to an additional 3 doses of pegaspargase at 6-week intervals or 10 doses at 2-week intervals during delayed intensification and the start of maintenance therapy. A predefined substudy cohort of 1115 patients was included who were assigned nontruncated status if they completed pegaspargase therapy and had normal enzyme activity or truncated status if they stopped treatment due to toxicity or demonstrated inactivation of asparaginase activity. In this cohort, 7-year cumulative incidence of relapse was 11.1% versus 6.7% in patients receiving truncated versus nontruncated pegaspargase treatment, respectively (adjusted relapse-specific hazard ratio [HR], 1.69; 95% confidence interval [CI], 1.05–2.74; p = 0.03; Figure 1) [21]. However, it is important to note the reasons for patients not receiving all therapy are varied, therefore it is difficult to assess the precise causative factors contributing to differences observed in outcomes.

Figure 1. Cumulative incidence of relapse based on pegaspargase truncation^a and activity. Figure reprinted from Gottschalk Højfeldt S, et al. Blood 2021;137:2373-2382 with permission from Elsevier. ^aNontruncated status indicates the patient completed pegaspargase therapy and had normal enzyme activity; truncated status indicates the patient stopped treatment due to toxicity or demonstrated inactivation of asparaginase activity. AEA: asparaginase enzyme activity; ALL: acute lymphoblastic leukemia.

In an analysis from two Children’s Oncology Group (COG) clinical trials of >8000 children (AALL0331 and AALL0232), adolescents and young adults with newly diagnosed B-cell ALL were categorized according to whether or not they had received all prescribed doses of pegaspargase [22]. In the National Cancer Institute (NCI) standard risk trial, AALL0331, noncompletion of pegaspargase therapy was not associated with significantly inferior DFS when compared with that of patients who received all planned doses (HR, 1.2; 95% CI, 0.9–1.6). However, in the subgroup of patients with standard risk-high ALL, multivariate analysis showed significant impact on DFS of not completing pegaspargase therapy (HR, 1.7; 95% CI, 1.0–2.6; p = 0.03). In the NCI high-risk trial, AALL0232, for patients who discontinued pegaspargase but switched to native Erwinia asparaginase and received all doses, there was no difference in DFS when compared to patients who received all planned doses of pegaspargase (HR, 1.1; 95% CI, 0.8–1.7). In contrast, reduction of therapy from missing pegaspargase or native Erwinia asparaginase doses was associated with significantly worse DFS when compared to patients who completed asparaginase therapy (HR, 1.5; 95% CI, 1.1–1.9; p = 0.002) [22].

Recombinant Erwinia asparaginase showed complete asparagine depletion in a phase 1 study of healthy volunteers [14]. Results from the phase 2/3 study demonstrated attainment of nadir serum asparaginase activity (SAA) levels ≥0.1 IU/mL in 90% of patients at 48 and 72 hours with the IM dosing regimen of 25 mg/m² Monday/Wednesday and 50 mg/m² Friday [23].

Safety and tolerability

Antibody-mediated reactions

Asparaginase therapies are derived from bacterial enzymes and can potentiate undesired antigenicity resulting in the development of anti-asparaginase antibodies, which diminish their effect. Although anti-asparaginase antibodies against native E. coli asparaginase are most frequently reported (39%–61% of patients) [24–26], antibody formation is also common in patients receiving pegaspargase (21%–29%) and native Erwinia asparaginase (8%–38%) [27–31]. It is important to note that antibodies are not always directed to the protein itself, but can be directed to the polyethylene glycol moiety or linker [32]. Development of anti-asparaginase antibodies may have a negative impact on clinical outcomes, as evidenced in a study of 47 children with ALL; those who developed antibodies against native E. coli asparaginase had significantly lower SAA levels and subsequently worse EFS (0.57 vs 0.79; p < 0.02) and OS (0.57 vs 0.89; p < 0.01) than those without antibodies [33]. Reports of anti–polyethylene glycol antibody formation in patients receiving pegaspargase have shown an association with clinical hypersensitivity reactions (HSRs) and reduced asparaginase activity [28,34]. Similarly, development of a pegylated Erwinia asparaginase formulation was abandoned after pilot study results showed overlapping incidence of HSRs in patients who previously reacted to pegaspargase [35].

Clinical HSRs are antibody-mediated responses, with reactions ranging from localized erythema to systemic anaphylaxis [10]. HSR incidence during asparaginase therapy is generally higher with native E. coli asparaginase (10%–75%) than pegaspargase (3%–24%), calaspargase pegol (17%), native Erwinia asparaginase (3%–37%), and recombinant Erwinia asparaginase (25%) [5,11,19,36,37]. Two recent clinical trials revealed HSRs as the most common reason for asparaginase treatment discontinuation (62%–77% of children discontinuing pegaspargase therapy) [21,22].

The phenomenon known as silent inactivation is characterized by the development of anti-asparaginase antibodies and subsequent asparaginase enzymatic activity reduction, absent clinical symptoms [36]. Due to a lack of adequate asparagine depletion, silent inactivation has been associated with poorer outcomes, including shorter EFS [26].

Ammonia-based reactions versus HSRs with pegaspargase

In addition to HSRs, pegaspargase poses the risk of immediate infusion reactions caused by significant increases in serum ammonia levels following rapid hydrolysis of asparagine [38]. Symptoms of hyperammonemia include nausea, vomiting, headache, dizziness, and rash; although typically mild, these may be severe and require hospital admission and discontinuation of pegaspargase therapy [39,40]. Hyperammonemia and clinical HSRs share similar symptoms, but reactions related to increased ammonia levels are not antibody mediated and often occur at the beginning of infusion and can occur with the first dose. Although a number of attempts have been made to correlate hyperammonemia with asparaginase activity, definitive evidence of the association is lacking [41–43]. In contrast, HSRs are more likely to occur from the second asparaginase dose onwards, as sensitization is required [10,44].

Differentiating between antibody-mediated HSRs and non–antibody-mediated infusion reactions impacts treatment decisions (i.e. whether to switch asparaginase therapies or rechallenge with pegaspargase) [36]. Two such approaches are the assessment of threshold values of serum ammonia (>50 µmol/L for hyperammonemia and >100 µmol/L for clinically significant hyperammonemia) [39] and measurement of tryptase levels immediately after emergency treatment has started and again within 1–2 h, as these may be indicators of non–antibody-mediated allergic reactions. It has been suggested that an increase in serum tryptase of 20% plus 2 ng/mL within 4 h of a reaction can indicate mast cell activation [40,45,46]. Measuring SAA can help differentiate between HSRs and nonallergic reactions because SAA levels should remain robust in patients experiencing hyperammonemia [36].

Other safety concerns

Asparaginase therapy is associated with potentially life-threatening toxicities, most notably pancreatitis and thrombosis, which may lead to permanent treatment discontinuation. Acute clinical pancreatitis has been reported in 2%–12% of patients treated with asparaginase and is more common in older than younger patients [7,11,18,47–53]. In large clinical trials of patients discontinuing pegaspargase therapy, 12%–25% of cases were due to pancreatitis [21,22]. Further, an analysis of the NOPHO ALL2008 study showed an association between elevated asparaginase enzyme activity levels and incidence of pancreatitis and osteonecrosis [54].

Asparaginase therapy–related thrombosis has been reported in 2%–11% of pediatric patients and 17%–34% of adults with ALL [55–57]. It is more common in 10 to 18 year olds and adults than in patients aged <10 years and is associated with an increased risk of mortality in patients aged <18 years [49,55–59]. In a large clinical trial, thrombosis was cited as the reason for discontinuation of pegaspargase therapy in 5.5% of patients [21]. Prophylactic strategies for mitigating thrombosis risk during asparaginase therapy, such as antithrombin supplementation, fibrinogen administration, and heparin prophylaxis, have not proven to be effective [60]. Guidance from the International Society on Thrombosis and Haemostasis suggests use of low-molecular-weight heparin for acute management of asparaginase therapy–related thrombosis in adults, with monitoring of anti–factor Xa levels. It is recommended asparaginase treatment be suspended until stabilization of the thrombotic event and anticoagulation be continued for ≥6 months for most patients, with a minimum of 4–6 weeks following completion of asparaginase therapy being considered on a case-by-case basis [61,62].

Pharmacokinetic profiles and dosing

Pharmacokinetic profiles of asparaginase therapies differ considerably (Table 1) [4,7,14]. Longer half-lives provide sustained asparagine depletion with fewer administrations [4].

Table 1. Dosing regimens and pharmacokinetic profiles for asparaginase therapies.

Asparaginase preparation	Route of administration	Mean plasma half-life	Dosing schedule	Substitution
Native E. coli asparaginase [4,63,96]	IM	34–49 h	6000 IU/m^2/dose 3 times/week; × 9 doses in Induction × 6 doses in each Delayed Intensification phase	Pegaspargase: 2500 IU/m^2 × 1 dose for each scheduled course (6-9 doses) of native E. coli asparaginase Native Erwinia asparaginase: 25 000 IU/m^2 × 1 dose for each scheduled dose of native E. coli asparaginase (maximum 6 doses) Recombinant Erwinia asparaginase: 25 mg/m^2 × 1 dose for each scheduled dose of native E. coli asparaginase
	IV	8–30 h
Pegaspargase [4,7,18,19,64]	IM	5.7 days	Patients aged ≤21 years: 2500 IU/m^2 no more frequently than every 14 days Patients aged >21 years: 2000 IU/m^2 no more frequently than every 14 days	Native Erwinia asparaginase: 25 000 IU/m^2 × 6 doses for each scheduled dose of pegaspargase Recombinant Erwinia asparaginase: 25 mg/m^2 every 48 h × 7 doses^a or 25/25/50 mg/m^2 Monday morning, Wednesday morning, and Friday afternoon × 6 doses^a for each scheduled dose of pegaspargase
	IV	4.9–5.3 days
Calaspargase pegol [7,19,60]	IV	12.7–17.3 days	2500 IU/m^2 no more frequently than every 21 days	Native Erwinia asparaginase: 25 000 IU/m^2 × 6 doses for each scheduled dose of calaspargase pegol Recombinant Erwinia asparaginase: 25 mg/m^2 every 48 h × 11 doses^a or 25/25/50 mg/m^2 Monday morning, Wednesday morning, and Friday afternoon × 9 doses^a for each scheduled dose of calaspargase pegol
Native Erwinia asparaginase [4,65]	IM	15.6 h	25 000 IU/m^2or 25 000 IU/m^2 3 times/week (MWF)	NA
	IV	7.5 h
Recombinant Erwinia asparaginase [11,14]	IM	15.9 h	25 mg/m^2 every 48 h × 7 doses^a or	NA
			25/25/50 mg/m^2 Monday morning, Wednesday morning, and Friday afternoon × 6 doses^a	NA

^aInstitutional differences in practice exist.

IM: intramuscular; IV: intravenous; MWF: Monday/Wednesday/Friday; NA: not available.

Dosing regimens for asparaginase therapies differ between agents, are not interchangeable, and require dosing conversions when switching preparations (Table 1) [60,63–65]. Incorrect dosing can have an important impact on clinical outcomes. In one study of children with ALL, administration of native E. coli asparaginase and native Erwinia asparaginase using identical dosing regimens found a significantly higher relapse rate and shorter EFS in the Erwinia asparaginase group (given at a lower dose than recommended per the approved label) due to its shorter half-life and lower percentage of patients achieving adequate asparagine depletion [66].

Anti-asparaginase antibody development is associated with increased clearance of asparaginases [67,68]. Half-lives of both native E. coli asparaginase and pegaspargase are significantly reduced in patients experiencing HSRs [69].

Recently, a study reported a population pharmacokinetic model constructed with SAA data from 120 pediatric patients with newly diagnosed ALL. Patients received biweekly pegaspargase (1,500 IU/m²) dosing during induction and subsequent doses were individualized based on trough SAA levels. Dose adjustments for biweekly pegaspargase were developed to maintain target trough SAA levels of 0.1–0.25 IU/mL or 0.25–0.4 IU/mL [70]. Individualized dosing strategies show potential for maintaining therapeutic SAA levels; however, further clinical validation of individualized dosing strategies is required.

Use and administration of asparaginase in ALL

Asparaginase is one of the cornerstones of ALL treatment; thus, it requires clinicians to appropriately manage its use to facilitate therapy completion for as many patients as possible. Pegaspargase is the predominate first-line asparaginase therapy, due to its more favorable pharmacokinetics, longer half-life, and reduced immunogenicity relative to native E. coli asparaginase [1,6]. In patients who experience HSRs to E. coli–derived asparaginases, switching to Erwinia-derived asparaginase is recommended. However, due to prior global shortages of asparaginase E. chrysanthemi (Erwinaze^®/Erwinase^®) [12,13], treatment switching was not always viable, prompting use of desensitization protocols [44]. For low-grade HSRs or suspected ammonia-based reactions, it is possible to rechallenge with pegaspargase by implementing mitigation strategies (discussed below). In light of ongoing asparaginase E. chrysanthemi global shortages, the recent FDA approval of recombinant Erwinia asparaginase (asparaginase erwinia chrysanthemi (recombinant)-rywn) provides another option for patients experiencing high-grade HSRs [11].

Asparaginase therapies, including pegaspargase, may be administered via IV or IM routes [1]. Conflicting data exist regarding the incidence of ammonia-related reactions and HSRs with IM injections [44,71,72]. In a meta-analysis of four clinical studies, higher rates of grade 2 HSRs were associated with IV pegaspargase and higher rates of grade 3 HSRs were associated with IM pegaspargase [71]. In a separate analysis of data from >52 000 doses of pegaspargase administered to 16 534 children with ALL during six clinical trials, incidence of grade ≥3 HSRs was lower with IV infusion than IM injection [72]. National Comprehensive Cancer Network guidelines recommend IV administration for both pegaspargase and calaspargase pegol [73]. Erwinia asparaginase is most often given by IM injection; greater risk of adverse events has been observed with IV administration, including more frequent HSRs and gastrointestinal symptoms [65]. Recombinant Erwinia asparaginase is currently only approved for administration by IM injection [11].

Therapeutic drug monitoring (TDM)

Trough SAA ≥0.1 IU/mL has been defined as a target level for ensuring effective depletion of asparagine [36,74]; however, a COG pilot study with pegaspargase proposed a lower threshold of 0.02 IU/mL as associated with adequate asparagine depletion [75].

TDM allows for regular measurement of asparaginase activity and is crucial in determining whether patients experience silent inactivation, and thus, should be considered as part of routine practice for patients receiving asparaginase therapy. Additionally, TDM can be useful for distinguishing between antibody-mediated HSRs and hyperammonemia/infusion reactions, the former necessitating transition to an alternative agent and the latter enabling retrial of pegaspargase (Figure 2) [74]. In some circumstances, the results of TDM can be used to guide adjustments in asparaginase therapy dosing [76]. Salzer et al. recommend SAA checks 3–7 days after each dose of pegaspargase [74]. Therapy should be continued without further testing if SAA is ≥0.5 IU/mL. If SAA is ≥0.1-<0.5 IU/mL, rechecking is recommended 12–15 days postdose If SAA is <0.1 IU/mL, recheck immediately; if resulting SAA is ≥0.1 IU/mL, activity should be retested again at 12–15 days postdose, but if SAA is confirmed <0.1 IU/mL, therapy should be switched to an Erwinia-derived asparaginase. Due to variable turnaround times for SAA levels, some institutions have opted to check at both 7- and 14-day postdose time points for all pegaspargase doses. Use of a systematic approach to checking SAA levels is critical, as studies have shown significant interpatient variability in asparaginase activity, even when administering identical treatment schedules [4]. Due to the risk of masking HSRs, SAA should be routinely measured in all patients receiving premedication.

Figure 2. TDM for SAA during PEG-asparaginase therapy.^a Figure reprinted from Salzer W, et al. Leuk Lymphoma 2018;59:1797-1806, published under Creative Commons license. ^aAsparaginase Erwinia chrysanthemi is no longer licensed in the United States; recombinant Erwinia asparaginase is available. PEG: polyethylene glycol; SAA: serum asparaginase activity; TDM: therapeutic drug monitoring.

Managing HSRS

Occurrence of any severe reactions (suspected HSRs or hyperammonemia) requires immediate infusion cessation [77]. For patients with suspected anaphylaxis, the suggested first-line treatment is IM epinephrine, as it has effects against multiple mediators of anaphylaxis and rapid onset of action (Figure 3) [40]. Although protocols differ between centers, IV antihistamines and corticosteroids are commonly administered. Recommendations from Bade et al. indicate switching from pegaspargase to Erwinia-derived asparaginase for Common Terminology Criteria for Adverse Events grade ≥3 HSRs [77].

Figure 3. Management of suspected HSRs during PEG-asparaginase therapy [36,40,44,77,81,97]. ^aPatients who experience silent inactivation should not be considered candidates for desensitization. CTCAE: Common Terminology Criteria for Adverse Events; HSR: hypersensitivity reaction; IM: intramuscular; IV: intravenous; PEG: polyethylene glycol; SAA: serum asparaginase activity.

SAA can help distinguish between HSRs and hyperammonemia to determine whether retrialing pegaspargase is feasible. For nonsevere reactions, treatment with pegaspargase may be restarted at half rate postintervention after symptoms resolve, and the infusion can be titrated to tolerance [44,77]. Hyperammonemia-related reaction mitigation strategies that have been tried by various centers, but not extensively studied, include (1) running pegaspargase at 50 mL/h (100 mL total volume) concurrently with normal saline, also at 50 mL/h, for a total infusion time of 2 hours or (2) administering 10% of the infusion over the first hour and the remaining 90% over the second hour [78].

Premedication with antihistamines and corticosteroids has been theorized to reduce the incidence of infusion reactions, with varying reports of efficacy [77,79]. In a retrospective review of patients receiving IV pegaspargase, universal premedication was associated with decreased switching to native Erwinia asparaginase and lower rates of acute adverse reactions compared with no routine premedication [80]. However, due to the risk of premedication masking symptoms of HSRs, patients should be routinely monitored for silent inactivation of asparaginase activity (defined as SAA <0.1 IU/mL) [36,77].

Drug desensitization has been an option for patients experiencing HSRs with E. coli–derived asparaginases when switching asparaginase therapy was not possible (e.g. due to global shortage of asparaginase E. chrysanthemi). Several protocols have been published that utilized incremental administration of increasing doses of pegaspargase over 12–13 steps (achieved by serial dilutions and adjusted infusion rates) together with close monitoring to identify and manage allergic reactions [13,81,82]. Studies in patients with ALL experiencing HSRs during pegaspargase therapy have shown this approach permits administration of the full pegaspargase dose in many cases while also maintaining SAA >0.1 IU/mL [13,81,82].

Considerations in pediatric versus adolescent and adult patients with ALL

Adolescent and adult patients with ALL often receive lower doses of asparaginase therapies relative to children due to perceived higher rates of toxicities with pediatric-inspired regimens when used in this older patient population [83]. In the CALGB 10403 study of patients aged 18–39 years, a pediatric-inspired regimen used pegaspargase at a dose of 2500 IU/m² [84]. When compared with results from the pediatric companion study, COG AALL0232, incidences of grade 3/4 thrombosis, liver enzyme disturbances, pancreatitis, and hyperglycemia were all significantly higher in older patients. However, prior to the protocol amendment in older patients mandating use of routine premedication with corticosteroids, acetaminophen, and diphenhydramine, incidence of grade 3/4 HSRs was similar in adults and pediatrics (10% vs. 14.6%). In a study comparing native E. coli asparaginase with native Erwinia asparaginase, patients aged 10–18 years were more likely to experience pancreatitis and thrombosis than younger patients, but these two groups had a similar incidence of HSRs [55]. Further, in a study of patients with ALL (aged 1–17) years who received pegaspargase, multivariate regression analysis showed no significant association between sex, age, white blood cell count at diagnosis, or immunophenotype and HSRs [85]. It has been suggested age may not be the only influencing factor on occurrence of pancreatitis and hepatotoxicity in adolescents and adults; higher body mass index (BMI) has shown a positive correlation with these adverse effects [86,87].

Some studies have evaluated lower doses and dose capping of pegaspargase as alternative approaches for decreasing toxicity risk in older patients. Standard-dose pegaspargase (>1000 IU/m²; median, 2500 IU/m²) has been compared with reduced-dose pegaspargase (≤1000 IU/m²; median, 500 IU/m²) in adults with ALL aged ≥18 years [88]. Overall incidence of grade 3/4 toxicities was reduced among the reduced-dose pegaspargase group compared to the standard-dose group (46% vs 80%; p = 0.02). Median relapse-free survival was not significantly different between treatment arms. Dose capping is an alternative approach for decreasing toxicity risk in older patients. Practically, this entails administration of a maximum dose of 3750 IU in adults, equivalent to 1 vial of pegaspargase, at doses of 2000–2500 IU/m² [77,89,90]. In one study of 85 adults with ALL who received pegaspargase 2000 IU/m² capped at 3750 IU, 63 (74%) achieved asparagine depletion, defined as pegaspargase levels >0.03 U/mL [90]. An alternative approach is to start with lower initial doses of pegaspargase, check SAA levels, and uptitrate, if necessary, to achieve adequate asparagine depletion [91,92]. However, a need remains for clinical trials to determine the safest uniform dose of pegaspargase achieving adequate enzymatic activity and asparagine depletion in adolescent and adult patients, including those who are overweight or obese [93].

An expert consensus specifically addressing asparaginase-related toxicities in adults was recently published [94]. The authors recommend universal premedication in adults with ALL receiving asparaginase and differentiation between HSRs and nonallergic reactions. In the case of high-grade clinical HSR, switching to Erwinia-derived asparaginase is advised. At the occurrence of symptomatic (grade 3) pancreatitis, they recommended asparaginase treatment be permanently discontinued; however, for asymptomatic (biochemical) alterations in pancreatic function, treatment may be resumed upon resolution. On observation of thromboembolism, the authors suggest that asparaginase therapy may be continued with concurrent administration of low-molecular-weight heparin. Hypertriglyceridemia does not necessitate dose adjustment or cessation of asparaginase, but lipid monitoring is recommended, with fibrate initiation indicated for triglycerides ≥1000 mg/dL. To mitigate hepatotoxicity risk in adults with ALL, the authors suggest pegaspargase doses be limited to 2000 IU/m², with further reductions to 1000 IU/m² or 500 IU/m² in patients at high risk of severe clinical liver toxicity (age >45–50 years, BMI >30–35 kg/m², and history of liver disease). Some data exist to support administration of levocarnitine and vitamin B complex to ameliorate hyperbilirubinemia [95].

Conclusions/future directions

Several ongoing questions related to asparaginase therapy are raised: (1) how can strategies for differentiating HSRs and hyperammonemia be improved?; (2) what is the optimal pegaspargase administration strategy to limit asparaginase switching?; (3) what role will supplemental strategies (dose capping, TDM, biomarkers, levocarnitine, etc.) play in safe and effective asparaginase dosing?; (4) what are the implications of asparagine depletion in sanctuary sites?; (5) how will calaspargase pegol and recombinant Erwinia asparaginase be integrated into treatment regimens and how will their incorporation affect outcomes?

Although asparaginase therapies continue to play an integral role in the ALL therapy armamentarium, their use is associated with multiple toxicities, including HSRs, pancreatitis, thrombosis, and hepatotoxicity. These toxicities can necessitate treatment delays and discontinuation, the latter of which is associated with poorer outcomes, highlighting the importance of full asparaginase course completion for as many patients as possible. HSRs are typically antibody-mediated reactions and can be severe, most often occurring from the second dose onwards. Development of anti-asparaginase antibodies is associated with inactivation of enzyme activity, resulting in inadequate asparagine depletion and loss of therapeutic efficacy. Silent inactivation occurs when anti-asparaginase antibodies form without associated clinical symptoms and are identified using SAA monitoring. High-grade HSRs to or silent inactivation of pegaspargase warrants switching to an Erwinia-derived asparaginase for the duration of treatment. In patients with low-grade HSRs or non–antibody-mediated reactions, continuation of pegaspargase therapy may be possible with premedication, alternative infusion strategies, and adjustments to infusion rate. However, distinguishing between HSRs and hyperammonemia can be difficult, as there is significant symptom overlap, which further necessitates the use of SAA-level algorithms. Owing to differences in pharmacokinetic profiles, dosing of individual asparaginase therapies is not interchangeable and dosing conversions are required.

Acknowledgments

Medical writing and editorial assistance were provided by Michelle Preston, MSc (Lumanity Scientific Inc.), and were financially supported by Jazz Pharmaceuticals.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability statement

Data sharing not applicable—no new data generated.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.