Toxicity of Very Prolonged Pegasparaginase and Erwinia Asparaginase Courses in Relation to Asparaginase Activity Levels with a Special Focus on Dyslipidemia

Abstract Purpose We prospectively studied the incidence and clinical course of hypertriglyceridemia and hypercholesterolemia during very prolonged use of PEGasparaginase or Erwinia asparaginase in relation to asparaginase activity levels in children with acute lymphoblastic leukemia (ALL). Also, the incidence of pancreatitis, thrombosis, hyperammonemia and central neurotoxicity and their association with asparaginase activity levels were evaluated. Patients and Methods Patients were treated according to Dutch Childhood Oncology Group (DCOG) ALL-10 medium risk intensification protocol, which includes 15 doses of PEGasparaginase (2,500 IU/m2) for 30 weeks. Erwinia asparaginase (20,000 IU/m2) was administered when an allergy to or silent inactivation of PEGasparaginase occurred. Definitions of silent inactivation of PEGasparaginase and Erwinia asparaginase were previously described (Tong et al., Blood, 2014 Mar;123(13):2026-33). Hypertriglyceridemia, hypercholesterolemia, hyperammonemia, pancreatitis, thrombosis and central neurotoxicity were graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE). Changes over time of triglyceride, cholesterol, and ammonia levels were evaluated using mixed models analysis of variance (ANOVA). Changes related to age and gender were also investigated using mixed models ANOVA. The incidence of toxicities (pancreatitis, thrombosis, central neurotoxicity) related to treatment (PEGasparaginase or Erwinia asparaginase) was investigated with the Fisher's exact tests. Finally, Spearman correlation coefficients were used to evaluate the relations between triglyceride, cholesterol, and asparaginase activity levels. Results In total, 89 patients were enrolled from two pediatric oncology centers. Triglyceride, cholesterol and ammonia levels increased rapidly in children with PEGasparaginase and remained temporary elevated, but normalized after the finishing the last asparaginase dose. Hypertriglyceridemia and hypercholesterolemia (grade 3/4) were found in 47% and in 25%, respectively, of the patients treated with PEGasparaginase. Studying the correlations between PEGasparaginase activity levels and triglyceride levels showed the strongest correlation at week 5 (Rs = 0.36, p=0.005). Children >= 10 years had higher triglyceride levels as compared to younger patients (< 10 years) adjusted for asparaginase preparations: median levels of 4.9 mmol/L versus 1.6 mmol/L (p<0.001). In patients receiving Erwinia asparaginase, triglyceride levels increased in the first weeks as well, but no hypertriglyceridemia and hypercholesterolemia (grade 3/4) were found. Hyperammonemia (grade 3/4) was only found in Erwinia asparaginase treated patients (9%). No associations were found between pancreatitis and hypertriglyceridemia nor between ammonia and central neurotoxicity. Thrombosis occurred in 4.5%, pancreatitis in 7% and central neurotoxicity in 9% of the patients using each of both asparaginase agents; these toxicities were not related to asparaginase activity levels nor to triglyceride levels. Conclusions Severe dyslipidemia occurred frequently, but was temporary and was not associated with relevant clinical events and therefore should not be considered a reason for asparaginase treatment modifications. We show that high asparaginase activity levels are associated with high triglyceride and high cholesterol levels. However, pancreatitis, thrombosis and central neurotoxicity appear unrelated to asparaginase activity levels. Also, no associations were found between pancreatitis and hypertriglyceridemia and between ammonia level and central neurotoxicity. Table 1 Toxicity table, p-values are given for comparisons of grade 3/4 toxicities between both asparaginase agents, ns; not significant. PEGasparaginase (n=67) Erwinia asparaginase (n=22) p-value Grade 1/2 Grade 3/4 Grade 1/2 Grade 3/4 n % n % n % n % Pancreatitis 0 0 4 6 1 5 2 9 ns Hypertriglyceridemia 15 22 31 47 7 32 0 0 p<0.001 Hypercholesterolemia 6 9 17 25 8 37 0 0 p=0.01 Hyperammonemia 34 51 0 0 9 41 2 9 ns Thrombosis 0 0 2 3 0 0 2 9 ns Central neurotoxicity 0 0 7 10 0 0 1 5 ns Disclosures Tong: EUSA Pharma: Research Funding.

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Individualized Asparaginase Dosing in Childhood Acute Lymphoblastic Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.19.02292 ◽

2020 ◽

Vol 38 (7) ◽

pp. 715-724

Author(s):

Robin Q.H. Kloos ◽

Rob Pieters ◽

Florine M.V. Jumelet ◽

Hester A. de Groot-Kruseman ◽

Cor van den Bos ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Hypersensitivity Reaction ◽

Lymphoblastic Leukemia ◽

Activity Levels ◽

Medium Risk ◽

Risk Patients ◽

Asparaginase Activity ◽

Erwinia Asparaginase ◽

Grade 3 ◽

Trough Levels

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.

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A prospective study on drug monitoring of PEGasparaginase and Erwinia asparaginase and asparaginase antibodies in pediatric acute lymphoblastic leukemia

Blood ◽

10.1182/blood-2013-10-534347 ◽

2014 ◽

Vol 123 (13) ◽

pp. 2026-2033 ◽

Cited By ~ 95

Author(s):

Wing H. Tong ◽

Rob Pieters ◽

Gertjan J. L. Kaspers ◽

D. Maroeska W. M. te Loo ◽

Marc B. Bierings ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Prospective Study ◽

Lymphoblastic Leukemia ◽

Activity Levels ◽

Pediatric Acute Lymphoblastic Leukemia ◽

E Coli ◽

Key Points ◽

Asparaginase Activity ◽

Erwinia Asparaginase ◽

A Prospective Study

Key Points Use of native E coli asparaginase in induction leads to high hypersensitivity rates to PEGasparaginase in intensification. Switching to Erwinia asparaginase leads to effective asparaginase activity levels in most patients who experienced an allergy to PEGasparaginase.

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A Prospective Study On Drug Monitoring Of Pegasparaginase and Erwinia Asparaginase and Asparaginase Antibodies In Pediatric Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood.v122.21.2634.2634 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2634-2634 ◽

Cited By ~ 2

Author(s):

Wing H. Tong ◽

Rob Pieters ◽

Gertjan Kaspers ◽

Maroeska D.W.M. te Loo ◽

Marc Bierings ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Drug Monitoring ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Activity Level ◽

Therapeutic Drug ◽

Activity Levels ◽

Asparaginase Activity ◽

Erwinia Asparaginase ◽

Pre Treatment

Abstract Purpose A prospective drug monitoring study was performed to analyse the efficacy of very prolonged use of PEGasparaginase and Erwiniaasparaginase by assessing asparaginase activity, asparagine, glutamine levels and asparaginase antibodies in children with newly diagnosed acute lymphoblastic leukemia (ALL). Patients and Methods Children received 15 PEGasparaginase infusions (2,500 IU/m2 every other week) according to the Dutch Childhood Oncology Group (DCOG)-ALL-10 medium risk intensification protocol after having received native E.coli asparaginase (5,000 IU/m2 every 3 days, 8 doses in total) in the induction course. In case of an allergy to or silent inactivation of PEGasparaginase, Erwinia asparaginase (20,000 IU/m22x-3x per week) was given. All asparaginase preparations were administered intravenously in one hour. Serum asparaginase activity, asparagine, glutamine levels and asparaginase antibodies were measured. Results 89 patients were enrolled in two centers to monitor the PEGasparaginase courses. 62/89 (70%) patients without clinical allergy to and without silent inactivation of PEGasparaginase had serum mean trough activity levels of 899 U/L which were much higher than requested. 20/89 (22%) of the patients showed an allergy and 7/89 (8%) silent inactivation in intensification. All 20 allergic patients (grade 1-4 Common Terminology Criteria Adverse Events) showed PEGasparaginase activity levels of zero. This was not due to the fact that the PEGasparaginase infusion was stopped, as 18 patients showed their allergic reactions at the second dose whereas the serum asparaginase activity level after the first full dose already appeared to be zero in all 18 cases. Moreover, in 4 patients with grade 1 allergy, the second full PEGasparaginase dose was given with pre-treatment of clemastine and hydrocortisone, also resulting in unmeasurable serum activity levels of PEGasparaginase. 59 children from 7 centers with allergy to or silent inactivation of PEGasparaginase who were switched to Erwinia asparaginase were enrolled to monitor the Erwiniaasparaginase courses. Only 2/59 (3%) of the patients developed an allergy to Erwinia asparaginase. No patients with silent inactivation of Erwinia asparaginase were seen. Of the non-allergic Erwinia asparaginase patients, 55/57 (96%) had at least one serum Erwinia asparaginase trough activity level ≥ 100 U/L and 57/57 (100%) ≥ 50 U/L. In 65% and 85% of all samples had serum trough activity levels ≥ 100 U/L and ≥ 50 U/L, respectively. In 33% of patients, the administration frequency could be reduced from 3 times to 2 times per week based upon serum Erwinia asparaginase activity levels ≥ 100 U/L at 72 hours. Serum asparagine level was strongly depleted, but not always completely depleted in Erwinia asparaginase treated patients in contrast to PEGasparaginase. Serum glutamine level was slightly lowered by Erwiniaasparaginase, but no glutamine depletion was observed with both compounds. The presence of serum asparaginase antibodies is related to allergy to and silent inactivation of asparaginase, but predicting asparaginase allergy or silent inactivation is clinically not applicable because of the low specificity, 64% (95%-CI: 43%-82%). Conclusion The use of native E.coli asparaginase in induction leads to 22% allergy and 8% silent inactivation rates of PEGasparaginase in intensification. Therefore, PEGasparaginase should be used upfront already in the induction course instead of native E.coli asparaginase. The dose of PEGasparaginase of 2,500 IU/m2 can be lowered. Switching to Erwinia asparaginase in case of allergy to or silent inactivation of PEGasparaginase leads to effective asparaginase activity levels in the majority of patients. Measuring serum asparaginase activity levels to monitor efficacy of asparaginase is preferred over serum asparagine levels and serum asparaginase antibodies. Therapeutic drug monitoring has now been implemented to individualize PEGasparaginase and Erwinia asparaginase dose and to detect silent inactivation in the current DCOG-ALL-11 protocol. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽

10.1182/blood-2020-138840 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 30-31

Author(s):

Lynda M. Vrooman ◽

Yael Flamand ◽

Victoria Koch ◽

Melissa A. Burns ◽

Sarah M. Cronholm ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Allergic Reaction ◽

Lymphoblastic Leukemia ◽

Advisory Board ◽

Challenge Dose ◽

Post Induction ◽

Asparaginase Activity ◽

Erwinia Asparaginase ◽

Grade 3 ◽

Experienced Grade

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.

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Should We Use a Desensitization Protocol In Acute Lymphoblastic Leukemia Patients With Silent Inactivation Of Pegasparaginase?

Blood ◽

10.1182/blood.v122.21.1434.1434 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1434-1434

Author(s):

Wing H. Tong ◽

Rob Pieters ◽

Wim J Tissing ◽

Inge M. van der Sluis

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Real Time ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Significant Proportion ◽

Monitoring Program ◽

Activity Levels ◽

Activity Measurements ◽

Asparaginase Activity ◽

Erwinia Asparaginase

Abstract Purpose Previous studies have shown that children with silent inactivation of asparaginase had poorer outcomes as they were not switched to another asparaginase preparation that retained its activity. Recently, a case report was published that described the successful use of desensitization courses in a patient with severe hypersensitivity reaction to asparaginase. We analyzed whether continuation of asparaginase in case of silent inactivation may result in desensitization, disappearance of asparaginase antibodies (AAA) and recovery of asparaginase activity levels in children with newly diagnosed acute lymphoblastic leukemia (ALL). Patients and Methods Children who received intensified PEGasparaginase or Erwinia asparaginase for 30 weeks according to the intensification phase of the Dutch Childhood Oncology Group-ALL-10 medium-risk protocol were studied. All children had received native E.coli asparaginase in induction and all asparaginase preparations were administered intravenously in one hour. AAA against native E.coli asparaginase (Coli-AAA), PEGasparaginase (PEG-AAA), and Erwinia asparaginase (Erwinia-AAA) and PEGasparaginase and Erwiniaasparaginase activity levels were analyzed in serum. Results 7/89 patients had silent inactivation of PEGasparaginase. Two were detected by real-time asparaginase activity measurements and were switched to Erwinia asparaginase. Five patients continued PEGasparaginase because no real-time asparaginase measurements were available at the starting phase of our drug monitoring program. Those patients with silent inactivation were, therefore, not recognized in time. PEGasparaginase activity levels recovered in all 5 patients after 2-7 PEGasparaginase infusions. In all 5 patients, Coli-AAA were present at start of the intensification phase which declined over time coinciding with the rise of PEGasparaginase activity levels. PEG-AAA were absent at the start of intensification but also increased after 1-2 doses of PEGasparaginase, and declined thereafter also coinciding with recovery of the PEGasparaginase activity levels. 29% of the PEGasparaginase patients without an allergy and without silent inactivation were positive for Coli-AAA. Also in this group, the Coli-AAA gradually decreased to undetectable levels after 5 PEGasparaginase courses. In a different cohort of 59 patients treated with Erwinia asparaginase, there were no cases of silent inactivation and two developed allergic reactions. In 50% of the non-allergic patients, the Erwinia-AAA were absent at start of therapy, gradually increased and decreased to absent baseline values during 30 weeks of Erwiniaasparaginase therapy. Conclusion This unintended desensitization program applied in five patients with silent inactivation of PEGasparaginase leads to recovery of PEGasparaginase activity levels. However, this takes an unpredictable and sometimes long time period. Therefore, we do not advise such desensitization approaches, but recommend switching to Erwinia asparaginase. A significant proportion of patients treated for prolonged period with PEGasparaginase or Erwinia asparaginase develops antibodies without influencing asparaginase activity levels that disappear with continued use of the same asparaginase product. Disclosures: No relevant conflicts of interest to declare.

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Asparaginase activity levels and monitoring in patients with acute lymphoblastic leukemia

Leukemia & Lymphoma ◽

10.1080/10428194.2017.1386305 ◽

2017 ◽

Vol 59 (8) ◽

pp. 1797-1806 ◽

Cited By ~ 25

Author(s):

Wanda Salzer ◽

Bruce Bostrom ◽

Yoav Messinger ◽

Anthony J. Perissinotti ◽

Bernard Marini

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Activity Levels ◽

Asparaginase Activity

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

Blood ◽

10.1182/blood-2021-144674 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2308-2308

Author(s):

Leiah Brigitha ◽

Marta Fiocco ◽

Rob Pieters ◽

Birgitte Klug Albertsen ◽

Gabriele Escherich ◽

...

Keyword(s):

Lymphoblastic Leukemia ◽

Induction Treatment ◽

Induction Phase ◽

Allergic Reactions ◽

Line Treatment ◽

First Line ◽

Post Induction ◽

Asparaginase Activity ◽

Erwinia Asparaginase ◽

First Line Treatment

Abstract 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.

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Intramuscular PEG-Asparaginase At 1000 U/m2 Achieves Adequate Trough Activity Levels in the Majority of Patients Treated on the UKALL 2003 Childhood Acute Lymphoblastic Leukemia (ALL) Protocol

Blood ◽

10.1182/blood.v118.21.2573.2573 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2573-2573 ◽

Cited By ~ 1

Author(s):

Caroline YK Fong ◽

Catriona Anne Parker ◽

Adiba Hussain ◽

Jizhong Liu ◽

Monika Essink ◽

...

Keyword(s):

Residual Disease ◽

Lymphoblastic Leukemia ◽

Early Response ◽

Antibody Detection ◽

Activity Levels ◽

Post Induction ◽

Chi Squared ◽

Drug Induction ◽

Asparaginase Activity ◽

Time Point

Abstract Abstract 2573 Introduction: Polyethylene glycol conjugated L-asparaginase (PEG-ASNase) is used in varying doses between 1000–2500 U/m2 in the therapy of ALL and associated with a wide variation in pharmacokinetics. UKALL 2003 used intramuscular PEG-ASNase at 1000 U/m2. Patients & Methods: Patients enrolled in the UKALL 2003 trial (ISRCTN: 07355119), were consented for trough asparaginase activity analysis during therapy. National Cancer Institute (NCI) standard risk (SR) patients with rapid early response and non-high risk (HR) cytogenetics (Lancet Oncol. 2010;11:429) received a 3 drug induction (Dexamethasone, Vincristine & PEG-ASNase). All other patients received additional Daunorubicin. PEG-ASNase was given on days 4 and 18 of induction, and at least once post induction. Trough plasma asparaginase activity was measured by the indooxine method (Anal. Biochem. 2002;309:117). The lower limit of assay detection was 34 U/L. Adequate asparaginase activity was defined as a trough level of > 100 U/L. IgG and IgM antibodies to PEG-ASNase and native asparaginase were measured by indirect ELISA. Asparaginase activity was correlated with defined risk factors, minimal residual disease (MRD) at day 28 of induction and development of anti-asparaginase antibodies using the chi-squared test. Results: Between July 2008 to July 2011, 482 patients aged 1–25 years from 27 centres were recruited. Numbers of samples assayed in induction were 335 & 371 after first and second doses respectively. Overall, 86% (n=606/706) of samples had adequate activity during induction time points. There was > 10 fold variation in activity levels (Figure 1). Three hundred and nine out of 706 samples had activity > 3 times the therapeutic threshold, while 51/100 samples with inadequate activity had no detectable drug levels (median: below detection limit, range: < 34–99 U/L). Thus, increasing the dose of PEG-ASNase in induction is unlikely to benefit patients with inadequate activity. Compared to SR patients, NCI HR patients had a higher incidence of inadequate asparaginase activity in induction (p=0.002). Inadequate asparaginase activity correlated with high MRD (≥ 10−4) in SR patients (p=0.045), especially those with good risk cytogenetics (p=0.012), and in particular the high hyperdiploid subgroup (p=0.03). Inadequate asparaginase activity during induction did not correlate with MRD in HR patients (p=0.699), possibly because these patients received in addition Daunorubicin (Table 1). Results of serial asparaginase activity (at least one time point each in induction and post induction), measured in 282 patients are summarised in Table 2. Antibodies were detected in 18 of 81 patients tested. All had anti-PEG and 7 in addition also had anti-asparaginase antibodies. While all antibody positive patients had inadequate asparaginase activity at one time point, 17 had adequate activity prior to antibody detection, suggesting immune-mediated drug inactivation at re-exposure. Antibodies were not detected in 14/15 patients who had inadequate activity at first exposure, so the mechanism here remains unclear. The reported incidence of asparaginase toxicity in this study was 6.6% (n=32/482). This included hypersensitivity (n=17/482) that was almost exclusively seen in HR patients (n=16/17), thrombosis (n=10/482) and pancreatitis (n=5/482). Conclusions: Intramuscular PEG-ASNase given fortnightly at 1000 U/m2 during induction provides adequate asparaginase activity in 86% of patients. Monitoring asparaginase activity may benefit patients who receive 3 drug induction and improve the resolution of the current prognostic classification. Disclosures: Off Label Use: PEG-asparaginase. Essink:medac: Employment. Kuehnel:medac: Employment.

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Phase I/II Clinical Trial of Erwinia Asparaginase (ErwinaseR) in Combination with Prednisolone, Vincristine and Pirarubicin in Children and Young Adults with Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LBL)

Blood ◽

10.1182/blood.v124.21.3657.3657 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3657-3657

Author(s):

Chitose Ogawa ◽

Atsushi Manabe ◽

Hiroaki Goto ◽

Katsuyoshi Koh ◽

Daisuke Tomizawa ◽

...

Keyword(s):

Young Adults ◽

Phase I ◽

Phase Ii ◽

Safety And Efficacy ◽

E Coli ◽

Asparaginase Activity ◽

Erwinia Asparaginase ◽

Children And Young Adults ◽

Level 1 ◽

Grade 3

Abstract Introduction: L-asparaginase is an important component of multi-agent chemotherapy for children and young adults with ALL. In Japan, only one asparaginase preparation, native-E-coli-asparaginase (LeunaseR), has been approved so far by the Health, Labour and Welfare Ministry. The incidence of clinical allergy to native-E-coli -asparaginase can be more than 30% with repeated administration. To continue treatment with asparaginase, Erwinia asparaginase (ErwinaseR), deriving from Erwinia chrysanthemi, is recommended for patients who develop clinical allergy to native-E-coli-asparaginase, because the drug has no cross reactivity. We planned phase I/II trial OP-01-001 to investigate the safety and efficacy of Erwinase in combination chemotherapy consist of prednisolone, vincristine and pirarubicin. Patients and Methods: Eligible patients on this study were children and young adults with ALL/ LBL in remission, >=1 to =<25 years of age, and had developed allergy to E-coli-asparaginase. Patients with a history of pancreatitis or previous administration of Erwinase were excluded. The study was approved by IRB at each institution and patients/guardians provided informed consent/assent. In this trial regimen OP-01-001, level 1 (25,000) or level 0 (20,000 IU/m2) x 6 doses of Erwinase were planned to administer intramuscularly (IM) on day 2, 5, 7, 9, 11 and 13 with 40 mg/m2/day x15 days of prednisolone, 1.5mg/m2 x 3 doses of vincristine and 20 mg/m2x 2 doses of pirarubicin. In phase I, we determined the maximum tolerated dose, dose limiting toxicity (DLT), and the recommended phase II dose (RP2D) of Erwinase. Safety, efficacy and pharmacokinetic/dynamic study were evaluated in all patients. Blood samples were obtained at scheduled time points during Erwinase therapy and assayed for asparaginase activity and asparagine concentration in plasma. Primary endpoint was asparaginase activity in plasma at 48h after the first dosing. Results: A total of 24 eligible patients were enrolled to phase I/II study from February 2012 to January 2014. In phase I study, 6 eligible/evaluable patients were enrolled to level 1, starting at 25,000 IU/m2. Since all patients completed the scheduled treatments without DLT in level 1, RP2D was determined 25,000 IU/m2and 18 patients were enrolled in phase II study. PK, PD, safety and efficacy were evaluated as phase I/II study. The median age of 24 evaluated patients was 7.5 years (range 2-16) and 15 patients (62.5%) were male. In PK/PD study, one patient was excluded because essential clinical dataset was not obtained. After the first dosing, serum asparaginase activity exceeded 0.1 IU/mL in 23/23 patients (100%) at 48 hours and it did in 18/23 patients (78.3%) at 72 hours. After the sixth dosing, the activity at 72 hours was higher than 0.1 IU/mL in 19/23 (82.6%). Plasma asparagine was significantly depleted (<1.0 μM) in 22/23 (95.7%) 48 hours after the first dosing and it was also depleted in 22/23 (95.7%) 72 hours after the last dosing in all but one patients. All patients maintained remission status during the trial. No allergic reaction related to Erwinase was reported. Hypertriglyceridemia or blood triglycerides increased was reported in 12/24 (50%), 4 cases in grade 3 and 1 in grade 4. Increase in blood sugar was observed in 3 patients (12.5%), 2 in grade 1 and 1 in grade 2. In addition, 23 (95.8%) and 1 (4.2%) developed decrease in fibrinogen and increase in ammonia at grade 2-4. Grade 3 febrile neutropenia and bacteremia were reported in 8 patients (33.3%) and in 1 patient (4.2%), respectively. There were no reports of hemorrhage, thrombosis, pancreatitis, or death. Conclusion: Erwinase as administered using the OP-01-001 regimen was well tolerated without unexpected toxicities and achieved good serum asparaginase activity at both 48 and 72 hours after dosing. In previous reports, a much lower dose of Erwinase at 10,000 IU/m2/dose was used in the study of EORTC (Duval M. Blood 2002;99:2734), which was subsequently assessed as suboptimal and the identical dose of erwinase at 25,000 IU/m2/dose was used in the study of COG (Salzer WL. Blood 2013;122:507). We herein showed that following allergy to E-coli native-asparaginase, erwinase 25,000 IU/m2 x 6 doses IM in 2 or 3 days interval in 2 weeks was effective and safe in children and young adults in Japan. Disclosures Ogawa: OHARA Pharmaceutical Co., Ltd.: Honoraria. Manabe:OHARA Pharmaceutical Co., Ltd.: Honoraria. Fukushima:OHARA Pharmaceutical Co., Ltd.: Honoraria. Horibe:OHARA Pharmaceutical Co., Ltd.: Honoraria. Hamada:OHARA Pharmaceutical Co., Ltd.: Employment. Ohara:OHARA Pharmaceutical Co., Ltd.: Honoraria.

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Administration of Erwinia Asparaginase (Erwinase®) Following Allergy to PEG-Asparaginase In Children and Young Adults with Acute Lymphoblastic Leukemia Treated on AALL07P2 Achieves Therapeutic Nadir Serum Asparaginase Activity: A Report From the Children's Oncology Group (COG)

Blood ◽

10.1182/blood.v116.21.2134.2134 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2134-2134

Author(s):

Wanda Salzer ◽

Barbara Asselin ◽

Jeffrey Supko ◽

Meenakshi Devidas ◽

Nicole Kaiser ◽

...

Keyword(s):

United States ◽

Young Adults ◽

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

The United States ◽

E Coli ◽

Clinical Allergy ◽

Asparaginase Activity ◽

Erwinia Asparaginase ◽

Children And Young Adults

Abstract Abstract 2134 Introduction: L-asparaginase is a vital component of multi-agent chemotherapy for children and young adults with acute lymphoblastic leukemia (ALL). In the United States, there are 2 asparaginase preparations approved by the Food and Drug Administration, native E. coli (Elspar®) and PEG-asparaginase (Oncaspar®). PEG-asparaginase is the most commonly utilized asparaginase product due to its longer half-life and decreased immunogenicity. However, the incidence of clinical allergy to PEG-asparaginase approaches 20%, with repeated administration. Due to cross reactivity with native E. coli asparaginase, there is no FDA-approved preparation available for patients who develop clinical allergy to PEG-asparaginase. A third preparation, Erwinia asparaginase (Erwinase®), derived from Erwinia chrysanthemi, is not commercially available in the United States. The optimal dosing of Erwinase® necessary to obtain nadir asparaginase activity > 0.1 IU/mL similar to that obtained after conventional dosing of PEG-asparaginase is unknown. Patients and Methods: We hypothesized that substitution of Erwinase® 25,000 IU/m2 × 6 doses intramuscularly (IM) on a Monday/Wednesday/Friday schedule in children and young adults with ALL would provide a 48 hour nadir serum asparaginase activity ≥ 0.1 IU/mL, and effectively deplete plasma asparagine, a surrogate marker of asparaginase activity. Eligible patients on COG study AALL07P2 were >1 to <30 years of age, concurrently enrolled on a frontline COG ALL treatment study, and had documented ≥ grade 2 allergy (NCI Common Terminology Criteria 3.0) to PEG-asparaginase. Results: A total of 55 eligible/evaluable patients were enrolled from February 2008 to April 2010. Blood samples were obtained at scheduled time points during Erwinase® therapy and assayed for serum asparaginase activity and asparagine concentration in plasma. Nadir serum asparaginase activity ≥ 0.1 IU/mL was achieved in 49/53 patients (92.5%) at 48 hours after dosing and in 46/52 patients (88.5%) at 72 hours after dosing. Plasma asparagine was significantly depleted (<1.0 μM) in all 49 patients for whom samples were satisfactorily obtained. Grade 2–3 allergic reaction and grade 1–2 hyperglycemia related to Erwinase® were reported in 5 and 3 patients, respectively. There were no reports of hemorrhage, thrombosis, pancreatitis, or death. Conclusion: Erwinase® as administered using the AALL07P2 regimen was well tolerated and achieved nadir serum asparaginase activity at both 48 and 72 hours after dosing that was similar to that achieved with PEG-asparaginase. We conclude that following allergy to PEG-asparaginase, Erwinase® 25,000 IU/m2 × 6 doses IM on a Monday/Wednesday/Friday schedule can be substituted for a single dose of PEG-asparaginase. Disclosures: Supko: EUSA Pharma: Research Funding. Plourde: EUSA Pharma: Employment. Winick: EUSA Pharma: EUSA Advisory Board.

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