Pegaspargase Research Articles

Retrospective review of the toxicities and change in dosing patterns for pegaspargase in patients with acute lymphoblastic leukemia/lymphoma and T-cell lymphoma.

Pegaspargase (PEG) is a key component of standard regimens for acute lymphoblastic leukemia/lymphoma (ALL) and extranodal natural killer/T-cell lymphoma (NKTCL). Emerging evidence suggests an opportunity to decrease incidence of PEG-associated toxicities with dose capping, but evidence is limited. This study aims to evaluate whether a significant difference in PEG-associated toxicities related to dosing strategy exists and to identify patient-specific or regimen-specific factors for PEG-related toxicity. A retrospective analysis of PEG-associated toxicities was completed in adult patients with ALL or NKTCL who received PEG within Cancer and Leukemia Group B (CALGB) 10403 or modified dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide (mSMILE) regimens at the UW Medical Center/Fred Hutchinson Cancer Center. PEG-associated toxicities that occurred through 8 weeks after PEG doses were noted. Twenty-eight patients received dose-capped PEG, and 29 received noncapped PEG. Fewer all-grade and grade 3/4 toxicities were observed in the dose-capped cohort. Grade 3/4 toxicities observed were hepatotoxicity, hyperglycemia, hypersensitivity, and hypertriglyceridemia. In addition, fewer grade 3/4 pancreatitis and thrombosis events occurred in the dose-capped cohort. Hypertriglyceridemia and hepatotoxicity were associated with the highest cumulative incidence proportions among all toxicities. Dose capping of PEG was associated with a similar or later median onset for most toxicities, a less heterogeneic toxicity profile, and a lower recurrence of most toxicities upon PEG rechallenge compared to the non-dose-capped cohort. Standardizing PEG dose capping in the CALGB 10403 and mSMILE regimens may translate to improved tolerance compared to a historical standard of no dose capping PEG.

Asparaginase-Associated Toxicities and Hypersensitivity Reactions in Pediatric and Adolescent Down Syndrome Patients with Acute Lymphoblastic Leukemia or Lymphoma

Children with Down syndrome acute lymphoblastic leukemia (DS-ALL) have worse prognosis compared to those with non-DS-ALL, largely due to higher treatment related mortality. Pegaspargase (PEG) is integral in protocols for the treatment of pediatric ALL and lymphoblastic lymphoma (LBL), and full exposure to all doses of PEG can be limited by toxicities, including hypersensitivity reactions (HSR) due to the production of anti-asparaginase antibodies rendering PEG therapy ineffective. To date, minimal data has been reported on the use of PEG in children with DS-ALL/LBL. We conducted a prospective, multicenter study to evaluate the efficacy of premedicating pediatric and adolescent ALL/LBL patients receiving PEG with antihistamines-H1 and -H2 blockers with subsequent therapeutic drug monitoring (TDM) to better identify patients with true HSR versus those with non-antibody mediated infusion reactions. Here, we report on the incidence of HSRs and PEG-associated toxicities in the cohort of children with DS-ALL/LBL. Eligible patients from six centers received PEG, as per a Children's Oncology Group protocol, beginning in induction therapy. An H1 blocker (diphenhydramine) and H2 blocker (ranitidine, famotidine or cimetidine) were administered prior to PEG administration in consolidation and subsequent cycles. TDM was performed at 7 and 14 days post each PEG. PEG was administered at 2500 International units/m 2/dose that was capped for obesity or age > 22 years. Patients were monitored for HSR and other PEG-related toxicities using CTCAE version 5 criteria. Therapeutic asparaginase activity (AA) was defined as ≥ 0.1 IU/mL (≥100 IU/L) at 7 days post infusion and greater than the lower level of quantification at 14 days. We observed for silent inactivation (subtherapeutic levels without symptoms) and accelerated clearance (levels below quantification at 14 days without symptoms). Descriptive statistics summarized patient characteristics and mixed effects modeling procedure assessed mean AA levels at 7 and 14 days with specification of repeat measures and compound symmetry covariance structure. Out of 148 patients, 9 DS (8 B-ALL, 1 B-LBL) were enrolled between 10/2019 - 3/2022. The median age at diagnosis was 5.0 years [IQR: 4.3, 14.9], 4 were National Cancer Institute (NCI) High Risk (HR) at diagnosis, 4 were Hispanic and none were obese. ALL 9 DS patients received a total of 26 doses of PEG at the standard dose without dose capping required. The mean unadjusted AA levels at 7 and 14 days post PEG were 0.76 IU/ml (SE=0.11) and 0.54 IU/ml (SE=0.11), respectively, p<.001. None of the DS patients experienced HSR or silent inactivation. Accelerated clearance was observed in 1 patient. Nineteen episodes of grade >3 PEG-associated toxicity were observed in 5 DS-ALL patients (5/9; 55.6%). PEG-associated toxicity was observed more frequently in older patients whose mean age was 13 years (SD=6.2) versus 4.3 years in those without toxicity (SDE=0.9), p=.028. Four of the DS-ALL who experienced toxicities were NCI HR at diagnosis and > 10 years of age. For the 19 episodes of toxicities: 6 occurred during induction, 9 during consolidation, and 4 during delayed intensification. The most common toxicity observed was hepatoxicity (increased alanine transaminase) which was experienced by 3 DS-ALL patients. There were no grade > 3 hyperbilirubinemia. All 4 DS-ALL patients who experienced PEG toxicity during induction also had toxicity with subsequent cycles. One DS-ALL patient had a dose limiting toxicity (grade 3 pancreatic pseudocyst), requiring discontinuation of subsequent PEG therapy. There were no grade 4 or 5 toxicities observed. All 4 DS patients who did not experience toxicities were NCI Standard Risk patients. All DS patients had undetectable minimal residual disease (MRD) that was < 0.01 at the end of induction therapy. We noted that in this small DS-ALL/LBL cohort, none of the patients experienced HSR, and all achieved therapeutic AA at both time points of 7 and 10 days post PEG. Five (55.6%) of the DS-ALL patients experienced at least one grade > 3 asparaginase toxicity, and they were older than those without toxicity. Most toxicity occurred during the consolidation phase and no grade 4 or 5 toxicities were observed. Given the PEG-associated toxicity observed in DS ALL/LBL, we are conducting pharmacokinetic analysis to propose a lower dose of PEG which may minimize toxicity while maintaining therapeutic efficacy.

Pharmacogenomics to Predict Asparaginase Premedication-Related Hypersensitivity in Pediatric and Adolescent Young Adults (AYAs) with Acute Lymphoblastic Leukemia or Lymphoma

Pediatric acute lymphoblastic leukemia (ALL) patients have had significantly improved outcomes over the last few decades with overall survival (OS) rates exceeding 90%. Several factors, including the incorporation of asparaginase therapy in chemotherapy regimens of pediatric and AYA patients with ALL have played a critical role in improving outcomes. Asparaginase is a bacteria-derived enzyme which depletes the non-essential amino acid asparagine and leads to subsequent apoptosis in lymphoblastic leukemia cells. One of the main limitations of the frontline pegaspargase (PEG) chemotherapy is the development of hypersensitivity reactions and subsequent development of anti-asparaginase neutralizing antibodies that lead to PEG inactivation. When hypersensitivity reactions to PEG occur, patients are often switched to alternative forms of asparaginase, such as that isolated from Erwinia chrysanthemi. A prospective multi-institutional study initiated by Children's Hospital of Orange County (CHOC) and conducted at 6 pediatric cancer centers: 1) evaluated the efficacy of premedicating pediatric and AYA patients with B or T-ALL or lymphoblastic lymphoma (LBL) receiving PEG with antihistamines (H1 and H2 blockers), and 2) performed therapeutic drug monitoring to better identify patients with true hypersensitivity reactions versus those with non-antibody mediated infusion reactions with the goal of reducing incidences of substitution to Erwinia asparaginase. This study also aimed to characterize the pharmacogenomics which may be driving differences in asparaginase hypersensitivity to better understand which single nucleotide polymorphisms (SNPs) are involved in the immunogenicity of PEG and whether certain populations are more at risk for hypersensitivity. Here, we report preliminary evidence showing an association between a combination of 3 SNPs in 3 genes and incidence of hypersensitivity to PEG. The analysis cohort consisted of 126 non-Down syndrome patients premedicated prior to PEG treatment. In this cohort, the median age was 7.7 years, 48 were female (38%) and 78 male (62%), 65 patients identified as Hispanic (52%), 56 as non-Hispanic (44%) and 5 declined to state (4%). Overall, 28 patients had a hypersensitive reaction to PEG within 15 minutes of infusion. Patient characteristics by hypersensitivity incidence are summarized in Fig 1A, with age and National Cancer Institute (NCI) risk groups being the factors that significantly differ by hypersensitivity. DNA from all 126 patients was used to genotype for 6 SNPs in 5 genes involved in pathways implicated in hypersensitivity to PEG. We tested each SNP genotype in 3 modes of inheritance (additive, dominant, and recessive) in all possible combinations of up to two SNPs per model using Cox-proportional hazard models for association with incidences of hypersensitivity post-infusion in 126 patients for whom clinical data was available. We then performed 1000 permutation tests for each model to determine the likelihood of obtaining them falsely. Models were ordered according to their Bayesian Information Criterion (BIC) and weight in favor of each model and those with least BIC and a 1000 permutation p<0.05 were selected for development of Asp_PGx3 score. This was defined by adding the genotype scores of 3 SNPs in 3 genes ( ARHGAP28, CNOT3, and NFATC2), accounting for the mode of inheritance and the direction of their association with outcome. This score ranged from -5 to 0, with patients with score <0 stratified as low score and those with scores of 0 as high score groups. A significantly higher proportion of patients in the low Asp_PGx3 score group (29%) had an incidence of PEG hypersensitivity compared to those in the high Asp_PGx3 score group (16%) (Fig 1B). In conclusion, we show a combination of 3 SNPs (in ARHGAP28, CNOT3, and NFATC2) associated with PEG hypersensitivity in a cohort of 126 pediatric and AYA ALL/LBL patients. Instead of a single SNP association approach, identifying combinations of variations in pathway specific genes provides a more robust means to predict drug response. Our preliminary results provide a rationale for identification of genome level variations in this cohort and association analysis to establish clinically relevant pharmacogenomics score to optimize PEG treatment. Funding for this study was provided by CHOC PSF Tithe Grant, CHOC Hyundai Cancer Institute Research Grant, and Servier Pharmaceuticals.

Abstract #1407741: Pegaspargase-Induced Severe Hyptriglyceridemia

Pegaspargase (PEG) a critical medication for acute lymphoblastic leukemia (ALL). As a long-acting formulation of L-asparaginase, it leads to degradation and depletion of the amino acid asparagine and selective leukemic cell apoptosis. Despite significantly improving treatment response rates, its use can be challenging due to a complex toxicity profile, including thrombosis, hepatotoxicity, hyperglycemia, pancreatitis, and hypertriglyceridemia (HTG). We report a case of a young man who developed severe hypertriglyceridemia secondary to PEG. A 26-year-old man with no significant past medical history presented with refractory upper respiratory symptoms and cervical lymphadenopathy. He was subsequently found to have severe leukocytosis with 70% blasts and 7cm mediastinal mass with superior vena cava compression. Flow cytometry and bone marrow biopsy diagnosed T-cell ALL and he was started on chemotherapy via the GIMEMA LAL1913 protocol (a chemotherapy regimen that includes prephase cyclophosphamide and induction phase with vincristine, idarubicin, dexamethasone, and PEG). About 12 days after having received PEG, the patient developed unexplained acute hyponatremia to 123 mmol/L and other lab tests such as potassium and hepatic function tests were not able to be processed. Further workup revealed pseudohyponatremia and that lab interference was occurring from lipemia. A triglyceride (TG) level was found to be >4425 mg/dL. LDL direct was measured to be 95 mg/dL, and lipid analysis showed absent chylomicrons. Clinically, he had stable mild abdominal tenderness and a serum lipase level resulted marginally above the upper limit of reference range. At this point, he was transitioned to a low-fat diet (<20g per day). Omega-3-acid ethyl esters (EPA/DHA) and fenofibrate were started. In the next 2 weeks his TG steadily decreased to 163 mg/dL. His mild abdominal pain resolved and lipase normalized. The patient is currently undergoing cycle 2 of his chemotherapy and remains on low fat diet, EPA/DHA, and fenofibrate therapy. After 1 week of receiving his second dose of PEG, his triglycerides were 105 mg/dL. Apo E genotyping was performed and revealed normal E3/E3 genotype. He denies any family history of lipid disorders. The incidence of PEG-induced HTG is poorly described in the adult population, and recent studies have shown the condition is becoming more frequently recognized. Its underlying mechanism is not fully understood, but TG levels often rise dramatically and can lead to severe pancreatitis. Clinicians should be aware of this adverse effect and consider baseline lipid analysis prior to induction chemotherapy and TG surveillance, in addition to clinical monitoring for pancreatitis.

The Effects of Dietary Asparagine on Pegaspargase Therapy and Blood and Stool Metabolites. a Pilot Study in Mice

Introduction: Pegaspargase (PEG) is key to the treatment of pediatric Acute Lymphoblastic Leukemia. PEG depletes blood asparagine (Asn), killing leukemic but not healthy cells. Guidelines on optimum dosing of PEG are ambiguous. Dietary and gut Asn can diffuse from the gut into the bloodstream through epithelial cells. We also know that some patients have bacteria in the gut that produce asparaginase. It is unclear whether dietary Asn impacts PEG efficacy. In this study we sought to determine if dietary Asn can impact PEG-mediated plasma Asn depletion in a pre-clinical model. Methods: Pre-diet blood and stool samples from 10 healthy, non-tumor-bearing C57BL/6 mice were collected. The mice were then divided into 2 cages and given an Asn rich (4% Asn, cage A) or depleted (0%, cage B) diet. Blood and stool were sampled again 35 and 72 days after commencing the diet. The mice were then injected with 200 IU/kg PEG intraperitoneally. 5-days post-PEG blood and stool samples were collected. Blood PEG activity was immediately quenched following collection using a solution of 20% formic acid to ensure that Asn was not catabolized post collection. Mouse A2 unfortunately received roughly half the PEG in comparison to the other mice and was excluded from the final data summaries. Over 200 blood and stool metabolites were analyzed using LC-MS/MS at each timepoint. ANCOVA was used to test for between-diet significance. MetaboAnalyst 5.0 was used to identify pathways that were different between diets. A p value of ≤0.05 was considered significant. Results: Blood Asn levels were similar between the 2 diets at all time points. Blood and stool metabolomic PCA plots each showed two distinct clusters, with the day 0 samples clustering together and all other sample timepoints in a second cluster. There were some outliers present in the blood PCA plot with mice of both diets on day 77 and one mouse on high Asn on day 35 positioned outside of the clusters. In the stool plot, 3 mice on the 0% diet on day 77 did not cluster with other samples, as well as 1 mouse on the 4% diet, on day 77 (Figure 1). Blood Asn levels were depleted below the level of detection in all the 5-day post PEG samples, the last timepoint of the experiment. There were 5 pathways in pre-diet, 10 on day 35, 12 on day 72, and 4 on day 77 that were significantly different between diets. One pathway of interest that was significantly different on day 72 was aspartate (Asp) metabolism. Asp was significantly higher in the Asn rich group compared to the Asn depleted group. L-acetylaspartylglutamate was higher in the Asn depleted group compared to the Asn rich group (Figure 2). Stool Asn levels were significantly lower in the Asn rich group after 72 days on diet. There were 20 pathways in pre-diet, 5 on day 35, 4 on day 72, and 1 on day 77, that were significantly different between diets. None of the pathways that were different in the blood were also affected at the same time in the stool. Conclusions and Interpretations: Our outcome showing differences late in the diet period demonstrate that diet can have a profound effect on metabolites, not necessarily including Asn. Nevertheless, we provide no evidence that controlling dietary Asn will impact blood Asn levels and PEG efficacy. We found corresponding low stool Asn and high blood Asp in the Asn rich diet after 72 days on the diet. One possible explanation for this is the high Asn diet caused an increase in asparaginase-producing bacteria, which converted the dietary Asn into Asp. The Asp then diffused into the blood from the gut. Further studies examining the genomes of the bacteria present to confirm this theory are underway. Despite changes in metabolites, PEG depleted Asn in mice on both diets. PCA plots revealed that some post-PEG samples did not cluster with the others, indicating that PEG, like diet, could have a profound impact on metabolites. Further studies should examine the microbial and blood changes leading to these outliers. It is also important to take a closer look at the replenishment of Asn post-PEG to see if diet can affect the rate at which blood Asn is restored. The changes we observed and the consequences of these changes, will need to be confirmed in mice with leukemia. Acknowledgement: This research was funded from a grant from the Beatrice Hunter Cancer Research Institute, Dalhousie Medical Research Institute, and ZF was funded by an IWK Health Graduate Studentship. The pegaspargase was kindly provided by Servier Canada Inc. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Premedication and Therapeutic Drug Monitoring (TDM) for Pegaspargase: A Prospective Multicenter Multi-Ethnic Study of Pediatric and Adolescent Patients

Background: Pegaspargase (PEG) is integral in the treatment of patients with acute lymphoblastic leukemia/lymphoma (ALL/LBL). However, full exposure to all doses of PEG can be limited by hypersensitivity reactions (HSR), which necessitate a switch to alternative asparaginase formulations. Previous studies in the pediatric population evaluating the use of premedication with antihistamines (H1 and H2) to decrease the incidence of HSR have largely been retrospective and showed mixed results. We conducted the first prospective, multicenter study to evaluate the efficacy of premedicating pediatric and adolescent patients receiving PEG with H1 and H2 blockers to decrease the rate of HSR. We report on our interim analysis with a special focus on ethnic disparities in asparaginase activity and HSR. Methods: We enrolled patients with ALL/LBL treated according to a Children's Oncology Group protocol at six centers across the US. Starting with the first dose of PEG in consolidation and subsequently, patients received an H1 blocker (diphenhydramine) and an H2 blocker (ranitidine, famotidine or cimetidine) 30-60 minutes prior to every dose of PEG, which was infused over 60-120 minutes. TDM was performed at 7-10 and 14-17 days post each PEG infusion. Therapeutic asparaginase activity was defined as ≥ 0.1 IU/mL (≥100 IU/L ) at 7-10 days post infusion and greater than the lower level of quantification at 14-17 days. We observed for silent inactivation (subtherapeutic levels without symptoms) and accelerated clearance (levels below quantification at 14-17 days without symptoms). Ethnicity differences were assessed using Chi-square and independent t-tests, increased odds of HSR by GLM procedure, and average asparaginase activity across treatments using GEE analyses. Results: We report on the 74 patients enrolled from 10/2019 to 7/2021 who completed all PEG therapy at the time of analysis. The median age at diagnosis was 7.7 years [range 1.3-19.8], 63.5% were male, 90.5% had B-ALL, 35.1% were NCI High Risk (HR) at diagnosis, and 8.1% had Down Syndrome (Table 1). A majority self-identified as Hispanic ethnicity (56.8%). We noted a disparity in obesity/overweight status by ethnicity. Overall, 50.0% of Hispanics were obese (31.0%) or overweight (19.0%) compared to 12.6% of non-Hispanics (6.3% obese and 6.3% overweight), p=.007. The average body mass index (BMI, kg/m2) in Hispanic compared to non-Hispanic patients was 20.7 (SD=6.5) vs. 16.9 (SD=2.7), p=.001. A total of 157 infusions of PEG was administered to 74 patients. The average dose of PEG was 2780 IU with an average time of infusion of 128 minutes in those without HSR. The incidence of HSR for Hispanic patients was 31% compared to 18.8% for non-Hispanics, although this was non-significant (p=0.234). In 19 patients who experienced HSR, 84% were Grade 3 and one was a Grade 4. Most HSR occurred during consolidation (79.9%). Silent inactivation occurred in 3 patients (4%) and one patient experienced delayed clearance. The average asparaginase activity level at 7-10 and 14-17 days was 1.03 IU/mL (SD=0.35) and 0.71 IU/mL (SD=0.30), respectively. There was no significance in asparaginase activity levels between Hispanics and non-Hispanics (p>.05). Overall, 81% of all patients achieved a (-) minimal residual disease (MRD) at the end of induction with no difference in Hispanic (83.3%) versus non-Hispanics (78.1%). In an adjusted analysis to evaluate potential determinants of HSR, we noted that NCI HR at diagnosis (p=0.019) was associated with increased incidence of HSR, while obesity, sex and ethnicity were not (Table 2). Interestingly, age >8 years was associated with higher odds of HSR unadjusted for NCI HR (OR=3.83, p=.016). Conclusion: We found that the two factors which increase the odds of HSR are age > 8 years and NCI high risk at diagnosis. We will be able to confirm the efficacy of premedication with a larger cohort upon the completion of all patients enrolled. Both silent inactivation and delayed clearance was infrequent. Although the standard therapeutic asparaginase activity is widely accepted to be ≥ 0.1 IU/mL, we observed supratherapeutic levels at 1 and 2 weeks post PEG at 1.03 IU/mL and 0.71, respectively. We are currently performing additional analysis to evaluate PEG related toxicity in various ethnic groups, determining the single nucleotide polymorphisms (SNPs) involved in HSR and toxicity, and creating a dose model based on pharmacokinetic analysis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Safety and Pharmacokinetics of Calaspargase Pegol in Adults with Newly Diagnosed Philadelphia-Negative ALL: A Phase 2/3 Study

Safety and Pharmacokinetics of Calaspargase Pegol in Adults with Newly Diagnosed Philadelphia-Negative ALL: A Phase 2/3 Study

Outcomes in Adult Philadelphia-Positive Acute Lymphoblastic Leukemia Patients Using Tyrosine Kinase Inhibitors Combined with the Modified University of Southern California (USC ALL) Regimen without Pegaspargase in the Era of Novel Agents; A Retrospective Study

Introduction:Prior to the introduction of tyrosine kinase inhibitors (TKIs), the presence of BCR-ABL1 conferred a poor prognosis in patients with acute lymphoblastic leukemia (ALL). We published in 2017 in Br J Haematology our analysis comparing the survival of Ph-Positive (Ph+) and Ph-negative ALL during the period when TKIs were universally available in the United States for Ph+ ALL using a Surveillance, Epidemiology, and End Results (SEER) Database analysis. Despite using TKIs, we have continued to remain reliant on cytotoxic chemotherapy regimens and allogeneic hematopoietic stem cell transplant (allo-HSCT) to achieve the best long-term outcomes. However, with the introduction of more potent TKIs and other novel agents, as well as better methods for monitoring minimal/measurable residual disease (MRD) the best approach is yet to be determined. In this study we present data from our institution with incorporation of TKIs in our modified USC ALL pediatric-based regimen without pegaspargase (PEG) (Table 1).Methods:This retrospective, single institution chart review included adults aged >18 with newly diagnosed Ph+ ALL between 2016 and 2020. Primary objectives were Overall survival (OS) and event-free survival (EFS) at 3 years for Ph+ ALL patients and secondary objectives were rates of complete remission/complete remission with incomplete recovery (CR/CRi), minimal residual disease (MRD) by flow cytometry and presence of BCR-ABL1 fusion transcript by real time polymerase chain reaction. Descriptive statistics of patients were reported and evaluated using Fisher's exact test. OS and EFS were reported through Kaplan Meier curves and Log-rank tests. Two-sided p value ≤0.05 was significant.RESULTS: 26 Ph+ ALL patients were identified. Median age at diagnosis was 42.5 years, with 42.3% males and 57.7% females. Median BMI was 31.1 kg/m 2, 42.3% had hepatic steatosis and 34.6% had CNS disease pre-induction.After induction 1, 91.3% of patients achieved CR/CRi, 8.7% were refractory, and 64.3% were MRD flow negative with 24% of patients with undetectable BCR-ABL1. After induction 2, 94.1% had achieved CR/CRi, 64.3% were MRD flow negative with 44.4% of patients with undetectable BCR-ABL1. After consolidation I, 78.6% were MRD flow negative. 50% of patients had received blinatumomab for MRD flow positivity early in the course and 34.6% underwent allo-HSCT. Of note, 65.4% of patients received Dasatinib only and 30.8% received at least 2 TKIs. Overall, 11.5% had known relapse, 12.5% died. 3-year OS was 83.3% and 3-year EFS was 86.6% (Table 2).When survival was stratified by transplant status, 3-year OS with allo-HSCT was 100% versus 70% without allo-HSCT (p=0.15) and 3-year EFS with allo-HSCT was 100% compared to 77.9% without allo-HSCT (Table 3).CONCLUSIONS: The use of the modified USC ALL regimen without PEG for the treatment of newly diagnosed Ph+ ALL combined with TKI at our institution led to an excellent 3-year OS (83.3%) and 3-year EFS (86.6%). All patients received TKI, half of the patients received blinatumomab and at least one third received allo-HSCT which likely led to higher OS even without PEG. We also observed a trend towards improved OS in recipients of allo-HSCT compared to patients who did not receive allo-HSCT (100% vs. 70%, p=0.15) although statistically not significant, it highlights the role of allo-HSCT in the management of Ph+ ALL patients. [Display omitted] DisclosuresChaudhary: TCR2: Current equity holder in publicly-traded company; Celldex: Current equity holder in publicly-traded company; Moderna: Current equity holder in publicly-traded company; Pancella: Consultancy; Oncotartis: Consultancy; Athelas: Consultancy, Current holder of stock options in a privately-held company; Angeles Therapeutics: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Founder, Patents & Royalties: Cell therapy ; Allogene: Current equity holder in publicly-traded company. Douer: Adaptive: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Speakers Bureau; Jazz: Consultancy; Servier: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Yaghmour: Agios: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; BMS: Speakers Bureau; Alexion: Speakers Bureau; Astellas: Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Jazz: Speakers Bureau.

Impact of Age, Body Surface Area, and Body Mass Index on Pegaspargase Toxicity and Pharmacokinetics: A Report from the DFCI ALL Consortium

Introduction: Increased toxicity with pegaspargase (PEG) in older and higher body mass index (BMI) patients (pts) with acute lymphoblastic leukemia (ALL) has recently led to dose capping practices. We assessed the influence of age, body surface area (BSA), and BMI on PEG-related toxicity and pharmacokinetics from two consecutive DFCI ALL Consortium trials without dose capping.Methods: Patient (pts) aged 1 to <19 years (DFCI 05-001) or 1 to <22 years (DFCI 11-001) with newly diagnosed ALL were eligible for enrollment. Those who received PEG (2500 IU/m 2) were included in this analysis. Pts received 1 dose of IV PEG on day 7 of Induction and every 2 weeks for 15 doses post-induction. Serum asparaginase activity (SAA), considered therapeutic at >0.1 IU/mL, was assessed 4, 11, 18, and 25 days after the Induction dose and nadir SAA was assessed before each Post-Induction dose.Asparaginase-related toxicities were prospectively assessed and graded by CTCAE version 3.0 (DFCI 05-001) or 4.0 (DFCI 11-001). Asparaginase toxicity for this analysis was defined as ≥1 of the following: pancreatitis, thrombosis, ≥grade 4 hyperbilirubinemia, ≥grade 4 hypertriglyceridemia. Allergy was analyzed separately (due to presumed dose independence). Height and weight at diagnosis were used for analyses. BMI categories were assigned using standard percentile ranges based on gender specific 2000 CDC growth charts. BSA was calculated using the Mosteller formula.Univariate analyses evaluated the relationship of age, BMI, and BSA with asparaginase toxicity. Comparisons of toxicity across BMI and BSA categories were performed using a Jonckheere-Terpstra test. Categorical comparisons for dichotomized BMI and BSA utilized a Fisher's exact test or chi square test. The relationships between BMI and BSA with toxicity were explored using multivariable models.Results: Between 4/2005-12/2011 802 pts enrolled on DFCI 05-001 and between 6/2012-6/2015 240 pts enrolled on DFCI 11-001. Both trials included random assignment of asparaginase formulation. In total 911 patients received pegaspargase during Induction and 351 during Post-Induction.During Induction, pts ≥15 years of age had higher asparaginase toxicity rates (17.1% vs 6.2%, p=0.0003) (Figure 1a). Toxicity differed significantly across BSA categories (<1.5 m 2, 1.5 to <2.0 m 2, ≥2.0 m 2, p= 0.007) with increased toxicity in those with BSA ≥2.0m 2 (22.7% vs. 6.8% for those <2.0 m 2, p = 0.016) (Figure 1b). Age was highly correlated with BSA (Pearson r = 0.93, p <0.0001). There was numerically higher toxicity in the BMI category of overweight vs. those underweight or normal weight (11.3% vs 6.5%) however this did not extend to the obese category, and overall, increasing BMI was not associated with statistically higher toxicity (p= 0.13, Figure 1c).Post-Induction, age ≥15 years was associated with increased asparaginase toxicity (57.1% vs 21%, p<0.0001) (Figure 1d). Toxicity differed significantly across BSA categories (p<0.0001) but was similar between BMI categories (p=0.19, Figure 1e-f). The impact of BSA was observed when dichotomized at thresholds of 1.5m 2 (54% vs. 19%, p<0.0001) and 2.0m 2 (70% vs. 23%, p=0.003) (Figure 1e). Considering only those ≥10 years of age, trends for BSA/BMI and toxicity were similar. There was no significant association between BMI or BSA and allergy. In multivariable analysis, BSA was a significant predictor of Post-Induction toxicity (OR 4.21, p<0.0001). Age was significant in the univariate setting (OR 1.14, p<0.0001) however due to high correlation with BSA, was not included with BSA in the multivariable model.Post-Induction, median nadir SAA levels were ≥0.1IU/mL for all BSA and age categories. Median SAA was similar or lower at all time-points for those ≥15 years of age compared with younger children. Median SAA for pts with BSA ≥1.5m 2 were similar or lower compared to those with BSA <1.5m 2 (Figure 2a-d).Conclusion: Age ≥15 years and BSA ≥2m 2 were each associated with significantly increased asparaginase toxicity. Older patients and those with higher BSA had similar or lower median SAA levels at all time-points. These results suggest that the differential toxicity seen in older patients and those with higher BSA is not explained by these patients having higher SAA levels. Prospective exploration of interventions to decrease toxicity in older patients and those with high BSA are needed. [Display omitted] DisclosuresNeuberg: Madrigal Pharmaceuticals: Other: Stock ownership; Pharmacyclics: Research Funding. Silverman: Takeda, Servier, Syndax, Jazz Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.

Levocarnitine for pegaspargase-induced hepatotoxicity in older children and young adults with acute lymphoblastic leukemia.

BackgroundPegaspargase (PEG‐ASP) is an integral component of therapy for acute lymphoblastic leukemia (ALL) but is associated with hepatotoxicity that may delay or limit future therapy. Obese and adolescent and young adult (AYA) patients are at high risk. Levocarnitine has been described as potentially beneficial for the treatment or prevention of PEG‐ASP‐associated hepatotoxicity.MethodsWe collected data for patients age ≥10 years who received levocarnitine during induction therapy for ALL, compared to a similar patient cohort who did not receive levocarnitine. The primary endpoint was conjugated bilirubin (c.bili) >3 mg/dl. Secondary endpoints were transaminases >10× the upper limit of normal and any Grade ≥3 hepatotoxicity.ResultsFifty‐two patients received levocarnitine for prophylaxis (n = 29) or rescue (n = 32) of hepatotoxicity. Compared to 109 patients without levocarnitine, more patients receiving levocarnitine were obese and/or older and had significantly higher values for some hepatotoxicity markers at diagnosis and after PEG‐ASP. Levocarnitine regimens varied widely; no adverse effects of levocarnitine were identified. Obesity and AYA status were associated with an increased risk of conjugated hyperbilirubinemia and severe transaminitis. Multivariable analysis identified a protective effect of levocarnitine on the development of c.bili >3 mg/dl (OR 0.12, p = 0.029). There was no difference between groups in CTCAE Grade ≥3 hepatotoxicity. C.bili >3 mg/dl during induction was associated with lower event‐free survival.ConclusionsThis real‐world data on levocarnitine supplementation during ALL induction highlights the risk of PEG‐ASP‐associated hepatotoxicity in obese and AYA patients, and hepatotoxicity's potential impact on survival. Levocarnitine supplementation may be protective, but prospective studies are needed to confirm these findings.

ALL-323: Preliminary, Updated Outcomes of the Modified, Pediatric-Based USC ALL Frontline Regimen in Hispanics and Non-Hispanics

<h3>Context:</h3> In 2014, USC reported use of multiple doses of pegaspargase (PEG) for newly diagnosed ALL patients (7-year overall survival [OS] 51%). This is currently part of the NCCN Guidelines for frontline ALL treatment. Since then, the regimen consisting of 2 induction phases (IP) was modified, with fractionated doses of cytarabine changed to a single dose and consolidations increased to six cycles (six doses of PEG total). <h3>Objective:</h3> Outcomes since modification of the USC ALL induction regimen, with immunotherapies given when appropriate, in Hispanics <i>versus</i> non-Hispanics. <h3>Design:</h3> Retrospective chart review. <h3>Setting:</h3> Single institution, academic center/county hospital. <h3>Patients or Other Participants:</h3> Male/female patients (18–99 years) with any type of ALL diagnosed by bone-marrow/tissue biopsies during 1/2016–12/2020, treated at our institution. Patients who did not receive the modified USC ALL induction regimen with/without PEG were excluded. <h3>Interventions:</h3> Ninety-four ALL patient chart reviews. <h3>Main Outcomes Measures:</h3> OS, event-free survival (EFS) at 5 years, CR/CRi, minimal residual disease (MRD) flow; 2-sided p-value ≤0.05 was considered significant. <h3>Results:</h3> Among 63 Hispanics and 31 non-Hispanics, 67 achieved CR/CRi, 39 had MRD flow negativity after IP1; 50 CR/CRi, and 29 had MRD flow negativity after IP2. PEG was given in 59% Hispanics and 60% non-Hispanics. Salvage BiTE was given to 30 patients (Hispanic, 63%). Median follow-up for Hispanics was 17 (0.5–60) months and 21 (0.1–53) months for non-Hispanics. Median OS not-reached (NR) in both groups. Estimated OS for Hispanics at 5 years was 80% and 51% for non-Hispanics (p=0.020). Median EFS for Hispanics was 46 months and 34 months for non-Hispanics (p=0.306). <h3>Conclusions:</h3> CR/CRi and MRD flow negativity were appreciable with the median OS NR. Interestingly, a significant improvement in Hispanic OS <i>versus</i> non-Hispanics was noted. An explanation could be on how more Hispanics received salvage BiTE (63.3% of 30 patients). Also, 40% of Hispanics were able to receive stem cell transplant <i>versus</i> 33% of non-Hispanics. No significant difference in median EFS between Hispanics and non-Hispanics was noted.

Combination of sintilimab, anlotinib and pegaspargase "sandwich" with radiotherapy in localized natural killer/T cell lymphoma: A multicenter, phase 2 study.

7537 Background: NK/T-cell lymphoma (NKTL) is a rare and distinct subtype NHL. Most newly diagnosed NKTL cases were localized-stage. For localized NKTL, RT alone is inadequate due to high systemic failure rate. Chemoradiation has been increasingly applied. However, current chemotherapy (CT) regimens have severe toxicity and infection, which reduce the completion of RT and patients’ medical compliance. Therefore, novel regimens with mild toxicity are needed. Sintilimab, a fully human anti-PD-1 monoclonal antibody, has showed encouraging antitumor efficacy in pts with r/r NKTL. Anlotinib, a multiple-targeted TKI that mainly blocks VEGF/VEGFR pathway, has been approved for several solid tumor types in china. Anti-angiogenesis therapy could improve efficacy of ICI in multiple tumor types. This multicenter, single-arm, phase 2 study aims to evaluate the efficacy and safety of sandwich chemoradiotion of sintilimab combined with anlotinib and pegaspargase (PEG-ASP) in newly diagnosed localized NKTL pts. Methods: Patients with pathologically confirmed previously untreated stage NKTL were enrolled. All enrolled patients received 3 cycles of sintilimab (200mg D1 ivdrip) combined with anlotinib (12mg po D1-14) and PEG-ASP (2500U/m2 D1) every 3 weeks followed by RT, then received additional 3 cycles of combination therapy as described above. The primary endpoint was overall response rate (ORR) by LUGANO 2014 criteria. Results: A total of 39 pts were enrolled, and 24 pts eligible for response evaluation (70.8% men; median age, 46 y [range 20-64]; 58.3% stage). According to PINK-E system, 8 pts (33.3%) were identified as intermediate risk group and 16 patients were low risk group. 23 of 24 patients completed protocol-specified therapeutic schemes, one patient discontinued the study after the second cycle due to disease progression. ORR was 95.8% (23/24, 95%CI: 76.9%-84.1%). Surprisingly, all the responded patients achieved CR, while 66.7% (16/24, 95%CI: 44.7%-83.6%) patients achieved CR after the second cycle. Median PFS and OS have not been reached. 1-year OS and PFS was 100% and 95.8%, respectively. All grade TRAEs occurred in 84.6% of all enrolled patients and 92.1% were grade 1-2. The most common TRAE was lymphocytopenia (9.9%). Of note, grade 3-4 hematological toxicity was reported in only one patient (4.2%). All AEs were resolved after symptomatic treatment, without systematic corticosteroid intervention. Conclusions: Sintilimab combined with anlotinib and PEG-ASP upfront and after radiotherapy was effective and could be well tolerated in localized NKTL, achieving promising CRR and rapid and long-term remission with mild toxicity. Further investigation of survival outcome is warranted. Clinical trial information: NCT03936452.

Venous thromboembolism following pegaspargase in adults receiving antithrombin supplementation

Pegaspargase (PEG) increases venous thromboembolism (VTE) in acute lymphoblastic leukemia (ALL) potentially due to depletion of anticoagulation factors, including antithrombin (AT). The benefit and cost of AT supplementation in adults is unclear. We aimed to characterize VTE incidence and risk factors following AT and determine the characteristics and costs of supplementation. Fifty-three adults received PEG and AT. VTE occurred in 21% (grade ≥3 8%). T cell ALL and patients receiving prednisone during induction were at highest risk. Repeat AT levels post supplementation were subtherapeutic forty-four percent of the time. A median of 18 days elapsed between PEG and two sequential therapeutic AT levels despite supplementation. Patients received a median of 2 AT doses per PEG dose at a median cost of $11,145. VTE remains common in adults despite AT supplementation. More aggressive AT supplementation may reduce VTE but warrant prospective evaluation given the significant cost.

Comparison of chemotherapy dose intensity for AYAs on COG AALL1131 versus CALGB 10403.

10520 Background: Outcomes for adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) are superior with pediatric-inspired therapy. CALGB 10403, the first US adult cooperative group prospective trial using a pediatric-inspired augmented BFM (ABFM)-based regimen, demonstrated feasibility and improved survival. We examined differences in drug delivery and targeted toxicities in AYAs who received the same therapy on C10403 vs the Children’s Oncology Group (COG) study AALL1131. Methods: The proportion of AYAs receiving full dose (within 10% of protocol- specified) vincristine (VCR) and pegaspargase (PEG) during induction (IND), consolidation (CON), and delayed intensification (DI); the likelihood of selected grade ≥3 adverse events (AEs); and the impact of patient characteristics were compared in AYAs 16-30 years. Targeted AEs with analogous reporting requirements in both studies included hyperbilirubinemia, pancreatitis, sensory neuropathy, and GI/intracranial hemorrhage. Thrombosis, transaminitis and hyperglycemia were not comparably captured. Fisher’s Exact test and logistic regression models were used for analyses. Results: After excluding AYAs removed from study after induction, 87 AALL1131 AYAs (accrued 2012-2016) and 188 C10403 AYAs (accrued 2007-2012) were analyzed with median ages of 17 (16-26) vs 22 (17-30) years, p &lt; 0.001. There was no difference in the intensity of VCR delivery during IND, but in CON and DI, AALL1131 AYAs were more likely to receive all specified VCR (93.1% vs 81.9%, p = 0.02; 92.7% vs 72.1%, p = 0.01). Women were less likely to receive all specified VCR (OR 0.57, 95% CI 0.34-0.94, p = 0.03), and overweight/obese AYAs were somewhat less likely to receive all VCR compared to those considered normal weight (OR 0.88 and 0.59, p = 0.09). More C10403 AYAs were obese/overweight compared to AALL1131 AYAs (p = 0.04). There were no significant differences in dosing of PEG during IND/CON, but in DI AALL1131 AYAs were more likely to receive both doses (75.6% vs 57.1%, p = 0.03). No patient variables impacted delivery of PEG. There was no significant difference in grade ≥3 toxicities captured similarly on both studies. Conclusions: AYAs enrolled on AALL1131 were more likely to receive all protocol-specified VCR and PEG compared to those on C10403. Selected AE rates were comparable, suggesting that older AYAs do not tolerate doses of VCR and PEG for reasons other than toxicity, with body habitus as one potential variable. Further analyses to compare dose density, toxicities, and outcomes experienced by younger AYAs versus older are ongoing.

Clinical observation of primary extranasal nasal-type NK/T cell lymphoma treated with P-GEMOX as a first-line regimen

Objective To investigate the clinical efficacy of P-GEMOX (pegaspargase, gemcitabine and oxaliplatin) as a first-line regimen for the treatment of primary extranasal nasal-type NK/T cell lymphoma (NKTCL). Methods The clinical manifestations, treatment response and prognosis of 7 patients with primary extranasal nasal-type NKTCL who underwent P-GEMOX chemotherapy as a first-line therapy in Shenzhen People's Hospital from September 2015 to October 2018 were retrospectively analyzed. Results The median age of 7 patients with primary extranasal nasal-type NKTCL was 41 years old (27-74 years old), which was more commonly found in males (6 cases); the primary and invading extranasal sites included ileocecal, lymph nodes, skin, testis, adrenal gland, central nervous system, etc. The P-GEMOX regimen was used as a first-line therapy, although some patients had a short-term effect, all patients eventually progressed rapidly and died. The overall survival time was 2 weeks to 21 months. Conclusion The short-term efficacy of P-GEMOX as a first-line therapy for the treatment of primary extranasal nasal-type NKTCL is acceptable, but the long-term efficacy is poor. Key words: Lymphoma, NK/T cell; Extranasal; Antineoplastic combined chemotherapy protocols; P-GEMOX regimen

FDA Approval Summary: Calaspargase Pegol-mknl For Treatment of Acute Lymphoblastic Leukemia in Children and Young Adults

On December 20, 2018, the Food and Drug Administration approved calaspargase pegol-mknl (CALASP), an asparagine-specific enzyme, as a component of a multi-agent chemotherapeutic regimen for acute lymphoblastic leukemia (ALL) in pediatric and young adult patients age 1 month to 21 years. Efficacy was determined on the basis of achievement and maintenance of steady-state nadir serum asparaginase activity (NSAA) above 0.1 U/mL when using CALASP, 2,500 U/m2 intravenously, every 3 weeks. In a randomized comparison to pegaspargase (PEGASP) every 2 weeks, treatment with CALASP every 3 weeks had a similar safety profile and no substantial impairment in event-free survival. The pharmacokinetics of CALASP were studied when administered in combination with multiagent chemotherapy in 124 patients with B-cell ALL in Study AALL07P4 and Study DFCI 11-001. The results showed that 123 [99%, 95% confidence interval (CI), 96%-100%] of the 124 patients maintained NSAA >0.1 U/mL at weeks 6, 12, 18, 24, and 30 of post-induction phase. Maintaining adequate NSAA levels is critical to successful treatment of ALL. Herein, we describe the FDA review and approval of CALASP.See related commentary by Lew, p. 325.

Outcome in Children With Standard-Risk B-Cell Acute Lymphoblastic Leukemia: Results of Children's Oncology Group Trial AALL0331.

Children's Oncology Group (COG) AALL0331 tested whether intensified postinduction therapy that improves survival in children with high-risk B-cell acute lymphoblastic leukemia (ALL) would also improve outcomes for those with standard-risk (SR) ALL. AALL0331 enrolled 5,377 patients between 2005 and 2010. All patients received a 3-drug induction with dexamethasone, vincristine, and pegaspargase (PEG) and were then classified as SR low, SR average, or SR high. Patients with SR-average disease were randomly assigned to receive either standard 4-week consolidation (SC) or 8-week intensified augmented Berlin-Frankfurt-Münster (BFM) consolidation (IC). Those with SR-high disease were nonrandomly assigned to the full COG-augmented BFM regimen, including 2 interim maintenance and delayed intensification phases. The 6-year event-free survival (EFS) rate for all patients enrolled in AALL0331 was 88.96% ± 0.46%, and overall survival (OS) was 95.54% ± 0.31%. For patients with SR-average disease, the 6-year continuous complete remission (CCR) and OS rates for SC versus IC were 87.8% ± 1.3% versus 89.1% ± 1.2% (P = .52) and 95.8% ± 0.8% versus 95.2% ± 0.8% (P = 1.0), respectively. Those with SR-average disease with end-induction minimal residual disease (MRD) of 0.01% to < 0.1% had an inferior outcome compared with those with lower MRD and no improvement with IC (6-year CCR: SC, 77.5% ± 4.8%; IC, 77.1% ± 4.8%; P = .71). At 6 years, the CCR and OS rates among 635 nonrandomly treated patients with SR-high disease were 85.55% ± 1.49% and 92.97% ± 1.08%, respectively. The 6-year OS rate for > 5,000 children with SR ALL enrolled in AALL0331 exceeded 95%. The addition of IC to treatment for patients with SR-average disease did not improve CCR or OS, even in patients with higher MRD, in whom it might have been predicted to provide more value. The EFS and OS rates are excellent for this group of patients with SR ALL, with particularly good outcomes for those with SR-high disease.

Pegaspargase Can Safely be Administered in Adults Age 40 and Older with Acute Lymphoblastic Leukemia

Pegaspargase Can Safely be Administered in Adults Age 40 and Older with Acute Lymphoblastic Leukemia

Clinical analysis of Pegaspargase associated hypertriglyceridemia in 5 children with acute lymphoblastic leukemia

目的 提高对儿童急性淋巴细胞白血病应用培门冬酶化疗所致高三酰甘油血症(HTG)的认识。 方法 收集2016年3月至2018年8月福建医科大学附属协和医院确诊为儿童急性淋巴细胞白血病(ALL)5例患儿的临床资料，5例患儿化疗前三酰甘油(TG)、肝肾功能均正常，在诱导缓解及延迟强化期，均予VDLD方案联合化疗，化疗后均出现HTG。 结果 5例患儿合并HTG期间均伴高密度脂蛋白下降，而胆固醇、低密度脂蛋白正常，同步监测血糖、血淀粉酶均正常，凝血功能障碍表现为低纤维蛋白原血症。均未发现合并临床症状，常规监测时发现，其中2例表现为乳糜血。5例患儿中1例通过控制低脂饮食后TG恢复正常，2例低脂饮食联合使用非诺贝特治疗后逐渐恢复正常，1例患儿通过严格低脂饮食、胰岛素、肝素及联合非诺贝特治疗效果不佳，并出现乳糜血，予血浆置换治疗1次后继续口服非诺贝特降脂治疗后恢复正常。另外1例患儿严格低脂饮食及口服非诺贝特治疗效果不佳，出现乳糜血，予血浆置换治疗1次后继续口服非诺贝特降脂治疗后恢复正常。其中1例后续疗程中严格控制低脂饮食，继续培门冬酶化疗，未再出现HTG；1例放弃治疗，另外3例疗程结束，均未再使用培门冬酶化疗。 结论 在应用门冬酰胺酶化疗期间需低脂饮食、监测血脂水平，出现高三酰甘油血症时治疗需个体化及综合治疗，对药物治疗效果不佳的严重HTG予血浆置换治疗可快速降低血脂。

Antibodies Predict Pegaspargase Allergic Reactions and Failure of Rechallenge.

Pegaspargase (PEG-ASP) has largely replaced native Escherichia coli asparaginase (L-ASP) in the treatment of acute lymphoblastic leukemia because of its longer half-life and lower immunogenicity. Risk factors for allergic reactions to PEG-ASP remain unclear. Here, we identify risk factors for reactions in a front-line acute lymphoblastic leukemia trial and assess the usefulness of serum antibodies for diagnosing allergy and predicting rechallenge outcome. PEG-ASP was administered to 598 patients in St Jude's Total XVI study. Results were compared with Total XV study (ClinicalTrials.gov identifiers: NCT00549848 and NCT00137111), which used native L-ASP. Serum samples (n = 5,369) were analyzed for anti-PEG-ASP immunoglobulin G by enzyme-linked immunosorbent assay. Positive samples were tested for anti-polyethylene glycol (PEG) and anti-L-ASP. We analyzed potential risk factors for reactions and associations between antibodies and reactions, rechallenge outcomes, and PEG-ASP pharmacokinetics. Grade 2 to 4 reactions were less common in the Total XVI study with PEG-ASP (81 [13.5%] of 598) than in the Total XV study with L-ASP (169 [41.2%] of 410; P = 1.4 × 10-23). For Total XVI, anti-PEG, not anti-L-ASP, was the predominant component of anti-PEG-ASP antibodies (96%). In a multivariable analysis, more intrathecal therapy (IT) predicted fewer reactions (P = 2.4 × 10-5), which is consistent with an immunosuppressant contribution of IT. Anti-PEG-ASP was associated with accelerated drug clearance (P = 5.0 × 10-6). Failure of rechallenge after initial reactions was associated with anti-PEG-ASP (P = .0078) and was predicted by the occurrence of angioedema with first reaction (P = .01). Less IT therapy was the only independent clinical risk factor for reactions to PEG-ASP. PEG, and not L-ASP, is the major antigen that causes allergic reactions. Anti-PEG-ASP has utility in predicting and confirming clinical reactions to PEG-ASP as well as in identifying patients who are most likely to experience failure with rechallenge.