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The history of asparaginase clinical use is inextricably linked to the improvement of treatment programs for acute lymphoblastic leukaemia (ALL). Asparaginase, obtained from E. coli, has become the crucial part in the protocols for the treatment of ALL in children and adults since the 1960s-1970s due to its antitumor effect on lymphoid leukemia cells. Despite the evolution of therapeutic approaches in ALL management, changes in used chemotherapeutic agents, their administration regimens and doses, the asparaginase remains one of the leading therapeutic agents in ALL patients. With time ideas about the asparaginase mechanisms have expanded, new data have been accumulated on adverse effects (allergic reactions, thrombotic complications, pancreatitis, hepatic dysfunction, etc.). The asparaginase obtained from Erwinia chrysanthemi and PEGylated forms of the drug were used to reduce the frequency of any of such adverse effects. This literature review provides current concepts on the mechanism of L-asparaginase dosage forms action, describes side effects associated with the use of this medication. We also present our own clinical case of L-asparaginase (obtained from Erwinia chrysanthemi) administration in ALL patient with allergic reaction to PEG-L-asparaginase.

Background: Intensive chemotherapy has improved complete remission (CR) rates in T-ALL/LBL. However, long-term overall survival (OS) continues to be suboptimal at about 50%. Nelarabine (NEL) is active in relapsed/refractory T-ALL. PEG-asparaginase (PEG) containing regimens have demonstrated significant activity in the pediatric population (Dunsmore et al. COG AALL0434. J Clin Oncol. 2018 Abstr #10500). We hypothesized that incorporating NEL and PEG in the frontline setting may further improve outcomes in adult T-ALL/LBL (NCT00501826). We had previously reported on the addition of nelarabine to the hyper-CVAD regimen (Abaza Y, Am J Hematol. 2018). Here, we report outcomes with the addition of PEG and longer follow-up. Methods Pts with T-ALL/LBL, either newly diagnosed or minimally treated (no CR with 1 cycle or CR after ≤2 cycles of induction) were eligible. Pts needed to have ECOG performance status (PS) ≤3, creatinine ≤2 mg/dL, bilirubin ≤2 mg/dL and ALT/AST ≤4 x ULN. The objectives were to determine safety, CR rate, progression-free survival (PFS), and OS with this combination. Pts received 8 cycles of with HCVAD (odd cycles 1,3,5,7) alternating with methotrexate (MTX) and cytarabine (ara-C; even cycles 2,4,6,8) at approximately 3-week intervals. Initially pts received NEL 650 mg/m2 IV daily for 5 days after 8 cycles as above. After enrollment of 30 pts, protocol was amended to deliver the 2 courses of NEL after cycle 4 and 5 of therapy in an attempt to reduce risk of early relapse. After enrollment of 79 pts, PEG (1500 IU/m2 IV capped at 3750 IU for pts ≤60 yrs and at 2000 IU for pts >60 yrs) was added to NEL courses on day 5. After completion of intensive phase, pts received 30 months of POMP maintenance (6-MP, vincristine, MTX, prednisone) with NEL/PEG replacing cycle 6 and 7 of POMP as early intensification. Late intensification consisted of MTX/PEG replacing cycle 18 and HCVAD replacing cycle 19 of POMP. CNS prophylaxis included 8 intrathecal doses of MTX alternating with ara-C. Pts with bulky mediastinal disease were considered for local radiation therapy prior to starting POMP maintenance. Results: Between August 16, 2007 and March 6, 2019, we enrolled 96 pts with T-ALL (n=57) and T-LBL (n=39). Median age was 35 yrs (range 18-78), 75 pts were male (78%) and 83 pts (86%) had PS 0-1. In pts with T-ALL, median bone marrow blast % was 79% (range 0-96), 70 pts (73%) had extramedullary disease with mediastinal involvement in 48 pts and CNS involvement in 5 pts. 60 pts (63%) had diploid cytogenetics, 13 pts (14%) had complex cytogenetics, 19 pts had miscellaneous abnormalities and 4 pts had insufficient metaphases. Based on immunophenotype, pts were further characterized as thymic (n=38), early T-cell precursor (ETP; n=38), mature (n=10), not otherwise specified (NOS; n=9), and early-non-ETP (n=3). 12 pts had received prior therapy with HCVAD (n=8), asparaginase-based regimen (n=2), and others (n=2). 30-day mortality was 0%. 9 pts were in CR at enrollment. There were 242 grade 3/4 non-hematological treatment-emergent adverse events (TEAE) with the most frequent grade 3/4 TEAEs being neutropenic infections in 74 pts (77%), hypokalemia in 42 pts (44%), hypophosphatemia in 42 pts (44%) and elevated ALT in 28 pts (29%). Overall response rate was 98% (85/87 pts) with CR in 95% pts (n=83), PR in 2% (n=2), and no response in 2% (n=2). The median no. of cycles to response was 1 (range 1-10) with CR reported based on achieving PET negativity as well as standard response criteria. CR rate in T-ALL was 88% (43/49) and T-LBL was 100% (38/38). At a median follow-up of 58.8 months (mo; 95% CI 42.2, 67.6), 61 pts (63%) are alive with a median PFS and OS of 135.3 and 135.1 mo, respectively (Fig 1a, b) and 55 pts (57%) remain in CR. For pts who received NEL after HCVAD cycle 4, the 7-year OS was 61% compared to 52% who received NEL after cycle 8, hazard ratio 0.91, 95% CI 0.46, 1.82, p=0.7. For pts receiving PEG in addition to NEL, the 2yr OS was 86% (Fig 1c). 30 pts (31%) relapsed and 35 pts (37%) have died including 9 pts who died in CR. 17 pts (18%) pts underwent allogeneic stem cell transplantation, 6 have relapsed, 10 are alive, and 1 pt died in remission. Rate of relapse was 37% with NEL after cycle 8, 33% (16/49) with NEL after cycle 4 and 21% (3/14) with NEL/PEG (p=.38). Conclusion: HCVAD with NEL with or without PEG is safe and effective as frontline therapy of adults with newly diagnosed T-ALL/LBL. Addition of PEG appears to confer a benefit. Figure Disclosures Maiti: Celgene: Research Funding. Jabbour:Adaptive Biotechnologies: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding. Jain:Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aprea Therapeutics: Research Funding; Fate Therapeutics: Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; ADC Therapeutics: Research Funding; Pfizer: Research Funding; BMS: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Borthakur:FTC Therapeutics: Consultancy; Curio Science LLC: Consultancy; Oncoceutics: Research Funding; Xbiotech USA: Research Funding; Cyclacel: Research Funding; PTC Therapeutics: Consultancy; BioLine Rx: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; BioLine Rx: Consultancy; Novartis: Research Funding; Abbvie: Research Funding; Jannsen: Research Funding; GSK: Research Funding; PTC Therapeutics: Research Funding; Polaris: Research Funding; BioTherix: Consultancy; Argenx: Consultancy; Incyte: Research Funding. Kadia:Incyte: Research Funding; Abbvie: Honoraria, Research Funding; Astellas: Research Funding; Astra Zeneca: Research Funding; Cyclacel: Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Research Funding; Celgene: Research Funding; Genentech: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Ascentage: Research Funding; Cellenkos: Research Funding; Novartis: Honoraria; Pulmotec: Research Funding. Burger:TG Therapeutics: Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Beigene: Research Funding, Speakers Bureau; Pharmacyclics, an AbbVie company: Consultancy, Research Funding, Speakers Bureau; Gilead Sciences: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy, Speakers Bureau. Konopleva:Kisoji: Consultancy; Agios: Research Funding; Genentech: Consultancy, Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Amgen: Consultancy; Calithera: Research Funding; Cellectis: Research Funding; Ablynx: Research Funding; AbbVie: Consultancy, Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Research Funding; AstraZeneca: Research Funding; Ascentage: Research Funding; Rafael Pharmaceutical: Research Funding; Forty-Seven: Consultancy, Research Funding; Eli Lilly: Research Funding; Sanofi: Research Funding. Alvarado:Jazz Pharmaceuticals: Research Funding; MEI Pharma: Research Funding; BerGenBio ASA: Research Funding; Sun Pharma: Research Funding; Daiichi-Sankyo: Research Funding; Tolero Pharmaceuticals: Research Funding; Astex Pharmaceuticals: Research Funding; FibroGen: Research Funding. Short:AstraZeneca: Consultancy; Amgen: Honoraria; Takeda Oncology: Consultancy, Honoraria, Research Funding; Astellas: Research Funding. Faderl:Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. O'Brien:Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc. Vaniam Group, AbbVie, Alexion, Verastem, Eisai, Juno Therapeutics, Vida Ventures: Consultancy; Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis: Consultancy, Research Funding; Kite, Regeneron, Acerta: Research Funding. Daver:Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding. Pemmaraju:Plexxikon: Research Funding; Affymetrix: Other: Grant Support, Research Funding; Pacylex Pharmaceuticals: Consultancy; Celgene: Honoraria; Daiichi Sankyo: Research Funding; DAVA Oncology: Honoraria; Samus Therapeutics: Research Funding; Cellectis: Research Funding; LFB Biotechnologies: Honoraria; Novartis: Honoraria, Research Funding; SagerStrong Foundation: Other: Grant Support; Incyte Corporation: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; Blueprint Medicines: Honoraria; Roche Diagnostics: Honoraria; AbbVie: Honoraria, Research Funding; MustangBio: Honoraria. Bose:Astellas Pharmaceuticals: Research Funding; CTI BioPharma: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Kartos Therapeutics: Honoraria, Research Funding; Constellation Pharmaceuticals: Research Funding; Blueprint Medicines Corporation: Honoraria, Research Funding; Pfizer, Inc.: Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Promedior, Inc.: Research Funding; NS Pharma: Research Funding. Thompson:AbbVie: Research Funding; Pharmacyclics: Research Funding; Janssen-Cilag: Honoraria; Adaptive Biotechnologies: Consultancy, Research Funding; Genentech: Consultancy. Garcia-Manero:Bristol-Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amphivena Therapeutics: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; AbbVie: Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Novartis: Research Funding; H3 Biomedicine: Research Funding; Onconova: Research Funding. Kantarjian:Amgen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Ascentage: Research Funding; Immunogen: Research Funding; Aptitute Health: Honoraria; BioAscend: Honoraria; Delta Fly: Honoraria; Janssen: Honoraria; Oxford Biomedical: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sanofi: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Honoraria; BMS: Research Funding; Jazz: Research Funding. Ravandi:Astellas: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Orsenix: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria.

Vaccinationis a critical tool in the prevention of COVID‐19 infection for individuals and for communities. The mRNA vaccines contain polyethylene glycol (PEG) as a stabilizer. Currently, in North America, only the BNT162b2 (Pfizer‐BioNTech) mRNA vaccine is approved for individuals aged 12–17. Most patients treated with contemporary regimens for acute lymphoblastic leukemia receive PEG‐asparaginase (PEG‐ASNase) and 10%–30% will develop allergic reactions. Optimizing access and safety for vaccine administration for these patients is critical. This report describes a process developed to support COVID vaccination in a cohort of adolescents and young adults with a history of PEG‐ASNase allergy.

Objectives: This is a protocol for a Cochrane Review (intervention). The objectives are as follows:. To assess the effect of the number of PEG-asparaginase doses on survival and relapse in children and adolescents with acute lymphoblastic leukaemia (ALL). Secondary objectives To assess the association between the number of doses of PEG-asparaginase and asparaginase-associated toxicities (e.g. hypersensitivity, thromboembolism, pancreatitis and osteonecrosis). To undertake a network meta-analysis (NMA) at dose-level in order to generate rankings of the number of doses of PEG-asparaginase used in the treatment for ALL, according to their benefits (survival and relapse) and harms (toxicity).

Background PEG-asparaginase is critical in pediatric acute lymphoblastic leukemia (ALL) therapy but is highly immunogenic. Severe allergic reactions lead to substitution of further PEG-asparaginase with Erwinia. Erwinia is associated with more frequent dosing, increased expense, and limited availability. Premedication may reduce rates of allergic reactions. Procedures This Markov model evaluated the cost-effectiveness of three strategies: premedication plus therapeutic drug monitoring (TDM), TDM alone, and no premedication or TDM. We modeled two scenarios: a standard-risk (SR) B-ALL patient receiving two asparaginase doses and a high-risk (HR) patient receiving seven asparaginase doses. The model incorporated costs of asparaginase, premedication, TDM and clinic visits, and lost parental wages associated with each additional Erwinia dose. We incorporated a five-year time horizon with a societal perspective. Outcomes were Erwinia substitutions avoided and differences in quality-adjusted life years (QALYs). Probabilistic and one-way sensitivity analyses evaluated model uncertainty. Results In both scenarios, premedication was the least costly strategy. In SR and HR scenarios, premedication with monitoring resulted in 8% and 7% fewer changes to Erwinia compared with monitoring alone and 3% and 2% fewer changes compared with no premedication/monitoring, respectively. Premedication resulted in the most QALYs gained in the SR patients. Individual variation of model inputs did not change premedication/monitoring favorability for either scenario. In probabilistic sensitivity analyses, premedication/monitoring was favored in >87% of iterations in both scenarios. Conclusion Compared with other strategies, premedication use and asparaginase level monitoring in children with B-ALL is potentially cost-saving.

BACKGROUND: Multiagent chemotherapy is the primary treatment for acute lymphoblastic leukemia (ALL), of which asparaginases including Escherichia coli L-asparaginase (E. coli L-Asp) and pegylated-asparaginase (PEG-Asp), are cornerstone components. The study aimed to conduct a meta-analysis to compare the efficacy and safety of PEG-Asp with E. coli L-Asp in Chinese children with ALL. METHODS: A systematic literature search was conducted to collect randomized controlled trials (RCTs) on PEG-Asp versus E. coli L-Asp in Chinese children with ALL. Two reviewers independently selected articles and extracted data. Risk-of-bias assessment was conducted with Cochrane recommendation tool. Pooled estimates and risk ratios (RRs) with 95% confidence intervals (CIs) were calculated for all outcomes in Review Manager 5.3. RESULTS: Out of the 470 publications screened, 15 studies were included, involving 1,194 patients. Pooled estimates showed that there were no significant differences in complete responses (CR), overall response rate (ORR), gastrointestinal symptoms, and coagulation abnormalities rate between the PEG-Asp and E. coli L-Asp groups (all P>0.05). Hypersensitivity (RR =0.63; 95% CI, 0.40–1.01; Ρ=0.05) and hepatic injury rate (RR =0.45; 95% CI, 0.27–0.75; Ρ=0.002) were lower in the PEG-Asp group. The frequency of administration and length of hospital stay of patients in the PEG-Asp group were less than those in the E. coli L-Asp group (both Ρ

Acute lymphoblastic leukemia (ALL) is a rare disease in infants. Asparaginase is an essential part of the treatment, and there Acute is a need to evaluate the efficiency and safety of this drug in this age group. We evaluated the pharmacokinetics of intramuscularly administered native E. coli asparaginase (Asparaginase Medac®) and PEG-asparaginase (Oncaspar®) as well as hypersensitivity reactions during treatment in Interfant-06 ( www.clinicaltrials.gov : NCT01025804). All patients without hypersensitivity had sufficiently high enzyme activity levels during treatment with both preparations. Patients with hypersensitivity reactions during treatment, characterized by the presence of either or not of clinical symptoms and no measurable enzyme activity, received ineffective therapy. For optimization of the bad prognosis in infant ALL, therapeutic drug monitoring should be performed for identification of patients who should be switched to a different asparaginase preparation because of inactivation of the drug.

Background: Asparaginase poses a substantial risk for hypersensitivity reactions during and after administration; however, these reactions vary by asparaginase formulation and administration route. It is imperative that nurses be knowledgeable of clinical symptoms associated with intravenous (IV) monomethoxypolyethylene glycol (PEG)-asparaginase reactions, as well as potential reaction timing. Purpose: This single institution retrospective study describes the clinical factors among patients with IV PEG-asparaginase hypersensitivity reactions. Methods: Reaction frequency and severity, dose, phase of treatment, and time between infusion initiation and reaction were collected on patients identified as having an IV PEG-asparaginase hypersensitivity reaction while undergoing acute lymphoblastic leukemia treatment. Results: Sixty-three patients (12.8%) developed a hypersensitivity reaction to IV PEG-asparaginase, with the reaction occurring during a median of 3 doses in both risk arms. Reactions were noted ≤60 minutes after infusion initiation in 98% of patients, and no reactions were fatal. Conclusion: Nurses should carefully observe patients throughout the infusion and anticipate adverse reactions, particularly during the first 3 doses and first 10 minutes of each infusion. Patient and family education should include the rare risk of delayed reactions.

Polyethylene glycosylated (PEG)-asparaginase is a cornerstone of treatment for acute lymphoblastic leukemia (ALL), and effective administration is associated with better outcomes. PEG-asparaginase is associated with a uniphasic hypersensitivity reaction in ∼10% to 20% of patients. We present a 17-year-old male individual diagnosed with very high-risk pre-B-ALL, who experienced protracted anaphylaxis 1 hour following administration of his second PEG-asparaginase dose. This type of allergic reaction has yet to be described in ALL patients treated with PEG-asparaginase. Here, we outline the time course and successful management of protracted anaphylaxis in an ALL patient.

Asparaginase (ASNase) is an integral part of pediatric induction chemotherapy that has also been shown to improve adult survival rates; however, pegylated (PEG)-ASNase induces severe hepatotoxicity in this population. Recent case reports describe the incorporation of levocarnitine (LC) supplementation into PEG-ASNase-containing induction regimens to prevent or treat hepatotoxicity. Because LC facilitates the metabolism of free fatty acids (FFA), a primary fuel source for ALL cells, LC could potentially interfere with ALL chemotherapy efficacy. To test this, we employed in vitro and in vivo models of ALL. We show in vitro that LC supplementation does not impact cytotoxicity from vincristine, daunorubicin, dexamethasone, or ASNase on human ALL cells nor lead to an increase in ALL cell metabolic rate. In vivo, we demonstrate LC does not impair PEG-ASNase monotherapy in mice with syngeneic ALL. Together, our findings show that LC supplementation is a safe strategy to prevent/reverse ASNase-induced toxicities in preclinical models.

PURPOSE Asparaginase is an essential drug in childhood acute lymphoblastic leukemia (ALL) therapy and is frequently given for months to obtain continuous asparagine depletion. We randomly assigned patients to continuous versus intermittent pegylated-asparaginase (PEG-asp) treatment, hypothesizing there would be decreased toxicity with unchanged efficacy. METHODS Children (median age, 4.2 years) treated for non–high-risk ALL according to the Nordic Society for Pediatric Hematology and Oncology ALL2008 protocol received five intramuscular PEG-asp injections (1,000 IU/m2) every two weeks and were then randomly assigned to additional three doses (6-week intervals [experimental arm], n = 309) versus 10 doses (2-week intervals [standard arm], n = 316). The primary end point was noninferior (6% margin) disease-free survival. Toxicity reduction was a secondary end point. Occurrence of asparaginase-associated hypersensitivity, pancreatitis, osteonecrosis, and thromboembolism were prospectively registered. RESULTS After a median follow-up of 4.1 years, the 5-year disease-free survival was 92.2% (95% CI, 88.6 to 95.8) and 90.8% (95% CI, 87.0 to 94.6) in the experimental and standard arms, respectively. The 3-year cumulative incidence of any first asparaginase-associated toxicity (hypersensitivity [n = 13]; osteonecrosis [n = 29]; pancreatitis [n = 24]; thromboembolism [n = 17]) was 9.3% in the experimental arm and 18.1% in the standard arm ( P = .001). Asparaginase-associated toxicity reduction was confirmed in sex- and risk-group–adjusted Cox regression analysis stratified by age (≥ 10 and < 10 years; hazard ratio, 0.48; P = .001). The experimental arm had the lowest incidences of all four toxicities, reaching significance for pancreatitis (6-month risk, 5.8% v 1.3%; P = .002). CONCLUSION The excellent cure rates and reduced toxicity risk support the use of intermittent PEG-asp therapy after the first 10 weeks in future childhood ALL trials that apply prolonged PEG-asp therapy.

Asparaginase is essential in childhood acute lymphoblastic leukaemia (ALL) treatment, however hypersensitivity reactions to pegylated asparaginase (PEG-asparaginase) hampers anti-neoplastic efficacy. Patients with PEG-asparaginase hypersensitivity have been shown to possess zero asparaginase enzyme activity. Using this measurement to define the phenotype, we investigated genetic predisposition to PEG-asparaginase hypersensitivity in a genome-wide association study (GWAS). From July 2008 to March 2016, 1494 children were treated on the Nordic Society of Paediatric Haematology and Oncology ALL2008 protocol. Cases were defined by clinical hypersensitivity and no enzyme activity, controls had enzyme activity ≥ 100 iu/l and no hypersensitivity symptoms. PEG-asparaginase hypersensitivity was reported in 13·8% (206/1494) of patients. Fifty-nine cases and 772 controls fulfilled GWAS inclusion criteria. The CNOT3 variant rs73062673 on 19q13.42, was associated with PEG-asparaginase allergy (P = 4·68 × 10-8 ). We further identified two signals on chromosome 6 in relation to HLA-DQA1 (P = 9·37 × 10-6 ) and TAP2 (P = 1·59 × 10-5 ). This study associated variants in CNOT3 and in the human leucocyte antigen (HLA) region with PEG-asparaginase hypersensitivity, suggesting that not only genetic variations in the HLA region, but also regulation of these genes are of importance in the biology of this toxicity. Furthermore, our study emphasizes the importance of using asparaginase enzyme activity measurements to identify PEG-asparaginase hypersensitivity.

Objective Although L-asparaginase (L-ASP) is a standard treatment for lymphoblastic lymphoma (LBL), hypersensitivity reactions by some patients limit its application. Polyethylene glycol-conjugated asparaginase (PEG-ASP) has a lower immunogenicity and is a standard treatment in all pediatric acute lymphoblastic leukemia (ALL). In this study, we investigated the efficacy and toxicity of PEG-ASP instead of L-ASP as used in the BFM-90 regimen (PEG-ASP-BFM-90) for adult LBL. Methods Between June 2012 and July 2015, we treated 30 adult patients with newly diagnosed LBL, using PEG-ASP-BFM-90 in a prospective, multicenter and single-arm clinical study at 5 participating institutions in China. Results All the 30 patients, including 19 males and 11 females with a median age of 30 (range: 18-62) years, completed 128 times of the PEG-ASP, with the median of 4 (range: 2-6) times. Patients did not receive radiotherapy at this time. The overall response rate was 86.7% (26/30), with 50.0% (15/30) complete response and 36.7% (11/30) partial response. The 3-year overall survival was 46.0% [95% confidence interval (95% CI), 28.2%-64.8%], and the 3-year progression-free survival was 43.0% (95% CI, 25.7%-62.0%). Major adverse events were myelosuppression, reduced fibrinogen, liver dysfunction and digestive tract toxicities. No allergic reaction and no treatment-related mortality or severe complications were recorded. Conclusions Our clinical data and observed outcomes indicate that 1 dose of PEG-ASP can replace multiple doses of native L-ASP in BFM-90, with predominantly grade 3-4 neutropenia for adult LBL, and no therapy-related deaths. The effect is similar to previous reports of PEG-ASP-containing regimens for adult ALL. Major advantages include less serious allergic reactions, 2-3 weeks of action duration, and convenience for patients and physicians.

Background: Asparaginase is a critical therapy component for childhood acute lymphoblastic leukemia (ALL). Hypersensitivity reactions and silent inactivation by neutralizing antibodies can lead to withholding further doses. Reactions occur in 10-20% of children receiving the commonly used, widely available pegylated asparaginase. The less immunogenic Erwinia asparaginase may allow continued administration, but requires more frequent dosing and is subject to limitations in availability. Inability to receive all recommended asparaginase doses decreases disease-free survival. Premedication with antihistamines, antipyretics and steroids decreases hypersensitivity reaction frequency, preventing the need for alternates. The cost-effectiveness of premedication strategies in childhood ALL is unclear. Methods: We used a Markov model to estimate strategy costs and quality-adjusted life years (QALYs) for two patient scenarios: a 3-year-old with standard-risk ALL receiving 2 asparaginase doses, and a 15-year-old with high-risk ALL receiving 7 asparaginase doses over a 5-year time horizon. Patients entering the model received premedication with serum asparaginase level monitoring, monitoring only, or no premedication/monitoring. Literature data were used for hypersensitivity reaction and silent inactivation risks following each asparaginase dose. Silent inactivation was not identified the non-monitoring strategy. Disease outcomes, therapy and associated additional care costs, and health state quality-of-life utilities were obtained from the literature and US databases. Evaluation took the societal perspective, with costs and effectiveness discounted at 3%/yr. Multiple sensitivity analyses were performed. Results: In both the standard-risk and high-risk analyses, premedication was the least costly strategy. In the standard-risk model, premedication with monitoring cost $4,586 less than monitoring alone, resulted in 8% fewer changes to Erwinia and 0.01 additional QALYs. It cost $1,993 less than no premedication/monitoring, resulted in 3% fewer changes and 0.08 additional QALYs. In the high-risk model, premedication cost $29,757 less than monitoring alone, resulted in 7% fewer medication changes and 0.01 fewer QALYS; thus, monitoring alone was expensive, costing >$2 million/QALY gained compared to premedication and monitoring. Premedication cost $11,255 less than no premedication/monitoring, resulted in 2% fewer changes and 0.07 additional QALYs. Individual variation of all model inputs did not change the favorability of premedication and monitoring for either model. In probabilistic sensitivity analyses varying all parameters simultaneously over distributions 1000 times, premedication and monitoring was favored in >86% of model iterations in both standard- and high-risk scenarios. Conclusion: Compared to other strategies, premedication use and asparaginase level monitoring in children with ALL is economically reasonable and potentially cost-saving. Disclosures No relevant conflicts of interest to declare.

Asparaginase (ASNase) use as a tumour-inhibitor drug has changed completely the natural course of paediatric acute lymphoblastic leukaemia (ALL) in such a way that it represents a paradigm shift in ALL management. ASNase treatment emergence has significantly improved pathologic responses and increased survival rates of ALL patients. Although different ASNase forms are currently available, only the pegylated form (PEG-ASNase) is recommended by relevant clinic guides. PEG-ASNase form shows longer elimination half-life, reducing the number of administrations, along with an enhanced safety profile. In spite of all of these advantages, PEG-ASNase elevated cost limits enormously its use. PEG-ASNase is commercialised as a lyophilised powder which according to the manufacturer it is stable for 24 hours once reconstituted, as a result, the leftover is usually discarded. In this study we analysed the enzymatic stability of reconstituted PEG-ASNase after conservation in three different temperature conditions for 5 and 14 days, aiming to take advantage of the remaining leftover for the subsequent administration. Our results have shown that PEG-ASNase is stable at 4°C, −20°C and −80°C for at least 14 days, retaining the 95% from the initial enzymatic activity in all three storage temperatures. According to our results, it is feasible to reuse the remaining content of PEG-ASNase vial after reconstitution, which means a 50% reduction of its cost for paediatric patient treatment and, consequently, removes the main barrier to use this drug in a wider population.

Hepatosplenic γδ T-cell lymphoma (HSTCL) is a rare aggressive peripheral T-cell lymphoma. Prognosis is usually poor with a median survival between 8 and 16 months after traditional chemotherapy. Stem cell transplantation (SCT) is promising and with a more intense induction regimen, has yielded positive results. We report the use of pegylated-asparaginase (PEG-asparaginase) along with a conventional anthracycline-containing regimen in a 51-year-old male who was diagnosed with HSTCL, achieved a complete remission, and subsequently underwent peripheral blood SCT and remained in remission at the time of this case report.

Peg-asparaginase has widely replaced the use of conventional asparaginase in treatment of children with acute lymphoblastic leukaemia in developed countries. In developing countries like India, with financial constraints being a part of clinical challenge to the treatment of cancers, uniform use of Peg-asparaginase in all children is not practically possible. However, we found by a retrospective analysis of 211 children treated for acute lymphoblastic leukaemia, uniform use of this drug was feasible with indigenous techniques like storing the drug with strict cold chain maintenance and sharing the drug amongst 2 or 3 patients to reduce the burden on each family. We have not found increased rates of infection or any loss of efficacy of the drug due to prolonged storage.

Adults with acute lymphoblastic leukemia (ALL) are known to have inferior outcomes compared to the pediatric population. Although the reasons for this are likely manyfold, the agents utilized and the increased intensity of pediatric treatments compared to adult treatments are likely significant contributing factors. Asparaginase, an enzyme that converts asparagine to aspartic acid, forms the backbone of almost all pediatric regimens and works by depleting extracellular asparagine, which ALL cells are unable to synthesize. Asparaginase toxicities, which include hypersensitivity reactions, pancreatitis, liver dysfunction, and thrombosis, have hindered its widespread use in the adult population. Here, we review the toxicity and efficacy of asparaginase in adult patients with ALL. With the proper precautions, it is a safe and effective agent in the treatment of younger adults with ALL with response rates in the frontline setting ranging from 78% to 96%, compared to most trials showing a 4-year overall survival of 50% or better. The age cutoff for consideration of treatment with pediatric-inspired regimens is not clear, but recent studies show promise particularly in the adolescent and young adult population. New formulations of asparaginase are actively in development, including erythrocyte-encapsulated asparaginase, which is designed to minimize the toxicity and improve the delivery of the drug.

Background L-Asparaginase is an effective drug in the treatment of childhood acute lymphoblastic leukemia (ALL). The use of L-asparaginase may be limited by serious adverse events of which allergy is the most frequent. The objective of this study was to describe the clinical aspects of PEG-asparaginase allergy in children treated according to the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol. Procedure Children (1–17 years) enrolled in the NOPHO ALL2008 protocol between July 2008 and August 2011, who developed PEG-asparaginase allergy were identified through the NOPHO ALL2008 toxicity registry. In the NOPHO ALL2008 protocol, patients are randomized to 8 or 15 doses of intramuscular PEG-asparaginase (Oncaspar®) 1,000 IU/m2/dose administered at 2 or 6 weeks intervals during a total period of 30 weeks. (Clinical trials.gov no: NCT00819351). Results Of 615 evaluable patients, 79 patients developed clinical PEG-asparaginase allergy (cumulative risk; 13.2%) and discontinued PEG-asparaginase therapy for that reason. PEG-asparaginase allergy occurred after a median of two doses (75% range 2–4, max 14). In 58% of PEG-asparaginase hypersensitive patients, the clinical allergic reactions appeared within 2 hr after PEG-asparaginase administration and ranged from mild symptoms to systemic anaphylaxis. Nine patients experienced an anaphylactic reaction within 1 hr and 50 min from asparaginase administration; none were fatal. Four of 68 patients (6%) who subsequently received Erwinase therapy also reacted allergic to Erwinase. Conclusion Clinical allergy to PEG-asparaginase occurred early in treatment, was in general moderate in severity, and mostly developed within 2 hr after PEG-asparaginase administration. The risk of subsequent Erwinase allergic reactions was low. Pediatr Blood Cancer 2015;62:427–433. © 2014 Wiley Periodicals, Inc.

Background: Asparaginase may improve outcomes in chemotherapy resistant malignancy, especially of lymphoid origin. L-asparaginase (L-ASP) was introduced in 1992 and hence has been incorporated in multiple regimens. An effective regimen including steroid (dexamethasone), methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) was developed by the NK-Cell Tumor Study Group as a unique chemotherapeutic regimen to combat chemo-resistant NK-cell neoplasms (Yamaguchi et al. 2008) and later shown to have efficacy in relapsed and refractory lymphoblastic lymphoma (Chang et al. 2014). The pegylated-asparaginase (PEG-ASP) is the only readily available commercial product as the other forms either have limited availability due to shortages (Erwinia asparaginase) or are no longer available in the United States (E-coli asparaginase). We present retrospective data incorporating PEG-ASP into a modified SMILE (mSMILE) regimen. To our knowledge, no prior comparison between the PEG-ASP and L-ASP based SMILE regimen is available in the literature. Methods: All adult patients treated with mSMILE for either extranodal NK/T-cell leukemia and lymphoma (ENKTL), T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LBL), adult T-cell leukemia/lymphoma (ATLL), or peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) from 12/1/2009-6/30/2019 at Moffitt Cancer Center were included. PEG-ASP replaced L-ASP in SMILE regimen at a dose of 2500 units/m2/dose IV on Day 8 only (maximum dose of 3750 units). Cycles were repeated every 28 days until disease progression, excessive toxicity, or consolidation with hematopoietic cell transplantion (HCT). Patients received appropriate supportive care with peg-filgrastim or filgrastim (until absolute neutrophil count > 1000/ul x 3Days or >3,000/ul) as well as antimicrobial prophylaxis with acyclovir, ciprofloxacin, and fluconazole once methotrexate cleared and post-chemotherapy. Toxicity assessment was analyzed retrospectively and graded based upon Common Terminology Criteria for Adverse Events (CTCAE) version 5. Toxicity profiles of PEG-ASP-based mSMILE in present study were compared to profiles of L-ASP-based SMILE in the recently published literature (Pokrovsky & Vinnikov Expert Rev Anticancer Ther, 2019). Results: A total of 13 patients were treated with mSMILE during the 10-year period (Table 1). Of these patients, the median age was 46 years (range, 19-69), caucasians (46%) and males (70%). Most of the patients were treated for ENKTL (46%). mSMILE was the first line therapy in 3 patients, while the median number of prior therapies was 1 (range 0-3). Toxicity assessment for mSMILE focused on PEG-ASP-induced toxicity as no patients had any hemorrhagic cystitis, neurotoxicity, or renal dysfunction that could be associated with ifosfamide, methotrexate, or etoposide. mSMILE was comparatively associated with more hematologic toxicity, likely related to inclusion of patients with lymphoblastic leukemia (table 2). Grade 3/4 hepatotoxicity rates are low, possibly owing to inclusion of carnitine prophylaxis (Schulte et al. 2018). Thrombosis was not observed. Hypertriglyceridemia was observed in 15% with no cases of pancreatitis. Hypersensitivity and neurotoxicity were not observed. Of the two patients who discontinued therapy due to toxicity, one was related to grade 3 hypofibrinogenemia and the other grade 4 bleeding. Mortality was attributable to disease progression in all cases, with 0% treatment related mortality. Efficacy is comparable, with ORR 54% (7/13), including 30% (4/13) successfully bridged to HCT. Conclusion: In a non-Asian population, modified SMILE regimen with PEG-ASP is a safe alternative to L-ASP-based SMILE regimen. There is increased hematological toxicity, which did not seem to affect chemotherapy delivery. Disclosures Chavez: Genentech: Speakers Bureau; Janssen Pharmaceuticals, Inc.: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Bello:Celgene: Speakers Bureau. Pinilla Ibarz:Sanofi: Speakers Bureau; Bayer: Speakers Bureau; TG Therapeutics: Consultancy; Teva: Consultancy; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Sokol:EUSA: Consultancy. Shah:AstraZeneca: Honoraria; Spectrum/Astrotech: Honoraria; Novartis: Honoraria; Celgene/Juno: Honoraria; Kite/Gilead: Honoraria; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Honoraria; Adaptive Biotechnologies: Honoraria.

Background and aim: The AIEOP-BFM ALL 2009 trial (https://www.clinicaltrials.gov/NCT01117441) is an international collaborative treatment protocol for children and adolescents with acute lymphoblastic leukemia (ALL) wherein PEG-ASP (Oncaspar®, Servier) was used as the front-line ASP product. Since HSR represent the most relevant limitation to the completion of ASP treatment schedules in the context of any study protocol, we evaluated the cumulative incidence of HSR following PEG-ASP treatment for better understanding the impact of this product on the HSR phenomenon in the context of the treatment strategy outlined in the AIEOP-BFM ALL 2009 study protocol. Patients and Methods: Children with newly diagnosed ALL were enrolled in the AIEOP-BFM ALL 2009 protocol and stratified as Standard (SR), Intermediate (IR) or High-Risk (HR) according to their presenting and response criteria. A first exposure to PEG-ASP, administered I.V. at 2,500 IU/sqm throughout the whole protocol, was scheduled in all patients during induction (phase IA, 2 doses, on day 12 and 26), whilst second or further exposures were scheduled as follows: a. in SR and MR patients during the reintensification (protocol II, 1 dose); and b. in HR patients during each of the three intensive blocks and of the three protocols III (1 dose in each of these phases). In addition, MR patients were randomized (RMR) at the start of reintensification (protocol II) to receive 0 (Standard Arm, SA) vs 9 (Experimental Arm, EA) additional biweekly PEG-ASP doses throughout protocol II and continuation therapy. Therefore, all the SR patients and the MR patients randomized to SA overall received 3 PEG-ASP doses with an 18-week-long interval between doses #1+#2 (induction, first exposure) and dose #3 (reintensification, second exposure) whilst the MR patients randomized to the EA overall received 12 PEG-ASP doses with an 18-week-long interval between doses #1+#2 (induction, first exposure) and doses #3 to #12 (reintensification and continuation therapy, second exposure). HR patients were randomized (RHR) at the start of the consolidation phase (protocol IB) to receive 0 (SA) vs 4 (EA) additional weekly PEG-ASP doses. Therefore, HR patients randomized to the EA received overall 12 PEG-ASP doses (first exposure: #1+#2 in IA; further exposures: #3 to #6 in IB, #7 to #9 in each of the 3 blocks and #10 to #12 in each of the protocols III) without relevant time-intervals among the various doses, whilst HR patients randomized to the SA received overall 8 doses with an 8-week-long interval between the doses #1+#2 (IA, first exposure) and the second and further exposures (3 blocks and 3 protocols III, doses #3 to #8). HSR were recorded by treating physicians and collected in the trial database and cumulative incidence (CI-HSR) was estimated adjusting for competing risks (death for any reasons and leuekemia recurrence). Results: Between June 01, 2010 and February 28, 2017, 6136 patients were eligible and evaluable in the study and are here reported. An HSR occurred in 468 patients, with a CI-HSR of 7.6% (SE 0.3). In particular, 121 (2.0%) occurred in IA, 20 (0.3%) in IB, 140 (2.3%) in Protocol II, 183 (3.0%) in blocks, 4 (0.07%) in Protocols III and maintenance. According to the stratification group, CI-HSR was 4.9%(0.5) in SR, 4.9% (0.4) in MR and 16.8% (1.0) in HR groups. In the RMR study, the CI-HSR was 3.1% (0.6) vs 4.3% (0.8) in the SA vs the EA, respectively (p-value=0.26), whilst in the RHR study the CI-HSR was 18.3% (1.9) vs 6.1% (1.3) in the SA vs the EA, respectively (p-value Conclusions: In the AIEOP-BFM ALL 2009 trial, the incidence of HSR was much lower with respect of historical experiences of previous AIEOP-BFM ALL protocols wherein the native E.Coli ASP product was used I.V. as first-line product. No difference in terms of HSR was found between patients belonging to the EA and SA of the RMR. As expected, due to the higher number of PEG-ASP doses administered, the cumulative incidence of HSR was much higher in the HR group. Interestingly and in keeping with the concept that continuous and prolonged exposures to PEG-ASP reduce the probability of developing an HSR, patients randomized to receive in the RHR the SA (long interval between the first and subsequent exposures) showed an incidence of HSR much higher (18.3%) than that observed in the EA control arm (6.1%). Disclosures Rizzari: Together with study group from Shire, medac , Sigma-Tau, Baxalta, Shire and Servier: Research Funding; JazzPharma, Shire, medac , Sigma-Tau, Baxalta, Shire and Servier: Consultancy, Honoraria. Locatelli:Miltenyi: Honoraria; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; BluebirdBio: Consultancy; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Boos:medac GmbH: Membership on an entity's Board of Directors or advisory committees, Other: Safety Boards, invited lectures, drug monitoring program; Eusa Pharma: Other: invited lectures, drug monitoring program; Jazz Pharmaceuticals: Other: invited lectures, drug monitoring program; Baxalta: Other: invited lectures, drug monitoring program; Shire: Other: invited lectures, drug monitoring program; Sigma-Tau: Other: invited lectures, drug monitoring program. Zucchetti:Together with study group from medac , Sigma-Tau, Baxalta, Shire and Servier: Research Funding. Schrappe:Together with study group from SHIRE, JazzPharma, Servier, SigmaTau, Amgen, and Novartis.: Research Funding; SHIRE, Servier, and JazzPharma: Honoraria.

e18520 Background: Venous thromboembolism (VTE) is common in acute lymphoblastic leukemia (ALL) patients (pts) receiving peg-asparaginase (ASNase) however there is limited data regarding the incidence of VTE and risk factors for VTE in adolescent and young adults (AYA) treated with ASNase. Methods: This is a single institutional retrospective analysis of AYA pts with ALL who received ASNase from January 2013 to December 2018. Time to VTE was calculated from date of starting treatment to onset of VTE or censored at last assessment date, treating death as a competing risk. The cumulative incidence of VTE was estimated and the Fine and Gray regression models accounting for competing risks were used to examine the association between risk factors and VTE. Results: Forty-six AYA ALL patients were included. Pt characteristics are shown in the Table. Twenty pts had a VTE following ASNase with the cumulative incidence rate of 35% (95% CI: 22-48%) at 100 days. The most common VTE sites were cerebral (n=6) and upper extremity (n=6). Nine pts (43%) had at least one recurrent VTE. After initial VTE, ASNase was continued in 13 pts (62%), stopped in 6 pts (29%), and dose reduced in 2 pts (10%). Nine pts (45%) of those who developed VTE received antithrombin. Out of the 6 pts with VTE who had ASNase discontinued or dose reduced, 2 (33%) had progression of ALL. The hazard ratios (HR) for risk of VTE from univariable regression models are listed in Table 1. Male sex was associated with increased VTE risk, with HR=3.33 (95% CI: 1.13-9.77). Conclusions: Our study estimated the incidence of VTE in the AYA cohort. Only male sex was identified as a risk factor for VTE. Additional studies are needed to assess VTE risk factors in AYA pts with ALL. Pt characteristics and hazard ratios for risk of VTE. [Table: see text]

PEG-aspariginase is a backbone chemotherapy agent in pediatric acute lymphoblastic leukemia and in some non-Hodgkin lymphoma therapies. Nurses lack standardized guidelines for monitoring patients receiving PEG-asparaginase and for educating patients/families about hypersensitivity reaction risks. An electronic search of 6 databases using publication years 2000-2015 and multiple professional organizations and clinical resources was conducted. Evidence sources were reviewed for topic applicability. Each of the final 23 sources was appraised by 2 team members. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) system was used to assign a quality and strength rating for each recommendation. Multiple recommendations were developed: 4 relating to nurse monitoring of patients during and after drug administration, 8 guiding hypersensitivity reaction management, and 4 concerning patient/family educational content. These strong recommendations were based on moderate, low, or very-low-quality evidence. Several recommendations relied on generalized drug hypersensitivity guidelines. Additional research is needed to safely guide PEG-asparaginase monitoring, hypersensitivity reaction management, and patient/family education. Nurses administering PEG-asparaginase play a critical role in the early identification and management of hypersensitivity reactions.

e18501 Background: Asparaginase (ASN) is a critical part of ALL therapy; however, in adults, a higher incidence of toxicities results in treatment delays and suboptimal exposure. We have reported a higher rate of PEG toxicity in pts > 50 yrs of age, baseline liver dysfunction, diabetes, and obesity (BMI ≥ 30). Thus, we hypothesized that reducing the PEG dose from 2500 units/m2 to 1000 units/m2 with further reduction to 500 units/m2 if any of those co-morbidities were present would reduce toxicities and still achieve therapeutic ASN levels. Methods: This is a single-center, retrospective study that included adult pts with ALL. Pts must have received at least one dose of PEG using a pediatric inspired regimen that includes 7 doses of PEG. The primary objective was to determine the rate of target ASN activity (≥ 0.1 IU/mL) one week after administration of reduced PEG during induction. Secondary objectives included the incidence of grade 3/4 toxicity based upon CTACE 4 criteria (hepatotoxicity, pancreatitis, hypertriglyceridemia, and VTE) between standard (SD) > 1000 units/m2 and reduced (RED) ≤1000 units/m2 PEG dosing. Results: 41 consecutive pts with ALL were included. Median age was 43 years (range 18-76). Median WBC upon admission was 7.6. At baseline, 25 pts (61%) had at least one comorbidity. 26 pts (63%) received SD PEG and 15 pts (37%) received RED PEG with median dose 1000 units/m2. 80% of pts achieved target ASN activity following administration of a RED PEG induction dose, median level of 0.1 IU/mL (IQR 0.1-0.24 IU/mL). 30 pts (73%) experienced grade 3/4 toxicity during induction, 81% in the SD group vs 60% in the RED group (p = 0.3). During induction, grade 3/4 hepatotoxicity was seen in 16 SD pts (62%) vs 6 RED pts (40%) (p = 0.211). Grade 3/4 hyperbilirubinemia was seen in 12 SD pts (46%) vs 1 RED pt (7%) (p = 0.014). Conclusions: The majority of pts attained a therapeutic ASN activity level with RED PEG. This resulted in a trend towards lower incidence of overall toxicity and a significant decrease in hyperbilirubinemia. A larger prospective study will be needed to determine whether decreased toxicity during induction correlates with fewer treatment delays, improved drug delivery, and better treatment outcome.

Use of asparaginase (ASNase) in the treatment of relapsed childhood acute lymphoblastic leukaemia (ALL) is associated with a high rate of hypersensitive reactions. 'Silent' inactivation may additionally reduce treatment intensity. Therefore, PEG-ASNase (Oncaspar), a polyethylene glycol conjugate of the native Escherichia coli-ASNase, was introduced into the Berlin-Frankfurt-Munster (BFM) 96 treatment protocol for relapsed ALL under drug monitoring conditions. A single i.v. dose of 500 IU/m2 PEG-ASNase, substituted for the native ASNases, was administered to supply a plasma activity of 100 IU/l for 1 week. From November 1997 to March 2000, 35 patients from 23 BFM-associated hospitals, with or without a previous allergic reaction to one or both native preparations, underwent monitoring. After 82 applications, a total of 270 samples were submitted to be tested for ASNase activity. The ASNase activity on the day of the administration and the following day ranged between 100 IU/l was seen on d 7 in 36 activity time courses of 52 interpretable applications (69%). Intraindividual variability of activity time courses was low. However, a rapid decrease in ASNase activity after repeated applications was observed in 4 out of 20 children. Previously experienced allergic reactions to native ASNases did not influence PEG-ASNase pharmacokinetics. PEG-ASNase is a useful alternative to the native ASNases in children with relapsed ALL. Whenever possible, drug monitoring should be performed to identify patients with 'silent' inactivation.

This study prospectively analyzed the efficacy of very prolonged courses of pegylated Escherichia coli asparaginase (PEGasparaginase) and Erwinia asparaginase in pediatric acute lymphoblastic leukemia (ALL) patients. Patients received 15 PEGasparaginase infusions (2500 IU/m(2) every 2 weeks) in intensification after receiving native E coli asparaginase in induction. In case of allergy to or silent inactivation of PEGasparaginase, Erwinia asparaginase (20 000 IU/m(2) 2-3 times weekly) was given. Eighty-nine patients were enrolled in the PEGasparaginase study. Twenty (22%) of the PEGasparaginase-treated patients developed an allergy; 7 (8%) showed silent inactivation. The PEGasparaginase level was 0 in all allergic patients (grade 1-4). Patients without hypersensitivity to PEGasparaginase had serum mean trough levels of 899 U/L. Fifty-nine patients were included in the Erwinia asparaginase study; 2 (3%) developed an allergy and none silent inactivation. Ninety-six percent had at least 1 trough level >= 100 U/L. The serum asparagine level was not always completely depleted with Erwinia asparaginase in contrast to PEGasparaginase. The presence of asparaginase antibodies was related to allergies and silent inactivation, but with low specificity (64%). Use of native E coli asparaginase in induction leads to high hypersensitivity rates to PEGasparaginase in intensification. Therefore, PEGasparaginase should be used upfront in induction, and we suggest that the dose could be lowered. Switching to Erwinia asparaginase leads to effective asparaginase levels in most patients. Therapeutic drug monitoring has been added to our ALL-11 protocol to individualize asparaginase therapy.

Polyethylene-glycolated (PEG)-asparaginase (PEG-ASP) is a crucial component of pediatric acute lymphoblastic leukemia therapy. Although hypersensitivity reactions to PEG-ASP occur less frequently than with other formulations, they are not uncommon and have an adverse impact on patient outcomes. Intravenous (IV) administration of PEG-ASP reduces patient pain and anxiety and is being used with increasing frequency in children.A retrospective review was performed to compare the incidence of hypersensitivity reactions to PEG-ASP in children when administered either by intramuscular (IM) or IV routes between January 2006 and May 2008.Of 68 patients studied, 7 experienced a hypersensitivity reaction (10.3%). Two of 16 patients (12.5%) who received only IV PEG-ASP and 3 of 27 patients (11.1%) exposed to only IM PEG-ASP experienced a hypersensitivity reaction. Severe reactions (grade 3 or 4) occurred only once after 119 total doses (0.8%) of IV PEG-ASP and once after 215 total doses (0.5%) of IM PEG-ASP (P=1.0). Thrombosis or pancreatitis were rare and were not increased after IV PEG-ASP administration.IV PEG-ASP is well tolerated and does not result in a significant increase in the incidence of hypersensitivity reactions in children.

Background: Peg-asparaginasecan cause dysregulationof pro-coagulant and anti-coagulant proteins, resulting in a significant risk of venous thromboembolism(VTE) in ALL, particularly in adults undergoing induction chemotherapy. In late 2014, we adopted a policy at our institution to use prophylactic dose ofenoxaparin 40 mg daily for up to 3 weeks following the administration of peg-asparaginase. Patients are also to undergo monitoring of complete blood count, and coagulation parameters including fibrinogen and anti-thrombin. Enoxaparin may be held if patients develop severe thrombocytopenia (platelet count Methods: This is a single-center study of17 consecutive adult patients (>18 years old) treated for ALL with peg-asparaginasecontaining induction regimen before and after the establishment of institutional policy to useenoxaparinprophylaxis. Patients were identified from hospital research database. The diagnoses were verified. Medical records were reviewed for the occurrence of any clinically relevant bleeding and VTE within 3 months of receiving peg-asparaginase. Levels of coagulation parameters, whenever available, were collected at baseline and at weekly intervals for up to 4 weeks after receiving peg-asparaginase. The risk of bleeding and VTE among patients receivingenoxaparinwas compared to those who did not receiveenoxaparin. Fisher exact test was used for testing the association of categorical variable, and binomial exact test was used for computing confidence intervals. T-test or nonparametric test was used for comparing the continuous variables depending on whether or not the data were normally distributed. Results: The patient population consisted of 59% females. Mean age was 35 years. Histology consisted of Pre-B ALL in 76%, pre-T ALL in 18% and mixed lineage leukemia in 6%. 88% percent received pediatric-type chemoregimenand intramuscular peg-asparaginase; the most common doses of peg-asparaginaseincluded 2000 mg/m2 (41%) and 2500 mg/m2 (35%). Duration ofenoxaparin prophylaxis was 21 days in 66.7% and 7 days in 33.3%. Average changes in coagulation parameters at baseline and at weekly intervals following the use of peg-asparaginase therapy are highlighted in figures 1 and 2. The drop inantithrombin and fibrinogen levels was the highest during the first two weeks after the administration of peg-asparaginase. 41% of patients required cryoprecipitate (median 15 units, range 5-35 units over 4 weeks). No patients, including theenoxaparin group, had any clinically relevant bleeding event. The risk of VTE was 18% (95% confidence 4-43%); 2 out of 3 VTE events were cerebral venous thrombosis. No VTE occurred in theenoxaparin prophylaxis group (n=9), whereas 37% of patients (3 out of 8 patients), who did not receiveenoxaparin, developed VTE.Enoxaparin prophylaxis was associated with a trend towards a lower risk of VTE, however, the difference was not statistically significant (p=0.08). Conclusion: Within the limits of this study, in adult ALL patients receiving peg-asparaginase, the use of daily prophylactic dose ofenoxaparinmay not be associated with an increased risk of clinically relevant bleeding, and may have a potential to lower the risk of VTE. Patients receivingenoxaparin, however, should be carefully monitored for the need of platelet transfusion and cryoprecipitate supplementation. The difference in the risk of VTE was not statistically significant, which may be, in part, due to a small sample size.Antithrombindepletion may also contribute to a reduction in the efficacy ofenoxaparin. Larger prospective studies should be performed to validate the preliminary findings. Figure 1 Changes in prothrombin time and partial thromboplastin time Figure 1. Changes in prothrombin time and partial thromboplastin time Figure 2 Changes in antithrombin and fibrinogen levels Figure 2. Changes in antithrombin and fibrinogen levels Disclosures Armitage: Spectrum Pharmaceuticals: Consultancy; Roche: Consultancy; Conatus - IDMC: Consultancy; GlaxoSmithKline IDMC: Consultancy; ZiopharmOncology: Consultancy; Tesaro bio Inc: Membership on an entity's Board of Directors or advisory committees. Lunning:Genentech: Consultancy; AbbVie: Consultancy; Bristol-Myer-Squibb: Consultancy; Juno: Consultancy; Spectrum: Consultancy; Pharmacyclics: Consultancy; Celgene: Consultancy; Gilead: Consultancy; TG Therapeutics: Consultancy.

10530Background: Acute Lymphoblastic Leukemia (ALL) remains a major cause of cancer-related deaths in children. We identified the AMP activated protein kinase (AMPK) as a potential target for ALL t...

Background and Procedure Pharmacological surrogate parameters are considered a useful tool in estimating the treatment intensity of asparaginase (ASNase) preparations. When a pegylated ASNase (single infusion of 2,500 IU/m2 polyethylene glycol (PEG)-ASNase, Oncaspar™) was introduced into the treatment protocols of the German Cooperative Acute Lymphoblastic Leukaemia (COALL) study group, this was accompanied by a drug monitoring programme measuring serum ASNase activity and asparagine (ASN) concentrations in the cerebrospinal fluid (CSF) in 70 children. Results Four hundred fifty-nine serum samples from 67 evaluable patients showed medians of ASNase activity of 1,189.5, 824.5, 310.5, 41 and 4 U/l on day 7 ± 1, 14 ± 1, 21 ± 1, 28 ± 1 and 35 ± 1 respectively. One hundred eighty-four samples from 59 patients were evaluable for ASN concentrations in the CSF. The medians of ASN concentration were 100 U/l, was not ensured. Nevertheless, one must also be aware that the minimum ASN concentration required for leukaemic cell growth is yet to be established. © 2005 Wiley-Liss, Inc.

Lack of asparagine depletion in the cerebrospinal fluid after one intravenous dose of PEG-asparaginase: a window study at initial diagnosis of childhood ALL

Asparaginase (ASNase) has long been considered to be an important element in the management of childhood ALL. Its antileukemic effect is thought to be related to a metabolic deficiency reflected by the blasts' incapability to synthesize asparagine (ASN) from aspartic acid. Treatment with ASNase aims

The aim of the study was to examine the results of PEG-L-Asparaginase administration in children with acute lymphoblastic leukemia and the symptoms of intolerance to L-Aspa E. Coli or Erwinase.

PEG-Asparaginase is an important part of many treatment protocols for ALL. In many centres Asparaginase activity is measured after administration of PEG-asparaginase. However, a predictive pharmacokinetic model is lacking. Such a model would be helpful for dose adjustment and decision making when to switch to another preparation due to the development of inactivating antibodies. Previously described models like linear one-compartment [V.I. Avramis et al., Blood 2002, 99: 1986–1994] or a one-compartment Michaelis-Menten model [H.J. Mueller et al., Cancer Chemother. Pharmacol. 2002, 49, 149–154] describe the data sufficiently for one dose alone, but cannot account for the phenomenom that the time to reach a lower activity limit after administration is not increasing with increasing the dose. Therefore, we analysed 1189 serum activity measurements in 185 children from the ALL-BFM 95 study. Patients received 500, 1000 or 2500 U/m2 PEG-Asp on up to 9 occasions. Serum asparaginase activity was measured using a semi-automatic enzymatic assay with a limit of quantification of 2 U/l [C. Lanvers et al. Anal. Biochem. 2002, 309, 117–126]. Data analysis was done using nonlinear mixed effects modelling (NONMEM Vers. V). Different models like Michaelis-Menten, linear first-order, Weibull and gamma models were tested. The best model applicable to all dosing groups was a modified first-order one-compartmental model with clearance increasing with time according to the formula: Cl = Cli*exp(0.0853*t) with Cli=initial clearance, and t=time. Addition of a second compartment did not improve the model. A typical activity-time course of a patient receiving 1000 U/m2 is shown below displaying the typical shape observable in all patients and in all doing groups. The population parameters found were: Volume of distribution (V) 1.05 ± 27.3% l/m2, Cli 60.3 ± 70.8% ml/day/m2 (mean ± interindividual variability). Interoccasion variability was substantial with 0.223 l/m2 for V and 37.7 ml/day/m2 for Cl, respectively. A subgroup of one third of the patients is identifiable showing a high clearance probably due to the development of inactivating antibodies. Drug monitoring of serum PEG-Asparaginase activity is required to identify these patients who do not benefit from PEG-Asp therapy. The pharmacokinetic model presented here should help to reduce the number of required serum samples per patient. Figure Figure