Pegaspargase 3,750unit powder for solution for injection vials

BACKGROUND: Asparaginase is a critical component of curative therapy for the treatment of pediatric acute lymphoblastic leukemia (ALL) and acute lymphoblastic lymphoma (LLy). Pegaspargase (PEG) increased the duration of asparagine depletion and lowered the incidence of hypersensitivity reactions (HSRs) compared with native asparaginase. When a second pegylated product, Calasparagase pegol-mknl (Cal-PEG) replaced PEG, we observed an increased incidence of HSR, defined as anaphylaxis or silent hypersensitivity. This led to a single center, retrospective review to determine the incidence of HSR in patients with ALL or LLy who received Cal-PEG or PEG. PROCEDURE: Electronic medical records of all patients who received at least two doses of Cal-PEG (December 2022-December 2023) or PEG (December 2019-December 2022) were reviewed. RESULT: Overall, patients who received Cal-PEG had a significantly increased rate of asparaginase-related HSR compared with patients who received PEG. Twenty-one of 44 (48%) patients receiving Cal-PEG and 35 out of 154 (23%) of patients receiving PEG experienced Grade 3 or higher anaphylaxis, or silent hypersensitivity (p = 0.001). After 2:1 matching based on propensity scoring for confounding variables, patients who received Cal-PEG continued to have a statistically significantly higher rates of HSR, with HSR occurring in 21 out of 44 (48%) and 26 out of 88 (30%) patients receiving Cal-PEG and PEG, respectively (p = 0.04). CONCLUSION: The current administration of Cal-PEG in large cooperative group trials will allow for a postmarketing exploration of the true risk of HSR and associated patient-specific risk factors.

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PURPOSE: The incidence of asparaginase-associated pancreatitis (AAP) in children with acute lymphoblastic leukemia (ALL) may lead to treatment delays and insufficient drug exposure, thereby increasing the risk of ALL relapse. We aimed to understand the clinical characteristics and management of AAP, which are crucial for improving treatment outcomes in children with ALL. METHODS: We retrospectively analyzed the medical records of children diagnosed with AAP and admitted to Hebei Children's Hospital between April 2019 and July 2024. We analyzed the clinical characteristics and management strategies of AAP in children with ALL, with a particular focus on the treatment strategies and AAP recurrence in children who were rechallenged with pegaspargase (PEG-ASP). RESULTS: Among 474 patients treated for ALL, 32 were diagnosed with AAP (incidence rate, 6.8%). Of these 32 cases, mild pancreatitis accounted for 50.0% (16/32), moderately severe pancreatitis for 43.8% (14/32), and severe pancreatitis for 6.3% (2/32). AAP occurred most frequently during the induction and early intensive therapy phases. The median time to onset of AAP was 10.5 (1-26) days, and the median number of PEG-ASP doses administered was three (range 1-11). Notably, 53.1% (17/32) patients were rechallenged with PEG-ASP, of whom seven experienced AAP recurrence, including one with three episodes. Despite these statuses, all patients either recovered or showed improvement in their disease status, and no mortality was reported. CONCLUSION: AAP in children with ALL can be effectively managed through early detection and appropriate treatment. Rechallenge with PEG-ASP should be individualized to balance the risk of recurrence against the benefits of continued therapy.

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Abstract Natural killer T cell lymphoma (NKTCL) is highly aggressive, with advanced stage patients poorly responding to intensive chemotherapy. To explore effective and safe treatment for newly diagnosed advanced stage NKTCL, we conducted a phase II study of anti-metabolic agent pegaspargase plus PD-1 antibody sintilimab (NCT04096690). Twenty-two patients with a median age of 51 years (range, 24–74) were enrolled and treated with induction treatment of pegaspargase 2500 IU/m 2 intramuscularly on day 1 and sintilimab 200 mg intravenously on day 2 for 6 cycles of 21 days, followed by maintenance treatment of sintilimab 200 mg for 28 cycles of 21 days. The complete response and overall response rate after induction treatment were 59% (95%CI, 43–79%) and 68% (95%CI, 47–84%), respectively. With a median follow-up of 30 months, the 2 year progression-free and overall survival rates were 68% (95%CI, 45–83%) and 86% (95%CI, 63–95%), respectively. The most frequently grade 3/4 adverse events were neutropenia (32%, n = 7) and hypofibrinogenemia (18%, n = 4), which were manageable and led to no discontinuation of treatment. Tumor proportion score of PD-L1, peripheral blood high-density lipoprotein cholesterol, and apolipoprotein A-I correlated with good response, while PD-1 on tumor infiltrating lymphocytes and peripheral Treg cells with poor response to pegaspargase plus sintilimab treatment. In conclusion, the chemo-free regimen pegaspargase plus sintilimab was effective and safe in newly diagnosed, advanced stage NKTCL. Dysregulated lipid profile and immunosuppressive signature contributed to treatment resistance, providing an alternative therapeutic approach dual targeting fatty acid metabolism and CTLA-4 in NKTCL.

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Asparaginase (ASNase)-based chemotherapy regimens significantly improve survival outcomes in children, adolescents and young adults (AYA), and even adults with acute lymphoblastic leukemia/lymphoma (ALL); however, the incidence and severity of ASNase-associated adverse events (AE) in adults may differ significantly from those reported in children. Strategies to mitigate, monitor for, and manage toxicities that allow adult ALL patients to receive full ASNase courses are needed. A representative 12-member panel of experts who treat AYA and adult ALL patients, incorporate ASNase into their treatment regimens, and conduct related research was assembled to consider opportunities to optimize the use of pediatric-inspired ALL regimens in these adult patients. Following 2 systematic biomedical literature searches from April 2009 through April 2024, a modified Delphi method was used to distill expert opinion into clinical statements that met a standardized definition of consensus. After 2 iterative Delphi method surveys, 23 statements met the standardized definition of consensus, whereas 19 statements did not. Five statements were merged to avoid redundancy. The clinical statements were grouped into 5 distinct categories: 1) hepatotoxicity; 2) hypersensitivity reactions; 3) thromboembolic and coagulopathy complications; 4) pancreatitis and metabolic complications; and 5) dosing. The intent of these statements is to provide health care providers with information that will help them mitigate, monitor for, and manage the most common and/or unique ASNase-induced AE in adult ALL patients, allowing these patients to receive more or all the planned ASNase doses and thereby improve outcomes.

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The multi-center randomized phase III NHL-004 study compared etoposide, dexamethasone and pegaspargase (ESA) versus the methotrexate, etoposide, dexamethasone and pegaspargase (MESA) regimen, combined with sandwiched radiotherapy, in newly diagnosed early-stage nasal natural killer / T-cell lymphoma (NKTCL). Here we report the long-term outcomes (median follow-up, 64 months) and biomarker analysis. A total of 256 eligible patients aged 14-70 years were randomly assigned (1:1) to the ESA or the MESA arm. The 5-year progression-free survival (PFS) rates were 80.3% and 74.9% in the ESA and MESA arms (hazard ratio [HR]=0.78 [95% CI: 0.46-1.33], P=0.371), and the 5-year overall survival (OS) rates were 85.1% and 80.9% (HR=0.74 [95% CI: 0.40-1.37], P=0.332), respectively. No new safety signals related to treatments were observed. Interim plasma Epstein-Barr virus (EBV) DNA positivity and stable disease / progressive disease response were independent predictors of inferior PFS and OS. No prognostic significance was observed according to molecular subtypes. Interim EBV DNA positivity correlated with up-regulated chromatin remodeling alterations, immune escape-related genes, and decreased infiltrating monocytes / M1 macrophages. With low toxicity, non-intravenous administration, and an outpatient design, ESA with sandwiched radiotherapy achieved long-term durable response in patients with newly diagnosed early-stage NKTCL. Dynamic monitoring of plasma EBV DNA provided a clinical rationale for future mechanism-based therapy in NKTCL.

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Asparaginase is a critical component in the treatment of pediatric acute lymphoblastic leukemia (ALL), and children who are unable to complete their intended course of asparaginase therapy tend to have poorer outcomes. 1This underscores the importance of optimizing the delivery of planned asparaginase therapy.Pegaspargase, a pegylated asparaginase product, has been the preferred asparaginase formulation in the United States since the withdrawal of native L-asparaginase from the market in 2012. 2 As of 1 December 2022, pegaspargase became unavailable for patients aged one month to 21.5 years of age, leaving calaspargase pegol (CAL-PEG) as the only primary asparaginase option for pediatric patients in the United States.CAL-PEG was approved by the US Food and Drug Administration in 2018 for pediatric patients based on results from the Children's Oncology Group study AALL07P4 and Dana-Farber Cancer Institute (DFCI) trial 11-001. 3DFCI 11-001 protocol reported a postinduction CAL-PEG allergy rate (grade 2) of 15%, while the AALL07P4 study reported allergy rates up to 27.3% (grades 1-4). 4,5though literature supports the effectiveness of desensitization following pegaspargase allergy, data on the feasibility or success of CAL-PEG desensitization remain limited, with only 2 cases reported to date. [6][7]][8][9][10][11][12] Here, we describe our experience with CAL-PEG desensitization in both front-line and relapsed ALL therapy.Patients desensitized to CAL-PEG from 1 December 2022 to 30 September 2024 at St. Jude Children's Research Hospital were retrospectively reviewed.This research received approval from the St. Jude institutional review board.A 12-step, 3-bag method was used for CAL-PEG desensitization (Table 1). 6Premedications given to all patients before desensitization included diphenhydramine, hydrocortisone, famotidine, and montelukast.The prepared CAL-PEG desensitization bags were infused within 4 hours when stored at room temperature and within 24 hours when refrigerated after preparation. 13Nurses were instructed to keep bag 3 refrigerated until step 6.Desensitization was considered successful if the infusion was completed and serum asparaginase activity (SAA) was estimated to remain 0.1 IU/mL for at least 21 days.If the first desensitization was successful, subsequent desensitization doses were administered.Measurement of SAA levels was carried out by our Clinical Laboratory Improvement Amendments-certified pharmacokinetics laboratory using methods previously described. 14linear 1-compartment model with Michaelis-Menten elimination (parameterized in terms of Vmax, Km, and V) was applied to the data using non-linear mixed-effects modeling with the stochastic approximation expectation-maximization approach (Monolix, 2023R1).The inter-individual variability and interoccasion variability of the parameters were assumed to be log-normally distributed.Activity values below the lower limit of quantification (0.06 IU/mL) were treated as censored, and the M3 method was used for handling these values (as implemented in Monolix; Beal JPP, 2001).A proportional residual error model was used, assuming a normal distribution of the residuals.Individual post hoc estimates (the

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Objectives: The optimal treatment strategy for early-stage natural killer/T-cell lymphoma (NKTCL) remains unclear. This study aimed to evaluate and compare the clinical outcomes and adverse events (AEs) associated with two treatment regimens for early-stage NKTCL: pegaspargase with concurrent radiation therapy (P+CCRT) and pegaspargase, gemcitabine, and oxaliplatin (P-GEMOX) with sequential radiation therapy (SERT). Propensity score matching (PSM) was employed to ensure balanced comparison between these regimens. Methods: We assessed the efficacy of P+CCRT from a phase II trial and P-GEMOX combined with SERT using real-world data. PSM was conducted at a 1:1 ratio with a caliper of 0.18 to align baseline characteristics between the treatment groups. Key outcomes analyzed included overall response rate (ORR), complete response rate (CR), progression-free survival (PFS), overall survival (OS), and AEs. Results: . 76.9%, respectively. The 3-year OS and PFS rates were both 92.3% for P+CCRT, while P-GEMOX showed 92.3% OS and 80.8% PFS. Adverse events, including hematological toxicity, hepatotoxicity, and coagulation dysfunction, were comparable between the two regimens. Conclusion: P+CCRT is associated with comparable clinical outcomes compared to P-GEMOX + SERT in early-stage NKTCL, with comparable adverse events. Additionally, P+CCRT offers the benefit of a more streamlined treatment regimen with a shorter cycle. Given these encouraging results, further cohort studies are needed to validate these results.

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