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Summary: Studies on asparaginase enzyme activity (AEA) monitoring in Chinese patients receiving PEG‐asparaginase remain limited. We monitored AEA in paediatric patients diagnosed with acute lymphoblastic leukaemia (ALL) and treated according to the Chinese Children's Cancer Group study protocols, CCCG‐ALL‐2015/CCCG‐ALL‐2020 protocols. We measured the AEA at days 7 ± 1 and 14 ± 1 and analysed their association with patient characteristics and PEG‐asparaginase‐related adverse effects (AEs). We measured 2147 samples from 329 patients. Mean AEA levels (interquartile range) were 931 iu/L (654–1174 iu/L) at day 7 ± 1 and 664 iu/L (463–860 iu/L) at day 14 ± 1. The AEA levels were higher in younger children and increased with the cumulative dose numbers. PEG‐asparaginase inactivation rate was 19.1%, and the silent inactivation (SI) rate was 12.5%. Nine patients were identified with allergic‐like reactions. Hypofibrinogenaemia, hypertriglyceridaemia, pancreatitis and thrombosis were associated with older age, whereas hypoglycaemia was associated with younger age. The risk of hypertriglyceridaemia and hypoglycaemia increased with cumulative dose numbers of PEG‐asparaginase. Except for hypofibrinogenaemia, elevated AEA levels did not increase the risk of PEG‐asparaginase‐related AEs. Drug monitoring can be utilized as guidance for treatment decision‐making. Individualizing asparaginase doses do not reduce toxicities. The treatment target of PEG‐asparaginase remains to achieve sustained and adequate activity. [ABSTRACT FROM AUTHOR]

Background: Leukemia is the most prevalent type of cancer affecting children, representing approximately 35% of cancer diagnoses in Saudi Arabia. Notably, significant improvement in the overall survival and cure rates for pediatrics with acute lymphoblastic leukemia (ALL) has been attributed to adding asparaginase to the chemotherapy regimen. However, the administration of these agents may lead to a multifactorial range of toxicities that often alter treatment outcomes. Objective: The study aimed to characterize the prevalence of common toxicities related to polyethylene glycol (PEG) asparaginase in children aged 0–14 years diagnosed with ALL. Additionally, it assessed the types of toxicities associated with intravenous (IV) and intramuscular (IM) administration of Peg-asparaginase. Method: It was an observational retrospective cross-sectional study. Data was extracted from the hospital's electronic health record (EPIC). Using EPIC, we reviewed medical charts of all pediatric patients below 14 years old diagnosed with ALL who received at least one dose of PEG-asparaginase between January 2020 and March 2023. The toxicity grading was based on the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). Results: One hundred and ninety-one patients with ALL were included in the study. Overall, 79 toxicity episodes were experienced by the study patients. Anaphylaxis/hypersensitivity (36.7%) and hepatotoxicity (31.6%) were the most prevalent toxicities reported, followed by pancreatitis and hyperglycemia (12.7% each). According to the CTCAE grading, approximately 70% of toxicities were categorized as Grade 3 and 4. Notably, 60% of the events occurred during the induction and consolidation phase of therapy. Interestingly, there was no significant difference in rates of toxicities between patients receiving IV or IM PEG-asparaginase. Conclusion: The distribution of toxicities highlighted in our study aligns with findings from previously published studies. Furthermore, multivariate analysis indicated that patients with high-risk ALL and T-ALL were more likely to develop toxicities compared to other forms of ALL.

Aggressive natural killer cell leukemia (ANKL) is a rare, aggressive hematologic malignancy which often presents as fulminant Epstein-Barr virus (EBV)- driven hemophagocytic lymphohistiocytosis (HLH). ANKL lacks a distinct immunologic and morphologic signature, making early diagnosis particularly challenging. Here we present a case of ANKL in a patient presenting with EBV-HLH. After poor treatment response to the HLH-2004 protocol (etoposide and dexamethasone), bone marrow biopsy demonstrated an atypical CD3-/CD56+ natural killer (NK) cell population with diminished CD7 expression consistent with EBV+ ANKL. Asparaginase-based chemotherapy was initiated but his disease progressed and he died from multiorgan failure. This case highlights the diagnostic challenges of ANKL given the lack of standardized diagnostic criteria, the importance of considering T/NK cell malignancies in the differential diagnosis of EBV-HLH, and adds to the literature on this rare disease.

Abstract Mixed phenotype acute leukaemia (MPAL) is associated with worse overall survival, compared with other acute leukaemias in adults. Lack of clear treatment guidelines makes the therapy challenging. ALL-like induction and consolidation treatment followed by allo-HSCT is the preferred first-line treatment. We present a case of a 36-year-old woman diagnosed with MPAL (EGIL Myelo/B) with KMT2A rearrangement, treated with the PALG-ALL-7 (including PEG-asparaginase) protocol. On day 25 after the induction therapy initiation, numbness of limbs and dizziness were observed. Therefore, the imaging studies (CT and MRI) were performed and a diagnosis of thrombosis of superior sagittal sinus of the brain was established. Routinely performed blood coagulation tests showed prolonged APTT and PT, decreased antithrombin III activity and decreased free protein S concentration. LMWH treatment and substitutional therapy with antithrombin III were started, which resulted in a significant reduction in the thrombosis associated symptoms and improvement of the neurological status after 3 days. After induction and consolidation therapy, the patient obtained complete haematological remission and negative measurable residual disease. Six months after the diagnosis, allo-HSCT was successfully performed. During the 4 months follow-up, the patient remained MRD negative and thrombotic symptoms free. To the best of our knowledge, our communication has been the first report of such complication in an MPAL patient treated with PEG-asparaginase containing protocol in adults. We recommend increased vigilance in patients manifesting any mild neurological symptoms and early decision about the MRI study performance.

Currently no therapy of acute lymphoblastic leukemia is conceivable without L-asparaginase drugs, with its antileukemic effect by extracellular asparagine depletion, thus preventing its admission to leukemic cell. Besides high antitumor effect, L-asparaginase drugs have side and toxic effects, such as hypersensitivity reactions, thrombosis, pancreatitis / pancreatic necrosis, and hepatotoxicity. For L-asparaginase safety profile improvement a technology of pegylation was lay down and PEG-aspargase drug produced. This drug has less toxic effects and recommended as first-line therapy of acute lymphoblastic leukemia. Drug monitoring for assessment the effectiveness and toxicity of L-asparaginase is optimal. Such therapy individualization helps for L-asparaginase dose finding and decrease frequency and severity of side effects.

Simple Summary: This report presents the results of the randomized use of PEG-ASP at a dose of 1000 U/m2 administered on day 3 of induction therapy in children with B-cell precursor ALL (BCP-ALL) studied for MRD response. At the start of induction therapy, 502 patients were randomized, standard-risk patients into three and intermediate-risk patients into two groups. The single dose of PEG-ASP resulted in a significantly larger proportion of rapidly responding patients. Despite only low or moderately intensive therapy (no or only low-dose anthracyclines, no oxazaphosphorines, no high-dose therapy), these rapid responders also showed excellent long-term outcomes. This report presents the results of the assessment of MRD response by multicolor flow cytometry (MFC) with regard to the randomized use of pegylated asparaginase (PEG). In this study, PEG was randomly administered at a dose of 1000 U/m2 on day 3 of induction therapy in children with B-lineage ALL. Methods. Conventional induction therapy consisted of dexamethasone, vincristine, and daunorubicin. MRD data was available in 502 patients who were randomized at the start of induction therapy, standard-risk (SR) patients into three (conventional induction without PEG, induction with additional PEG and with PEG but without daunorubicin) and intermediate-risk (ImR) patients into two groups (with additional PEG and without PEG). Results. The single administration of PEG resulted in a significantly higher proportion of rapid responders, in SR patients even when no anthracyclines were used for induction. In the SR group, the event-free survival of the MFC-MRD fast responders was similar in the PEG− and PEG+ arms (92.0 ± 3.1% vs. 96.2 ± 1.5%, respectively), and the same unfavorable trend was observed for MFC-MRD slow responders (57.5 ± 12.3% vs. 66.7 ± 15.7%, respectively). Results were similar in ImR patients: (94.3 ± 3.2% vs. 95.1 ± 2.4%, for fast responders and 63.3 ± 7.6% vs. 78.1 ± 7.9%, for slow responders in PEG− and PEG+ arms, respectively). However, there is a large difference between the proportion of MFC-MRD slow responders in the PEG− and PEG+ groups (18.3% vs. 5.2% for the SR group and 44.2% vs. 25.0% for the ImR group). Conclusions. Therefore, early use of PEG-ASP not only leads to an accelerated reduction of blasts, but also to an excellent outcome in a significantly larger proportion of patients in both risk groups. [ABSTRACT FROM AUTHOR]

Asparaginase-associated pancreatitis (AAP) is a common and fatal complication after ASNase treatment in acute lymphoblastic leukemia(ALL). Here, a total of 1063 pediatric ALL patients treated with SCCLG-ALL-2016 regimen were collected since October 2016 to June 2020, including 35 patients with AAP. The clinical characteristics of AAP and non-AAP patients were compared. In AAP patients, the possible factors that affected the recurrence of AAP were analyzed, and the possible risk factors related to ALL-relapse were discussed. The results showed that age was a risk factor (P =.017) that affect the occurrence of AAP. In AAP patients, AAP tended to develop after the second use of PEG-ASNase (25.71%). In the follow-up chemotherapy, 17 patients re-exposed to ASNase and 7 cases developed AAP again with a percentage was 41.2%. There were no special factors that related with the recurrence of AAP. This study also found no association between the occurrence of AAP and prognosis of ALL, with the 4-year incidence of ALL relapse in AAP and non-AAP patients were 15.9% v.s.11.7% (HR: 1.009, 95% CI:0.370–2.752, P =.986), and there were no special factors that related with the ALL relapse among AAP patients. Based on the above results, the occurrence of AAP is related to age and should be vigilant after the second use of PEG-ASNase after use in pediatric ALL patients. Moreover, AAP is not associated with ALL relapse, but there is a high AAP recurrence rate when re-exposure to ASNase. [ABSTRACT FROM AUTHOR]

Mixed phenotype acute leukaemia (MPAL) is associated with worse overall survival, compared with other acute leukaemias in adults. Lack of clear treatment guidelines makes the therapy challenging. ALL-like induction and consolidation treatment followed by allo-HSCT is the preferred first-line treatment. We present a case of a 36-year-old woman diagnosed with MPAL (EGIL Myelo/B) with KMT2A rearrangement, treated with the PALG-ALL-7 (including PEG-asparaginase) protocol. On day 25 after the induction therapy initiation, numbness of limbs and dizziness were observed. Therefore, the imaging studies (CT and MRI) were performed and a diagnosis of thrombosis of superior sagittal sinus of the brain was established. Routinely performed blood coagulation tests showed prolonged APTT and PT, decreased antithrombin III activity and decreased free protein S concentration. LMWH treatment and substitutional therapy with antithrombin III were started, which resulted in a significant reduction in the thrombosis associated symptoms and improvement of the neurological status after 3 days. After induction and consolidation therapy, the patient obtained complete haematological remission and negative measurable residual disease. Six months after the diagnosis, allo-HSCT was successfully performed. During the 4 months follow-up, the patient remained MRD negative and thrombotic symptoms free. To the best of our knowledge, our communication has been the first report of such complication in an MPAL patient treated with PEG-asparaginase containing protocol in adults. We recommend increased vigilance in patients manifesting any mild neurological symptoms and early decision about the MRI study performance. [ABSTRACT FROM AUTHOR]

Objectives: The present study aimed to investigate pegylated- l -asparaginase monotherapy for feline large cell lymphoma as a potential alternative to palliative corticosteroids treatment in animals whose owners declined cytotoxic chemotherapy. Methods: A retrospective, descriptive case series of cats treated initially with pegylated- l -asparaginase as a sole therapy for feline large cell lymphoma is reported. The treatment protocol consisted of 12 intramuscular injections of pegylated- l -asparaginase with increasing intervals. If cats were unresponsive to pegylated- l -asparaginase monotherapy, a second-line treatment was initiated. Signalment, origin of lymphoma, staging, treatment, possible adverse events and follow-up data were extracted from the medical records. Responses and survival data were analysed. Results: Eighty-two cats with lymphoma of five different anatomic types were included: alimentary, abdominal extra-alimentary, peripheral nodal, nasal/nasopharyngeal and other (mediastinal, renal [solitary] and miscellaneous combined in one group for analytical purposes). The response rate was 74.1% (95% confidence interval = 63.4–83.5) with 38.3% (95% confidence interval = 27.8–48.8) in complete remission. The median disease-free period and calculated overall survival time were 70 days (12–1702+) and 79 days (1–1715+), respectively. The response rate was significantly correlated with the origin of the lymphoma and the combined group had a significantly lower response rate (P = 0.035). Twenty-four cats were also treated with corticosteroids. There was no significant difference in outcomes between the group treated with or without corticosteroids. Adverse events were present in a small number of cats (14/82). The majority of these adverse events were mild to moderate in 5/14 cats; however, the adverse events were severe enough to cause discontinuation of therapy. Conclusions and relevance: Based on the response rate and median disease-free period, treatment with pegylated- l -asparaginase is inferior when compared with historical chemotherapy protocols. However, some cats demonstrated an exceptional long disease-free period. Therefore, pegylated- l -asparaginase could be offered as an alternative to corticosteroid therapy alone. Further studies are needed to evaluate the additional benefit over palliative corticosteroid monotherapy. [ABSTRACT FROM AUTHOR]

Abstract PEG‐asparaginase is used as a treatment for Philadelphia‐negative acute lymphoblastic leukemia. In pediatric studies, triglycerides (TGs) were affected more by PEG‐asparaginase than by native L‐asparaginase (10.0% vs. 5.5%). We conducted a retrospective study to determine the safety of re‐challenging adult patients with PEG‐asparaginase after experiencing an episode of severe hypertriglyceridemia (>1000 mg/dl or 11.4 mmol/L). The incidence of hypertriglyceridemia associated with PEG‐asparaginase in adult patients was high (67.5%). Therefore, checking TGs at baseline and monitoring levels while receiving PEG‐asparaginase need to be considered and studied in prospective studies. However, in patients with hypertriglyceridemia not complicated by acute pancreatitis, re‐challenging is safe once TG levels normalize.

Summary/background: Native Ecoli-Asparaginase (NEA)-containing regimens is an integral part of the ALL-treatment protocol for pediatric and young adults. By observation, polyethylene glycol-asparaginase (PEG-a) recipients have experienced heightened rates of thrombosis. We conducted a meta-analysis investigating which ASP formulation, instigated thrombosis more intensely. We examined potential risk factors and whether LMWH intervention influence VTE prevention. Methods: 209 studies were reviewed and analyzed. 18 PEG-a- and 15 NEA-containing studies are selected. Of these, 23 Non-LMWH and 10 LMWH thromboprophylaxis interventions are used for VTE rates comparison. One single-center and four comparative studies sought to determine the impact of LMWH on VTE prevention. Results: The combined data set indicated a significantly higher proportion of VTE incidences in the PEG-a population compared to the NEA recipients. The non-LMWH study data showed a significantly higher proportion of VTE incidences in the PEG-a recipients. In the LMWH-containing data, PEG-a recipients had only slightly higher VTE outcome. LMWH has a favorable effect on VTE prevention as shown by the Forest plot. ASPs exposure and age ≥10 years ranked high-risk for VTE. Conclusion: PEG-a- compared to NEA-treated adult patients are at significantly higher risk of developing VTE. LMWH demonstrated a protective effect on VTE prevention.

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: MEITL is a very rare and highly aggressive peripheral T cell lymphoma with poor prognosis and for which there is no standard treatment. Treatment options for patients patients with relapsed/refractory disease are scarce and the choice of an appropriate rescue still represents an unmet need. Methods: Here, we report the case of a 65-year-old woman affected by MEITL, progressing after initial treatment with an anthracycline-based chemotherapy and surgery, who received single-agent PEG-asparaginase salvage therapy at our institution. Results: PEG-asparaginase single-agent rescue proved to be rapidly effective in controlling the disease and its associated paraneoplastic features. Nevertheless, toxicity was high and the patient died due to a treatment-related complication. Conclusion: The case we described brings new evidences on the effectiveness of PEG-asparaginase therapy in MEITL patients. Whether PEG-asparaginase should be included in the treatment course of MEITL patients could be the subject of future studies. [ABSTRACT FROM AUTHOR]

Latar belakang. L-asparaginase (L-asp) adalah regimen kemoterapi utama dalam terapi LLA pada anak. Kejadian reaksi hipersensitivitas akibat L-asp sangat tinggi, menyebabkan terapi tidak dapat dilanjutkan dan memengaruhi angka kesintasan. Dibutuhkan sediaan lain yang lebih hipoalergenik untuk dapat menggantikan L-asp. Tujuan. Melakukan telaah kritis untuk membandingkan reaksi hipersensitivitas dan efektivitas antara PEG-asp dan L-asp pada pasien anak dengan LLA. Metode. Pencarian artikel dilakukan secara daring menggunakan instrumen kata kunci yang sesuai melalui basis data Pubmed, Cochrane dan Google Scholar pada bulan Febaruari 2021. Hasil. Didapatkan 3 artikel berupa meta-analisis, uji klinis acak dan kohort retrospektif. Reaksi hipersensitivitas dengan L-asp adalah 30-41%, sedangkan dengan PEG-asp 13-14% (p0,005). Kesimpulan. PEG-asp dapat menurunkan angka kejadian reaksi hipersensitivitas dan memiliki efektivitas yang sama dengan L-asp.

Pegylated (PEG)-asparaginase is an established treatment for acute lymphoblastic leukemias that exhibits an antitumor effect by depleting asparagine, an amino acid essential for leukemia cell protein synthesis. Pancreatitis with hypertriglyceridemia is a well-established toxidrome associated with PEG-asparaginase. However, impaired pancreatic synthetic function and hormone release have rarely been reported as a result of PEG-asparaginase pancreatitis. In this report, we present a 22-year-old woman recently diagnosed with T-acute lymphoblastic leukemia (TALL), who presented to the hospital with progressive weakness, confusion, blurry vision, hallucinations, and abdominal pain after induction treatment with daunorubicin, vincristine, PEG-asparaginase, and dexamethasone following the AYA protocol. She was found to have hypertriglyceridemia, acute pancreatitis, and hyperosmolar hyperglycemic syndrome. While pancreat it is and hypertriglyceridemia are commonly reported side effects of PEG-asparaginase, HHS related to these conditions has been sparsely reported. Providers should maintain awareness of this association and consider routine serial glucose monitoring of patients receiving PEG-asparaginase. [ABSTRACT FROM AUTHOR]

Background: Pediatric patients have a better survival rate for lymphoid malignancies than adolescents and young adult patients (AYA) and current evidence suggests that asparaginase plays a role in improved response to treatment. This study aimed to evaluate if increasing age as a continuous variable demonstrated increasing toxicities to PEG‐asparaginase (PEG‐ASP) for those patients treated at a tertiary care pediatric hospital. Methods: A retrospective chart review from 2007 to 2017 was conducted in the pediatric population at the Children's Hospital of Eastern Ontario (CHEO). Patients having received PEG‐ASP were included. Event incidence and risk related to age at diagnosis were assessed through parameter estimates and Wald chi‐square analysis. Results: In total, 75 adverse events were observed: 34/186 (18.3%) experienced allergic reactions, 8/186 (4.3%) pancreatitis, 31/186 (16.7%) thrombosis, and 2/186 (1.1%) hemorrhage. One hundred and eighty two patients had complete information for inclusion in our model. A correlation between age at diagnosis and higher risk of allergic reaction (p <.001) and pancreatitis (p <.035) was observed. Conclusion: Allergic reaction and pancreatitis following administration of PEG‐ASP have a higher risk of occurrence as age of diagnosis increases up to 18 years of age. This includes the lower limit of traditionally defined AYA population of 15–39 and warrants precaution as PEG‐ASP is included in older populations treatment regimens at pediatric centers. [ABSTRACT FROM AUTHOR]

PEG-asparaginase is a key component in treatment regimens for acute lymphoblastic leukemia (ALL). Major side effects include thrombosis and bleeding; however, there is currently no consensus on methods to prevent these complications. In this multi-center retrospective cohort study of 101 adults, we compared two prophylaxis strategies: cryoprecipitate and fresh frozen plasma (Cryo/FFP) versus cryoprecipitate and antithrombin (ATIII). The overall incidence of venous thromboembolism (VTE) was not significantly different between the two groups (19.7% for Cryo/FFP and 8.6% in Cryo/ATIII, p = 0.17), and neither was grade ≥3 bleeding (3% for Cryo/FFP and 11.4% for Cryo/ATIII, p = 0.18). Given the significant cost associated with ATIII without a clear benefit, a careful benefit and risk analysis should be considered before utilizing ATIII as a prophylaxis strategy to prevent thrombosis or bleeding following asparaginase administration. [ABSTRACT FROM AUTHOR]

Pegylated (PEG)-asparaginase is an established treatment for acute lymphoblastic leukemias that exhibits an antitumor effect by depleting asparagine, an amino acid essential for leukemia cell protein synthesis. Pancreatitis with hypertriglyceridemia is a well-established toxidrome associated with PEG-asparaginase. However, impaired pancreatic synthetic function and hormone release have rarely been reported as a result of PEG-asparaginase pancreatitis. In this report, we present a 22-year-old woman recently diagnosed with T-acute lymphoblastic leukemia (T-ALL), who presented to the hospital with progressive weakness, confusion, blurry vision, hallucinations, and abdominal pain after induction treatment with daunorubicin, vincristine, PEG-asparaginase, and dexamethasone following the AYA protocol. She was found to have hypertriglyceridemia, acute pancreatitis, and hyperosmolar hyperglycemic syndrome. While pancreatitis and hypertriglyceridemia are commonly reported side effects of PEG-asparaginase, HHS related to these conditions has been sparsely reported. Providers should maintain awareness of this association and consider routine serial glucose monitoring of patients receiving PEG-asparaginase.

Background: Children treated for a malignancy are at risk to develop serious illness from a COVID-19 infection. Pegylated E. coli asparaginase (PEG-asparaginase) is used in the treatment of acute lymphoblastic leukemia. Allergy to this drug is common and both asparaginase and polyethylene glycol (PEG) are identified as possible antigens. The mRNA-based vaccines against COVID-19 contain PEG as a stabilizing component. Methods: We developed a protocol to be able to safely vaccinate children with a PEG-asparaginase allergy. All patients with a history of allergy to PEG-asparaginase have been included and skin prick testing for various PEGs was performed before vaccination with the mRNA Pfizer-BioNTech COVID-19 vaccine. Results: Twelve children between six and 16 years old were vaccinated, without allergic reaction. None of them got a positive skin prick test for PEG. Ten patients had pre-existing IgG or IgM antibodies against PEG. Conclusion: Children with a PEG-asparaginase allergy can be safely vaccinated against COVID-19 with mRNA vaccines containing PEG irrespective of IgG/IgM antibodies to PEG-asparaginase. Routine skin prick testing in patients with PEG-asparaginase allergy does not seem to be of added value.

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.

Summary: In successive UK clinical trials (UKALL 2003, UKALL 2011) for paediatric acute lymphoblastic leukaemia (ALL), polyethylene glycol‐conjugated E. coli L‐asparaginase (PEG‐EcASNase) 1000 iu/m2 was administered intramuscularly with risk‐stratified treatment. In induction, patients received two PEG‐EcASNase doses, 14 days apart. Post‐induction, non‐high‐risk patients (Regimens A, B) received 1–2 doses in delayed intensification (DI) while high‐risk Regimen C patients received 6–10 PEG‐EcASNase doses, including two in DI. Trial substudies monitored asparaginase (ASNase) activity, ASNase‐related toxicity and ASNase‐associated antibodies (total, 1112 patients). Median (interquartile range) trough plasma ASNase activity (14 ± 2 days post dose) following first and second induction doses and first DI dose was respectively 217 iu/l (144–307 iu/l), 265 iu/l (165–401 iu/l) and 292 iu/l (194–386 iu/l); 15% (138/910) samples showed subthreshold ASNase activity (<100 iu/l) at any trough time point. Older age was associated with lower (regression coefficient −9.5; p < 0.0001) and DI time point with higher ASNase activity (regression coefficient 29.9; p < 0.0001). Clinical hypersensitivity was observed in 3.8% (UKALL 2003) and 6% (UKALL 2011) of patients, and in 90% or more in Regimen C. A 7% (10/149) silent inactivation rate was observed in UKALL 2003. PEG‐EcASNase schedule in UKALL paediatric trials is associated with low toxicity but wide interpatient variability. Therapeutic drug monitoring potentially permits optimisation through individualised asparaginase dosing. [ABSTRACT FROM AUTHOR]

Keywords: COVID-19; hypersensitivity; PEG-asparaginase; vaccination EN COVID-19 hypersensitivity PEG-asparaginase vaccination 1 3 3 03/30/23 20230301 NES 230301 Polyethylene glycol (PEG)-asparaginase (PEG-ASNase) is a key component in the treatment of acute lymphoblastic leukemia (ALL). This study aimed at evaluating the safety of delivering COVID-19-mRNA vaccination to pediatric patients with a history of PEG-ASNase allergy. Prevaccination skin prick and/or intradermal testing for the COVID-19 mRNA vaccine, PEG, and/or Polysorbate 80 was not offered as patients were prioritized to be seen urgently and skin testing may have delayed the vaccination process. [Extracted from the article]

Successful bridging to cell therapy for relapsed/refractory acute lymphoblastic leukaemia with a combination of venetoclax and PEG-asparaginase Keywords: cell therapy; leukaemia; PEG-asparaginase; refractory; venetoclax EN cell therapy leukaemia PEG-asparaginase refractory venetoclax e37 e39 3 02/07/23 20230215 NES 230215 Relapse is still the main cause of treatment failure in adult patients with acute lymphoblastic leukaemia (ALL). Six patients (75%) achieved complete remission (CR) after one VEN/PEG-ASP cycle and were successfully bridged to cell therapy (second allo-HSCT or donor lymphocyte infusion for three patients and CD19 CAR-T cell therapy for three patients). [Extracted from the article]

Asparaginase is commonly used in combination therapy of acute lymphoblastic leukemia. However, as an immunogenic protein, hypersensitivity reactions (HSRs) during asparaginase therapy are frequent, indicating the development of anti-asparaginase antibodies. These can be associated with diminished clinical effectiveness, including poorer survival. Therapeutic drug monitoring of serum asparaginase activity to confirm complete asparagine depletion is therefore crucial during asparaginase therapy. Switching to alternative types of asparaginase is recommended for patients experiencing HSRs or silent inactivation; those with HSRs or silent inactivation on Escherichia coli-derived asparaginases should switch to another preparation. However, prior global shortages of Erwinia asparaginase highlight the importance of alternative non-E.coli-derived asparaginase, including recombinant Erwinia asparaginase. [ABSTRACT FROM AUTHOR]

PEG-Asparaginase (also known as Pegaspargase), along with glucocorticoids (predominantly prednisolone or dexamethasone) and other chemotherapeutic agents (such as cyclophosphamide, idarubicin, vincristine, cytarabine, methotrexate and 6-mercaptopurine) is the current standard treatment for acute lymphoblastic leukaemia in both children and adults. High doses of PEG-asparaginase are associated with side effects such as hepatotoxicity, pancreatitis, venous thrombosis, hypersensitivity reactions against the drug and severe hypertriglyceridemia. We report a case of a 28-year-old male who was normolipidemic at baseline and developed severe hypertriglyceridemia (triglycerides of 1793 mg/dl) following treatment with PEG-asparaginase for acute lymphoblastic leukaemia. Thorough genetic analysis was conducted to assess whether genetic variants could suggest a predisposition to this drug-induced metabolic condition. This genetic analysis showed the presence of a rare heterozygous missense variant c.11G > A-p.(Arg4Gln) in the APOC3 gene, classified as a variant of uncertain significance, as well as its association with four common single nucleotide polymorphisms (SNPs; c.*40C > G in APOC3 and c.*158T > C; c.162-43G > A; c.-3A > G in APOA5) related to increased plasma triglyceride levels. To our knowledge this is the first case that a rare genetic variant associated to SNPs has been related to the onset of severe drug-induced hypertriglyceridemia. [ABSTRACT FROM AUTHOR]

Background: Asparaginase (ASP), a chemotherapy component in the acute lymphoblastic leukemia (ALL) treatment, could impair normal coagulation state. Usually, a decline in the levels of several coagulation factors occurs which ultimately could lead to thrombotic events and abnormal coagulation tests. In this study, we aimed to compare the effects of two different subtypes of ASP, pegylated asparaginase (PEG-ASP) and L-asparaginase (L-ASP) on coagulation markers and test among 40 pediatric patients with ALL. Methods: In this cohort study a total of 40 pediatric patients with newly diagnosed ALL were enrolled and divided into two groups by simple randomization. In group A, 20 patients received PEG-ASP while in group B, 20 patients received L-ASP during the induction treatment. Coagulation markers included prothrombin time (PT), partial thrombin time (PTT), protein-C (Pr-C), protein-S (Pr-S), and antithrombin III (ATIII) and were assessed before start and after of induction chemotherapy. Results: Coagulation profile including PT, PTT, INR, Pr-C, Pr-S, and ATIII before start of treatment were not statistically significant between the two groups. Anticoagulant factors decreased significantly after consuming both drugs. Tests for PT and INR of those who took L-ASP decreased significantly. Overall, when comparing the changes of the six studied factors, ATIII and Pr-C were the significant factors which were different between groups. Conclusions: ASP has a negative effect on anticoagulant factors including (ATIII, Pr-C, Pr-S). Additionally, the negative effect of L-ASP on anticoagulant factors was more prominent than PEG-ASP. Therefore, the risk of thrombosis probably was negligible in PEG-ASP in comparison with L-ASP. [ABSTRACT FROM AUTHOR]

Objetivos: Apresentar um caso raro de cetoacidose diabética (CAD) e pancreatite secundários ao uso de PEG-asparaginase em paciente pediátrico em tratamento para leucemia linfoblástica aguda (LLA) e alertar quanto aos sinais que remetem a esses diagnósticos. Descrição do caso: Adolescente do sexo feminino, 10 anos e 11 meses, em tratamento para LLA e uso prévio de PEG-asparaginase há seis dias da internação, admitida com choque hipotensivo grave e encaminhada à Unidade de Terapia Intensiva. Inicialmente o quadro foi interpretado como choque séptico. Em seguida a anamnese detalhada e os exames laboratoriais direcionaram para os diagnósticos de CAD e pancreatite, iniciando-se as intervenções específicas. Recebe alta hospitalar após 30 dias, sem necessidade de insulinoterapia, mas com reposição de enzimas pancreáticas. Comentários: Geralmente, às crianças com LLA gravemente enfermos e leucopênicos, atribui-se apenas o diagnóstico de sepse, que é um diagnóstico prioritário. Entretanto, no grupo em uso de PEG-asparaginase, o pediatra emergencista deve estar alerta ao raciocínio diferencial envolvendo CAD e pancreatite, o que pode ser bem difícil inicialmente. O alerta dos diagnósticos diferenciais do choque séptico, mesmo que raros, na assistência a pacientes oncológicos pediátricos, além da correta e pronta identificação do quadro e seu manejo apropriado, correlacionam-se diretamente ao sucesso terapêutico e, em algumas situações, à sobrevivência do paciente.

PEG-Asparaginase (also known as Pegaspargase), along with glucocorticoids (predominantly prednisolone or dexamethasone) and other chemotherapeutic agents (such as cyclophosphamide, idarubicin, vincristine, cytarabine, methotrexate and 6-mercaptopurine) is the current standard treatment for acute lymphoblastic leukaemia in both children and adults. High doses of PEG-asparaginase are associated with side effects such as hepatotoxicity, pancreatitis, venous thrombosis, hypersensitivity reactions against the drug and severe hypertriglyceridemia. We report a case of a 28-year-old male who was normolipidemic at baseline and developed severe hypertriglyceridemia (triglycerides of 1793 mg/dl) following treatment with PEG-asparaginase for acute lymphoblastic leukaemia. Thorough genetic analysis was conducted to assess whether genetic variants could suggest a predisposition to this drug-induced metabolic condition. This genetic analysis showed the presence of a rare heterozygous missense variant c.11G > A-p.(Arg4Gln) in the APOC3 gene, classified as a variant of uncertain significance, as well as its association with four common single nucleotide polymorphisms (SNPs; c.*40C > G in APOC3 and c.*158T > C; c.162-43G > A; c.-3A > G in APOA5) related to increased plasma triglyceride levels. To our knowledge this is the first case that a rare genetic variant associated to SNPs has been related to the onset of severe drug-induced hypertriglyceridemia.

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. [ABSTRACT FROM AUTHOR]

Pegylated (PEG)-asparaginase is used during the induction and intensification phases of treatment for B-cell acute lymphoblastic leukemia (B-ALL). It works by depleting the external sources of asparagine, causing the death of lymphoblasts. It has several adverse effects, including pancreatitis and hypertriglyceridemia; however, the simultaneous occurrence of both is uncommon. We present the case of an 18-year-old man with B-ALL who developed acute epigastric pain radiating to the back and non-bloody, non-bilious emesis following treatment with PEG-asparaginase. He was diagnosed with acute interstitial pancreatitis and severe hypertriglyceridemia. Conservative management was used for the pancreatitis, while hypertriglyceridemia was treated with an insulin infusion. Pancreatic toxicity and hypertriglyceridemia can necessitate the discontinuation of PEG-asparaginase, limiting treatment options and potentially increasing the risk of relapse. Therefore, further studies are needed to identify the factors contributing to hypertriglyceridemia and pancreatitis, aiding clinicians in monitoring and prevention., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Rai et al.)

Yong Zhang,1,* Yongren Wang,2,3,* Ru Wang,4 Yan Shen,4 Jing Xu,1 Thomas J Webster,5 Yongjun Fang2,3 1Department of Pharmacy, Children’s Hospital of Nanjing Medical University, Nanjing 210008, China; 2Department of Hematology and Oncology, Children’s Hospital of Nanjing Medical University, Nanjing 210008, China; 3Key Laboratory of Hematology, Nanjing Medical University, Nanjing 210008, China; 4State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China; 5Department of Chemical Engineering, Northeastern University, Boston, MA 02115, USA *These authors contributed equally to this work Purpose: PEGylated asparaginase (PEG-ASNase), which hydrolyzes asparagine to ammonia and aspartic acid, is an effective nanostructured antitumor agent for acute lymphoblastic leukemia (ALL). In order to monitor the activity of PEG-ASNase in plasma and design an individualization project, a rapid and sensitive method to determine PEG-ASNase activity in plasma using ultraviolet–visible spectrophotometry was established. Methods: PEG-ASNase is commonly used in acute lymphoblastic leukemia. With Nessler’s reagent as the chromogenic reagent of ammonia, a stable yellow complex was produced. The units of enzyme activity were defined as micromoles of ammonia released per minute. Results: Calibration curves fitted by plotting the OD at 450 nm of the Nessler product vs concentration were linear in the range of 27.8–1,111.0 IU/L with r2=0.999. The lower limit of quantification for PEG-ASNase activity in human plasma was 20 IU/L with good accuracy and precision. The intra- and interday precision (relative standard deviation) values were below 10% and accuracy ranged from 90% to 110% at all quality control levels. Analytical recoveries were determined between 90% and 110% for all quality control samples. Conclusion: This study proved that the Nessler method is well validated and can be successfully applied in the determination of plasma samples in the clinical setting for patients with ALL. It takes personalized nanomedicine to an entirely new level. Keywords: PEG-ASNase, Nessler’s reagent, UV–vis spectrophotometry, enzyme activity, personalized nanomedicine, ALL, Nessler method, plasma

Summary: Epstein–Barr virus‐associated haemophagocytic lymphohistiocytosis (EBV‐HLH) is one of the most common subtypes of secondary HLH. However, more than 30% of patients do not respond to traditional treatment. Here, we investigated the efficacy and safety of the L‐DEP regimen as a salvage therapy for paediatric refractory EBV‐HLH. We retrospectively analysed 26 paediatric patients with refractory EBV‐HLH who received the L‐DEP regimen at Beijing Children's Hospital from 1 January 2016 to 31 March 2019. Five of the patients achieved complete response (CR) and 11 achieved partial response (PR), indicating an overall response rate of 61·5% (CR + PR). Ten of the 16 patients who achieved CR or PR received allogenic haematopoietic stem cell transplantation (allo‐HSCT), and seven were still alive at the last follow‐up on 30 April 2020. Two of the 10 patients who did not respond were alive after allo‐HSCT. Major side effects included increased amylase, bone marrow suppression and coagulation disorders, though these could be controlled by supportive therapy in most cases. Thus, we conclude that the L‐DEP regimen is an effective and relatively safe salvage therapy for children with refractory EBV‐HLH. This regimen also provides a bridge to allo‐HSCT. [ABSTRACT FROM AUTHOR]

Management of children with pancreatic pseudocysts has historically been adopted from the adult experience where pancreatic pseudocysts greater than 6 cm are unlikely to resolve without intervention. We reviewed the clinical course of pediatric oncology patients with pancreatic pseudocysts. A retrospective review of patients treated over a 15-year period was performed. Variables evaluated included cancer type, medications administered, clinical and imaging characteristics of the pancreatic pseudocysts, treatment and outcome. A total of 132 patients with a median age of 13 (IQR, 9–17) years were identified with pancreatitis. Thirty-one (23.5%) patients developed a pancreatic pseudocyst, of which 84% were associated with PEG-asparaginase treatment. The median pseudocyst size was 7.6 (IQR, 4.4–9.9) cm with 59% being greater than 6 cm. Twenty-two (71%) patients with a pancreatic pseudocyst underwent successful conservative management, while only 9 (29%) required procedural intervention including six percutaneous drainage, one of whom recurred and required surgical cyst-enteric drainage. Two other patients had primary surgical cyst-enteric drainage and one patient underwent endoscopic retrograde cholangiopancreatography with stenting. The indication for intervention was worsening pain rather than pseudocyst imaging characteristics, size or serum amylase/lipase. Most medication-induced pancreatic pseudocysts in children being treated for cancer, regardless of pseudocyst size, can be managed non-operatively or with transgastric percutaneous drainage. The need for intervention can be safely dictated by patient symptoms. III [ABSTRACT FROM AUTHOR]

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 (: 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. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

N-hydroxysuccinimide ester of monomethoxy polyethylene glycol hemisuccinate was synthesized. It acylated amino groups in a molecule of recombinant L-asparaginase from Erwinia carotovora. A method of L-asparaginase modification by the obtained activated polyethylene glycol derivative was developed. The best results were produced by modification of the enzyme with a 25-fold excess of reagent relative to the enzyme tetramer. The modified L-asparaginase was isolated from the reaction mixture by gel filtration on Sepharose CL-6B. The purified bioconjugate did not contain PEG unbound to the protein, demonstrated high catalytic activity, and exhibited antiproliferative action on cell cultures. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

l -Asparaginase (EC3.5.1.1) is an enzyme, which is used for treatment of acute lymphoblastic leukaemia (ALL) and other related blood cancers from a long time. This enzyme selectively hydrolyzes the extracellular amino acid l -asparagine into l -aspartate and ammonia, leading to nutritional deficiencies, protein synthesis inhibition, and ultimately death of lymphoblastic cells by apoptosis. Currently, bacterial asparaginases are used for treatment purpose but offers scepticism due to a number of toxicities, including thrombosis, pancreatitis, hyperglycemia, and hepatotoxicity. Resistance towards bacterial asparaginase is another major disadvantage during cancer management. This situation attracted attention of researchers towards alternative sources of l -asparaginase, including plants and fungi. Present article discusses about potential of l -asparaginase as an anticancer agent, its mechanism of action, and adverse effects related to current asparaginase formulations. This article also provides an outlook for recent developments in l -asparaginase discovery from alternative sources and their potential as a less toxic alternative to current formulations. [ABSTRACT FROM AUTHOR]

Despite having been long regarded as too toxic for adult patients, pediatric-like regimens containing L-asparaginase have resulted in improved outcomes for adults with acute lymphoblastic leukemia (ALL). To characterize the spectrum of toxicity of repeated doses of polyethylene glycolated-asparaginase (PEG-asp) in adults, we reviewed all doses (2000 IU/m2) administered as part of a pediatric-inspired regimen in adult ALL at our center. Subjects aged 18-60 yr with ALL (n = 152, 69.1% male) contributed 522 dose cycles to the study. Hepatotoxicity was the most common adverse event: grades 3-4 transaminitis and hyperbilirubinemia occurred in 53.9% and 23.7% of subjects, respectively. Hepatotoxicity was reversible; no cases of fulminate hepatic failure were observed. Other toxicities affecting at least 5% of subjects were grades 3-4 triglyceridemia in 50.9%, hypofibrinogenemia (<100 mg/dL) in 47.9%, clinical pancreatitis in 12.6%, venous thromboembolism in 11.2%, allergic reaction in 7.2%, and any grade bleeding in 5.3%. PEG-asp was always discontinued after grades 3-4 pancreatitis or allergic reaction. Otherwise, toxicities did not preclude administration of additional cycles of the drug. Our results suggest that repeated PEG-asp dosing is safe in adults aged 18-60 yr, even after occurrence of a drug-related toxicity. [ABSTRACT FROM AUTHOR]

Monomethoxypolyethylene glycol l -asparaginase (PEG-ASNASE) is the PEGylated version of the enzyme l -asparaginase (ASNASE). Both are used for remission induction in acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL). The treatment control is generally carried out by performing activity assays, though methods to determine the actual enzyme rather than its activity are rare. Using asymmetrical flow field-flow fractionation (AF4) offered the chance to develop a method capable of simultaneously measuring PEG-ASNASE and PEG. A method validation was performed in accordance with FDA guidelines for PEG-ASNASE from non-biological solutions. The method unfolded a linearity of 15–750 U/mL with coefficients of correlation of r 2 >0.99. The coefficients of variation (CV) for within-run and between-run variability were 1.18–10.15% and 2.43–8.73%, respectively. Furthermore, the method was used to perform stability tests of the product Oncaspar® (PEG-ASNASE) and estimation of the molecular weight by multi-angle light scattering (MALS) of stressed samples to correlate them with the corresponding activity. The findings indicate that Oncaspar® stock solution should not be stored any longer than 24 h at room temperature and cannot be frozen in pure aqueous media. The validated method might be useful for the pharmaceutical industry and its quality control of PEG-ASNASE production. [ABSTRACT FROM AUTHOR]