Native Asparaginase Research Articles

Outcomes and adverse events in older acute lymphoblastic Leukemia patients treated with a pediatric-inspired protocol with Pegylated or native Asparaginase

ABSTRACT This retrospective report presents the outcomes and adverse events (AEs) observed in 73 patients aged 60 years or older diagnosed with Philadelphia Chromosome-negative Acute Lymphoblastic Leukemia (Ph-negative ALL) treated with a pediatric-inspired protocol incorporating either Pegylated (PEG-ASP) or Native Asparaginase (EC-ASP). Notably, 61% of patients experienced AEs of Grade III-IV severity. The most prevalent AEs included thrombosis (35.6%), febrile neutropenia (38.4%), and transaminitis (34.2%). AEs did not translate into significant differences concerning overall survival, leukemia-free survival, or early mortality. Furthermore, we observed a reduction in early mortality rates (11% vs. 20%) and an increase in median overall survival (54 vs. 48 months) compared to our previous data. These findings suggest that the utilization of a pediatric-inspired chemotherapy protocol, with ASP, is an effective and well-tolerated therapeutic option for older patients with Ph-negative ALL. However, it emphasizes the importance of diligent monitoring and close follow-up throughout treatment.

Central Retinal Vein Occlusion (CRVO) in Acute Lymphoblastic Leukaemia (ALL) Adult Patient Treated with Peg Asparaginase

ntroduction Asparaginase, available as native asparaginase or polyethylene glycol (Peg-aspa), is an essential component of multi-agent treatment protocols for Acute Lymphoblastic Leukaemia (ALL). It works by deaminating L-asparagine, leading to apoptosis and cell cycle arrest in leukemic cells. However, peg-asp is associated with various toxicities, including thrombotic complications mainly cavernous sinuses thrombosis and venous thrombosis. Methods and Results: We report a 48-year-old Indian gentleman, known to be hypertensive, diagnosed to have Precursor T-Lymphoblastic leukaemia/ lymphoma (NOS), when he presented with bicytopenia and a mediastinal mass. He was treated as per ALL protocol for adult at National centre for cancer care and research (NCCCR)Doha, which is adopted from UKALL-14 protocol. He received induction treatment (1A& 1B) and has achieved a morphological remission. He received prophylactic anticoagulation with low molecular weight heparin (LMWH) which was stopped only in the cytopenic nadir. During the ascending phase of induction 1B, He presented with acute onset of floaters and blurred vision in the left eye. Urgent CT head scan revealed vitreous haemorrhage. Full blood count was normal except Platelets of 20*10 9ul. Coagulation screen, fibrinogen level and anti-thrombin level was within normal limit. Ophthalmological evaluation revealed vitreous and retinal haemorrhages, indicating Central Retinal Vein Occlusion (CRV). MRI/MRV brain ruled out intracranial venous thrombosis. CSF analysis excluded CNS disease. He received supportive transfusion; however, he has progressed to permanent loss of vision in the left eye. Therapeutic anticoagulation is not indicated in his case. Thrombotic events can occur during induction therapy for ALL mainly cavernous sinuses thrombosis and venous thrombosis, yet CRVO is an unusual site for thrombotic events and associated predominately with age-associated vasculopathies. In the reported case, several factors contribute to thrombosis, including acute leukaemia, prolonged hospitalization, age, presentation with a mediastinal mass, steroid use as well as Peg-aspa and the patient was managed with prophylactic anticoagulation while on therapy. Asparaginase induces a hypercoagulable state by decreasing antithrombin III, protein C, and protein S levels, leading to hypofibrinogenemia and augmenting the risk of thrombotic events. Thrombosis can negatively impact disease-free survival and long-term outcomes, resulting in complications such as therapy delays, post-thrombotic syndrome, and central nervous system-related issues (seizures, neurocognitive deficits, blindness). While these complications may lead to hesitancy or discontinuation of peg-asp use, early recognition and vigilant monitoring of antithrombin III and fibrinogen levels can help to guide management. In cases where the treatment course is complicated by thrombotic events, a high index of suspicion should arise considering strongly the causative agent to be Asparaginase. Thromboprophylaxis with low-molecular-weight heparin (LMWH) is widely accepted as supportive therapy in ALL management. Conclusion: ALL patients receiving Asparaginase therapy are at risk of developing thrombotic events. Early identification of symptoms and risk stratification are essential for improved disease outcomes. Awareness and understanding of peg-asp-induced thrombosis, including unusual site thrombosis can help guide treatment decisions and improve patient outcomes in ALL therapy.

Practice of L-Asparaginase Usage: A Survey among Healthcare Providers Treating Children with Cancer in India

Introduction L-asparaginase is an essential chemotherapeutic agent in the therapy of acute lymphoblastic leukemia (ALL), which has led to improvement in survival. In low- and middle-income countries like India, the outcomes in ALL are inferior compared with the published literature, one of the causes of which is believed to be due to the inferior quality of bioequivalent asparaginase. Objective The following survey attempts to understand the practice of using this agent among oncologists treating children with cancer in our country. Methods The researchers designed a structured online questionnaire comprising 25 aspects of L-asparaginase usage in the study. The questionnaire was directed to the healthcare providers involved in treating children with cancer in India. Results Of the total 80 responses recorded, 51 (64%) respondents had more than 5 years of experience in pediatric oncology and were treating at least 5 to 10 newly diagnosed ALL patients per month. Forty-one (51%) respondents utilized native asparaginase, and 21 (26.3%) oncologists used PEGylated-asparaginase exclusively. The most common route of administration was the intramuscular route (66.3%). Seventy percent of respondents utilized native form at a dose of 10,000 IU/m2 and 20% at 6,000 IU/m2. The amounts used for PEGylated L-asparaginase were 1,000,IU/m2, 2,500,IU/m2, and variable doses in 48, 40, and 10% of responses, respectively. Though serum asparaginase assay (SAA) was not measured routinely in most of the centers, 39 (48.8%) healthcare providers perceived performing SAA helps to make the clinical decision. Conclusion This survey shows a wide variation in L-asparaginase usage among healthcare providers caring for children with cancer in our country. As L-asparaginase is the pivotal component of ALL therapy, uniformity in its usage and dosing with the possibility of monitoring SAA due to the quality of bioequivalent may be one of the critical steps toward improving outcomes in ALL in our country.

Clinical Utility of Pegaspargase in Children, Adolescents and Young Adult Patients with Acute Lymphoblastic Leukemia: A Review.

Acute lymphoblastic leukemia (ALL) is a heterogenous hematological malignancy representing 25% of all cancers in children less than 15 years of age. Significant improvements in survival and cure rates have been made over the past four decades in pediatric ALL treatment. Asparaginases, derived from Escherichia coli and Erwinia chrysanthemi, have become a critical component of ALL therapy since the 1960s. Asparaginases cause depletion of serum asparagine, leading to deprivation of this critical amino acid for protein synthesis, and hence limit survival of lymphoblasts. Pegaspargase, a conjugate of monomethoxypolyethylene glycol (mPEG) and L-asparaginase, has become an integral component of pediatric upfront and relapsed ALL protocols due to its longer half-life and improved immunogenicity profile compared to native asparaginase preparations. Over the past two decades great strides have been made in outcomes for pediatric ALL due to risk stratification, incorporation of multiagent chemotherapy protocols, and central nervous system prophylaxis with pegaspargase having played an important role in this success. However, adolescents and young adults (AYA) with ALL when treated on contemporaneous trials using adult ALL regimens, continue to have poor outcomes. There is increasing realization of adapting pediatric trial regimens for treating AYAs, especially those incorporating higher intensity of chemotherapeutic agents with pegaspargase being one such agent. Dose or treatment-limiting toxicity is observed in 25–30% of patients, most notable being hypersensitivity reactions. Other toxicities include asparaginase-associated pancreatitis, thrombosis, liver dysfunction, osteonecrosis, and dyslipidemia. Discontinuation or subtherapeutic levels of asparaginase are associated with inferior disease-free survival leading to higher risk of relapse, and in cases of relapse, a higher risk for remission failure. This article provides an overview of available evidence for use of pegaspargase in pediatric acute lymphoblastic leukemia.

Randomized, Parallel Group, Open-Label Bioequivalence Trial of Intramuscular Pegaspargase in Patients With Relapsed Acute Lymphoblastic Leukemia.

PURPOSEPegylated asparaginase is comparatively safer than native asparaginase in the management of acute lymphoblastic leukemia (ALL). However, the high price and nonavailability in low- and middle-income countries limits its use. In 2014, the first generic of pegaspargase (Hamsyl) was approved in India for use as a second-line treatment option for ALL. The aim of this study was to assess whether the generic pegaspargase (the test product) was bioequivalent with the reference product (Oncaspar).PATIENTS AND METHODSThis study was an open-label, parallel-group, comparative pharmacokinetic study in pediatric patients with relapsed ALL receiving their first dose (1,000 IU/m2) of pegaspargase administered intramuscularly. Patients were randomly assigned 1-to-1 to either the test or the reference product. The 2 formulations were considered equivalent if the 90% CIs for area under the plasma asparaginase activity–time curve (AUC0-t) geometric mean test-to-reference ratio was within 75% to 133%.RESULTSTwenty-nine patients (6-18 years of age) were enrolled in this study, of whom 24 completed the study criteria and were considered for safety analysis (5 patients were ineligible for the assessment). Three patients were excluded from analysis, because of presence of anti-asparaginase antibodies, leaving 21 patients who were considered for bioequivalence pharmacokinetics data. The point estimate of AUC0-t for the test-to-reference ratio was 95.05 (90% CI, 75.07% to 120.33%). Maximum plasma concentration, trough concentrations (day 14), half-life, volume of distribution, drug clearance, and changes in the asparagine and glutamine levels were not significantly different between products. Adverse events were comparable in both groups.CONCLUSIONGeneric and reference pegaspargase had equivalent pharmacokinetics with comparable safety. This could be a safe and cost-effective alternative for patients with ALL, especially in low- and middle-income countries.

The cost-effectiveness of pegaspargase versus native asparaginase for first-line treatment of acute lymphoblastic leukaemia: a UK-based cost-utility analysis

BackgroundL-asparaginase is a key component of treatment for patients with acute lymphoblastic leukaemia (ALL) in the UK. Commonly used forms of asparaginase are native E. coli-derived asparaginase (native asparaginase) and pegaspargase in first-line combination therapy, and native Erwinia chrysanthemi-derived asparaginase (Erwinia asparaginase) as second-line treatment. The objective of this study was to evaluate the cost-effectiveness of pegaspargase versus native asparaginase in first-line combination therapy for patients with newly diagnosed ALL. A combined decision tree and health-state transition Markov cost-effectiveness model was developed to assess the relative costs and health outcomes of pegaspargase versus native asparaginase in the UK setting.ResultsIn base case analyses, first-line pegaspargase (followed by Erwinia asparaginase in cases of hypersensitivity) dominated first-line native asparaginase followed by Erwinia asparaginase; i.e. resulted in lower costs and more quality-adjusted life year gain. The favourable hypersensitivity rates and administration profile of pegaspargase led to lifetime cost savings of £4741 versus native asparaginase. Pegaspargase remained cost-effective versus all treatment strategies in all scenario analyses, including use of the 2500 IU/m2 dose, recommended for patients ≤21 years of age.ConclusionsPegaspargase, as part of multi-drug chemotherapy, is a cost-effective option for the treatment of newly diagnosed ALL. Based on this study, The National Institute for Health and Care Excellence Technology Appraisal Committee concluded that it could recommend pegaspargase as a cost-effective use of National Health Service resources in England & Wales for treating ALL in children, young people and adults with untreated, newly diagnosed disease.Trial registrationUKALL 2011, EudraCT number 2010-020924-22; UKALL 2003, EudraCT number 2007-004013-34; UKALL14, EudraCT number 2009-012717-22.

A 12-steps desensitization protocol for pediatric patients with hypersensitivity to pegylated asparaginase

Asparaginase is a chemotherapeutic used to treat hematologic malignant tumors. Hypersensitivity reactions to native asparaginase (l-asparaginase) are described in up to 60% of patients 1 Rau R.E. Dreyer Z. Choi M.R. et al. Outcome of pediatric patients with acute lymphoblastic leukemia/lymphoblastic lymphoma with hypersensitivity to pegasparaginase treated with PEGylated Erwinia asparaginase, pegcrisantaspase: a report from the Children's Oncology Group. Pediatr Blood Cancer. 2018; 65e26873 Crossref Scopus (42) Google Scholar in whom case switching to alternative forms of asparaginase is recommended: pegylated asparaginase (PEG-asparaginase), a readily available formulation, or Erwinia-asparaginase, 2 van der Sluis I.M. Vrooman L.M. Pieters R. et al. Consensus expert recommendations for identification and management of asparaginase hypersensitivity and silent inactivation. Haematologica. 2016; 101: 279 Crossref PubMed Scopus (134) Google Scholar which is currently scarce. Although PEG-asparaginase is considered hypoallergenic, up to 25% of patients receiving it have allergic reactions. 3 Burke Michael J. Devidas Meenakshi Maloney Kelly et al. Severe peg-asparaginase hypersensitivity reaction rates (grade ≥3) with intravenous infusion vs. intramuscular injection: analysis of 54,280 doses administered to 16,534 patients on children’s oncology group (COG) clinical trials. Leuk Lymphoma. 2018; 59: 1624-1633 Crossref PubMed Scopus (28) Google Scholar If no additional asparaginase formulations are available, hypersensitivity to PEG-asparaginase is an important cause of drug use discontinuation, which may compromise disease-free survival. 4 Kyonen M. Folatre I. Zolezzi P. et al. Adverse reactions to l-asparaginase in children with acute lymphatic leukemia. Rev Méd Chile. 2006; 134: 1530-1534 PubMed Google Scholar Because of the importance of asparaginase to treat hematologic malignant tumors, desensitization to PEG-asparaginase has been previously attempted, with mixed results. 5 Sahiner U.M. Yavuz S.T. Gökce M. Anaphylactic reaction to polyethylene-glycol conjugated-asparaginase: premedication and desensitization may not be sufficient. Pediatr Int. 2013; 55: 531-533 Crossref PubMed Scopus (21) Google Scholar ,6 Verma A. Chen K. Bender C. Gorney N. Leonard W. Barnette P. PEGylated E. coli asparaginase desensitization: an effective and feasible option for pediatric patients with acute lymphoblastic leukemia who have developed hypersensitivity to pegaspargase in the absence of asparaginase Erwinia chrysanthemi availability. Pediatr Hematol Oncol. 2019; 36: 277-286 Crossref PubMed Scopus (20) Google Scholar

Risk Factors of Acute Pancreatitis in Pediatric Acute Lymphoblastic Leukemia Patients: A Single-Center Experience

Background: Acute pancreatitis during chemotherapy of acute lymphoblastic leukemia (ALL) is an often fatal complication which is mainly associated with asparaginase. Despite of the improvement of supportive care during treatment of ALL, the prediction of acute pancreatitis has not been feasible. The aim of this study was to identify the risk factors of acute pancreatitis in pediatric ALL patients. Patients and methods: This study included total 421 patients under 18 years old of age who were newly diagnosed with ALL and treated at Asan Medical Center Children's Hospital between January 2000 and December 2018. Patients in standard-risk group received a modified COG AALL0331 based treatment, and those in high-risk group received Korean multicenter high-risk ALL treatment. For national insurance coverage, native L-asparaginase was used as a first choice in all patients except patients who accepted the expanses of Pegylated-asparaginase (PEG). Patients who developed hypersensitivities to native asparaginase or PEGs, Erwinia-asparaginase was administered. Fibrinogen, triglyceride, amylase, lipase, and coagulation battery were checked before every asparaginases in all patients. The diagnosis and grading of acute pancreatitis were based on Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The cases of acute pancreatitis after relapse or allogenic hematopoietic stem cell transplantation were excluded. All the laboratory data were collected and analyzed retrospectively. Results: The incidence of acute pancreatitis in pediatric ALL was 3.3% (14 patients) and asparaginase associated acute pancreatitis was 2.8% (12 patients). Acute pancreatitis occurred in mainly in induction chemotherapy (n=8, 67%). Two patients were developed acute pancreatitis in consolidation chemotherapy, 1 in interim maintenance chemotherapy. Among 8 patients who developed acute pancreatitis in their induction chemotherapy, 1 patient was not associated with asparaginase. Among 14 patients, 2 patients were expired of disease progression and none of patient died of acute pancreatitis. Grade 2, 3 of acute pancreatitis patients were 6 and 8 respectively. There was no grade 5 acute pancreatitis. Eleven out of twelve patients who developed acute pancreatitis associated with asparaginase medication re-challenged asparaginase medication after experiencing acute pancreatitis. Among re-challenged patients, only 1 had second acute pancreatitis and discontinued asparaginase medication. There was no significant difference in incidence of acute pancreatitis with initial BSA, protein C, protein S, and age at diagnosis. Multivariate analysis identified prolonged activated partial thromboplastin time (aPTT) before acute pancreatitis in 1 week was significantly involved with risk factor of acute pancreatitis (p=0.013) Eight patients (67%) received a fresh frozen blood transfusion(FFP) before acute pancreatitis in a week. Conclusions: Prolonged aPTT and FFP transfusion are particularly at risk for acute pancreatitis in pediatric ALL patients. Cautious re-challenging asparaginase medication after experiencing grade 2 and grade 3 acute pancreatitis is needed. Early diagnosis and manage asparaginase-associated acute pancreatitis will contribute patients with sufficient effect of asparaginase medication. Disclosures No relevant conflicts of interest to declare.

Experience with generic pegylated L-asparaginase in children with acute lymphoblastic leukemia and monitoring of serum asparaginase activity

Background: Pegylated asparaginase (P-Asp) though integral to acute lymphoblastic leukemia (ALL) therapy is often not accessible to patients in developing countries. We share our clinical experience with generic P-Asp along with monitoring of asparaginase activity. Methods: In this prospective observational study, patients ≤18 years of age with ALL were assigned to receive either generic P-Asp or native asparaginase (N-Asp) in a non-randomized manner. Treatment protocol was based on ALL BFM-95 backbone. The dose of P-Asp was 1500 IU/m2 by intravenous route during induction (Ia) and re-induction (IIa) phase of therapy. Results: N-Asp or P-Asp was administered to 52 and 54 of the 106 eligible patients respectively. Demographic and disease characteristics were comparable in both arms. The mean trough levels for N-Asp and P-Asp were 156.87 ± 22.35 IU/L and 216.03 ± 73.40 IU/L, respectively (p value <0.001) and all patients achieved therapeutic levels during Ia. Incidence of asparaginase-attributable toxicity was similar in the two arms in both phases of treatment, although hospitalization due to noninfectious causes was more common in P-Asp arm during Ia (13% versus 0%, p value, 0.01). Clinical hypersensitivity and silent inactivation were not observed during Ia while these occurred in 13% and 5% of patients in the N-Asp arm and P-Asp arms of IIa, respectively. The 2-year event free survival for P-Asp and N-Asp groups was 84% and 80.7%, respectively (p value 0.85). Conclusion: Generic P-Asp was observed to be efficacious and well tolerated in our patients and adequate therapeutic levels were sustained for 2 weeks.

Systematic Literature Review Evidence of Pegaspargase for Treatment of Acute Lymphoblastic Leukemia (ALL)

Introduction: Advances in chemotherapeutic regimens have improved pediatric ALL survival rates from less than 10% in the 1960s to approximately 90% currently (Hunger et al NEJM 2015). Asparaginase (ASP), as a component of the multi-agent chemotherapy regimen has become a cornerstone treatment for ALL. Pegaspargase (Oncaspar, PEG) is a pegylated asparaginase with sustained asparaginase activity, offering less frequent administration and associated with less treatment-related anxiety compared to native E.coli L-asparaginase (Place et al Lancet Oncol 2015). Due to the ample amount of data available for PEG, a systematic literature review and quantitative synthesis of evidence was previously performed to assess the relative benefit of PEG versus native ASP in newly diagnosed ALL patients in terms of event free survival (EFS) and overall survival (OS) (Kilpatrick et al ICPE 2016). The main objective of this investigation was to update the literature review by identifying additional relevant scientific clinical evidence of PEG in first line treatment of ALL in pediatric patients, and to expand the investigation to include adult patients.Methods: All available evidence for newly diagnosed patients treated in pediatric and adult ALL protocols using PEG or native ASP was identified using a search algorithm. Randomized, observational and cohort studies were included. Outcomes were EFS and OS. Safety/immunogenicity was also examined. Feasibility was then explored in this order: direct comparison meta-analysis (MA) if at least two head-to-head trials were found, indirect comparison (network MA) if a common comparator could be identified or separate product MAs (pooled estimates) of PEG and native ASP using a random effects model. The individual product MA was analyzed for two important variables: risk category (standard & high risk) and by distinct age groups. Pooling was conducted, assuming normality, using the software Comprehensive Meta-Analysis, version 2.Results:There were 62 and 30 studies that met pre-specified inclusion criteria for abstraction for pediatric and adult populations, respectively. Some identified studies in both populations provided data for both asparaginases. Therefore, in pediatrics: 39 studies provided data for PEG and 41 for nativeASP, in adults: 10 studies provided data for PEG and 23 for nativeASP. Direct MA was not feasible as only one head-to-head study was identified. Also due to lack of common comparator, indirect MA was infeasible. Pooled estimate of EFS and OS data for pediatric ALL patients treated with PEG or native ASP is shown in table 1 below. Forest plot with pooled estimate of 5-year OS in adult ALL patients treated with PEG or native ASP is presented in figure 1, categorized by age group when available. Overall safety was consistent with product class for both asparaginases.Conclusions: A systematic literature review and quantitative synthesis constitute an important approach to critically appraise relevant research. Consistent with published data, better outcomes were observed in pediatric than adults patients. The result from this updated research synthesisdemonstrates a positive effectiveness profile of PEG in the treatment of newly diagnosed ALL patients with less frequent administration. [Display omitted] [Display omitted] DisclosuresLebedinsky:Shire: Employment. Hale:Shire: Employment. Patel:Shire: Employment. Casamayor:Shire: Other: Vendor; Quintiles: Employment. Wijnands:Shire: Other: Vendor; Quintiles: Employment. Desai:Shire: Employment.

Comparison of Efficacy and Safety of Two Types of E.coli Asparaginase (Native or Pegylated) for Treatment of Adult Patients with High-Risk (HR), Philadelphia (Ph) Chromosome-Negative ALL Included in the Prospective MRD-Oriented Protocol ALL-HR-11 from the Spanish Pethema Group

Background and objective. Asparaginase (ASP) is an essential drug for ALL treatment. Two types of E.coli ASP (native and pegylated) are used in clinical trials for treatment of children and adults with ALL, but to our knowledge direct comparison between these two types of ASP in the same protocol has not been performed. This study aimed to compare the efficacy and safety of native vs. PEG-ASP in adult patients with HR, Ph-negative ALL.Patients and methods. HR ALL included one or more of the following parameters at baseline: age 30-60 yr., WBC count >30x109/L for B-cell precursor ALL or >100x109/L for thymic T-ALL, pro-B, early or mature T-ALL, 11q23 or MLL rearrangements or complex karyotype. Induction therapy consisted of vincristine, prednisone, daunorubicin and ASP (native 10,000 IU/m2, i.v., days 16-20 and 23-27 or PEG 2,000 IU/m2, iv, day 15 depending on center decision) for 4 weeks (Induction-1). FLAG-Ida was administered as intensified induction (Induction-2) in patients not achieving CR or in those in CR with MRD≥0.1% at the end of induction, and those patients proceeded to allogeneic HSCT if CR was attained. Patients in CR and MRD<0.1% proceeded to early consolidation therapy including 3 cycles with rotating cytotoxic drugs with high-dose methotrexate, high-dose ARA-C and ASP (native 20,000 IU/m2 on day 3 of each cycle or PEG 2,000 IU/m2 on day 3 of each cycle). Patients continued with delayed consolidation (identical to that of early consolidation) followed by maintenance therapy up to 2 yr. in continuous CR if MRD levels after consolidation were <0.01%, otherwise they were assigned to allogeneic HSCT. The cumulated doses of native ASP and PEG-ASP for patients who completed the induction and early+delayed consolidation were 220,000 IU/m2 and 14,000 IU/m2, respectively. No ASP levels were assessed.Results. Ninety-onepatients received native ASP and 35 PEG-ASP in Induction-1. The two groups of patients were comparable for the main clinical and hematologic ALL parameters. No differences were observed in the CR rate (86% vs. 86%), in the frequency of MRD level <0.1% after Induction-1 (63% vs. 70%), and that of MRD level <0.01% after early consolidation (74% vs. 92%, p=0.19), as well as in the proportion of patients submitted to allogeneic HSCT (20% vs. 14%). No differences were found in overall survival or disease-free survival probabilities at 3-years according to the type of ASP (OS: 60% [95%CI: 47% ; 73%] vs. 57%[95%CI: 36% ; 78%], p=0.872 and DFS: 40% [95%CI: 25% ; 55%] vs. 58% [95%CI: 36% ; 80%], p=0.302). Abnormalities in the coagulation parameters were significantly more frequent in patients receiving PEG-ASP in Induction-1 (18% vs. 35%, p=0.045). These abnormalities, together with hepatic toxicity were significantly more frequent in patients receiving PEG-ASP in early consolidation (1% vs. 13%, p=0.003, and 5% vs. 34, p<0.001, respectively). A trend for more allergic reactions was seen in patients receiving native ASP (18% vs. 5%, p=0.1) No differences in the frequency of ASP discontinuation rate were observed (6 % vs. 3%).Conclusions. In HR, Ph-negative adult ALL patients included in the PETHEMA ALL-HR 11 protocol the type of E.coli ASP (native vs. PEG) did not have impact on response and outcome. Allergic reactions were more frequently seen with native ASP and coagulation abnormalities and hepatic toxicity were most frequent with PEG-ASP. Most of the differences in toxicity can be explained by the schedule of ASP given in consolidation (single dose of native ASP vs. single dose of PEG-ASP in each cycle).Supported in part by grants RD12/0036/0029 (RTICC, FEDER), PI14/01971 FIS, Instituto Carlos III, and SGR225 (GRE), Spain DisclosuresNo relevant conflicts of interest to declare.

Population Pharmacokinetics of Erwinia Asparaginase in Pediatric ALL Patients

▪Asparaginase is an important component in the treatment of pediatric acute lymphoblastic leukemia (ALL). Erwinia asparaginase is used in patients who develop hypersensitivity to the E. coli derived asparaginase (native asparaginase or PEGasparaginase). Little is known about the pharmacokinetics (PK) of Erwinia asparaginase, especially after intravenous administration. A 100-fold difference in Erwinia asparaginase serum trough levels between patients has been observed during therapeutic drug monitoring (TDM). Currently, in DCOG ALL-protocols dose alterations of asparaginase and erwinase are based on TDM, with the aim to keep the trough asparaginase activity above the 100 IU/L threshold. No formal guidelines for increasing or decreasing the dose are available, and dose-adaptations are based on empirical knowledge. With a PK model, individual dose requirements can be estimated based on their PK parameters like clearance. The final aim is to avoid under-exposure and relapse, or over-exposure which may induce side-effects and results in unnecessary costs. However the upper limit of the therapeutic window that causes toxicity is not known.AimsThe aim of this retrospective study was to describe the population PK of Erwinia asparaginase to gather insight in the inter-individual and intra-individual variability, and which co-variates influence exposure. Availability of a population PK model will allow the calculation of a starting dose and subsequent dosing in TDM-setting in the future.MethodsA total of 714 evaluable blood samples were collected from 51 children with ALL who received intravenous Erwinia asparaginase as a substitute for E. coli or PEG asparaginase, when treated according to the DCOG ALL-10 or 11 protocol. Patients (32 males and 19 females), had a median age of 6 years (range 1-17), median weight of 25 kg (12-99) and median BSA of 0.92 m2 (0.53-2.22). The median number of samples per patient was 11 (2 - 43). Samples were taken approximately 48 (52.2%) and 72 (36.8%) hours after administration. In addition, samples within 5h (2.4%), between 5-40h (1.3%) and between 80-120h (7.3%) after administration were available. The Erwinia starting dose was 20,000 IU/m2/3x per week, and was given IV over 1 hour, and was later adapted based on TDM to 5,000-50,400 IU/m2 twice (54.2%) or thrice (45.8%) weekly. A population pharmacokinetic model was developed using nonlinear mixed-effects modeling (NONMEM 7.2; pirana 2.7.1; Xpose4). Monte Carlo simulations were performed with different doses and stratification for body weight (n=5000 per dose per weight).ResultsThe concentration versus time profiles were best described with a 2-compartment model with allometric scaling (weight). The parameter estimates were: Cl 0.439 L/h/70kg, V1 (central compartment) 3.22 L/70kg, intercompartimental clearance 0.149 L/h/70kg and V2 (peripheral compartment) 1.14 L/70kg. The interindividual variability of clearance was 32.6%. There was an interoccasion variability of 12.7% based on monthly intervals. Clearance in the first month of treatment was 14% higher compared to the other months (p<0.01). Additional incorporation of age, DCOG protocol (ALL-10 or 11), treatment center, sex and BSA did not improve the model significantly.Based on the simulations, patients with a lower body weight appeared to require higher starting doses to achieve sufficient erwinase levels after 48 hours. With the current starting dose of 20,000 IU/m2, circa 75% of the patients >50kg would have levels >100 IU/L after 48h. For patients between 20-50 kg the dose starting dose should be 25,000 IU/m2 in order to achieve levels >100 IU/L at 48h in 75% of the patients. In our study, of 36 patients with evaluable starting doses (dosed 20,000 IU/m2 and with an available 48h sample), 38.7% (from a total of 31 patients <50 kg) and 20% (from a total of 5 patients ≥50kg group) had 48h trough levels below 100 IU/L.ConclusionsA population PK model was developed for Erwinia asparaginase in pediatric ALL patients. Depending on the weight of the patients the currently used starting dose of 20,000 IU/m2 may need to be adjusted to produce similar trough asparaginase activity, which needs to be confirmed prospectively. The PK model can be used for TDM to calculate dose adjustments in individual patients based on single PK samples, which might result in better dose-predictions than used in current practice. DisclosuresPieters:Eusa Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Kaspers:Celgene: Consultancy; Boehringer Ingelheim: Consultancy; Galen Pharmaceuticals: Consultancy. van der Sluis:Eusa Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Haemostatic alterations induced by treatment with asparaginases and clinical consequences.

The benefit of asparaginase for treating acute lymphoid leukaemia (ALL) has been well established. Native asparaginase derives from Escherichia coli (colaspase) or Erwinia chrysanthemi (crisantaspase); in a third preparation, colaspase is pegylated. Depletion of asparagine leads to decreased synthesis of procoagulant, anticoagulant, and fibrinolytic proteins, with resultant hypercoagulability and greater risk of venous thromboembolism (VTE). Colaspase and crisantaspase are not dose-equivalent, with crisantaspase displaying haemostatic toxicity only at dosages much higher and administered more frequently than those of colaspase. Cerebral venous thrombosis and pulmonary embolism are two life-endangering manifestations that occur during treatment with asparaginase particularly in children and in adults with ALL, respectively. Approximately one-third of VTEs are located in the upper extremities and are central venous line-related. Other risk factors are longer duration of asparaginase treatment and concomitant use of prednisone, anthracyclines, and oral contraceptives. The risk associated with inherited thrombophilia is uncertain but is clearly enhanced by other risk factors or by the use of prednisone. VTE prevention with fresh frozen plasma is not recommended; the efficacy of antithrombin (AT) concentrates has occasionally been reported, but these reports should be confirmed by proper studies, and AT should not be routinely employed. Therapeutic or prophylactic heparin doses are only partially effective, and direct thrombin or factor Xa inhibitors could play significant roles in the near future.

Optimizing asparaginase therapy for acute lymphoblastic leukemia

Asparaginases are important agents used in the treatment of children with acute lymphoblastic leukemia (ALL). Three types of asparaginase are currently available: two are derived from Escherichia coli [native asparaginase and pegylated asparaginase (PEG-asparaginase)] and one from Erwinia chrysanthemi (crisantaspase). All three products share the same mechanism of action but have different pharmacokinetic properties, which do not make them easily interchangeable. Among the known toxicities and side-effects, allergic reactions and silent inactivation represent the most important limitations to the prolonged use of any asparaginase product, with associated reduced therapeutic effects and poorer outcomes. Routine real time monitoring can help to identify patients with silent inactivation and facilitate a switch to a different product to ensure continued depletion of asparagine, completion of the treatment schedule and maintenance of outcomes. However, the most appropriate second-line treatment is still a matter of debate. PEG-asparaginase has lower immunogenicity and a longer half-life than native Escherichia coli (E. coli) asparaginase, which makes it useful for both first-line and second-line use with a reduced number of doses. However, PEG-asparaginase displays cross-reactivity with native E. coli asparaginase that may harm its therapeutic effects. Crisantaspase does not display cross-reactivity to either of the E. coli-derived products, which has made crisantaspase the second-line treatment option in a number of recent protocols. As crisantaspase has a much shorter biological half-life than the E. coli-derived products, the appropriate dosage and administration schedule are of paramount importance in delivering treatment with this product. In the ongoing trial AIEOP-BFM ALL 2009 (Associazione Italiana Ematologia Oncologia Pediatrica - Berlin-Franklin-Munster), in which PEG-asparaginase is used first-line, one dose of PEG-asparaginase is substituted by seven doses of crisantaspase given intravenously at 20,000 IU/m2 on alternate days when clinical allergy or silent inactivation is present. Based on the indications of different protocols, lack of cross-reactivity to the E. coli-derived products and taking into consideration regulatory factors and availability, crisantaspase may be considered a viable second-line therapy.

Polyethylene Glycol-conjugated L-asparaginase Versus Native L-asparaginase in Combination With Standard Agents for Children With Acute Lymphoblastic Leukemia in Second Bone Marrow Relapse

Administration of L-asparaginase is limited by hypersensitivity reactions mediated by anti-asparaginase antibodies. To overcome this problem, native Escherichia coli L-asparaginase was conjugated to polyethylene glycol (PEG) to formulate PEG-L-asparaginase, a preparation with decreased immunogenicity and increased circulating half-life. In early trials, PEG-L-asparaginase was tolerated by patients known to be hypersensitive to the native E. coli product. The Pediatric Oncology Group conducted a phase II, randomized trial to compare the efficacy and toxicity of PEG-L-asparaginase compared with native E. coli asparaginase in children with acute lymphoblastic leukemia in second bone marrow relapse. All patients (n=76) received standard doses of vincristine and prednisone. Nonhypersensitive patients (n=34) were randomized to receive either PEG-L-asparaginase of 2500 IU/m/dose intramuscularly on days 1 and 15 (treatment I) or native E. coli asparaginase of 10,000 IU/m/dose intramuscularly on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 (treatment II). Patients with a clinical history of an allergic reaction to unmodified asparaginase were directly assigned to treatment with PEG-L-asparaginase (n=42). Asparaginase levels and anti-asparaginase antibody titers were monitored in all patients. Response and toxicity were scored using conventional criteria. The complete response rate for the total study population was 41%. There was no difference in complete response between patients randomized to PEG (47%) and native asparaginase (41%). PEG was well tolerated even in patients with prior allergic reactions to native asparaginase. PEG half-life was shorter in patients with prior allergy. PEG asparaginase is a useful agent in patients with allergic reactions to native asparaginase.

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

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

L‐asparaginase treatment in acute lymphoblastic leukemia

Asparaginases are a cornerstone of treatment protocols for acute lymphoblastic leukemia (ALL) and are used for remission induction and intensification treatment in all pediatric regimens and in the majority of adult treatment protocols. Extensive clinical data have shown that intensive asparaginase treatment improves clinical outcomes in childhood ALL. Three asparaginase preparations are available: the native asparaginase derived from Escherichia coli (E. coli asparaginase), a pegylated form of this enzyme (PEG-asparaginase), and a product isolated from Erwinia chrysanthemi, ie, Erwinia asparaginase. Clinical hypersensitivity reactions and silent inactivation due to antibodies against E. coli asparaginase, lead to inactivation of E. coli asparaginase in up to 60% of cases. Current treatment protocols include E. coli asparaginase or PEG-asparaginase for first-line treatment of ALL. Typically, patients exhibiting sensitivity to one formulation of asparaginase are switched to another to ensure they receive the most efficacious treatment regimen possible. Erwinia asparaginase is used as a second- or third-line treatment in European and US protocols. Despite the universal inclusion of asparaginase in such treatment protocols, debate on the optimal formulation and dosage of these agents continues. This article provides an overview of available evidence for optimal use of Erwinia asparaginase in the treatment of ALL.

Peg-asparaginase for acute lymphoblastic leukemia

Importance of the field: Asparaginase is a prominent component of pediatric and adolescent treatment for acute lymphoblastic leukemia. These treatment regimens are now being employed in adults. Knowledge of the efficacy and toxicity of asparaginase preparations is essential when using these treatments.Areas covered by this review: The search terms used were asparaginase, leukemia, pegylated, oncaspar, adolescent and young adult. Literature was searched in Pubmed/Medline with no limitations on year of publication. s from the American Society of Hematology meetings and the American Society of Clinical Oncology were searched from 2004 – 2008 using the same terms.What the reader will gain: The reader will gain knowledge of the tolerability and efficacy of pegylated asparaginase when treating acute lymphoblastic leukemia.Take home message: Pegylated asparaginase is generally well tolerated in adult patients with efficacy that appears to be at least equivalent to native asparaginase preparations.

Pharmacokinetics, pharmacodynamics, efficacy, and safety of a new recombinant asparaginase preparation in children with previously untreated acute lymphoblastic leukemia: a randomized phase 2 clinical trial

AbstractThe pharmacokinetics, pharmacodynamics, efficacy, and safety of a new recom-binant Escherichia coli–asparaginase preparation was compared with Asparaginase medac. Thirty-two children with acute lymphoblastic leukemia were randomized to receive one of both agents at a dose of 5000 U/m2 every 3 days, for a total of 8 doses during induction treatment. The serum activity-time profile after the first dose of recombinant asparaginase was similar to that of Asparaginase medac. The trough serum activities were greater than the desired threshold of 100 U/L in both treatment groups. Asparagine was completely depleted in serum and in cerebrospinal fluid, whereas glutamine levels were only moderately influenced. No significant difference between the 2 treatments regarding the degree of asparagine depletion, duration of depletion, complete remission rate, and minimal residual disease status at the end of induction, overall frequency or intensity of adverse events was seen. Observed adverse reactions are known as possible and labeled side effects of asparaginase treatment and chemotherapy. We conclude that the new recombinant asparaginase and other native Asparaginase medac are bioequivalent and have the same pharmacodynamic effects and the same direct toxicity profile in children with acute lymphoblastic leukemia. This trial was registered at http://www.controlled-trials.com as no. ISRCTN 75734403.

Incidence of adverse reactions to post-induction asparaginase (ASP) therapy in children and adolescents with high-risk acute lymphoblastic leukemia (ALL): A report from the Children’s Oncology Group Study CCG-1961

10021 Background: Asparagine depletion is an essential component of combination therapy for ALL. We report the incidence of reactions to three forms of ASP in children and adolescents with high-risk ALL enrolled on the Children’s Oncology Group study CCG- 1961. Methods: Between November 1996 and May 2002, 2078 patients with newly diagnosed high-risk ALL were enrolled on CCG- 1961. All were treated with a standard four-drug induction that included native E. coli ASP (native ASP). Rapid early responders randomized to augmented post induction intensification and all slow early responders were assigned 6 or 10 doses of pegylated ASP (PEG, 2500 IU/m2/dose) post-induction. Native ASP was given when PEG was unavailable (6000 IU/m2/dose × 6 per single dose PEG). Patients with adverse reactions to PEG received Erwinia ASP (10,000 IU/m2/dose × 6). Reaction incidence in PEG-assigned patients was analyzed by logistic regression. Results: 1,383 patients were assigned PEG-containing regimens and received 5,652 doses of PEG. Erwinia was substituted for 2,156 doses and native ASP for 912. Severe allergic reaction (respiratory distress ± hypotension) was reported in 188 (14%), pancreatitis in 51 (4%), and ischemic stroke in 9 (1%) of these patients. PEG had a higher incidence of severe allergic reactions; 60% of these reactions occurred during consolidation. Native ASP had a higher incidence of local reactions. Erwinia ASP had a lower incidence of allergic-type reactions, as well as of pancreatitis and liver dysfunction (See Table). Conclusions: Following native ASP in induction, PEG had the highest incidence of severe allergic reactions. Adverse reactions to PEG and native ASP were otherwise similar. Erwinia ASP had less toxicity. This is the largest cohort of ASP-treated patients reported to date. Incidence of adverse reactions per 1,000 dose equivalents* Reaction PEG Native ASP Erwinia ASP P ** Allergy type Any 82 80 28 <0.0001 Isolated local 9 47 9 <0.0001 Urticaria 39 20 14 <0.0001 Severe 31 7 4 <0.0001 Other Pancreatitis 7 9 2 0.03 Liver dysfunction 58 50 24 <0.0001 CNS events 2 3 2 0.73 * Dose-equivalents (see text): PEG x1, native ASP x6, Erwinia ASP x6. ** Wald test of global null hypothesis. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Enzon