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Drugs May 2019Pegaspargase (Oncaspar), a pegylated form of native Escherichia coli-derived L-asparaginase (hereafter referred as E. coliL-asparaginase), is indicated in the USA and EU... (Review)
Review
Pegaspargase (Oncaspar), a pegylated form of native Escherichia coli-derived L-asparaginase (hereafter referred as E. coliL-asparaginase), is indicated in the USA and EU for the treatment of acute lymphoblastic leukaemia (ALL) as a component of multi-agent chemotherapy in paediatric and adult patients. Relative to E. coliL-asparaginase, pegaspargase has a prolonged circulation time, thereby offering less frequent administration. Moreover, pegylation of E. coliL-asparaginase may diminish the immunogenicity of the enzyme. Based on extensive evidence, intramuscular (IM) or intravenous (IV) administration of pegaspargase as a component of a multi-agent chemotherapy is an effective first-line treatment for paediatric and adult patients with ALL, as well as for the treatment of paediatric and adult patients with ALL and hypersensitivity to E. coliL-asparaginase. Pegaspargase had a manageable tolerability profile in paediatric and adult patients with newly diagnosed ALL, with the most commonly occurring adverse events being generally consistent to that seen with E. coliL-asparaginase. Pegaspargase treatment in patients with relapsed ALL and hypersensitivity to E. coliL-asparaginase had a similar tolerability profile to that observed in patients with newly diagnosed ALL. Given the potentially reduced immunogenicity and more convenient dosage regimen over E. coliL-asparaginase, pegaspargase remains an important and effective treatment option for paediatric and adult patients with ALL, including those with hypersensitivity to E. coliL-asparaginase.
Topics: Administration, Intravenous; Adolescent; Adult; Antineoplastic Agents; Asparaginase; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Therapy, Combination; Escherichia coli; Humans; Infant; Injections, Intramuscular; Middle Aged; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Treatment Outcome
PubMed: 31030380
DOI: 10.1007/s40265-019-01120-1 -
Current Hematologic Malignancy Reports Jun 2021The incorporation of pegaspargase in chemotherapy regimens has significantly improved the prognosis of ALL in adults. However, pegaspargase use poses many challenges due... (Review)
Review
PURPOSE OF REVIEW
The incorporation of pegaspargase in chemotherapy regimens has significantly improved the prognosis of ALL in adults. However, pegaspargase use poses many challenges due to its unique toxicity profile. Here, we review pegaspargase's most clinically significant toxicities, and provide guidance for their prevention and management in order to avoid unnecessary drug discontinuation and achieve maximum clinical benefit.
RECENT FINDINGS
Clinically significant toxicities of pegaspargase include thrombosis, hypersensitivity and inactivation, hepatotoxicity, pancreatitis, and hypertriglyceridemia. The majority of these toxicities are temporary, nonfatal, and can be managed supportively without permanent pegaspargase discontinuation. Special attention should be paid to inactivation, which can lead to treatment failure, as well as pancreatitis, which necessitates complete cessation of asparaginase therapy. The question of how to best proceed in patients who cannot tolerate pegaspargase remains unanswered, and is an important area of future investigation. Pegaspargase is an essential component of the pediatric-inspired regimens that have improved survival in adult ALL. Although pegaspargase's toxicity profile is unique, it is also highly manageable and should not be a barrier to achieving maximum clinical benefit using this drug.
Topics: Antineoplastic Agents; Asparaginase; Clinical Decision-Making; Disease Management; Drug-Related Side Effects and Adverse Reactions; Humans; Polyethylene Glycols
PubMed: 33978914
DOI: 10.1007/s11899-021-00638-0 -
Journal of Clinical Oncology : Official... Nov 2021Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia (ALL) Consortium Protocol 11-001 assessed efficacy and toxicity of calaspargase pegol (calaspargase), a novel... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia (ALL) Consortium Protocol 11-001 assessed efficacy and toxicity of calaspargase pegol (calaspargase), a novel pegylated asparaginase formulation with longer half-life, compared with the standard formulation pegaspargase.
METHODS
Patients age 1 to ≤ 21 years with newly diagnosed ALL or lymphoblastic lymphoma were randomly assigned to intravenous pegaspargase or calaspargase, 2,500 IU/m/dose. Patients received one induction dose. Beginning week 7, pegaspargase was administered every 2 week for 15 doses and calaspargase every 3 week for 10 doses (30 weeks). Serum asparaginase activity (SAA) (≥ 0.1 IU/mL considered therapeutic) was assessed 4, 11, 18, and 25 days after the induction dose and before each postinduction dose.
RESULTS
Between 2012 and 2015, 239 eligible patients enrolled (230 ALL, nine lymphoblastic lymphoma); 120 were assigned to pegaspargase and 119 to calaspargase. After the induction dose, SAA was ≥ 0.1 IU/mL in ≥ 95% of patients on both arms 18 days after dosing. At day 25, more patients had SAA ≥ 0.1 IU/mL with calaspargase (88% 17%; ˂ .001). Postinduction, median nadir SAAs were similar (≥ 1.0 IU/mL) for both arms. Of 230 evaluable patients, 99% of pegaspargase and 95% of calaspargase patients achieved complete remission ( = .12), with no difference in frequency of high end-induction minimal residual disease among evaluable patients with B acute lymphoblastic leukemia (B-ALL). There were no differences in frequencies of asparaginase allergy, pancreatitis, thrombosis, or hyperbilirubinemia. With 5.3 years median follow-up, 5-year event-free survival for pegaspargase was 84.9% (SE ± 3.4%) and 88.1% (± SE 3.0%) for calaspargase ( = .65).
CONCLUSION
Every 3-week calaspargase had similar nadir SAA, toxicity, and survival outcomes compared with every 2-week pegaspargase. The high nadir SAA observed for both preparations suggest dosing strategies can be further optimized.
Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Humans; Infant; Male; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Survival Rate; United States; Young Adult
PubMed: 34228505
DOI: 10.1200/JCO.20.03692 -
Journal of Oncology Pharmacy Practice :... Jan 2020Pegaspargase, a long acting formulation of L-asparaginase, is an asparagine specific enzyme that selectively kills leukemic cells by depleting plasma asparagine.... (Review)
Review
Pegaspargase, a long acting formulation of L-asparaginase, is an asparagine specific enzyme that selectively kills leukemic cells by depleting plasma asparagine. Pegaspargase is FDA approved for the first-line treatment of adult acute lymphoblastic leukemia and is a critical component of numerous multi-chemotherapeutic regimens. Pegaspargase is associated with well-described toxicities including hypersensitivity reactions, hepatotoxicity, and thrombosis. However, hypertriglyceridemia is a much rarer complication of pegaspargase and has only been described in a limited number of reports. We present a case of severe hypertriglyceridemia after a single dose of pegaspargase. The patient was re-challenged with pegaspargase and again developed hypertriglyceridemia which was complicated by pancreatitis. Here, we summarize published reports and a literature review describing the incidence of pegaspargase-induced hypertriglyceridemia in common acute lymphoblastic leukemia protocols.
Topics: Adult; Antineoplastic Agents; Asparaginase; Female; Humans; Hypertriglyceridemia; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 30823860
DOI: 10.1177/1078155219833438 -
The Annals of Pharmacotherapy May 1997To review the chemistry, pharmacology, pharmacokinetics, clinical activity, adverse effects, dosage, and administration guidelines for pegaspargase. (Review)
Review
OBJECTIVE
To review the chemistry, pharmacology, pharmacokinetics, clinical activity, adverse effects, dosage, and administration guidelines for pegaspargase.
DATA SOURCES
A MEDLINE search (1980-1996), a CANCERLIT search (1983-1996), and a CURRENT CONTENTS search (1980-1996) using the terms pegaspargase, PEG-asparaginase, PEG-L-asparaginase, polyethylene glycol L-asparaginase, polyethylene glycol conjugated L-asparaginase, and Oncaspar were conducted.
STUDY SELECTION AND DATA EXTRACTION
All articles were considered for possible inclusion in this review. Abstracts were included only when they were judged to add critical information not otherwise available in the medical literature.
DATA SYNTHESIS
L-Asparaginase has been a main component of treatment regimens for acute lymphocytic leukemia. A key limiting factor of L-asparaginase use has been the development of hypersensitivity to the drug. Recently, a polyethylene glycol (PEG) conjugated form of L-asparaginase, pegaspargase, has been made available. PEG modification of L-asparaginase has been shown to alter the tendency of the enzyme to induce an immune response and to extend the half-life of the drug. The majority of patients with hypersensitivity to the native enzyme preparations tolerate pegaspargase without further clinical hypersensitivity. The adverse effect profile of pegaspargase is similar to that of the native forms of L-asparaginase. The recommended dosage of pegaspargase is 2500 IU/m2 administered by intramuscular or intravenous injection every 2 weeks in combination with other chemotherapeutic agents.
CONCLUSIONS
Pegaspargase is a safe, effective alternative to L-asparaginase in patients who have had clinical hypersensitivity reactions to both Escherichia coli- and Erwinia carotovora-derived L-asparaginase. However, pegaspargase should not be routinely substituted for L-asparaginase.
Topics: Antineoplastic Agents; Asparaginase; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 9161659
DOI: 10.1177/106002809703100517 -
Leukemia & Lymphoma Apr 2017Pegaspargase is a mainstay in the treatment of acute lymphoblastic leukemia. When intravenous (IV) infusion replaced intramuscular (IM) injection as the standard route... (Meta-Analysis)
Meta-Analysis Review
Pegaspargase is a mainstay in the treatment of acute lymphoblastic leukemia. When intravenous (IV) infusion replaced intramuscular (IM) injection as the standard route of administration, there were early reports suggested an increased hypersensitivity reactions (HSRs) rate with IV administration. There have since been eight published reports comparing the incidence of HSRs occurring with IV versus IM pegaspargase. This review analyzes the reports and summarizes their consistent findings where feasible. For grade 3-4 HSRs, the rates are comparable with IV and IM administration. Grade 2 HSRs appear to be more likely with IV than IM administration but the validity of the difference is uncertain. Multiple factors confound the analyses, including the historically controlled nature of the comparisons and the increased likelihood of reporting adverse reactions with IV administration. In summary, the reports do not support the conclusion that pegaspargase-induced HSR rate is more frequent with IV administration.
Topics: Age Factors; Antineoplastic Agents; Asparaginase; Drug Hypersensitivity; Humans; Incidence; Infusions, Intravenous; Injections, Intramuscular; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Severity of Illness Index
PubMed: 27643446
DOI: 10.1080/10428194.2016.1218004 -
Blood Advances Aug 2023Pediatric-inspired chemotherapy is the standard of care for younger adults with Philadelphia chromosome-negative acute lymphoblastic leukemia/lymphoma (Ph- ALL/LL). In...
Pediatric-inspired chemotherapy is the standard of care for younger adults with Philadelphia chromosome-negative acute lymphoblastic leukemia/lymphoma (Ph- ALL/LL). In LAL1913 trial, the Gruppo Italiano Malattie EMatologiche dell'Adulto added pegaspargase 2000 IU/m2 to courses 1, 2, 5, and 6 of an 8-block protocol for patients aged from 18 to 65 years, with dose reductions in patients aged >55 years. Responders were risk stratified for allogeneic hematopoietic cell transplantation (HCT) or maintenance per clinical characteristics and minimal residual disease (MRD). Of 203 study patients (median age, 39.8 years), 91% achieved a complete remission. The 3-year overall survival, event-free, and disease-free survival (DFS) rates were 66.7%, 57.7%, and 63.3%, respectively, fulfilling the primary study end point of a 2-year DFS >55%. Although based on the intention-to-treat, the DFS being 74% and 50% in the chemotherapy (n = 94) and HCT (n = 91) assignment cohorts, respectively, a time-dependent analysis proved the value of HCT in patients who were eligible (DFS HCT 70% vs no HCT 26%; P <.0001). In multivariate analysis, age and MRD were independent factors predicting DFS rates of 86% (age ≤ 40 and MRD-negative), 64%-65% (MRD-positive or age > 40) and 25% (age > 40 and MRD-positive); P < .0001. Grade ≥2 pegaspargase toxicity was mainly observed at course 1, contributing to induction death in 2 patients but was rare thereafter. This program improved outcomes of patients with Ph- ALL/LL aged up to 65 years in a multicenter national setting. This trial was registered at www.clinicaltrials.gov as #NCT02067143.
Topics: Humans; Adult; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Hematopoietic Stem Cell Transplantation; Disease-Free Survival; Remission Induction; Acute Disease
PubMed: 37276451
DOI: 10.1182/bloodadvances.2022009596 -
Journal of Clinical Apheresis Feb 2018
Topics: Asparaginase; Clinical Trials as Topic; Humans; Hypertriglyceridemia; Male; Middle Aged; Plasma Exchange; Polyethylene Glycols; Triglycerides
PubMed: 28752901
DOI: 10.1002/jca.21571 -
Leukemia & Lymphoma Nov 2022
Topics: Humans; Asparaginase; Polyethylene Glycols; Drug Hypersensitivity; Antineoplastic Agents
PubMed: 35727258
DOI: 10.1080/10428194.2022.2086251