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Journal of Clinical Oncology : Official... Dec 2019Despite contemporary treatment, up to 10% of children with acute lymphoblastic leukemia still experience relapse. We evaluated whether a higher dosage of... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Despite contemporary treatment, up to 10% of children with acute lymphoblastic leukemia still experience relapse. We evaluated whether a higher dosage of PEG-asparaginase and early intensification of triple intrathecal therapy would improve systemic and CNS control.
PATIENTS AND METHODS
Between 2007 and 2017, 598 consecutive patients age 0 to 18 years received risk-directed chemotherapy without prophylactic cranial irradiation in the St Jude Total Therapy Study 16. Patients were randomly assigned to receive PEG-asparaginase 3,500 U/m versus the conventional 2,500 U/m. Patients presenting features that were associated with increased risk of CNS relapse received two extra doses of intrathecal therapy during the first 2 weeks of remission induction.
RESULTS
The 5-year event-free survival and overall survival rates for the 598 patients were 88.2% (95% CI, 84.9% to 91.5%) and 94.1% (95% CI, 91.7% to 96.5%), respectively. Cumulative risk of any-isolated or combined-CNS relapse was 1.5% (95% CI, 0.5% to 2.5%). Higher doses of PEG-asparaginase did not affect treatment outcome. T-cell phenotype was the only independent risk factor for any CNS relapse (hazard ratio, 5.15; 95% CI, 1.3 to 20.6; = . 021). Among 359 patients with features that were associated with increased risk for CNS relapse, the 5-year rate of any CNS relapse was significantly lower than that among 248 patients with the same features treated in the previous Total Therapy Study 15 (1.8% [95% CI, 0.4% to 3.3%] 5.7% [95% CI, 2.8% to 8.6%]; = .008). There were no significant differences in the cumulative risk of seizure or infection during induction between patients who did or did not receive the two extra doses of intrathecal treatment.
CONCLUSION
Higher doses of PEG-asparaginase failed to improve outcome, but additional intrathecal therapy during early induction seemed to contribute to improved CNS control without excessive toxicity for high-risk patients.
Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Central Nervous System Neoplasms; Child; Child, Preschool; Cranial Irradiation; Cytarabine; Female; Follow-Up Studies; Humans; Infant; Infant, Newborn; Male; Methotrexate; Neoplasm Recurrence, Local; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Remission Induction; Survival Rate
PubMed: 31657981
DOI: 10.1200/JCO.19.01692 -
Hepatology International Sep 2019L-Asparaginase is a bacterial enzyme used in the treatment of acute lymphoblastic leukemia. In the ongoing U.S. Drug-Induced Liver Injury Network (DILIN) prospective...
BACKGROUND
L-Asparaginase is a bacterial enzyme used in the treatment of acute lymphoblastic leukemia. In the ongoing U.S. Drug-Induced Liver Injury Network (DILIN) prospective study, standard and pegylated asparaginase were the most frequent cause of liver injury with jaundice among anti-cancer agents (8 of 40: 20%). The unique features of this hepatotoxicity are described.
METHODS
Eight cases from 5 DILIN centers were reviewed for clinical course, laboratory values, imaging, and histopathology.
RESULTS
Seven females, aged 29-59 years, and one 8-year-old boy, all with leukemia, developed jaundice within 9-21 days (median 15 days) of starting asparaginase or pegaspargase, during the first (n = 6) or second (n = 2) cycle. Prominent symptoms were jaundice (n = 8), fatigue (6), abdominal pain (6) but rarely pruritus (1). Initial median ALT level was 284 U/L (range 83-1076), Alk P 159 U/L (64-452), and bilirubin 4.4 mg/dL (3.7-8.4). Bilirubin levels rose thereafter in all patients to median peak of 17.5 mg/dL (11.7-25.7), INR rose to 1.1-1.7 and serum albumin fell to 1.5-2.6 g/dL. Hepatic imaging revealed fatty liver in all patients. Liver biopsy showed steatosis but minimal hepatocyte necrosis. One patient restarted on pegaspargase re-developed less severe injury.
CONCLUSION
Asparaginase is a common cause of antineoplastic-induced liver injury with jaundice, typically with short latency, marked steatosis, and prolonged jaundice, which can lead to delays in antileukemic therapy. The cause of injury is likely direct inhibition of hepatic protein synthesis caused by asparagine depletion.
Topics: Adult; Antineoplastic Agents; Asparaginase; Bilirubin; Chemical and Drug Induced Liver Injury; Cholestasis; Fatty Liver; Female; Humans; Liver; Male; Middle Aged; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 31392570
DOI: 10.1007/s12072-019-09971-2 -
Journal of Clinical Oncology : Official... Aug 2019Pegaspargase (PEG-ASP) has largely replaced native asparaginase (L-ASP) in the treatment of acute lymphoblastic leukemia because of its longer half-life and lower...
PURPOSE
Pegaspargase (PEG-ASP) has largely replaced native asparaginase (L-ASP) in the treatment of acute lymphoblastic leukemia because of its longer half-life and lower immunogenicity. Risk factors for allergic reactions to PEG-ASP remain unclear. Here, we identify risk factors for reactions in a front-line acute lymphoblastic leukemia trial and assess the usefulness of serum antibodies for diagnosing allergy and predicting rechallenge outcome.
PATIENTS AND METHODS
PEG-ASP was administered to 598 patients in St Jude's Total XVI study. Results were compared with Total XV study (ClinicalTrials.gov identifiers: NCT00549848 and NCT00137111), which used native L-ASP. Serum samples (n = 5,369) were analyzed for anti-PEG-ASP immunoglobulin G by enzyme-linked immunosorbent assay. Positive samples were tested for anti-polyethylene glycol (PEG) and anti-L-ASP. We analyzed potential risk factors for reactions and associations between antibodies and reactions, rechallenge outcomes, and PEG-ASP pharmacokinetics.
RESULTS
Grade 2 to 4 reactions were less common in the Total XVI study with PEG-ASP (81 [13.5%] of 598) than in the Total XV study with L-ASP (169 [41.2%] of 410; = 1.4 × 10). For Total XVI, anti-PEG, not anti-L-ASP, was the predominant component of anti-PEG-ASP antibodies (96%). In a multivariable analysis, more intrathecal therapy (IT) predicted fewer reactions ( = 2.4 × 10), which is consistent with an immunosuppressant contribution of IT. Anti-PEG-ASP was associated with accelerated drug clearance ( = 5.0 × 10). Failure of rechallenge after initial reactions was associated with anti-PEG-ASP ( = .0078) and was predicted by the occurrence of angioedema with first reaction ( = .01).
CONCLUSION
Less IT therapy was the only independent clinical risk factor for reactions to PEG-ASP. PEG, and not L-ASP, is the major antigen that causes allergic reactions. Anti-PEG-ASP has utility in predicting and confirming clinical reactions to PEG-ASP as well as in identifying patients who are most likely to experience failure with rechallenge.
Topics: Antibodies; Antineoplastic Agents; Asparaginase; Female; Humans; Hypersensitivity; Male; Polyethylene Glycols; Risk Factors
PubMed: 31188727
DOI: 10.1200/JCO.18.02439 -
Advances in Therapy Aug 2019Pegaspargase, a pegylated asparaginase, is a core component in the treatment of acute lymphoblastic leukemia. Pegaspargase in liquid form has a limited shelf life of... (Comparative Study)
Comparative Study
INTRODUCTION
Pegaspargase, a pegylated asparaginase, is a core component in the treatment of acute lymphoblastic leukemia. Pegaspargase in liquid form has a limited shelf life of 8 months due to depegylation, leading to changes in purity and potency over time. Lyophilization is an approach that can improve the stability of biological drug conjugates.
METHODS
Here we describe the development of a lyophilized formulation of pegaspargase and present results of a series of tests demonstrating that the lyophilized form has comparable physicochemical properties to the liquid form.
RESULTS
Stability tests of critical quality attributes, including purity, potency, aggregates and total free polyethylene glycol, demonstrate that lyophilized pegaspargase remains stable for at least 3 years, with optimum stability achieved with storage under refrigerated conditions (2-8 °C).
CONCLUSIONS
Lyophilization improved the stability of pegaspargase without altering other physicochemical properties, permitting a prolonged shelf life of at least 2 years when stored at 2-8 °C. This may enable greater storage flexibility and allow for better management of pegaspargase.
FUNDING
Study Sponsor: Baxalta (now part of Takeda). Publication Sponsor: Servier Affaires Médicales.
Topics: Antineoplastic Agents; Asparaginase; Drug Compounding; Drug Stability; Freeze Drying; Humans; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 31140125
DOI: 10.1007/s12325-019-00988-5 -
Cancer Management and Research 2019To evaluate the clinical efficacy and safety of the DDGP regimen in treating extranodal NK/T-cell lymphoma and investigate the correlation between Epstein-Barr virus...
Clinical efficacy of cisplatin, dexamethasone, gemcitabine and pegaspargase (DDGP) in the initial treatment of advanced stage (stage III-IV) extranodal NK/T-cell lymphoma, and its correlation with Epstein-Barr virus.
To evaluate the clinical efficacy and safety of the DDGP regimen in treating extranodal NK/T-cell lymphoma and investigate the correlation between Epstein-Barr virus (EBV)-DNA variation after treatment and the clinical efficacy of NK/T-cell lymphoma. Sixty-four patients with extranodal NK/T-cell lymphoma received DDGP regimen-based chemotherapy. Short-term and long-term clinical efficacy and adverse reactions were observed. The relationship between EBV-DNA changes before and after therapy and clinical efficacy was investigated. After the DDGP regimen was used as the initial treatment, the short-term clinical efficacy included 39 complete remission (CR) (60.94%), 12 partial remission (PR) (18.75%), 2 stable disease (SD) (3.13%) and 11 progressive disease (PD) (17.18%). Objective response rate (ORR) was 79.69% and 82.82% for disease control rate (DCR). 3-year progression-free survival (PFS) was 62.00% and 3-year overall survive (OS) was 74.90%. Hemocytopenia was the predominant adverse effect. Between EBV-DNA positive group and its negative counterpart, a significant difference was noted in OS (=0.046), but no difference in ORR, DCR or PFS was observed. In the EBV-DNA positive group, ORR, DCR, PFS and OS were higher for patients whose EBV-DNA copy number decreased within a normal range than patients remained positive (93.33% versus 61.53%, =0.041 for ORR; 93.33% versus 61.53%, =0.041 for DCR, =0.003 for PFS, =0.017 for OS). The main adverse reactions included bone marrow suppression, gastrointestinal reaction and coagulation dysfunction, which were mitigated and treated after expectant or dose-decrement treatment. DDGP regimen can significantly improve the clinical prognosis of NK/T-cell lymphoma patients with tolerable adverse reactions. The variation in EBV-DNA is correlated with clinical efficacy and prognosis, which provides a theoretical basis for NK/T-cell lymphoma therapy. : In November 2011, this clinical trial was registered on the website: www.ClinicalTrials.gov (No. NCT01501149).
PubMed: 31118779
DOI: 10.2147/CMAR.S191929 -
Hematological Oncology Feb 2020
Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Chemoradiotherapy; Child; Cisplatin; Deoxycytidine; Dexamethasone; Female; Follow-Up Studies; Humans; Lymphoma, Extranodal NK-T-Cell; Male; Middle Aged; Nose Neoplasms; Polyethylene Glycols; Prognosis; Retrospective Studies; Survival Rate; Young Adult; Gemcitabine
PubMed: 31102421
DOI: 10.1002/hon.2637 -
Pediatric Blood & Cancer Aug 2019Asparaginase is a critical component of lymphoblastic leukemia therapy, with intravenous pegaspargase (PEG) as the current standard product. Acute adverse events (aAEs)...
BACKGROUND
Asparaginase is a critical component of lymphoblastic leukemia therapy, with intravenous pegaspargase (PEG) as the current standard product. Acute adverse events (aAEs) during PEG infusion are difficult to interpret, representing a mix of drug-inactivating hypersensitivity and noninactivating reactions. Asparaginase Erwinia chrysanthemi (ERW) is approved for PEG hypersensitivity, but is less convenient, more expensive, and yields lower serum asparaginase activity (SAA). We began a policy of universal premedication and SAA testing for PEG, hypothesizing this would reduce aAEs and unnecessary drug substitutions.
PROCEDURE
Retrospective chart review of patients receiving asparaginase before and after universal premedication before PEG was conducted, with SAA performed 1 week later. We excluded patients who had nonallergic asparaginase AEs. Primary end point was substitution to ERW. Secondary end points included aAEs, SAA testing, and cost.
RESULTS
We substituted to ERW in 21 of 122 (17.2%) patients pre-policy, and 5 of 68 (7.4%) post-policy (RR, 0.427; 95% CI, 0.27-0.69, P = 0.028). All completed doses of PEG yielded excellent SAA (mean, 0.90 units/mL), compared with ERW (mean, 0.15 units/mL). PEG inactivation post-policy was seen in 2 of 68 (2.9%), one silent and one with breakthrough aAE. The rate of aAEs pre/post-policy was 17.2% versus 5.9% (RR, 0.342; 95% CI, 0.20-0.58, P = 0.017). Grade 4 aAE rate pre/post-policy was 15% versus 0%. Cost analysis predicts $125 779 drug savings alone per substitution prevented ($12 402/premedicated patient).
CONCLUSIONS
Universal premedication reduced substitutions to ERW and aAE rate. SAA testing demonstrated low rates of silent inactivation, and higher SAA for PEG. A substantial savings was achieved. We propose universal premedication for PEG be standard of care.
Topics: Administration, Intravenous; Adolescent; Adult; Antineoplastic Agents; Asparaginase; Child; Child, Preschool; Drug Hypersensitivity; Drug Monitoring; Drug Substitution; Female; Follow-Up Studies; Hematologic Neoplasms; Humans; Infant; Male; Premedication; Prognosis; Retrospective Studies; Tissue Distribution; Young Adult
PubMed: 31099154
DOI: 10.1002/pbc.27797 -
Drugs Jun 2019The original article has been corrected.
The original article has been corrected.
PubMed: 31098897
DOI: 10.1007/s40265-019-01137-6 -
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 -
Cancer Cell Apr 2019Resistance to asparaginase, an antileukemic enzyme that depletes asparagine, is a common clinical problem. Using a genome-wide CRISPR/Cas9 screen, we found a synthetic...
Resistance to asparaginase, an antileukemic enzyme that depletes asparagine, is a common clinical problem. Using a genome-wide CRISPR/Cas9 screen, we found a synthetic lethal interaction between Wnt pathway activation and asparaginase in acute leukemias resistant to this enzyme. Wnt pathway activation induced asparaginase sensitivity in distinct treatment-resistant subtypes of acute leukemia, but not in normal hematopoietic progenitors. Sensitization to asparaginase was mediated by Wnt-dependent stabilization of proteins (Wnt/STOP), which inhibits glycogen synthase kinase 3 (GSK3)-dependent protein ubiquitination and proteasomal degradation, a catabolic source of asparagine. Inhibiting the alpha isoform of GSK3 phenocopied this effect, and pharmacologic GSK3α inhibition profoundly sensitized drug-resistant leukemias to asparaginase. Our findings provide a molecular rationale for activation of Wnt/STOP signaling to improve the therapeutic index of asparaginase.
Topics: Animals; Antineoplastic Agents; Asparaginase; Cell Death; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Glycogen Synthase Kinase 3 beta; Humans; Jurkat Cells; Leukemia; Male; Mice, Inbred NOD; Mice, Transgenic; Polyethylene Glycols; Proteasome Endopeptidase Complex; Protein Kinase Inhibitors; Protein Stability; Proteolysis; Synthetic Lethal Mutations; THP-1 Cells; Ubiquitination; Wnt Signaling Pathway; Wnt3A Protein; Xenograft Model Antitumor Assays
PubMed: 30991026
DOI: 10.1016/j.ccell.2019.03.004