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Barroso A, Estevinho F, Hespanhol V, Teixeira E, Ramalho-Carvalho J, Araújo A. Management of infusion-related reactions in cancer therapy: strategies and challenges. ESMO Open 2024; 9:102922. [PMID: 38452439 PMCID: PMC10937241 DOI: 10.1016/j.esmoop.2024.102922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 02/06/2024] [Accepted: 02/06/2024] [Indexed: 03/09/2024] Open
Abstract
Several anticancer therapies have the potential to cause infusion-related reactions (IRRs) in the form of adverse events that typically occur within minutes to hours after drug infusion. IRRs can range in severity from mild to severe anaphylaxis-like reactions. Careful monitoring at infusion initiation, prompt recognition, and appropriate clinical assessment of the IRR and its severity, followed by immediate management, are required to ensure patient safety and optimal outcomes. Lack of standardization in the prevention, management, and reporting of IRRs across cancer-treating institutions represents not only a quality and safety gap but also a disparity in cancer care. The present article, supported by recently published data, was developed to standardize these procedures across institutions and provide a useful tool for health care providers in clinical practice to recognize early signs and symptoms of an IRR and promptly and appropriately manage the event.
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Affiliation(s)
- A Barroso
- Multidisciplinary Unit of Thoracic Tumours, Centro Hospitalar de Vila Nova de Gaia e Espinho, Vila Nova de Gaia, Portugal
| | - F Estevinho
- Hospital Pedro Hispano, Unidade Local de Saúde de Matosinhos, Matosinhos, Portugal
| | - V Hespanhol
- Departamento de Medicina Faculty of Medicine, University of Porto, Porto, Portugal; Department of Pulmonology, Centro Hospitalar de São João, Porto, Portugal
| | - E Teixeira
- Lung Cancer Unit, CUF Descobertas, Lisboa, Portugal
| | | | - A Araújo
- Medical Oncology Department, Centro Hospitalar Universitário do Porto, Porto, Portugal; Oncology Research Unit, UMIB-Unit for Multidisciplinary Research in Biomedicine, ICBAS-School of Medicine and Biomedical Sciences, Universidade do Porto, Porto, Portugal.
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2
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Ateş B, Ulu A, Asiltürk M, Noma SAA, Topel SD, Dik G, Özhan O, Bakar B, Yıldız A, Vardı N, Parlakpınar H. Enhancement of enzyme activity by laser-induced energy propulsion of upconverting nanoparticles under near-infrared light: A comprehensive methodology for in vitro and in vivo applications. Int J Biol Macromol 2024; 260:129343. [PMID: 38242401 DOI: 10.1016/j.ijbiomac.2024.129343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 01/05/2024] [Accepted: 01/07/2024] [Indexed: 01/21/2024]
Abstract
If the appropriate immobilization method and carrier support are not selected, partial decreases in the activity of enzymes may occur after immobilization. Herein, to overcome this challenge, an excitation mechanism that enables energy transfer was proposed. Modified upconverting nanoparticles (UCNPs) were constructed and the important role of near-infrared (NIR) excitation in enhancing the catalytic activity of the enzyme was demonstrated. For this purpose, UCNPs were first synthesized via the hydrothermal method, functionalized with isocyanate groups, and then, PEG-L-ASNase was immobilized via covalent binding. UCNPs with and without PEG-L-ASNase were extensively characterized by different methods. These supports had immobilization yield and activity efficiency of >96 % and 78 %, respectively. Moreover, immobilized enzymes exhibited improved pH, thermal, and storage stability. In addition, they retained >65 % of their initial activity even after 20 catalytic cycles. Biochemical and histological findings did not indicate a trend of toxicity in rats due to UCNPs. Most importantly, PEG-L-ASNase activity was triggered approximately 5- and 2-fold under in vitro and in vivo conditions, respectively. Overall, it is anticipated that this pioneering work will shed new light on the realistic and promising usage of NIR-excited UCNPs for the immobilization of enzymes in expensive and extensive applications.
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Affiliation(s)
- Burhan Ateş
- Biochemistry and Biomaterials Research Laboratory, Department of Chemistry, Faculty of Arts and Science, İnönü University, 44280 Malatya, Türkiye.
| | - Ahmet Ulu
- Biochemistry and Biomaterials Research Laboratory, Department of Chemistry, Faculty of Arts and Science, İnönü University, 44280 Malatya, Türkiye.
| | - Meltem Asiltürk
- Department of Material Science and Engineering, Faculty of Engineering, Akdeniz University, 07070 Antalya, Türkiye
| | - Samir Abbas Ali Noma
- Biochemistry and Biomaterials Research Laboratory, Department of Chemistry, Faculty of Arts and Science, İnönü University, 44280 Malatya, Türkiye; Department of Chemistry, Faculty of Arts and Science, Bursa Uludag University, Bursa, Türkiye
| | - Seda Demirel Topel
- Department of Electrical and Electronics Engineering, Faculty of Engineering, Antalya Bilim University, 07190 Antalya, Türkiye
| | - Gamze Dik
- Biochemistry and Biomaterials Research Laboratory, Department of Chemistry, Faculty of Arts and Science, İnönü University, 44280 Malatya, Türkiye
| | - Onural Özhan
- Department of Medicinal Pharmacology, Medical Faculty, İnönü University, 44210 Malatya, Türkiye
| | - Büşra Bakar
- Biochemistry and Biomaterials Research Laboratory, Department of Chemistry, Faculty of Arts and Science, İnönü University, 44280 Malatya, Türkiye
| | - Azibe Yıldız
- Department of Histology and Embryology, Medical Faculty, İnönü University, 44210 Malatya, Türkiye
| | - Nigar Vardı
- Department of Histology and Embryology, Medical Faculty, İnönü University, 44210 Malatya, Türkiye
| | - Hakan Parlakpınar
- Department of Medicinal Pharmacology, Medical Faculty, İnönü University, 44210 Malatya, Türkiye
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Yang KH, Zeng JQ, Ding S, Zhang TA, Wang WY, Zhang JY, Wang L, Xiao J, Gong B, Deng ZH. Efficacy and safety of endoscopic retrograde cholangiopancreatography in recurrent pancreatitis of pediatric asparaginase-associated pancreatitis. World J Gastrointest Endosc 2023; 15:614-622. [PMID: 37900113 PMCID: PMC10600691 DOI: 10.4253/wjge.v15.i10.614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 08/26/2023] [Accepted: 09/14/2023] [Indexed: 10/12/2023] Open
Abstract
BACKGROUND Asparaginase (ASP) is an important drug in combined chemotherapy regimens for pediatric acute lymphoblastic leukemia (ALL); ASP-associated pancreatitis (AAP) is the main adverse reaction of ASP. Recurrent pancreatitis is a complication of AAP, for which medication is ineffective. AIM To evaluate the efficacy and safety of endoscopic retrograde cholangiopancreatography (ERCP) in treating recurrent pancreatitis due to AAP. METHODS From May 2018 to August 2021, ten children (five males and five females; age range: 4-13 years) with AAP were treated using ERCP due to recurrent pancreatitis. Clinical data of the ten children were collected, including their sex, age, weight, ALL risk grading, clinical symptoms at the onset of pancreatitis, time from the first pancreatitis onset to ERCP, ERCP operation status, and postoperative complications. The symptomatic relief, weight change, and number of pancreatitis onsets before and after ERCP were compared. RESULTS The preoperative symptoms were abdominal pain, vomiting, inability to eat, weight loss of 2-7 kg, and 2-9 pancreatitis onsets. After the operation, nine of ten patients did not develop pancreatitis, had no abdominal pain, could eat normally; the remaining patient developed three pancreatitis onsets due to the continuous administration of ASP, but eating was not affected. The postoperative weight gain was 1.5-8 kg. There was one case of post ERCP pancreatitis and two cases of postoperative infections; all recovered after medication. CONCLUSION ERCP improved clinical symptoms and reduced the incidence of pancreatitis, and was shown to be a safe and effective method for improving the management of recurrent pancreatitis due to AAP.
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Affiliation(s)
- Kai-Hua Yang
- Department of Gastroenterology, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Jing-Qing Zeng
- Department of Gastroenterology, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Sheng Ding
- Department of Gastroenterology, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Tian-Ao Zhang
- Department of Gastroenterology, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Wen-Yu Wang
- Department of Gastroenterology, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Jia-Yu Zhang
- Department of Gastroenterology, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Lan Wang
- Department of Gastroenterology, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Jian Xiao
- Department of Gastroenterology, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Biao Gong
- Department of Gastroenterology, Shanghai Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200120, China
| | - Zhao-Hui Deng
- Department of Gastroenterology, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
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Tong WH, Rizzari C. Back to the future: the amazing journey of the therapeutic anti-leukemia enzyme asparaginase Erwinia chrysanthemi. Haematologica 2023; 108:2606-2615. [PMID: 37470157 PMCID: PMC10542841 DOI: 10.3324/haematol.2022.282324] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 07/10/2023] [Indexed: 07/21/2023] Open
Abstract
For several decades, asparaginase has been considered world-wide as an essential component of combination chemotherapy for the treatment of childhood acute lymphoblastic leukemia (ALL). Discovered over 60 years ago, two main unmanipulated asparaginase products originated from primary bacteria sources, namely Escherichia coli and Erwinia chrysanthemi, have been available for clinical use. A pegylated product of the Escherichia coli asparaginase was subsequently developed and is now the main product used by several international co-operative groups. The various asparaginase products all display the same mechanism of action (hydrolysis of circulating asparagine) and are associated with similar efficacy and toxicity patterns. However, their different pharmacokinetics, pharmacodynamics and immunological properties require distinctive modalities of application and monitoring. Erwinia chrysanthemi asparaginase was initially used as a first-line product, but subsequently became a preferred second-line product for children who experienced immunological reactions to the Escherichia coli asparaginase products. An asparaginase product displaying the same characteristics of the Erwinia chrysanthemi asparaginase has recently been produced by use of recombinant technology, thus securing a preparation available for use as an alternative, or as a back-up in case of shortages, for the non-recombinant product. The long journey of the Erwinia chrysanthemi asparaginase product as it has developed throughout the last several decades has made it possible for almost every child and adult with ALL to complete the asparaginase-based protocol treatment when an immunological reaction has occurred to any Escherichia coli asparaginase product.
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Affiliation(s)
- Wing H Tong
- Department of Public Health and Primary Care (PHEG), Leiden University Medical Center, Leiden, The Netherlands; Argos Zorggroep "DrieMaasStede", Center for Specialized Geriatric Care, Schiedam.
| | - Carmelo Rizzari
- Department of Pediatrics, Foundation IRCCS San Gerardo dei Tintori, Monza, Italy; Department of Medicine and Surgery, University of Milano-Bicocca
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5
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Osama S, El-Sherei MM, Al-Mahdy DA, Bishr M, Salama O, Raafat MM. Optimization and characterization of antileukemic L-asparaginase produced by Fusarium solani endophyte. AMB Express 2023; 13:96. [PMID: 37702815 PMCID: PMC10499768 DOI: 10.1186/s13568-023-01602-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Accepted: 08/30/2023] [Indexed: 09/14/2023] Open
Abstract
L-asparaginase is an antileukemic enzyme that hydrolyzes L-asparagine into L-aspartic acid and ammonia, causing cell starvation and apoptosis in susceptible leukemic cell populations. Currently, L-asparaginase obtained from bacterial sources is constrained by several issues, including lesser productivity, stability, selectivity, and higher toxicity. The goal of this study is to provide fungal L-asparaginase with in-vitro effectiveness towards different human carcinomas. L-asparaginase from endophytic Fusarium solani (Gene Bank accession number MW209717) isolated from the roots of the medicinal plant Hedera helix L. was characterized and optimized experimentally for maximum L-asparaginase production in addition to evaluating its subsequent cytotoxicity towards acute monocytic leukemia and human skin fibroblast cell lines. The enzyme production was maximized using potato dextrose media (15.44 IU/ml/hr) at the 5th and 6th days of fermentation with incubation temperature 30 °C, 3% asparagine, 150-180 rpm agitation rate and a 250 ml flask. Enzyme characterization studies revealed that the enzyme maintained its thermal stability with temperatures up to 60 °C. However, its optimal activity was achieved at 35 °C. On measuring the enzymatic activity at various temperatures and different pH, maximum enzyme activity was recorded at 40 °C and pH 8 using 0.1 M asparagine concentration. Results also revealed promising cytotoxic activity against acute monocytic leukemia with IC50 = 3.66 µg/ml and low cytotoxicity against tested normal human skin fibroblast cell line which suggested that it might have selective toxicity, and consequently it could be used as a less toxic alternative to the current formulations.
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Affiliation(s)
- Sarah Osama
- Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy, Future University in Egypt, Cairo, Egypt
| | - Moshera M El-Sherei
- Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt
| | - Dalia A Al-Mahdy
- Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt.
| | - Mokhtar Bishr
- Arab Company for Pharmaceuticals and Medicinal Plants (Mepaco), Cairo, Egypt
| | - Osama Salama
- Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy, Future University in Egypt, Cairo, Egypt
| | - Marwa M Raafat
- Microbiology and Immunology Department, Faculty of Pharmacy, Future University in Egypt, Cairo, 11835, Egypt.
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Vagrecha A, Tao V, Corless R, Colon C, Redner A, Atlas M. A comprehensive strategy to address shortage of Erwinia asparaginase in pediatric acute lymphoblastic leukemia. Expert Rev Clin Pharmacol 2023; 16:763-769. [PMID: 37294084 DOI: 10.1080/17512433.2023.2223970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 06/05/2023] [Indexed: 06/10/2023]
Abstract
BACKGROUND Pegylated form of E. coli derived asparaginase (PEG) is a crucial component of pediatric ALL therapy. Patients who develop a hypersensitivity (HSR) reaction with PEG receive an alternative form - Erwinia asparaginase (EA). However, an international shortage in 2017 had made it challenging to treat these patients. We have developed a comprehensive strategy to address this need. PATIENTS AND METHODS This is a single center, retrospective analysis. All patients receiving PEG were premedicated to reduce infusion reactions. Patients who developed HSR underwent PEG desensitization. Patients were compared to historic controls. RESULTS Fifty-six patients were treated within the study period. There was no difference in the frequency of reactions before and after the adoption of universal premedication (p = 0.78). Eight patients (14.2%) developed either ≥ Grade 2 HSR or silent inactivation and 5 patients (62.5%) successfully underwent desensitization. The remaining three patients received EA asparaginase. This intervention led to a decrease in PEG substitution, with 3 patients (5.3%) requiring EA compared to 8 patients (15.09%) in the pre-intervention period. (p = 0.11) PEG desensitization was more cost effective than EA administration. CONCLUSION PEG desensitization is a safe, cost effective, and practical alternative in children with ALL and a Grade 2 or higher HSR.
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Affiliation(s)
- Anshul Vagrecha
- Department of Pediatrics, Division of Hematology/Oncology and Cellular Therapy, Cohen Children's Medical Center, New Hyde Park, NY, USA
| | - Vincent Tao
- Department of Pediatrics, Division of Hematology/Oncology and Cellular Therapy, Cohen Children's Medical Center, New Hyde Park, NY, USA
| | - Rosemarie Corless
- Department of Pediatrics, Division of Hematology/Oncology and Cellular Therapy, Cohen Children's Medical Center, New Hyde Park, NY, USA
| | - Cassandra Colon
- Department of Pediatrics, Division of Hematology/Oncology and Cellular Therapy, Cohen Children's Medical Center, New Hyde Park, NY, USA
| | - Arlene Redner
- Department of Pediatrics, Division of Hematology/Oncology and Cellular Therapy, Cohen Children's Medical Center, New Hyde Park, NY, USA
- Department of Pediatrics, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
| | - Mark Atlas
- Department of Pediatrics, Division of Hematology/Oncology and Cellular Therapy, Cohen Children's Medical Center, New Hyde Park, NY, USA
- Department of Pediatrics, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
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7
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Lee A, Eldem I, Altintas B, Nguyen H, Willis D, Langley R, Shinawi M. Treatment and outcomes of symptomatic hyperammonemia following asparaginase therapy in children with acute lymphoblastic leukemia. Mol Genet Metab 2023; 139:107627. [PMID: 37327713 DOI: 10.1016/j.ymgme.2023.107627] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 05/31/2023] [Accepted: 06/02/2023] [Indexed: 06/18/2023]
Abstract
Hyperammonemia has been reported following asparaginase administration, consistent with the mechanisms of asparaginase, which catabolizes asparagine to aspartic acid and ammonia, and secondarily converts glutamine to glutamate and ammonia. However, there are only a few reports on the treatment of these patients, which varies widely from watchful waiting to treatment with lactulose, protein restriction, sodium benzoate, and phenylbutyrate to dialysis. While many patients with reported asparaginase-induced hyperammonemia (AIH) are asymptomatic, some have severe complications and even fatal outcomes despite medical intervention. Here, we present a cohort of five pediatric patients with symptomatic AIH, which occurred after switching patients from polyethylene glycolated (PEG)- asparaginase to recombinant Crisantaspase Pseudomonas fluorescens (4 patients) or Erwinia (1 patient) asparaginase, and discuss their subsequent management, metabolic workup, and genetic testing. We developed an institutional management plan, which gradually evolved based on our local experience and previous treatment modalities. Because of the significant reduction in glutamine levels after asparaginase administration, sodium benzoate should be used as a first-line ammonia scavenger for symptomatic AIH instead of sodium phenylacetate or phenylbutyrate. This approach facilitated continuation of asparaginase doses, which is known to improve cancer outcomes. We also discuss the potential contribution of genetic modifiers to AIH. Our data highlights the need for increased awareness of symptomatic AIH, especially when an asparaginase with higher glutaminase activity is used, and its prompt management. The utility and efficacy of this management approach should be systematically investigated in a larger cohort of patients.
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Affiliation(s)
- Angela Lee
- Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, Saint Louis, MO, USA.
| | - Irem Eldem
- Department of Pediatrics, Division of Hematology and Oncology, Washington University School of Medicine, Saint Louis, MO, USA
| | - Burak Altintas
- Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, Saint Louis, MO, USA
| | - Hoanh Nguyen
- Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, Saint Louis, MO, USA
| | - Daniel Willis
- Department of Pediatrics, Division of Hematology and Oncology, Washington University School of Medicine, Saint Louis, MO, USA
| | - Rachel Langley
- Department of Pharmacy, Washington University School of Medicine, Saint Louis, MO, USA
| | - Marwan Shinawi
- Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, Saint Louis, MO, USA
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Rizzari C, Möricke A, Valsecchi MG, Conter V, Zimmermann M, Silvestri D, Attarbaschi A, Niggli F, Barbaric D, Stary J, Elitzur S, Cario G, Vinti L, Boos J, Zucchetti M, Lanvers-Kaminsky C, von Stackelberg A, Biondi A, Schrappe M. Incidence and Characteristics of Hypersensitivity Reactions to PEG-asparaginase Observed in 6136 Children With Acute Lymphoblastic Leukemia Enrolled in the AIEOP-BFM ALL 2009 Study Protocol. Hemasphere 2023; 7:e893. [PMID: 37275740 PMCID: PMC10237686 DOI: 10.1097/hs9.0000000000000893] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Accepted: 04/12/2023] [Indexed: 06/07/2023] Open
Abstract
The incidence of hypersensitivity reactions (HSRs) to PEG-asparaginase (PEG-ASNase) was evaluated in 6136 children with ALL enrolled in the AIEOP-BFM ALL 2009 study. Patients with B-cell precursor-acute lymphoblastic leukemia (BCP-ALL) were stratified as standard-risk/medium-risk (MR)/high-risk (HR) and those with T-ALL as non-High/HR. PEG-ASNase was administered intravenously at 2500 IU/sqm/dose. All patients received 2 PEG-ASNase doses in induction; thereafter non-HR versus HR patients received 1 versus 6 PEG-ASNase doses, respectively. After the single regular dose of PEG-ASNase at the beginning of delayed intensification, BCP-ALL-MR patients were randomized to receive 9 additional PEG-ASNase doses every 2 weeks (experimental arm [EA]) versus none (standard arm [SA]); HR patients were randomized to receive, in consolidation, 4 weekly PEG-ASNase doses (EA) versus none (SA). The HSR cumulative incidence (CI) was estimated adjusting for competing risks. An HSR occurred in 472 of 6136 (7.7%) patients. T-non- HR/BCP-Standard-Risk, BCP-MR-SA, BCP-MR-EA, HR-SA and HR-EA patients had 1-year-CI-HSR (±SE) rates of 5.2% (0.5), 5.2% (0.5), 4.0% (0.8), 20.2% (1.2), and 6.4% (1.3), respectively. The randomized intensification of PEG-ASNase did not significantly impact on HSR incidence in BCP-MR patients (1-y-CI-HSR 3.8% [0.8] versus 3.2% [0.6] in MR-EA versus MR-SA; P = 0.55), while impacted significantly in HR patients (1-y-CI-HSR 6.4% [1.3] versus 17.9% [1.8] in HR-EA and HR-SA, respectively; P < 0.001). The CI-HSR was comparable among non-HR groups and was not increased by a substantial intensification of PEG-ASNase in the BCP-MR-EA group whilst it was markedly higher in HR-SA than in HR-EA patients, suggesting that, in such a chemotherapy context, a continuous exposure to PEG-ASNase reduces the risk of developing an HSR.
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Affiliation(s)
- Carmelo Rizzari
- Department of Pediatrics, IRCCS San Gerardo dei Tintori Foundation, Monza, Italy; Department of Medicine and Surgery, University of MIlano-Bicocca, Milano, Italy
| | - Anja Möricke
- Department of Pediatrics I, Pediatric Hematology/Oncology, ALL-BFM Study Group, Christian Albrechts University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Germany
| | - Maria Grazia Valsecchi
- Department of Pediatrics, IRCCS San Gerardo dei Tintori Foundation, Monza, Italy; Department of Medicine and Surgery, University of MIlano-Bicocca, Milano, Italy
- Bicocca Center of Bioinformatics, Biostatistics and Bioimaging, School of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy
| | - Valentino Conter
- Department of Pediatrics, IRCCS San Gerardo dei Tintori Foundation, Monza, Italy; Department of Medicine and Surgery, University of MIlano-Bicocca, Milano, Italy
| | - Martin Zimmermann
- Department of Pediatric Hematology/Oncology, Hannover Medical School, Hannover, Germany
| | - Daniela Silvestri
- Department of Pediatrics, IRCCS San Gerardo dei Tintori Foundation, Monza, Italy; Department of Medicine and Surgery, University of MIlano-Bicocca, Milano, Italy
- Bicocca Center of Bioinformatics, Biostatistics and Bioimaging, School of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy
| | - Andishe Attarbaschi
- Department of Pediatric Hematology and Oncology, St. Anna Children's Hospital, Medical University of Vienna, Austria
- St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria
| | - Felix Niggli
- University Children's Hospital, Zurich, Switzerland
| | - Draga Barbaric
- Cancer Centre for Children, Sydney Children's Hospital Network, Westmead, NSW, Australia
| | - Jan Stary
- Department of Pediatric Haematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
| | - Sarah Elitzur
- Pediatric Hematology-Oncology, Schneider Children's Medical Center, Petah Tikva, and Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva, Israel
| | - Gunnar Cario
- Department of Pediatrics I, Pediatric Hematology/Oncology, ALL-BFM Study Group, Christian Albrechts University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Germany
| | - Luciana Vinti
- Department of Onco-Hematology and Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Joachim Boos
- Department of Pediatric Hematology and Oncology, University Childrens' Hospital of Münster, Germany
| | - Massimo Zucchetti
- Department of Oncology Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Laboratory of Cancer Pharmacology, Milano, Italy
| | - Claudia Lanvers-Kaminsky
- Department of Pediatric Hematology and Oncology, University Childrens' Hospital of Münster, Germany
| | - Arend von Stackelberg
- Department of Pediatric Hematology and Oncology, Charité and Rudolf-Virchow-Hospital, Berlin, Germany
| | - Andrea Biondi
- Department of Pediatrics, IRCCS San Gerardo dei Tintori Foundation, Monza, Italy; Department of Medicine and Surgery, University of MIlano-Bicocca, Milano, Italy
| | - Martin Schrappe
- Department of Pediatrics I, Pediatric Hematology/Oncology, ALL-BFM Study Group, Christian Albrechts University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Germany
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Sandley M, Angus J. Asparaginase therapy in patients with acute lymphoblastic leukemia: expert opinion on use and toxicity management. Leuk Lymphoma 2023; 64:776-787. [PMID: 36781296 DOI: 10.1080/10428194.2023.2171267] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 01/05/2023] [Accepted: 01/16/2023] [Indexed: 02/15/2023]
Abstract
The addition of asparaginase to acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) treatment regimens provides significant patient benefits. Asparaginase therapies vary in origin (Escherichia coli- or Erwinia-derived) and preparation (native or pegylated), conferring distinct pharmacokinetic and immunogenic profiles. Clinical hypersensitivity reactions (HSRs) are commonly reported in patients and range from localized erythema to systemic anaphylaxis. Due to its favorable pharmacokinetic profile and reduced immunogenicity compared to native E. coli preparations, pegaspargase is the first-line asparaginase therapeutic option. Switching to an Erwinia-derived asparaginase is recommended for patients who experience HSRs or antibody-mediated inactivation to achieve the significant clinical benefit observed in patients who complete asparaginase treatment. Previous global shortages of asparaginase Erwinia chrysanthemi necessitated conversion mitigation strategies such as premedication protocols, desensitization, and asparaginase activity level monitoring. Here, we discuss the efficacy, safety, pharmacokinetics, current use, and administration of asparaginase therapies for pediatric and adolescent patients with ALL/LBL.
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Affiliation(s)
- Melissa Sandley
- Department of Pharmacy, Oregon Health and Science University, Portland, OR, USA
| | - Jonathan Angus
- Department of Pharmacy, Cancer and Blood Disorders Center, Seattle Children's Hospital, Seattle, WA, USA
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10
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da Silva LF, de Pádua APSL, de Oliveira Ferro L, Agamez-Montalvo GS, Bezerra JDP, Moreira KA, de Souza-Motta CM. Cacti as low-cost substrates to produce L-asparaginase by endophytic fungi. World J Microbiol Biotechnol 2022; 38:247. [DOI: 10.1007/s11274-022-03420-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 09/20/2022] [Indexed: 10/31/2022]
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11
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Skipper MT, Rank CU, Jarvis KB, Lynggaard LS, Andrés‐Jensen L, Quist‐Paulsen P, Semaskeviciene R, Hallböök H, Waitiovaara‐Kautto U, Ranta S, Trakymiene S, Abrahamsson J, Huttunen P, Albertsen BK, Schmiegelow K, Tuckuviene R. Cerebral sinovenous thrombosis and asparaginase re-exposure in patients aged 1-45 years with acute lymphoblastic leukaemia: A NOPHO ALL2008 study. EJHAEM 2022; 3:754-763. [PMID: 36051071 PMCID: PMC9422014 DOI: 10.1002/jha2.484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 05/06/2022] [Accepted: 05/11/2022] [Indexed: 11/22/2022]
Abstract
Cerebral sinovenous thrombosis (CSVT) is a serious complication during asparaginase therapy in patients with acute lymphoblastic leukaemia (ALL). We identified 46 patients with CSVT among 2651 patients (1‒45 years) treated according to the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol between 2008 and 2018. CSVT cases were prospectively registered in the NOPHO database with retrospective updates. We examined the frequency of asparaginase re-exposure after CSVT, potential factors associated with asparaginase truncation, and sequelae after CSVT. This work was supported by the Danish Cancer Society and the Danish Childhood Cancer Foundation. The 2.5-year cumulative incidence of CSVT was 1.9% (95% confidence interval 1.4%-2.5%). The majority of patients (74%, n = 31) were re-exposed to asparaginase (with low-molecular-weight heparin coverage), one of whom had a second CSVT, without neurological sequelae. Patients re-exposed to asparaginase were earlier in ALL treatment and lacked more asparaginase doses than non-re-exposed patients at CSVT diagnosis (median 50 vs. 81 days, p = 0.03; mean 11.2 vs. 8.4 asparaginase doses, p = 0.04). No other examined factors had an impact on asparaginase re-exposure. At the last follow-up (median 4.5 years after CSVT), 61% of patients had normal neurological status, and 57% had complete recanalisation of CSVT, with no significant difference between patients re-exposed and non-re-exposed to asparaginase. Our results indicate that re-exposure to asparaginase is safe after CSVT during anticoagulation.
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Affiliation(s)
- Mette Tiedemann Skipper
- Department of Paediatrics and Adolescent MedicineAarhus University HospitalAarhusDenmark
- Department of Clinical MedicineAarhus UniversityAarhusDenmark
| | - Cecilie Utke Rank
- Department of Paediatrics and Adolescent MedicineRigshospitalet University HospitalCopenhagenDenmark
| | | | - Line Stensig Lynggaard
- Department of Paediatrics and Adolescent MedicineAarhus University HospitalAarhusDenmark
| | - Liv Andrés‐Jensen
- Department of Paediatrics and Adolescent MedicineRigshospitalet University HospitalCopenhagenDenmark
| | | | - Ruta Semaskeviciene
- Oncology and Transfusion Medicine CentreVilnius University Hospital Santaros KlinikosVilniusLithuania
| | - Helene Hallböök
- Department of Medical SciencesUppsala UniversityUppsalaSweden
| | - Ulla Waitiovaara‐Kautto
- Department of HaematologyComprehensive Cancer CentreHelsinki University Hospital and University of HelsinkiHelsinkiFinland
| | - Susanna Ranta
- Astrid Lindgren Children's HospitalKarolinska University Hospital and Childhood Cancer Research UnitDepartment of Women's and Children's HealthKarolinska InstituteStockholmSweden
| | - Sonata Trakymiene
- Clinic of Children's DiseasesFaculty of MedicineVilnius UniversityVilnius University Hospital Santaros KlinikosVilniusLithuania
| | - Jonas Abrahamsson
- Department of PaediatricsInstitution of Clinical ScienceSahlgrenska Academy University of GothenburgGothenburgSweden
| | - Pasi Huttunen
- Department of Paediatric HaematologyOncology and SCTNew Children's HospitalHelsinki University HospitalHelsinkiFinland
| | - Birgitte Klug Albertsen
- Department of Paediatrics and Adolescent MedicineAarhus University HospitalAarhusDenmark
- Department of Clinical MedicineAarhus UniversityAarhusDenmark
| | - Kjeld Schmiegelow
- Department of Paediatrics and Adolescent MedicineRigshospitalet University HospitalCopenhagenDenmark
| | - Ruta Tuckuviene
- Department of Paediatrics and Adolescent MedicineRigshospitalet University HospitalCopenhagenDenmark
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12
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Maese L, Rau RE. Current Use of Asparaginase in Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma. Front Pediatr 2022; 10:902117. [PMID: 35844739 PMCID: PMC9279693 DOI: 10.3389/fped.2022.902117] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 06/06/2022] [Indexed: 01/19/2023] Open
Abstract
Pediatric Acute Lymphoblastic Leukemia (ALL) cure rates have improved exponentially over the past five decades with now over 90% of children achieving long-term survival. A direct contributor to this remarkable feat is the development and expanded understanding of combination chemotherapy. Asparaginase is the most recent addition to the ALL chemotherapy backbone and has now become a hallmark of therapy. It is generally accepted that the therapeutic effects of asparaginase is due to depletion of the essential amino acid asparagine, thus occupying a unique space within the therapeutic landscape of ALL. Pharmacokinetic and pharmacodynamic profiling have allowed a detailed and accessible insight into the biochemical effects of asparaginase resulting in regular clinical use of therapeutic drug monitoring (TDM). Asparaginase's derivation from bacteria, and in some cases conjugation with a polyethylene glycol (PEG) moiety, have contributed to a unique toxicity profile with hypersensitivity reactions being the most salient. Hypersensitivity, along with several other toxicities, has limited the use of asparaginase in some populations of ALL patients. Both TDM and toxicities have contributed to the variety of approaches to the incorporation of asparaginase into the treatment of ALL. Regardless of the approach to asparagine depletion, it has continually demonstrated to be among the most important components of ALL therapy. Despite regular use over the past 50 years, and its incorporation into the standard of care treatment for ALL, there remains much yet to be discovered and ample room for improvement within the utilization of asparaginase therapy.
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Affiliation(s)
- Luke Maese
- Huntsman Cancer Institute, University of Utah, Primary Children's Hospital, Salt Lake City, UT, United States
| | - Rachel E. Rau
- Department of Pediatrics, Baylor College of Medicine Texas Children's Hospital, Houston, TX, United States
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13
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Tong WH, Uyl-De Groot CA. Comment on: "Premedication prior to PEG-asparaginase is cost effective in pediatric patients with acute lymphoblastic leukemia". Pediatr Blood Cancer 2022; 69:e29474. [PMID: 34889044 DOI: 10.1002/pbc.29474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 11/03/2021] [Indexed: 11/10/2022]
Affiliation(s)
- Wing H Tong
- Department of Public Health and Primary Care (PHEG), Leiden University Medical Center, Leiden, The Netherlands.,Argos Zorggroep "DrieMaasStede", Center for Specialized Geriatric Care, Schiedam, The Netherlands
| | - Carin A Uyl-De Groot
- Erasmus School of Health Policy & Management, Erasmus University Rotterdam, Rotterdam, The Netherlands.,Institute for Medical Technology Assessment, Erasmus University Rotterdam, Rotterdam, The Netherlands
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14
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Sidhu J, Masurekar AN, Gogoi MP, Fong C, Ioannou T, Lodhi T, Parker C, Liu J, Kirkwood AA, Moorman AV, Das K, Goulden NJ, Vora A, Saha V, Krishnan S. Activity and toxicity of intramuscular 1000 iu/m 2 polyethylene glycol-E. coli L-asparaginase in the UKALL 2003 and UKALL 2011 clinical trials. Br J Haematol 2022; 198:142-150. [PMID: 35348200 PMCID: PMC9314843 DOI: 10.1111/bjh.18158] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 03/10/2022] [Accepted: 03/11/2022] [Indexed: 11/26/2022]
Abstract
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.
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Affiliation(s)
- Jasmeet Sidhu
- Tata Translational Cancer Research Centre, Tata Medical Center, Kolkata, India.,Department of Paediatric Haematology and Oncology, Tata Medical Center, Kolkata, India
| | - Ashish Narayan Masurekar
- Childrens Cancer Group, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Manash Pratim Gogoi
- Tata Translational Cancer Research Centre, Tata Medical Center, Kolkata, India
| | - Caroline Fong
- Childrens Cancer Group, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Tasos Ioannou
- Childrens Cancer Group, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Taha Lodhi
- Childrens Cancer Group, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Catriona Parker
- Childrens Cancer Group, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Jizhong Liu
- Childrens Cancer Group, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Amy A Kirkwood
- Cancer Research UK & UCL Cancer Trials Centre, UCL Cancer Institute, University College, London, UK
| | - Anthony V Moorman
- Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK
| | - Kiranmoy Das
- Interdisciplinary Statistical Research Unit, Indian Statistical Institute, Kolkata, India
| | - Nicholas J Goulden
- Department of Haematology, Great Ormond Street Hospital for Children, London, UK
| | - Ajay Vora
- Department of Haematology, Great Ormond Street Hospital for Children, London, UK
| | - Vaskar Saha
- Tata Translational Cancer Research Centre, Tata Medical Center, Kolkata, India.,Department of Paediatric Haematology and Oncology, Tata Medical Center, Kolkata, India.,Childrens Cancer Group, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Shekhar Krishnan
- Tata Translational Cancer Research Centre, Tata Medical Center, Kolkata, India.,Department of Paediatric Haematology and Oncology, Tata Medical Center, Kolkata, India.,Childrens Cancer Group, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
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15
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Burke MJ, Zalewska-Szewczyk B. Hypersensitivity reactions to asparaginase therapy in acute lymphoblastic leukemia: immunology and clinical consequences. Future Oncol 2022; 18:1285-1299. [PMID: 35107320 DOI: 10.2217/fon-2021-1288] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
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.
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Affiliation(s)
- Michael J Burke
- Department of Pediatrics, Division of Pediatric Hematology-Oncology-Blood & Marrow Transplantation, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Beata Zalewska-Szewczyk
- Department of Pediatrics, Oncology & Hematology, Medical University of Lodz, 91-738, Lodz, Poland
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16
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Tong WH. Comment on "Correlation of L-asp Activity, Anti-L-asp Antibody, asn and gln with Adverse Events Especially Anaphylaxis Risks in PEG-asp-Contained Regime Treated Pediatric ALL". Technol Cancer Res Treat 2021; 20:15330338211049902. [PMID: 34738840 PMCID: PMC8573475 DOI: 10.1177/15330338211049902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Affiliation(s)
- Wing H Tong
- Department of Public Health and Primary Care (PHEG), 4501Leiden University Medical Center, Leiden, the Netherlands.,Argos Zorggroep "DrieMaasStede", Center for Specialized Geriatric Care, Schiedam, the Netherlands
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17
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Tong WH. Does anticoagulation prophylaxis reduce the rate of venous thromboembolism in adult acute lymphoblastic leukaemia treated with asparaginase-based therapy? Br J Haematol 2021; 197:e24-e25. [PMID: 34713438 DOI: 10.1111/bjh.17931] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 10/18/2021] [Indexed: 11/29/2022]
Affiliation(s)
- Wing H Tong
- Department of Public Health and Primary Care (PHEG), Leiden University Medical Center, Leiden, The Netherlands.,Argos Zorggroep "DrieMaasStede", Center for Specialized Geriatric Care, Schiedam, The Netherlands
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18
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Brigitha LJ, Pieters R, van der Sluis IM. How much asparaginase is needed for optimal outcome in childhood acute lymphoblastic leukaemia? A systematic review. Eur J Cancer 2021; 157:238-249. [PMID: 34536947 DOI: 10.1016/j.ejca.2021.08.025] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 08/13/2021] [Accepted: 08/13/2021] [Indexed: 10/20/2022]
Abstract
This review focuses on asparaginase, a key component of childhood acute lymphoblastic leukaemia (ALL) treatment since the 1970s. This review evaluates how much asparaginase is needed for optimal outcome in childhood ALL. We provide an overview of asparaginase dose intensity, i.e. duration of total cumulative exposure in weeks and level of exposure reflected by dose and/or asparaginase activity level, and the corresponding outcome. We systematically searched papers published between January 1990 and March 2021 in the PubMed and MEDLINE databases and included 20 papers. The level and duration of exposure were based on the pharmacokinetic profile of the drug and the assumption that trough asparaginase activity levels of ≥100 IU/L should be achieved for complete l-asparagine depletion. The statistical meta-analysis of outcomes was not performed because different outcome measures were used. The level of exposure was not associated with the outcome as long as therapeutic asparaginase activity levels of ≥100 IU/L were reached. Conflicting results were found in the randomised controlled trials, but all truncation studies showed that the duration of exposure (expressed as weeks of l-asparagine depletion) does affect the outcome; however, no clear cutoff for optimal exposure duration was determined. Optimal exposure duration will also depend on immunophenotype, (cyto)genetic subgroups, risk group stratification and backbone therapy.
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Affiliation(s)
- Leiah J Brigitha
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
| | - Rob Pieters
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
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19
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Tong WH. Comment on "Pharmacodynamics of cerebrospinal fluid asparagine after asparaginase". Cancer Chemother Pharmacol 2021; 88:919-920. [PMID: 34468793 DOI: 10.1007/s00280-021-04345-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 08/18/2021] [Indexed: 11/24/2022]
Affiliation(s)
- Wing H Tong
- Department of Public Health and Primary Care (PHEG), Leiden University Medical Center (LUMC), Building 3, Hippocratespad 21, PO Box 9600, 2300 RC, Leiden, The Netherlands. .,Center for Specialized Geriatric Care, Argos Zorggroep "DrieMaasStede", Schiedam, The Netherlands.
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20
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Santos AC, Land MGP, Lima EC. Response to comment on Ammonia level as a proxy of asparaginase inactivation in children: A strategy for classification of infusion reactions. J Oncol Pharm Pract 2021; 27:1053-1054. [PMID: 33847194 DOI: 10.1177/10781552211007549] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Amanda C Santos
- Instituto de Puericultura e Pediatria Martagão Gesteira, PPGCM -- FM (Graduate program in medical clinic -- medical school) Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Marcelo G P Land
- Instituto de Puericultura e Pediatria Martagão Gesteira, PPGCM -- FM (Graduate program in medical clinic -- medical school) Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Elisangela C Lima
- School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
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21
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Production, purification, characterization, antioxidant and antiproliferative activities of extracellular L-asparaginase produced by Fusarium equiseti AHMF4. Saudi J Biol Sci 2021; 28:2540-2548. [PMID: 33911966 PMCID: PMC8071902 DOI: 10.1016/j.sjbs.2021.01.058] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 11/18/2020] [Accepted: 01/25/2021] [Indexed: 12/03/2022] Open
Abstract
L-Asparaginase is an antileukemic agent that depletes L-asparagine “an important nutrient for cancer cells” through the hydrolysis of L-asparagine into L-aspartic acid and ammonia leading to leukemia cell starvation and apoptosis in susceptible leukemic cell populations. Moreover currently, bacterial L-asparaginase has been limited by problems of lower productivity, stability, selectivity and a number of toxicities along with the resistance towards bacterial L-asparaginase. Then the current work aimed to provide pure L-asparaginase with in-vitro efficacy against various human carcinomas without adverse effects related to current L-asparaginase formulations. Submerged fermentation (SMF) bioprocess was applied and improved to maximize L-asparaginase production from Fusarium equiseti AHMF4 as alternative sources of bacteria. The enzyme production in SMF was maximized to reach 40.78 U mL−1 at the 7th day of fermentation with initial pH 7.0, incubation temperature 30 °C, 1.0% glucose as carbon source, 0.2% asparagine as nitrogen source, 0.1% alanine as amino acid supplement and 0.1% KH2PO4. The purification of AHMF4 L-asparaginase yielded 2.67-fold purification and 48% recovery with final specific activity of 488.1 U mg−1 of protein. Purified L-asparaginase was characterized as serine protease enzyme with molecular weight of 45.7 kDa beside stability at neutral pH and between 20 and 40 °C. Interestingly, purified L-asparaginase showed promising DPPH radical scavenging activity (IC50 69.12 μg mL−1) and anti-proliferative activity against cervical epitheloid carcinoma (Hela), epidermoid larynx carcinoma (Hep-2), hepatocellular carcinoma (HepG-2), Colorectal carcinoma (HCT-116), and breast adenocarcinoma (MCF-7) with IC50 equal to 2.0, 5.0, 12.40, 8.26 and 22.8 μg mL−1, respectively. The enzyme showed higher activity, selectivity and anti-proliferative activity against cancerous cells along with tiny cytotoxicity toward normal cells (WI-38) which indicates that it has selective toxicity and it could be applied as a less toxic alternative to the current formulations.
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22
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Kuo MT, Chen HHW, Feun LG, Savaraj N. Targeting the Proline-Glutamine-Asparagine-Arginine Metabolic Axis in Amino Acid Starvation Cancer Therapy. Pharmaceuticals (Basel) 2021; 14:ph14010072. [PMID: 33477430 PMCID: PMC7830038 DOI: 10.3390/ph14010072] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 01/14/2021] [Accepted: 01/15/2021] [Indexed: 12/22/2022] Open
Abstract
Proline, glutamine, asparagine, and arginine are conditionally non-essential amino acids that can be produced in our body. However, they are essential for the growth of highly proliferative cells such as cancers. Many cancers express reduced levels of these amino acids and thus require import from the environment. Meanwhile, the biosynthesis of these amino acids is inter-connected but can be intervened individually through the inhibition of key enzymes of the biosynthesis of these amino acids, resulting in amino acid starvation and cell death. Amino acid starvation strategies have been in various stages of clinical applications. Targeting asparagine using asparaginase has been approved for treating acute lymphoblastic leukemia. Targeting glutamine and arginine starvations are in various stages of clinical trials, and targeting proline starvation is in preclinical development. The most important obstacle of these therapies is drug resistance, which is mostly due to reactivation of the key enzymes involved in biosynthesis of the targeted amino acids and reprogramming of compensatory survival pathways via transcriptional, epigenetic, and post-translational mechanisms. Here, we review the interactive regulatory mechanisms that control cellular levels of these amino acids for amino acid starvation therapy and how drug resistance is evolved underlying treatment failure.
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Affiliation(s)
- Macus Tien Kuo
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Correspondence:
| | - Helen H. W. Chen
- Department of Radiation Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70428, Taiwan;
| | - Lynn G. Feun
- Department of Medicine, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA;
| | - Niramol Savaraj
- Division of Hematology and Oncology, Miami Veterans Affairs Heaithcare System, Miami, FL 33136, USA;
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