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Lin L, Yang KH, Chen CC, Shen SH, Hu WT, Deng ZH. Risk factors and a prediction model of severe asparaginase-associated pancreatitis in children. Ann Hematol 2025; 104:1015-1022. [PMID: 39680068 PMCID: PMC11971144 DOI: 10.1007/s00277-024-06133-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Accepted: 12/02/2024] [Indexed: 12/17/2024]
Abstract
We aimed to investigate whether early clinical indicators were associated with eventual disease severity, and to develop a predictive model for severe asparaginase-associated pancreatitis (AAP). Seventy-five acute lymphoblastic leukaemia (ALL) cases with AAP admitted to Shanghai Children's Medical Center from March 2013 to August 2023 were divided into non-severe (n = 44) and severe (n = 31) groups based on Atlanta diagnostic and AAP grading criteria. We compared essential information, asparaginase(ASP) dosage form, cumulative dose, clinical characteristics and laboratory tests between the groups. Statistically significant indicators were analysed with multifactorial logistic regression to identify independent risk factors for severe AAP. Receiver operating characteristic (ROC) curves assessed the early predictive value of age, C-reactive protein (CRP) and fibrinogen (FIB) levels. In the early stages of AAP onset, significant differences in age, CRP, platelet count, red blood cell distribution width, albumin, calcium, FIB, and D-dimer levels were found between the non-severe and severe AAP groups (p < 0.05). Multifactorial logistic regression identified age (odds ratio [OR] = 1.204, p = 0.035), CRP (OR = 1.334, p = 0.003), and FIB (OR = 0.85, p = 0.008) as independent predictors of severe AAP. ROC analysis showed an area under the curves (AUC) for age was 0.681 (95% CI: 0.557-0.805), CRP was 0.766 (95% CI: 0.653-0.880), FIB was 0.735 (95% CI: 0.612-0.857). Optimal cut-off values for age, CRP, and FIB were 9.46 years, 48.5 mg/L and 1.265 g/L respectively. The combined AUC was 0.916 (95% CI: 0.845-0.986), with 0.903 sensitivity and 0.818 specificity, outperforming individual predictors (p < 0.05). Age, CRP, and FIB levels are good early predictors of severe AAP, and their combination significantly improves predictive accuracy.
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Affiliation(s)
- Long Lin
- Department of Gastroenterology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, No. 1678 Dongfang Road, Shanghai, China
| | - Kai-Hua Yang
- Department of Gastroenterology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, No. 1678 Dongfang Road, Shanghai, China
| | - Chang-Cheng Chen
- Department of Hematology/Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, No. 1678 Dongfang Road, Shanghai, China
| | - Shu-Hong Shen
- Department of Hematology/Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, No. 1678 Dongfang Road, Shanghai, China
| | - Wen-Ting Hu
- Department of Hematology/Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, No. 1678 Dongfang Road, Shanghai, China
| | - Zhao-Hui Deng
- Department of Gastroenterology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, No. 1678 Dongfang Road, Shanghai, China.
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Maese L, Loh ML, Choi MR, Agarwal S, Aoki E, Liang Y, Lin T, Girgis S, Chen C, Roller S, Chandrasekaran V, Iannone R, Silverman LB, Raetz EA, Rau RE. Recombinant Erwinia asparaginase (JZP458) in ALL/LBL: complete follow-up of the Children's Oncology Group AALL1931 study. Blood Adv 2025; 9:66-77. [PMID: 39454281 PMCID: PMC11742576 DOI: 10.1182/bloodadvances.2024013346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 09/25/2024] [Accepted: 10/02/2024] [Indexed: 10/28/2024] Open
Abstract
ABSTRACT Children's Oncology Group study AALL1931 investigated the efficacy and safety of recombinant Erwinia asparaginase (JZP458) in patients with acute lymphoblastic leukemia/lymphoblastic lymphoma and hypersensitivity reactions/silent inactivation to Escherichia coli-derived asparaginases. Each pegylated Escherichia coli asparaginase dose remaining in a patient's treatment plan was replaced by intramuscular (IM) or IV JZP458 (6 doses) administered Monday/Wednesday/Friday (MWF). Three IM cohorts (1a [25 mg/m2 MWF], n = 33; 1b [37.5 mg/m2 MWF], n = 83; 1c [25/25/50 mg/m2 MWF], n = 51) and 1 IV cohort (25/25/50 mg/m2 MWF, n = 62) were evaluated. The proportion (95% confidence interval [CI]) of patients maintaining nadir serum asparaginase activity (NSAA) levels of ≥0.1 IU/mL at the last 72 (primary end point) and 48 hours during course 1 was 90% (95% CI, 81-98) and 96% (95% CI, 90-100) in IM cohort 1c, respectively, and 40% (95% CI, 26-54) and 90% (95% CI, 82-98) in the IV cohort. Population pharmacokinetic modeling results were comparable with observed data, predicting the vast majority of patients would maintain therapeutic NSAA levels when JZP458 is administered IM or IV 25 mg/m2 every 48 hours, or IM 25/25/50 mg/m2 MWF, or with mixed IM and IV administration (IV/IV/IM 25/25/50 mg/m2 MWF). Drug discontinuation occurred in 23% and 56% of patients in the IM and IV cohorts, respectively; 13% and 33% because of treatment-related adverse events (mainly allergic reactions and pancreatitis). JZP458 achieves therapeutic NSAA levels via multiple IM and IV dosing schedules based on combined observed and modeled data with a safety profile consistent with other asparaginases. This trial was registered at www.ClinicalTrials.gov as #NCT04145531.
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Affiliation(s)
- Luke Maese
- Department of Pediatrics, Division of Pediatric Hematology-Oncology, University of Utah, Huntsman Cancer Institute, Primary Children's Hospital, Salt Lake City, UT
| | - Mignon L. Loh
- Department of Pediatrics and the Ben Towne Center for Childhood Cancer Research, Seattle Children’s Hospital, University of Washington, Seattle, WA
| | | | | | | | | | - Tong Lin
- Jazz Pharmaceuticals, Palo Alto, CA
| | | | | | | | | | | | - Lewis B. Silverman
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Elizabeth A. Raetz
- Department of Pediatrics and Perlmutter Cancer Center, New York University, New York, NY
| | - Rachel E. Rau
- Department of Pediatrics and the Ben Towne Center for Childhood Cancer Research, Seattle Children’s Hospital, University of Washington, Seattle, WA
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Chen C, Li J, Chen Y, Gao Q, Li N, Le S. The correlation of asparaginase enzyme activity levels after PEG-asparaginase administration with clinical characteristics and adverse effects in Chinese paediatric patients with acute lymphoblastic leukaemia. Br J Haematol 2024; 205:624-633. [PMID: 38934331 DOI: 10.1111/bjh.19605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Accepted: 06/10/2024] [Indexed: 06/28/2024]
Abstract
Studies on asparaginase enzyme activity (AEA) monitoring in Chinese patients receiving PEG-asparaginase remain limited. We monitored AEA in paediatric patients diagnosed with acute lymphoblastic leukaemia (ALL) and treated according to the Chinese Children's Cancer Group study protocols, CCCG-ALL-2015/CCCG-ALL-2020 protocols. We measured the AEA at days 7 ± 1 and 14 ± 1 and analysed their association with patient characteristics and PEG-asparaginase-related adverse effects (AEs). We measured 2147 samples from 329 patients. Mean AEA levels (interquartile range) were 931 iu/L (654-1174 iu/L) at day 7 ± 1 and 664 iu/L (463-860 iu/L) at day 14 ± 1. The AEA levels were higher in younger children and increased with the cumulative dose numbers. PEG-asparaginase inactivation rate was 19.1%, and the silent inactivation (SI) rate was 12.5%. Nine patients were identified with allergic-like reactions. Hypofibrinogenaemia, hypertriglyceridaemia, pancreatitis and thrombosis were associated with older age, whereas hypoglycaemia was associated with younger age. The risk of hypertriglyceridaemia and hypoglycaemia increased with cumulative dose numbers of PEG-asparaginase. Except for hypofibrinogenaemia, elevated AEA levels did not increase the risk of PEG-asparaginase-related AEs. Drug monitoring can be utilized as guidance for treatment decision-making. Individualizing asparaginase doses do not reduce toxicities. The treatment target of PEG-asparaginase remains to achieve sustained and adequate activity.
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Affiliation(s)
- Cai Chen
- Department of Pediatric Hematology, Fujian Medical University, Union Hospital, Fuzhou, China
| | - Jian Li
- Department of Pediatric Hematology, Fujian Medical University, Union Hospital, Fuzhou, China
| | - Yiqiao Chen
- Department of Pediatric Hematology, Fujian Medical University, Union Hospital, Fuzhou, China
| | - Qinli Gao
- Department of Pediatric Hematology, Fujian Medical University, Union Hospital, Fuzhou, China
| | - Nainong Li
- Fujian Institute of Hematology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Shaohua Le
- Department of Pediatric Hematology, Fujian Medical University, Union Hospital, Fuzhou, China
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Morawiak A, Salamonowicz-Bodzioch M, Królak A, Kałwak K, Owoc-Lempach J, Kowalczyk J, Zawitkowska J, Szczepański T, Irga-Jaworska N, Adamkiewicz-Drożyńska E, Albrecht K, Szmydki-Baran A, Balwierz W, Czogała M, Wachowiak J, Derwich K, Młynarski W, Zalewska-Szewczyk B, Krawczuk-Rybak M, Sawicka-Żukowska M, Styczyński J, Kołtan A, Safranow K, Urasiński T, Ociepa T. Acute Pancreatitis in Pediatric Acute Lymphoblastic Leukemia (AcuPA Study): A Nationwide Survey in Poland. Cancers (Basel) 2024; 16:2640. [PMID: 39123368 PMCID: PMC11312082 DOI: 10.3390/cancers16152640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 07/19/2024] [Accepted: 07/23/2024] [Indexed: 08/12/2024] Open
Abstract
PURPOSE This study aimed to identify the risk factors for acute pancreatitis (AP) and its impact on outcomes in Polish children treated for ALL. METHODS The study group included 2303 children receiving intensive chemotherapy for ALL. The group was divided into patients with at least one episode of AP and those who did not develop AP after treatment for ALL. RESULTS The cumulative incidence of AP in the study group was 4.08%. Older age was an independent risk factor for the development of AP (OR = 1.05; 95%CI = 1.006-1.098; p = 0.03). The overall mortality associated with AP was 2.13%. The probabilities of disease-free survival (p-DFS) and event-free survival (p-EFS) in both subgroups were 0.84 vs. 0.86, log-rank p = 0.65 and 0.75 vs. 0.80, log-rank p = 0.12, respectively. A total of 22 out of 94 patients (23.4%) with AP were re-exposed to asparaginase (ASP) during the subsequent treatment phases. Only one patient re-exposed to ASP (4.5%) developed a second episode of AP. There were no significant differences in p-DFS and p-EFS between patients re-exposed and not re-exposed to asparaginase (0.78 vs. 0.86, log-rank p = 0.27 and 0.63 vs. 0.79, log-rank p = 0.09, respectively). CONCLUSIONS The incidence of AP in children with ALL is low and related to patients' age. The development of AP does not seem to influence p-DFS and p-EFS in children with ALL. Recurrence of AP after re-exposure to asparaginase in patients with ALL and a history of AP is low (4.5%). Re-exposure to asparaginase after the first episode of AP does not improve either p-DFS or p-EFS in children with ALL.
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Affiliation(s)
- Anna Morawiak
- Department of Pediatrics, Hemato-Oncology and Gastroenterology, Pomeranian Medical University, Unii Lubelskiej 1, 71-252 Szczecin, Poland; (A.M.); (A.K.); (T.U.)
| | - Małgorzata Salamonowicz-Bodzioch
- Department of Pediatric, Hematology, Oncology and BMT, Wrocław Medical University, 50-367 Wroclaw, Poland; (M.S.-B.); (K.K.); (J.O.-L.)
| | - Aleksandra Królak
- Department of Pediatrics, Hemato-Oncology and Gastroenterology, Pomeranian Medical University, Unii Lubelskiej 1, 71-252 Szczecin, Poland; (A.M.); (A.K.); (T.U.)
| | - Krzysztof Kałwak
- Department of Pediatric, Hematology, Oncology and BMT, Wrocław Medical University, 50-367 Wroclaw, Poland; (M.S.-B.); (K.K.); (J.O.-L.)
| | - Joanna Owoc-Lempach
- Department of Pediatric, Hematology, Oncology and BMT, Wrocław Medical University, 50-367 Wroclaw, Poland; (M.S.-B.); (K.K.); (J.O.-L.)
| | - Jerzy Kowalczyk
- Department of Pediatric Hematology, Oncology and Transplantology, Medical University of Lublin, 20-059 Lublin, Poland; (J.K.); (J.Z.)
| | - Joanna Zawitkowska
- Department of Pediatric Hematology, Oncology and Transplantology, Medical University of Lublin, 20-059 Lublin, Poland; (J.K.); (J.Z.)
| | - Tomasz Szczepański
- Department of Pediatric Hematology and Oncology, Silesian Medical University, 40-055 Zabrze, Poland;
| | - Ninela Irga-Jaworska
- Department of Pediatrics, Hematology and Oncology, Medical University, 80-210 Gdansk, Poland; (N.I.-J.); (E.A.-D.)
| | | | - Katarzyna Albrecht
- Department of Pediatric Hematology and Oncology, Medical University, 02-091 Warszawa, Poland; (K.A.); (A.S.-B.)
| | - Anna Szmydki-Baran
- Department of Pediatric Hematology and Oncology, Medical University, 02-091 Warszawa, Poland; (K.A.); (A.S.-B.)
| | - Walentyna Balwierz
- Department of Pediatric Oncology and Hematology, University Children’s Hospital, Collegium Medicum Jagiellonian University, 31-008 Krakow, Poland; (W.B.); (M.C.)
| | - Małgorzata Czogała
- Department of Pediatric Oncology and Hematology, University Children’s Hospital, Collegium Medicum Jagiellonian University, 31-008 Krakow, Poland; (W.B.); (M.C.)
| | - Jacek Wachowiak
- Department of Pediatric Oncology, Hematology and Transplantology, University of Medical Sciences, 61-701 Poznan, Poland; (J.W.); (K.D.)
| | - Katarzyna Derwich
- Department of Pediatric Oncology, Hematology and Transplantology, University of Medical Sciences, 61-701 Poznan, Poland; (J.W.); (K.D.)
| | - Wojciech Młynarski
- Department of Pediatrics, Hematology and Oncology, Medical University, 90-419 Lodz, Poland; (W.M.); (B.Z.-S.)
| | - Beata Zalewska-Szewczyk
- Department of Pediatrics, Hematology and Oncology, Medical University, 90-419 Lodz, Poland; (W.M.); (B.Z.-S.)
| | - Maryna Krawczuk-Rybak
- Department of Pediatrics, Oncology an Hematology, Medical University, 15-089 Bialystok, Poland; (M.K.-R.); (M.S.-Ż.)
| | - Małgorzata Sawicka-Żukowska
- Department of Pediatrics, Oncology an Hematology, Medical University, 15-089 Bialystok, Poland; (M.K.-R.); (M.S.-Ż.)
| | - Jan Styczyński
- Department of Pediatrics, Hematology and Oncology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 87-100 Toruń, Poland; (J.S.); (A.K.)
| | - Andrzej Kołtan
- Department of Pediatrics, Hematology and Oncology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 87-100 Toruń, Poland; (J.S.); (A.K.)
| | - Krzysztof Safranow
- Biostatistics Teaching Unit, Pomeranian Medical University, 70-204 Szczecin, Poland;
| | - Tomasz Urasiński
- Department of Pediatrics, Hemato-Oncology and Gastroenterology, Pomeranian Medical University, Unii Lubelskiej 1, 71-252 Szczecin, Poland; (A.M.); (A.K.); (T.U.)
| | - Tomasz Ociepa
- Department of Pediatrics, Hemato-Oncology and Gastroenterology, Pomeranian Medical University, Unii Lubelskiej 1, 71-252 Szczecin, Poland; (A.M.); (A.K.); (T.U.)
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Ishida H, Imamura T, Kobayashi R, Hashii Y, Deguchi T, Miyamura T, Oda M, Yamamoto M, Okada K, Sano H, Koh K, Yuza Y, Watanabe K, Nishimura N, Takimoto T, Moriya‐Saito A, Sekimizu M, Suenobu S, Sunami S, Horibe K. Differential impact of asparaginase discontinuation on outcomes of children with T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma. Cancer Med 2024; 13:e7246. [PMID: 38888368 PMCID: PMC11184648 DOI: 10.1002/cam4.7246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2023] [Revised: 04/09/2024] [Accepted: 04/27/2024] [Indexed: 06/20/2024] Open
Abstract
BACKGROUND Asparaginase is essential for treating T-cell acute lymphoblastic leukemia (T-ALL). Despite the ongoing debate on whether T-ALL and T-cell lymphoblastic lymphoma (T-LBL) are the same disease entity or two distinct diseases, patients with T-LBL often receive the same or similar treatment protocols as those with T-ALL. METHODS The outcomes of patients with or without L-asparaginase discontinuation were retrospectively analyzed among four national protocols: Japan Association of Childhood Leukemia Study (JACLS) ALL-02 and ALL-97 for T-ALL and Japanese Pediatric Leukemia/Lymphoma Study Group ALB-NHL03 and JACLS NHL-98 for T-LBL. The hazard ratio (HR) was calculated with the Cox regression model by considering L-asparaginase discontinuation as a time-dependent variable. RESULTS In total, 199 patients with T-ALL, and 133 patients with T-LBL were included. L-asparaginase discontinuation compromised event-free survival (EFS) of T-ALL patients (ALL-02: HR 3.32, 95% confidence interval [CI] 1.40-7.90; ALL-97: HR 3.39, 95%CI 1.19-9.67). Conversely, EFS compromise was not detected among T-LBL patients (ALB-NHL03: HR 1.39, 95%CI 0.41-4.68; NHL-98: HR 0.92, 95%CI 0.11-7.60). CONCLUSION The effects of L-asparaginase discontinuation differed between T-ALL and T-LBL. We assume that the differential impact results from (1) the inherent differential response to L-asparaginase between them and/or (2) a less stringent assessment of early treatment response in T-LBL than in T-ALL. Given the poor salvage rate of refractory or relapsed T-ALL and T-LBL, optimization of the frontline therapy is critical, and the current study provides a new suggestion for further treatment modifications. However, larger studies in contemporary intensified treatment protocols are required.
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Affiliation(s)
- Hisashi Ishida
- Department of PediatricsOkayama University HospitalOkayamaJapan
| | - Toshihiko Imamura
- Department of PediatricsKyoto Prefectural University of Medicine, Graduate School of Medical ScienceKyotoJapan
| | - Ryoji Kobayashi
- Department of Hematology/Oncology for Children and AdolescentsSapporo Hokuyu HospitalSapporoJapan
| | - Yoshiko Hashii
- Department of PediatricsOsaka International Cancer InstituteOsakaJapan
| | - Takao Deguchi
- Division of Cancer Immunodiagnostics, Children's Cancer CenterNational Center for Child Health and DevelopmentTokyoJapan
| | - Takako Miyamura
- Department of PediatricsOsaka University Graduate School of MedicineSuitaJapan
| | - Megumi Oda
- Department of PediatricsOkayama University HospitalOkayamaJapan
| | - Masaki Yamamoto
- Department of PediatricsSapporo Medical University School of MedicineSapporoJapan
| | - Keiko Okada
- Department of Pediatric Hematology/OncologyOsaka City General HospitalOsakaJapan
| | - Hideki Sano
- Department of Pediatric OncologyFukushima Medical University HospitalFukushimaJapan
| | - Katsuyoshi Koh
- Department of Hematology/OncologySaitama Children's Medical CenterSaitamaJapan
| | - Yuki Yuza
- Department of Hematology and OncologyTokyo Metropolitan Children's Medical CenterTokyoJapan
| | - Kenichiro Watanabe
- Department of Hematology and OncologyShizuoka Children's HospitalShizuokaJapan
| | - Noriyuki Nishimura
- Department of Public HealthKobe University Graduate School of Health ScienceKobeJapan
| | - Tetsuya Takimoto
- Department of Childhood Cancer Data ManagementNational Center for Child Health and DevelopmentTokyoJapan
| | - Akiko Moriya‐Saito
- Clinical Research CenterNational Hospital Organization Nagoya Medical CenterNagoyaJapan
| | - Masahiro Sekimizu
- Department of PediatricsNational Hospital Organization Nagoya Medical CenterNagoyaJapan
| | | | - Shosuke Sunami
- Department of Pediatrics, Japanese Red Cross Narita HospitalNaritaJapan
| | - Keizo Horibe
- Clinical Research CenterNational Hospital Organization Nagoya Medical CenterNagoyaJapan
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Fiumana G, Pancaldi A, Bertani H, Boarino V, Cellini M, Iughetti L. Asparaginase-associated Pancreatitis Complicated by Pancreatic Fluid Collection Treated with Endoscopic Cistogastrostomy in Pediatric Acute Lymphoblastic Leukemia: A Case Report and Systematic Review of the Literature. Clin Hematol Int 2023; 5:51-61. [PMID: 38817959 PMCID: PMC10742384 DOI: 10.46989/001c.90958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 07/21/2023] [Indexed: 06/01/2024] Open
Abstract
Asparaginase-associated pancreatitis complicates 2-10% of patients treated for acute lymphoblastic leukemia, causing morbidity and discontinuation of asparaginase administration. Among acute complications, pancreatic fluid collections can be managed conservatively, but intervention is indicated when associated with persistent insulin therapy need and recurrent abdominal pain. Endoscopic treatment has become the standard approach in adult patients, with increasing favorable evidence in children. This work compares the characteristics of a pediatric oncology patient treated at our institution with reported literature experiences, showing feasibility, safety and effectiveness of endoscopic approach.
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Affiliation(s)
- Giulia Fiumana
- Post Graduate School of Pediatrics, Department of Medical and Surgical Sciences of the Mothers, Children, and AdultsUniversity of Modena and Reggio Emilia
| | | | - Helga Bertani
- Gastroenterology and Endoscopy UnitPoliclinico di Modena
| | | | | | - Lorenzo Iughetti
- Post Graduate School of Pediatrics, Department of Medical and Surgical Sciences of the Mothers, Children, and AdultsUniversity of Modena and Reggio Emilia, Italy
- Pediatric Hematology Oncology UnitAzienda Ospedaliero Universitaria Policlinico di Modena, Italy
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7
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Wang J, Jia WG, Yang LH, Kuang WY, Huang LB, Chen HQ, Wang LN, Zhou DH, Liao N. Clinical summary of pediatric acute lymphoblastic leukemia patients complicated with asparaginase-associated pancreatitis in SCCLG-ALL-2016 protocol. HEMATOLOGY (AMSTERDAM, NETHERLANDS) 2023; 28:2171723. [PMID: 36752506 DOI: 10.1080/16078454.2023.2171723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
Asparaginase-associated pancreatitis (AAP) is a common and fatal complication after ASNase treatment in acute lymphoblastic leukemia(ALL). Here, a total of 1063 pediatric ALL patients treated with SCCLG-ALL-2016 regimen were collected since October 2016 to June 2020, including 35 patients with AAP. The clinical characteristics of AAP and non-AAP patients were compared. In AAP patients, the possible factors that affected the recurrence of AAP were analyzed, and the possible risk factors related to ALL-relapse were discussed. The results showed that age was a risk factor (P = .017) that affect the occurrence of AAP. In AAP patients, AAP tended to develop after the second use of PEG-ASNase (25.71%). In the follow-up chemotherapy, 17 patients re-exposed to ASNase and 7 cases developed AAP again with a percentage was 41.2%. There were no special factors that related with the recurrence of AAP. This study also found no association between the occurrence of AAP and prognosis of ALL, with the 4-year incidence of ALL relapse in AAP and non-AAP patients were 15.9% v.s.11.7% (HR: 1.009, 95% CI:0.370-2.752, P = .986), and there were no special factors that related with the ALL relapse among AAP patients. Based on the above results, the occurrence of AAP is related to age and should be vigilant after the second use of PEG-ASNase after use in pediatric ALL patients. Moreover, AAP is not associated with ALL relapse, but there is a high AAP recurrence rate when re-exposure to ASNase.
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Affiliation(s)
- Jian Wang
- Children's Medical Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat Sen University, Guangzhou, People's Republic of China
| | - Wen-Guang Jia
- Department of Paediatrics, First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Li-Hua Yang
- Department of Paediatrics, Zhujiang Hospital of Southern Medical University, Guangzhou, People's Republic of China
| | - Wen-Yong Kuang
- Department of Hematology, Hunan Children's Hospital, Changsha, People's Republic of China
| | - Li-Bin Huang
- Department of Paediatrics, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Hui-Qin Chen
- Department of Paediatrics, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Li-Na Wang
- Department of Paediatrics, Guangzhou First People's Hospital, Guangzhou, People's Republic of China
| | - Dun-Hua Zhou
- Children's Medical Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat Sen University, Guangzhou, People's Republic of China
| | - Ning Liao
- Department of Paediatrics, First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
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8
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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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Schilstra CE, McCleary K, Fardell JE, Donoghoe MW, McCormack E, Kotecha RS, Lourenco RDA, Ramachandran S, Cockcroft R, Conyers R, Cross S, Dalla-Pozza L, Downie P, Revesz T, Osborn M, Alvaro F, Wakefield CE, Marshall GM, Mateos MK, Trahair TN. Prospective longitudinal evaluation of treatment-related toxicity and health-related quality of life during the first year of treatment for pediatric acute lymphoblastic leukemia. BMC Cancer 2022; 22:985. [PMID: 36109702 PMCID: PMC9479356 DOI: 10.1186/s12885-022-10072-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Accepted: 09/09/2022] [Indexed: 01/19/2023] Open
Abstract
Background Pediatric acute lymphoblastic leukemia (ALL) therapy is accompanied by treatment-related toxicities (TRTs) and impaired quality of life. In Australia and New Zealand, children with ALL are treated with either Children’s Oncology Group (COG) or international Berlin-Frankfurt-Munster (iBFM) Study Group-based therapy. We conducted a prospective registry study to document symptomatic TRTs (venous thrombosis, neurotoxicity, pancreatitis and bone toxicity), compare TRT outcomes to retrospective TRT data, and measure the impact of TRTs on children’s general and cancer-related health-related quality of life (HRQoL) and parents’ emotional well-being. Methods Parents of children with newly diagnosed ALL were invited to participate in the ASSET (Acute Lymphoblastic Leukaemia Subtypes and Side Effects from Treatment) study and a prospective, longitudinal HRQoL study. TRTs were reported prospectively and families completed questionnaires for general (Healthy Utility Index Mark 3) and cancer specific (Pediatric Quality of Life Inventory (PedsQL)-Cancer Module) health related quality of life as well the Emotion Thermometer to assess emotional well-being. Results Beginning in 2016, 260 pediatric patients with ALL were enrolled on the TRT registry with a median age at diagnosis of 59 months (range 1–213 months), 144 males (55.4%), majority with Pre-B cell immunophenotype, n = 226 (86.9%), 173 patients (66.5%) treated according to COG platform with relatively equal distribution across risk classification sub-groups. From 2018, 79 families participated in the HRQoL study through the first year of treatment. There were 74 TRT recorded, reflecting a 28.5% risk of developing a TRT. Individual TRT incidence was consistent with previous studies, being 7.7% for symptomatic VTE, 11.9% neurotoxicity, 5.4% bone toxicity and 5.0% pancreatitis. Children’s HRQoL was significantly lower than population norms throughout the first year of treatment. An improvement in general HRQoL, measured by the HUI3, contrasted with the lack of improvement in cancer-related HRQoL measured by the PedsQL Cancer Module over the first 12 months. There were no persisting differences in the HRQoL impact of COG compared to iBFM therapy. Conclusions It is feasible to prospectively monitor TRT incidence and longitudinal HRQoL impacts during ALL therapy. Early phases of ALL therapy, regardless of treatment platform, result in prolonged reductions in cancer-related HRQoL. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-10072-x.
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Chen CB, Chang HH, Chou SW, Yang YL, Lu MY, Jou ST, Chen HL, Ni YH, Lin DT, Chang MH, Wu JF. Acute pancreatitis in children with acute lymphoblastic leukemia correlates with L-asparaginase dose intensity. Pediatr Res 2022; 92:459-465. [PMID: 34718353 DOI: 10.1038/s41390-021-01796-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 09/24/2021] [Accepted: 10/06/2021] [Indexed: 11/09/2022]
Abstract
BACKGROUND L-Asparaginase (L-Asp) is an important therapeutic for childhood acute lymphoblastic leukemia (ALL). Asparaginase-associated pancreatitis (AAP) is a severe complication of L-Asp related to the dosage. We investigated the incidence of, and risk factors for, AAP in pediatric patients with ALL. METHODS From January 2002 to December 2018, pediatric patients with ALL treated at National Taiwan University Hospital were enrolled in this study. The diagnosis of AAP was based on the criteria of the Ponte di Legno Toxicity Working Group. RESULTS Of the 353 patients enrolled in this study, 14 (4.0%) developed AAP. The incidence of AAP in ALL patients was significantly higher after treatment with the 2013 protocol compared with the 2002 protocol of the Taiwan Pediatric Oncology Group (9.5% vs. 1.3%). Multivariate analysis showed that a high peak L-Asp dose intensity (>45,000 U/m2/month) and older age at diagnosis (>6.8 years) were independently predictive of AAP development. CONCLUSIONS The incidence of acute pancreatitis in childhood ALL was correlated more strongly with the peak dose intensity than with the cumulative dose of L-Asp. These results could be used to reduce the treatment-related complications of ALL. IMPACT L-Asparaginase is an important therapeutic for childhood acute lymphoblastic leukemia, and the accumulated dosage of L-asparaginase is considered as a major risk factor of asparaginase-associated pancreatitis. This article demonstrated that the incidence of pancreatitis correlates with the dose-intensity of L-asparaginase, but not the accumulated dosage. Identification of patient group with high risk of pancreatitis could lead to early diagnosis and reduce the complication. This finding could aid in developing further new protocol or therapeutic strategy design to reduce treatment-related complications and improve clinical outcomes of childhood acute lymphoblastic leukemia.
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Affiliation(s)
- Chi-Bo Chen
- Department of Pediatrics, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan
| | - Hsiu-Hao Chang
- Department of Pediatrics, National Taiwan University Hospital and National Taiwa University, College of Medicine, Taipei, Taiwan.
| | - Shu-Wei Chou
- Department of Pediatrics, National Taiwan University Hospital and National Taiwa University, College of Medicine, Taipei, Taiwan
| | - Yung-Li Yang
- Department of Pediatrics, National Taiwan University Hospital and National Taiwa University, College of Medicine, Taipei, Taiwan
| | - Meng-Yao Lu
- Department of Pediatrics, National Taiwan University Hospital and National Taiwa University, College of Medicine, Taipei, Taiwan
| | - Shiann-Tarng Jou
- Department of Pediatrics, National Taiwan University Hospital and National Taiwa University, College of Medicine, Taipei, Taiwan
| | - Huey-Ling Chen
- Department of Pediatrics, National Taiwan University Hospital and National Taiwa University, College of Medicine, Taipei, Taiwan
| | - Yen-Hsuan Ni
- Department of Pediatrics, National Taiwan University Hospital and National Taiwa University, College of Medicine, Taipei, Taiwan
| | - Dong-Tsamn Lin
- Department of Pediatrics, National Taiwan University Hospital and National Taiwa University, College of Medicine, Taipei, Taiwan
| | - Mei-Hwei Chang
- Department of Pediatrics, National Taiwan University Hospital and National Taiwa University, College of Medicine, Taipei, Taiwan
| | - Jia-Feng Wu
- Department of Pediatrics, National Taiwan University Hospital and National Taiwa University, College of Medicine, Taipei, Taiwan.
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Kuo SH, Chen JS, Cheng CN, Lo HY, Chen WC, Lai FP, Yang YJ. The Characteristics and Risk Factors of Asparaginase-Associated Pancreatitis in Pediatric Acute Lymphoblastic Leukemia. Pancreas 2022; 51:366-371. [PMID: 35695827 DOI: 10.1097/mpa.0000000000002036] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVE This study aimed to elucidate the characteristics and the risk factors for asparaginase-associated pancreatitis (AAP) in pediatric acute lymphoblastic leukemia (ALL) under the Taiwan Pediatric Oncology Group (TPOG)-ALL regimen. METHODS The study was conducted by reviewing the chart records of 191 patients aged 1 to 18 years treated with TPOG-ALL (2002 and 2013) protocols at the National Cheng Kung University Hospital, Tainan, Taiwan, from 2002 to 2019. The disease incidence, clinical presentations, laboratory data, complications, and outcomes of AAP were investigated. RESULTS The incidence of AAP was 4.7%. The incidence was significantly higher in children treated with the TPOG-ALL-2013 (n = 62) than TPOG-ALL-2002 (n = 129) protocol (11.3% vs 1.6%, P = 0.006). Multivariate analysis identified using TPOG-ALL-2013 protocol was an independent risk factor for AAP. Pancreatic necrosis or pseudocysts developed in 7 patients (78%). Notably, 1 AAP case (11%) developed diabetes mellitus and 4 (44%) had chronic pancreatitis during a 1-year observational period. None were mortality. CONCLUSIONS The incidence of AAP was 4.7% in ALL patients treated with TPOG-ALL protocol. Although a higher cumulative dose of asparaginase in TPOG-ALL-2013 may attribute to the pancreatic toxicity, unidentified factors such as genetic predisposition or other drugs still need further study.
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Affiliation(s)
- Shu-Han Kuo
- From the Departments of Pediatrics, National Cheng Kung University Hospital
| | - Jiann-Shiuh Chen
- From the Departments of Pediatrics, National Cheng Kung University Hospital
| | - Chao-Neng Cheng
- From the Departments of Pediatrics, National Cheng Kung University Hospital
| | | | - Wei-Che Chen
- From the Departments of Pediatrics, National Cheng Kung University Hospital
| | - Fu-Ping Lai
- From the Departments of Pediatrics, National Cheng Kung University Hospital
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Liu CX, Zhang YY, Yang QS, Shen SH, Chen J, Tang YJ, Chen CC, Wang Z, Li BR, Qian J, Wang Y, Hu WT, Ning BT. Asparaginase-associated pancreatitis in chemotherapy-treated pediatric patients: a five-year retrospective study. World J Emerg Med 2022; 13:313-321. [PMID: 35837564 PMCID: PMC9233968 DOI: 10.5847/wjem.j.1920-8642.2022.062] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 02/20/2022] [Indexed: 07/04/2024] Open
Affiliation(s)
- Chen-xi Liu
- Department of Pediatric Hematology and Oncology, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Yun-yu Zhang
- Department of Pediatric Intensive Care Unit, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Qiu-shi Yang
- Department of Pediatric Intensive Care Unit, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Shu-hong Shen
- Department of Pediatric Hematology and Oncology, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Jing Chen
- Department of Pediatric Hematology and Oncology, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Yan-jing Tang
- Department of Pediatric Hematology and Oncology, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Chang-cheng Chen
- Department of Pediatric Hematology and Oncology, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Zhuo Wang
- Department of Pediatric Hematology and Oncology, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Bi-ru Li
- Department of Pediatric Intensive Care Unit, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Juan Qian
- Department of Pediatric Intensive Care Unit, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Ying Wang
- Department of Pediatric Intensive Care Unit, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Wen-ting Hu
- Department of Pediatric Hematology and Oncology, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Bo-tao Ning
- Department of Pediatric Intensive Care Unit, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
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Bartram T, Schütte P, Möricke A, Houlston RS, Ellinghaus E, Zimmermann M, Bergmann A, Löscher BS, Klein N, Hinze L, Junk SV, Forster M, Bartram CR, Köhler R, Franke A, Schrappe M, Kratz CP, Cario G, Stanulla M. Genetic Variation in ABCC4 and CFTR and Acute Pancreatitis during Treatment of Pediatric Acute Lymphoblastic Leukemia. J Clin Med 2021; 10:jcm10214815. [PMID: 34768335 PMCID: PMC8584334 DOI: 10.3390/jcm10214815] [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: 07/23/2021] [Revised: 10/17/2021] [Accepted: 10/18/2021] [Indexed: 12/12/2022] Open
Abstract
Background: Acute pancreatitis (AP) is a serious, mechanistically not entirely resolved side effect of L-asparaginase-containing treatment for acute lymphoblastic leukemia (ALL). To find new candidate variations for AP, we conducted a genome-wide association study (GWAS). Methods: In all, 1,004,623 single-nucleotide variants (SNVs) were analyzed in 51 pediatric ALL patients with AP (cases) and 1388 patients without AP (controls). Replication used independent patients. Results: The top-ranked SNV (rs4148513) was located within the ABCC4 gene (odds ratio (OR) 84.1; p = 1.04 × 10−14). Independent replication of our 20 top SNVs was not supportive of initial results, partly because rare variants were neither present in cases nor present in controls. However, results of combined analysis (GWAS and replication cohorts) remained significant (e.g., rs4148513; OR = 47.2; p = 7.31 × 10−9). Subsequently, we sequenced the entire ABCC4 gene and its close relative, the cystic fibrosis associated CFTR gene, a strong AP candidate gene, in 48 cases and 47 controls. Six AP-associated variants in ABCC4 and one variant in CFTR were detected. Replication confirmed the six ABCC4 variants but not the CFTR variant. Conclusions: Genetic variation within the ABCC4 gene was associated with AP during the treatment of ALL. No association of AP with CFTR was observed. Larger international studies are necessary to more conclusively assess the risk of rare clinical phenotypes.
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Affiliation(s)
- Thies Bartram
- Department of Pediatrics, University Hospital Schleswig-Holstein, 24105 Kiel, Germany; (T.B.); (A.M.); (M.S.); (G.C.)
- Department of Pediatric Hematology and Oncology, Hannover Medical School, 30625 Hannover, Germany; (P.S.); (M.Z.); (N.K.); (L.H.); (S.V.J.); (C.P.K.)
| | - Peter Schütte
- Department of Pediatric Hematology and Oncology, Hannover Medical School, 30625 Hannover, Germany; (P.S.); (M.Z.); (N.K.); (L.H.); (S.V.J.); (C.P.K.)
| | - Anja Möricke
- Department of Pediatrics, University Hospital Schleswig-Holstein, 24105 Kiel, Germany; (T.B.); (A.M.); (M.S.); (G.C.)
| | - Richard S. Houlston
- Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton SM2 5NG, UK;
| | - Eva Ellinghaus
- Institute of Clinical Molecular Biology, Kiel University, 24118 Kiel, Germany; (E.E.); (B.-S.L.); (M.F.); (A.F.)
| | - Martin Zimmermann
- Department of Pediatric Hematology and Oncology, Hannover Medical School, 30625 Hannover, Germany; (P.S.); (M.Z.); (N.K.); (L.H.); (S.V.J.); (C.P.K.)
| | - Anke Bergmann
- Department of Human Genetics, Hannover Medical School, 30625 Hannover, Germany;
| | - Britt-Sabina Löscher
- Institute of Clinical Molecular Biology, Kiel University, 24118 Kiel, Germany; (E.E.); (B.-S.L.); (M.F.); (A.F.)
| | - Norman Klein
- Department of Pediatric Hematology and Oncology, Hannover Medical School, 30625 Hannover, Germany; (P.S.); (M.Z.); (N.K.); (L.H.); (S.V.J.); (C.P.K.)
| | - Laura Hinze
- Department of Pediatric Hematology and Oncology, Hannover Medical School, 30625 Hannover, Germany; (P.S.); (M.Z.); (N.K.); (L.H.); (S.V.J.); (C.P.K.)
| | - Stefanie V. Junk
- Department of Pediatric Hematology and Oncology, Hannover Medical School, 30625 Hannover, Germany; (P.S.); (M.Z.); (N.K.); (L.H.); (S.V.J.); (C.P.K.)
| | - Michael Forster
- Institute of Clinical Molecular Biology, Kiel University, 24118 Kiel, Germany; (E.E.); (B.-S.L.); (M.F.); (A.F.)
| | - Claus R. Bartram
- Department of Human Genetics, University Hospital Heidelberg, 69120 Heidelberg, Germany; (C.R.B.); (R.K.)
| | - Rolf Köhler
- Department of Human Genetics, University Hospital Heidelberg, 69120 Heidelberg, Germany; (C.R.B.); (R.K.)
| | - Andre Franke
- Institute of Clinical Molecular Biology, Kiel University, 24118 Kiel, Germany; (E.E.); (B.-S.L.); (M.F.); (A.F.)
| | - Martin Schrappe
- Department of Pediatrics, University Hospital Schleswig-Holstein, 24105 Kiel, Germany; (T.B.); (A.M.); (M.S.); (G.C.)
| | - Christian P. Kratz
- Department of Pediatric Hematology and Oncology, Hannover Medical School, 30625 Hannover, Germany; (P.S.); (M.Z.); (N.K.); (L.H.); (S.V.J.); (C.P.K.)
| | - Gunnar Cario
- Department of Pediatrics, University Hospital Schleswig-Holstein, 24105 Kiel, Germany; (T.B.); (A.M.); (M.S.); (G.C.)
| | - Martin Stanulla
- Department of Pediatric Hematology and Oncology, Hannover Medical School, 30625 Hannover, Germany; (P.S.); (M.Z.); (N.K.); (L.H.); (S.V.J.); (C.P.K.)
- Correspondence: ; Tel.: +49-511-532-7978
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Asparaginase-Associated Pancreatitis in Pediatric Patients with Acute Lymphoblastic Leukemia: Current Perspectives. Paediatr Drugs 2021; 23:457-463. [PMID: 34351604 DOI: 10.1007/s40272-021-00463-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/25/2021] [Indexed: 10/20/2022]
Abstract
Asparaginase therapy is a vital agent in the treatment of acute lymphoblastic leukemia (ALL), with increasing evidence of its high importance in high-risk ALL populations. However, despite the clear clinical and biological benefits of asparaginase therapy, many patients experience toxicities. A well-known treatment-limiting toxicity is asparaginase-associated pancreatitis (AAP). If severe, it necessitates discontinuation of asparaginase therapy, which can lead to a higher risk of relapse in patients with ALL. New protocols for ALL therapy have increased overall total doses of asparaginase therapy in select high-risk populations and have incorporated longer half-life formulations of pegylated asparaginase. Treatment drug monitoring has also allowed assurance of adequate levels of asparagine depletion throughout treatment. It is currently unknown if these changes will increase rates of AAP. Interestingly, important pharmacogenomics data, such as single nucleotide polymorphisms, can identify patients at the highest risk for severe AAP. The incidence of AAP in recent trials, current pharmacogenomic data that could further our understanding of the disease, and the importance of cautiously re-exposing patients to further asparaginase treatment after an initial episode of AAP are discussed.
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Bender C, Maese L, Carter-Febres M, Verma A. Clinical Utility of Pegaspargase in Children, Adolescents and Young Adult Patients with Acute Lymphoblastic Leukemia: A Review. Blood Lymphat Cancer 2021; 11:25-40. [PMID: 33907490 PMCID: PMC8064615 DOI: 10.2147/blctt.s245210] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Accepted: 03/12/2021] [Indexed: 01/19/2023]
Abstract
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.
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Affiliation(s)
- Cynthia Bender
- Department of Pharmacy, Primary Children’s Hospital, Salt Lake City, UT, USA
| | - Luke Maese
- Division of Hematology/Oncology, Department of Pediatrics, University of Utah and Primary Children’s Hospital, Salt Lake City, UT, USA
| | - Maria Carter-Febres
- Division of Hematology/Oncology, Department of Pediatrics, University of Utah and Primary Children’s Hospital, Salt Lake City, UT, USA
| | - Anupam Verma
- Division of Hematology/Oncology, Department of Pediatrics, University of Utah and Primary Children’s Hospital, Salt Lake City, UT, USA
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Zhang YY, Yang QS, Qing X, Li BR, Qian J, Wang Y, Ning BT. Peg-Asparaginase-Associated Pancreatitis in Chemotherapy-Treated Pediatric Patients: A 5-Year Retrospective Study. Front Oncol 2020; 10:538779. [PMID: 33194600 PMCID: PMC7656008 DOI: 10.3389/fonc.2020.538779] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 08/31/2020] [Indexed: 01/19/2023] Open
Abstract
Background Asparaginase-associated pancreatitis (AAP) is one of the most common complications occurring in patients with asparaginase-treated acute lymphoblastic leukemia (ALL). Peg-asparaginase (peg-asp), a chemically recombined asparaginase with lower hyposensitivity and better patient tolerance, is now approved as the first line asparaginase formulation in ALL chemotherapy regimens. Due to the differences in pharmacokinetic characteristics and administration procedure between l-asp and peg-asp, this study aimed to investigate the clinical manifestations of peg-asp-associated pancreatitis. Method Patients with peg-asp-associated pancreatitis diagnosed within a 5-year period (July 2014 to July 2019) were identified and retrospectively studied. The clinical manifestations, laboratory findings, and imaging results of patients with AAP were analyzed. AAP patients were further classified into mild/moderate and severe groups based on criteria used in previous studies. Clinical outcomes were compared between groups. Results A total of 38 patients were enrolled in this study. The underlying disease included ALL (n=35) and lymphoma (n=3). The majority of patients developed AAP during the first phase, called remission induction (n=26, 68.4%), after a median of 2 peg-asp doses (range: 1–11). The DVLP regimen (n=23) is the most common peg-asp regimen used in AAP patients. Abdominal pain occurred after a median of 14.5 days (range: 1–50) from the last peg-asp administration, accompanied by abdominal distension (n=14), nausea (n=17), vomiting (n=21), and fever (n=19). Serum amylase elevation was reported in all AAP patients, of whom 65.8% (n=25) exhibited an elevation in the level of this enzyme three times the upper normal level, fulfilling the Atlanta criteria. The level of serum lipase (median days of elevation=23 days, range: 4–75) was significantly elevated compared with that of serum amylase (median days of elevation=9 days, range: 2–71) and persisted at a markedly high level after the level of serum amylase returned to normal. Common local complications included abdominal ascites (n=10) and peripancreatic fluid collection (n=8). Approximately 42.1% (n=16) of patients with severe AAP experienced systemic complications (septic shock or hypovolemic shock) or severe local complications (pseudocyst), among whom 5 failed to recover. Approximately 84.8% (n=28/33) of the remaining patients resumed chemotherapy; among them, peg-asp formulation in 30.3% (n=10/33) of these patients was adjusted, while asparaginase treatment in 39.4% (n=13/33) was permanently discontinued. Five patients experienced an AAP relapse in later stages of asparaginase treatment. Comparison between mild/moderate and severe AAP patients showed a statistically significant difference in the number of pediatric intensive care unit stays (p=0.047), survival rate (p=0.009), AAP prognosis (p=0.047), and impacts on chemotherapy (p=0.024), revealing a better clinical outcome in mild/moderate AAP patients. Conclusion Early recognition and management of AAP is essential in reversing the severity of AAP. The existing AAP criteria had a low strength in determining the severity of pediatric AAP. A well-defined AAP definition could help distinguish patients with high anticipated risk for redeveloping AAP and ALL relapse, in order to prevent unnecessary withdrawal of asparaginase. Our study could serve as a basis for conducting future large cohort studies and for establishing an accurate definition of pediatric AAP.
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Affiliation(s)
- Yun-Yu Zhang
- Department of Pediatric Intensive Care Unit, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qiu-Shi Yang
- Department of Pediatric Intensive Care Unit, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xia Qing
- Department of Pediatric Hematology and Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Bi-Ru Li
- Department of Pediatric Intensive Care Unit, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Juan Qian
- Department of Pediatric Intensive Care Unit, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ying Wang
- Department of Pediatric Intensive Care Unit, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Bo-Tao Ning
- Department of Pediatric Intensive Care Unit, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Gupta S, Wang C, Raetz EA, Schore R, Salzer WL, Larsen EC, Maloney KW, Mattano LA, Carroll WL, Winick NJ, Hunger SP, Loh ML, Devidas M. Impact of Asparaginase Discontinuation on Outcome in Childhood Acute Lymphoblastic Leukemia: A Report From the Children's Oncology Group. J Clin Oncol 2020; 38:1897-1905. [PMID: 32275469 DOI: 10.1200/jco.19.03024] [Citation(s) in RCA: 133] [Impact Index Per Article: 26.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
PURPOSE Asparaginase (ASNase) is an important component of acute lymphoblastic leukemia (ALL) treatment, but is often discontinued because of toxicity. Erwinia chrysanthemi ASNase (Erwinia) substitution was approved in 2011 for allergic reactions. Erwinia has, however, been intermittently unavailable because of drug supply issues. The impact of Erwinia substitution or complete ASNase discontinuation is unknown. METHODS Patients aged 1-30.99 years in frontline Children's Oncology Group trials for B-cell acute lymphoblastic leukemia between 2004 and 2011 (National Cancer Institute [NCI] standard risk [SR]: AALL0331; NCI high risk: AALL0232) were included. The number of prescribed pegaspargase (PEG-ASNase) doses varied by trial and strata. Maintenance therapy did not contain ASNase. Landmark analyses at maintenance compared disease-free survival (DFS) among those receiving all prescribed PEG-ASNase doses versus switching to Erwinia but receiving all doses versus not receiving all ASNase doses. RESULTS We included 5,195 AALL0331 and 3,001 AALL0232 patients. The cumulative incidence of PEG-ASNase discontinuation was 12.2% ± 4.6% in AALL0331 and 25.4% ± 0.8% in AALL0232. In multivariable analyses, NCI high-risk patients not receiving all prescribed ASNase doses had inferior DFS (hazard ratio [HR], 1.5; 95% CI, 1.2 to 1.9; P = .002) compared with those receiving all prescribed PEG-ASNase doses. Patients with Erwinia substitution who completed subsequent courses were not at increased risk (HR, 1.1; 95% CI, 0.7 to 1.6; P = .69). NCI SR patients who discontinued ASNase were not at elevated risk (HR, 1.2; 95% CI, 0.9 to 1.6; P = .23), except when restricted to those with slow early response, who were prescribed more ASNase because of therapy intensification (HR, 1.7; 95% CI, 1.1 to 2.7; P = .03). CONCLUSION Discontinuation of ASNase doses is associated with inferior DFS in higher-risk patients. Our results illustrate the severe consequences of Erwinia shortages.
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Affiliation(s)
- Sumit Gupta
- Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Cindy Wang
- Department of Biostatistics, University of Florida, Gainesville, FL
| | | | | | - Wanda L Salzer
- US Army Medical Research and Materiel Command, Fort Detrick, MD
| | - Eric C Larsen
- Department of Pediatrics, Maine Children's Cancer Program, Scarborough, ME
| | | | | | - William L Carroll
- Department of Pediatrics and Perlmutter Cancer Center, New York University Langone Health, New York, NY
| | - Naomi J Winick
- University of Texas Southwestern/Simmons Cancer Center, Dallas, TX
| | - Stephen P Hunger
- Department of Pediatrics and the Center for Childhood Cancer Research, Children's Hospital of Philadelphia, and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Mignon L Loh
- Department of Pediatrics, UCSF Benoiff Childen's Hospital and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA
| | - Meenakshi Devidas
- Department of Global Pediatric Medicine, St Jude Children's Research Hospital, Memphis, TN
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18
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Rank CU, Wolthers BO, Grell K, Albertsen BK, Frandsen TL, Overgaard UM, Toft N, Nielsen OJ, Wehner PS, Harila-Saari A, Heyman MM, Malmros J, Abrahamsson J, Norén-Nyström U, Tomaszewska-Toporska B, Lund B, Jarvis KB, Quist-Paulsen P, Vaitkevičienė GE, Griškevičius L, Taskinen M, Wartiovaara-Kautto U, Lepik K, Punab M, Jónsson ÓG, Schmiegelow K. Asparaginase-Associated Pancreatitis in Acute Lymphoblastic Leukemia: Results From the NOPHO ALL2008 Treatment of Patients 1-45 Years of Age. J Clin Oncol 2019; 38:145-154. [PMID: 31770057 PMCID: PMC6953441 DOI: 10.1200/jco.19.02208] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
PURPOSE Asparaginase-associated pancreatitis (AAP) is common in patients with acute lymphoblastic leukemia (ALL), but risk differences across age groups both in relation to first-time AAP and after asparaginase re-exposure have not been explored. PATIENTS AND METHODS We prospectively registered AAP (n = 168) during treatment of 2,448 consecutive ALL patients aged 1.0-45.9 years diagnosed from July 2008 to October 2018 and treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol. RESULTS Compared with patients aged 1.0-9.9 years, adjusted AAP hazard ratios (HRa) were associated with higher age with almost identical HRa (1.6; 95% CI, 1.1 to 2.3; P = .02) for adolescents (10.0-17.9 years) and adults (18.0-45.9 years). The day 280 cumulative incidences of AAP were 7.0% for children (1.0-9.9 years: 95% CI, 5.4 to 8.6), 10.1% for adolescents (10.0 to 17.9 years: 95% CI, 7.0 to 13.3), and 11.0% for adults (18.0-45.9 years: 95% CI, 7.1 to 14.9; P = .03). Adolescents had increased odds of both acute (odds ratio [OR], 5.2; 95% CI, 2.1 to 13.2; P = .0005) and persisting complications (OR, 6.7; 95% CI, 2.4 to 18.4; P = .0002) compared with children (1.0-9.9 years), whereas adults had increased odds of only persisting complications (OR, 4.1; 95% CI, 1.4 to 11.8; P = .01). Fifteen of 34 asparaginase-rechallenged patients developed a second AAP. Asparaginase was truncated in 17/21 patients with AAP who subsequently developed leukemic relapse, but neither AAP nor the asparaginase truncation was associated with increased risk of relapse. CONCLUSION Older children and adults had similar AAP risk, whereas morbidity was most pronounced among adolescents. Asparaginase re-exposure should be considered only for patients with an anticipated high risk of leukemic relapse, because multiple studies strongly indicate that reduction of asparaginase treatment intensity increases the risk of relapse.
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Affiliation(s)
- Cecilie U Rank
- Rigshospitalet, Copenhagen, Denmark.,University of Copenhagen, Copenhagen, Denmark
| | | | - Kathrine Grell
- Rigshospitalet, Copenhagen, Denmark.,University of Copenhagen, Copenhagen, Denmark
| | | | | | | | - Nina Toft
- Herlev University Hospital, Herlev, Denmark
| | | | | | | | | | | | | | | | | | - Bendik Lund
- Trondheim University Hospital, Trondheim, Norway
| | - Kirsten B Jarvis
- Oslo University Hospital, Oslo, Norway.,University of Oslo, Oslo, Norway
| | | | - Goda E Vaitkevičienė
- Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania.,Vilnius University, Vilnius, Lithuania
| | - Laimonas Griškevičius
- Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania.,Vilnius University, Vilnius, Lithuania
| | | | | | | | - Mari Punab
- Tartu University Hospital, Tartu, Estonia
| | | | - Kjeld Schmiegelow
- Rigshospitalet, Copenhagen, Denmark.,University of Copenhagen, Copenhagen, Denmark
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19
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Peng S, Gerasimenko JV, Tsugorka TM, Gryshchenko O, Samarasinghe S, Petersen OH, Gerasimenko OV. Galactose protects against cell damage in mouse models of acute pancreatitis. J Clin Invest 2018; 128:3769-3778. [PMID: 29893744 PMCID: PMC6118583 DOI: 10.1172/jci94714] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Accepted: 06/06/2018] [Indexed: 12/21/2022] Open
Abstract
Acute pancreatitis (AP), a human disease in which the pancreas digests itself, has substantial mortality with no specific therapy. The major causes of AP are alcohol abuse and gallstone complications, but it also occurs as an important side effect of the standard asparaginase-based therapy for childhood acute lymphoblastic leukemia. Previous investigations into the mechanisms underlying pancreatic acinar cell death induced by alcohol metabolites, bile acids, or asparaginase indicated that loss of intracellular ATP generation is an important factor. We now report that, in isolated mouse pancreatic acinar cells or cell clusters, removal of extracellular glucose had little effect on this ATP loss, suggesting that glucose metabolism was severely inhibited under these conditions. Surprisingly, we show that replacing glucose with galactose prevented or markedly reduced the loss of ATP and any subsequent necrosis. Addition of pyruvate had a similar protective effect. We also studied the effect of galactose in vivo in mouse models of AP induced either by a combination of fatty acids and ethanol or asparaginase. In both cases, galactose markedly reduced acinar necrosis and inflammation. Based on these data, we suggest that galactose feeding may be used to protect against AP.
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Affiliation(s)
- Shuang Peng
- Cardiff School of Biosciences, Cardiff University, Cardiff, United Kingdom.,Department of Physiology, School of Medicine, Jinan University, Guangzhou, China
| | | | - Tetyana M Tsugorka
- Cardiff School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | - Oleksiy Gryshchenko
- Cardiff School of Biosciences, Cardiff University, Cardiff, United Kingdom.,Bogomoletz Institute of Physiology, Kiev, Ukraine
| | - Sujith Samarasinghe
- Great Ormond Street Hospital for Children, NHS Foundation Trust, London, United Kingdom
| | - Ole H Petersen
- Cardiff School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | - Oleg V Gerasimenko
- Cardiff School of Biosciences, Cardiff University, Cardiff, United Kingdom
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20
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Thu Huynh V, Bergeron S. Asparaginase Toxicities: Identification and Management in Patients With Acute Lymphoblastic Leukemia
. Clin J Oncol Nurs 2018; 21:E248-E259. [PMID: 28945721 DOI: 10.1188/17.cjon.e248-e259] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
BACKGROUND Acute lymphoblastic leukemia (ALL) is a common cancer in children, and outcomes have greatly improved because of the refinement of multiagent chemotherapy regimens that include intensified asparaginase therapy. Asparaginase, a cornerstone of modern pediatric chemotherapy regimens for ALL and asparaginase-containing protocols, is increasingly used in adolescent and adult patients historically treated with asparaginase-free regimens.
. OBJECTIVES This article is an overview of commonly encountered asparaginase-
associated toxicities and offers recommendations for treatment management.
. METHODS A literature review was conducted, reviewing asparaginase and common toxicities, specifically hypersensitivity, pancreatitis, thrombosis, hyperbilirubinemia, and hyperglycemia.
. FINDINGS The rapid identification and management of common asparaginase-associated adverse events can reduce symptom severity and limit potential interruptions to therapy, possibly improving outcomes.
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21
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Denton CC, Rawlins YA, Oberley MJ, Bhojwani D, Orgel E. Predictors of hepatotoxicity and pancreatitis in children and adolescents with acute lymphoblastic leukemia treated according to contemporary regimens. Pediatr Blood Cancer 2018; 65:10.1002/pbc.26891. [PMID: 29218844 PMCID: PMC7522002 DOI: 10.1002/pbc.26891] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Revised: 10/12/2017] [Accepted: 10/14/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND Hepatotoxicity and pancreatitis are common treatment-related toxicities (TRTs) during contemporary treatment regimens for acute lymphoblastic leukemia (ALL). Limited detailed data from Children's Oncology Group (COG) regimens has been previously reported to enable identification of patient and treatment risk factors for these toxicities and their impact on outcomes. PROCEDURE We analyzed a retrospective pediatric ALL cohort treated at a single institution according to COG regimens from 2008 to 2015. The primary endpoint was cumulative incidence of study-defined "severe" hepatotoxicity (Common Terminology Criteria for Adverse Events [CTCAE] Grade ≥ 4 transaminitis or Grade ≥ 3 hyperbilirubinemia) and clinically significant pancreatitis (any grade). Pancreatitis was additionally classified using the Ponte di Legno (PdL) toxicity criteria. Secondary endpoints were chemotherapy interruptions, early disease response (end of induction [EOI] minimal residual disease [MRD]), and event-free survival (EFS). RESULTS We identified 262 patients, of whom 71 (27%) and 28 (11%) developed hepatotoxicity and pancreatitis, respectively. Three cases of pancreatitis did not fulfill PdL criteria despite otherwise consistent presentations. Both TRTs occurred throughout therapy, but approximately 25% of hepatotoxicity (18/71) and pancreatitis (8/28) occurred during induction alone. Both obesity and age (≥10 years) were identified as predictors of hepatotoxicity (subdistribution hazard ratio [SHR] obesity = 1.75, 95% confidence interval [95% CI] 1.04-2.96; SHR age ≥10 = 1.9, 95% CI 1.19-3.10) and pancreatitis (SHR obesity = 2.18, 95% CI 1.01-4.67; SHR age ≥ 10 = 2.76, 95% CI 1.19-6.39, P = 0.018). Dose interruptions were common but neither toxicity influenced EOI MRD nor EFS. CONCLUSIONS Obese and/or older children are particularly at risk for hepatotoxicity and pancreatitis, and may benefit from toxicity surveillance and chemoprotective strategies to prevent or mitigate associated morbidity.
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Affiliation(s)
- Christopher C. Denton
- Division of Hematology, Oncology, & BMT, Children’s Hospital Los Angeles, Los Angeles, California
| | - Yasmin A. Rawlins
- College of Physicians and Surgeons, Columbia University, New York, New York
| | - Matthew J. Oberley
- Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles, Los Angeles, California,Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Deepa Bhojwani
- Division of Hematology, Oncology, & BMT, Children’s Hospital Los Angeles, Los Angeles, California,Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Etan Orgel
- Division of Hematology, Oncology, & BMT, Children’s Hospital Los Angeles, Los Angeles, California,Keck School of Medicine, University of Southern California, Los Angeles, California
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22
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Oparaji JA, Rose F, Okafor D, Howard A, Turner RL, Orabi AI, Byersdorfer C, Mi Q, Ritchey K, Lowe ME, Husain SZ. Risk Factors for Asparaginase-associated Pancreatitis: A Systematic Review. J Clin Gastroenterol 2018; 51:907-913. [PMID: 28375864 PMCID: PMC11488675 DOI: 10.1097/mcg.0000000000000827] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
GOALS To evaluate potential risk factors for the development of asparaginase-associated pancreatitis (AAP), we performed a systematic review of the current literature from January 1946 through May 2015. BACKGROUND Asparaginase, a primary treatment for the most common childhood cancer, acute lymphoblastic leukemia (ALL), is a well-described cause of pancreatitis. Further, pancreatitis is among the most burdensome and common complications of asparaginase treatment and represents a major reason for early-drug termination and inferior outcomes. The literature lacks clarity about the risk factors for AAP, and this knowledge gap has hampered the ability to reliably predict which patients are likely to develop AAP. STUDY In an expansive screen, 1842 citations were funneled into a review of 59 full articles, of which 10 were deemed eligible based on predetermined inclusion criteria. RESULTS Of the 10 identified studies, only 2 studies showed that children above 10 years of age had a >2-fold risk of AAP compared with younger children. Patients placed in high-risk ALL categories had a greater incidence of pancreatitis in 2 studies. In addition, use of pegylated asparaginase resulted in a higher incidence of AAP in 1 study. CONCLUSIONS In this systematic review, older age, asparaginase formulation, higher ALL risk stratification, and higher asparaginase dosing appear to play a limited role in the development of AAP. Further studies are needed to probe the underlying mechanisms contributing to the development of pancreatitis in patients receiving asparaginase.
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Affiliation(s)
- Judy-April Oparaji
- Department of Pediatrics, Walter Reed National Military Medical Center, Bethesda, MD
| | - Fateema Rose
- Departments of Pediatrics, University of Pittsburgh, Pittsburgh, PA
| | - Debra Okafor
- Departments of Pediatrics, University of Pittsburgh, Pittsburgh, PA
| | - Amari Howard
- Departments of Pediatrics, University of Pittsburgh, Pittsburgh, PA
| | - Rose L Turner
- Health Sciences Library System, University of Pittsburgh, Pittsburgh, PA
| | - Abrahim I. Orabi
- Departments of Pediatrics, University of Pittsburgh, Pittsburgh, PA
| | | | - Qi Mi
- Sports Medicine and Nutrition, University of Pittsburgh, Pittsburgh, PA
| | - Kim Ritchey
- Departments of Pediatrics, University of Pittsburgh, Pittsburgh, PA
| | - Mark E. Lowe
- Departments of Pediatrics, University of Pittsburgh, Pittsburgh, PA
| | - Sohail Z. Husain
- Departments of Pediatrics, University of Pittsburgh, Pittsburgh, PA
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23
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Steroid-induced Hypertension During Induction Chemotherapy for Acute Lymphoblastic Leukemia in US Children's Hospitals. J Pediatr Hematol Oncol 2018; 40:27-30. [PMID: 29189508 DOI: 10.1097/mph.0000000000000997] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Childhood acute lymphoblastic leukemia achieves excellent cure rates in part due to induction chemotherapy including high dose corticosteroids. Hypertension (HTN) is a known complication of corticosteroids, but incidence and risk factors for steroid-induced HTN are poorly understood. We sought to describe these using a large pediatric health database. Of the 5578 unique patients receiving induction chemotherapy, 14.7% received anti-HTN medications during their initial hospital admission. We found that age below 1 year, obesity, secondary diabetes mellitus, and abnormal glucose were associated with developing steroid-induced HTN. We also found that ICD-9 codes had poor sensitivity for detecting treatment of HTN, suggesting underreporting by physicians.
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24
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Hough R, Vora A. Crisis management in the treatment of childhood acute lymphoblastic leukemia: putting right what can go wrong (emergency complications of disease and treatment). HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2017; 2017:251-258. [PMID: 29222263 PMCID: PMC6142611 DOI: 10.1182/asheducation-2017.1.251] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
The improvement in overall survival in children with acute lymphoblastic leukemia (ALL) over the last 5 decades has been considerable, with around 90% now surviving long term. The risk of relapse has been reduced to such an extent that the risk of treatment-related mortality is now approaching that of mortality caused by relapse. Toxicities may also lead to the suboptimal delivery of chemotherapy (treatment delays, dose reductions, dose omissions), potentially increasing relapse risk, and short- and long-term morbidity, adding to the "burden of therapy" in an increasing number of survivors. Thus, the need to reduce toxicity in pediatric ALL is becoming increasingly important. This work focuses on the risk factors, pathogenesis, clinical features, and emergency management of the life-threatening complications of ALL at presentation and during subsequent chemotherapy, including leucostasis, tumor lysis syndrome, infection, methotrexate encephalopathy, thrombosis, and pancreatitis. Potential strategies to abrogate these toxicities in the future are also discussed.
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Affiliation(s)
- Rachael Hough
- Department of Adolescent Haematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom; and
| | - Ajay Vora
- Department of Haematology, Great Ormond Street Hospital for Children, London, United Kingdom
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25
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Peng S, Gerasimenko JV, Tsugorka T, Gryshchenko O, Samarasinghe S, Petersen OH, Gerasimenko OV. Calcium and adenosine triphosphate control of cellular pathology: asparaginase-induced pancreatitis elicited via protease-activated receptor 2. Philos Trans R Soc Lond B Biol Sci 2017; 371:rstb.2015.0423. [PMID: 27377732 PMCID: PMC4938023 DOI: 10.1098/rstb.2015.0423] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/20/2016] [Indexed: 12/16/2022] Open
Abstract
Exocytotic secretion of digestive enzymes from pancreatic acinar cells is elicited by physiological cytosolic Ca2+ signals, occurring as repetitive short-lasting spikes largely confined to the secretory granule region, that stimulate mitochondrial adenosine triphosphate (ATP) production. By contrast, sustained global cytosolic Ca2+ elevations decrease ATP levels and cause necrosis, leading to the disease acute pancreatitis (AP). Toxic Ca2+ signals can be evoked by products of alcohol and fatty acids as well as bile acids. Here, we have investigated the mechanism by which l-asparaginase evokes AP. Asparaginase is an essential element in the successful treatment of acute lymphoblastic leukaemia, the most common type of cancer affecting children, but AP is a side-effect occurring in about 5–10% of cases. Like other pancreatitis-inducing agents, asparaginase evoked intracellular Ca2+ release followed by Ca2+ entry and also substantially reduced Ca2+ extrusion because of decreased intracellular ATP levels. The toxic Ca2+ signals caused extensive necrosis. The asparaginase-induced pathology depended on protease-activated receptor 2 and its inhibition prevented the toxic Ca2+ signals and necrosis. We tested the effects of inhibiting the Ca2+ release-activated Ca2+ entry by the Ca2+ channel inhibitor GSK-7975A. This markedly reduced asparaginase-induced Ca2+ entry and also protected effectively against the development of necrosis. This article is part of the themed issue ‘Evolution brings Ca2+ and ATP together to control life and death’.
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Affiliation(s)
- Shuang Peng
- Cardiff School of Biosciences, Cardiff University, Cardiff CF10 3AX, Wales, UK Department of Pathophysiology, Medical College, Jinan University, Guangzhou 510632, People's Republic of China
| | - Julia V Gerasimenko
- Cardiff School of Biosciences, Cardiff University, Cardiff CF10 3AX, Wales, UK
| | - Tatiana Tsugorka
- Cardiff School of Biosciences, Cardiff University, Cardiff CF10 3AX, Wales, UK
| | - Oleksiy Gryshchenko
- Cardiff School of Biosciences, Cardiff University, Cardiff CF10 3AX, Wales, UK Bogomoletz Institute of Physiology, Kiev 01024, Ukraine
| | - Sujith Samarasinghe
- Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, London WC1N 3JH, UK
| | - Ole H Petersen
- Cardiff School of Biosciences, Cardiff University, Cardiff CF10 3AX, Wales, UK Systems Immunity Research Institute, Cardiff University, Cardiff CF14 4XN, Wales, UK
| | - Oleg V Gerasimenko
- Cardiff School of Biosciences, Cardiff University, Cardiff CF10 3AX, Wales, UK
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26
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Wolthers BO, Frandsen TL, Baruchel A, Attarbaschi A, Barzilai S, Colombini A, Escherich G, Grell K, Inaba H, Kovacs G, Liang DC, Mateos M, Mondelaers V, Möricke A, Ociepa T, Samarasinghe S, Silverman LB, van der Sluis IM, Stanulla M, Vrooman LM, Yano M, Zapotocka E, Schmiegelow K. Asparaginase-associated pancreatitis in childhood acute lymphoblastic leukaemia: an observational Ponte di Legno Toxicity Working Group study. Lancet Oncol 2017; 18:1238-1248. [PMID: 28736188 DOI: 10.1016/s1470-2045(17)30424-2] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Revised: 05/19/2017] [Accepted: 05/19/2017] [Indexed: 12/14/2022]
Abstract
BACKGROUND Survival for childhood acute lymphoblastic leukaemia surpasses 90% with contemporary therapy; however, patients remain burdened by the severe toxic effects of treatment, including asparaginase-associated pancreatitis. To investigate the risk of complications and risk of re-exposing patients with asparaginase-associated pancreatitis to asparaginase, 18 acute lymphoblastic leukaemia trial groups merged data for this observational study. METHODS Patient files from 26 trials run by 18 trial groups were reviewed on children (aged 1·0-17·9 years) diagnosed with t(9;22)-negative acute lymphoblastic leukaemia between June 1, 1996, and Jan 1, 2016, who within 50 days of asparaginase exposure developed asparaginase-associated pancreatitis. Asparaginase-associated pancreatitis was defined by at least two criteria: abdominal pain, pancreatic enzymes at least three times the upper limit of normal (ULN), and imaging compatible with pancreatitis. Patients without sufficient data for diagnostic criteria were excluded. Primary outcomes were defined as acute and persisting complications of asparaginase-associated pancreatitis and risk of re-exposing patients who suffered an episode of asparaginase-associated pancreatitis to asparaginase. Data were collected from Feb 2, 2015, to June 30, 2016, and analysed and stored in a common database at Rigshospitalet, Copenhagen, Denmark. FINDINGS Of 465 patients with asparaginase-associated pancreatitis, 33 (8%) of 424 with available data needed mechanical ventilation, 109 (26%) of 422 developed pseudocysts, acute insulin therapy was needed in 81 (21%) of 393, and seven (2%) of 458 patients died. Risk of assisted mechanical ventilation, need for insulin, pseudocysts, or death was associated with older age (median age for patients with complications 10·5 years [IQR 6·4-13·8] vs without complications 6·1 years [IQR 3·6-12·2], p<0·0001), and having one or more affected vital signs (fever, hypotension, tachycardia, or tachypnoea; 96 [44%] of 217 patients with affected vital signs vs 11 [24%] of 46 patients without affected vital signs, p=0·02). 1 year after diagnosis of asparaginase-associated pancreatitis, 31 (11%) of 275 patients still needed insulin or had recurrent abdominal pain or both. Both the risk of persisting need for insulin therapy and recurrent abdominal pain were associated with having had pseudocysts (odds ratio [OR] 9·48 [95% CI 3·01-35·49], p=0·0002 for insulin therapy; OR 11·79 [4·30-37·98], p<0·0001 for recurrent abdominal pain). Within 8 years of asparaginase-associated pancreatitis, risk of abdominal symptoms dropped from 8% (26 of 312) to 0% (0 of 35) but the need for insulin therapy remained constant (9%, three of 35). 96 patients were re-exposed to asparaginase, including 59 after a severe asparaginase-associated pancreatitis (abdominal pain or pancreatic enzymes at least three times the ULN or both lasting longer than 72 h). 44 (46%) patients developed a second asparaginase-associated pancreatitis, 22 (52%) of 43 being severe. Risk of persisting need for insulin or abdominal pain after having had two versus one asparaginase-associated pancreatitis did not differ (three [7%] of 42 vs 28 [12%] of 233, p=0·51). Risk of a second asparaginase-associated pancreatitis was not associated with any baseline patient characteristics. INTERPRETATION Since the risk of a second asparaginase-associated pancreatitis was not associated with severity of the first asparaginase-associated pancreatitis and a second asparaginase-associated pancreatitis did not involve an increased risk of complications, asparaginase re-exposure should be determined mainly by the anticipated need for asparaginase for antileukaemic efficacy. A study of the genetic risk factors identifying patients in whom asparaginase exposure should be restricted is needed. FUNDING The Danish Childhood Cancer Foundation and The Danish Cancer Society (R150-A10181).
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Affiliation(s)
- Benjamin O Wolthers
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Thomas L Frandsen
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark
| | - André Baruchel
- Pediatric Hematology-Immunology Department, University Hospital Robert Debré, Paris Diderot University, Paris, France
| | - Andishe Attarbaschi
- Department of Pediatric Hematology and Oncology, St Anna Children's Hospital and Department of Pediatric and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
| | - Shlomit Barzilai
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Antonella Colombini
- Department of Pediatrics, Ospedale San Gerardo, University of Milano-Bicocca, Fondazione MBBM, Monza, Italy
| | - Gabriele Escherich
- University Medical Center Eppendorf, Clinic of Pediatric Hematology and Oncology, Hamburg, Germany
| | - Kathrine Grell
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark; Section of Biostatistics, Department of Public Health, University of Copenhagen, Copenhagen, Denmark
| | - Hiroto Inaba
- Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA
| | - Gábor Kovacs
- Second Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Der-Cherng Liang
- Division of Pediatric Hematology-Oncology, Mackay Memorial Hospital, Taipei, Taiwan
| | - Marion Mateos
- Kids Cancer Centre, Sydney Children's Hospital, Randwick, and School of Women and Children's Health, University of New South Wales, Sydney, NSW, Australia
| | - Veerle Mondelaers
- Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium
| | - Anja Möricke
- Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Department of Pediatrics, Kiel, Germany
| | - Tomasz Ociepa
- Department of Pediatrics, Hematology and Oncology, Pomeranian Medical University, Szczecin, Poland
| | | | - Lewis B Silverman
- Department of Pediatric Oncology, Dana Farber Cancer Institute and Division of Pediatric Hematology-Oncology, Boston Children's Hospital, Boston, MA, USA
| | - Inge M van der Sluis
- Dutch Childhood Oncology Group, The Hague, Erasmus Medical Center, Sophia Children's Hospital, Department of Pediatric Hematology-Oncology, Rotterdam, Netherlands; Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
| | - Martin Stanulla
- Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
| | - Lynda M Vrooman
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Michihiro Yano
- Department of Pediatrics, Akita University Hospital, Akita, Japan
| | - Ester Zapotocka
- University Hospital Motol, Department of Pediatric Hematology/Oncology, Prague, Czech Republic
| | - Kjeld Schmiegelow
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark; Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
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Schmiegelow K, Müller K, Mogensen SS, Mogensen PR, Wolthers BO, Stoltze UK, Tuckuviene R, Frandsen T. Non-infectious chemotherapy-associated acute toxicities during childhood acute lymphoblastic leukemia therapy. F1000Res 2017; 6:444. [PMID: 28413626 PMCID: PMC5389408 DOI: 10.12688/f1000research.10768.1] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/04/2017] [Indexed: 01/19/2023] Open
Abstract
During chemotherapy for childhood acute lymphoblastic leukemia, all organs can be affected by severe acute side effects, the most common being opportunistic infections, mucositis, central or peripheral neuropathy (or both), bone toxicities (including osteonecrosis), thromboembolism, sinusoidal obstruction syndrome, endocrinopathies (especially steroid-induced adrenal insufficiency and hyperglycemia), high-dose methotrexate-induced nephrotoxicity, asparaginase-associated hypersensitivity, pancreatitis, and hyperlipidemia. Few of the non-infectious acute toxicities are associated with clinically useful risk factors, and across study groups there has been wide diversity in toxicity definitions, capture strategies, and reporting, thus hampering meaningful comparisons of toxicity incidences for different leukemia protocols. Since treatment of acute lymphoblastic leukemia now yields 5-year overall survival rates above 90%, there is a need for strategies for assessing the burden of toxicities in the overall evaluation of anti-leukemic therapy programs.
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Affiliation(s)
- Kjeld Schmiegelow
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark
- Institute of Clinical Medicine, Faculty of Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Klaus Müller
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark
- Institute of Clinical Medicine, Faculty of Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Signe Sloth Mogensen
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Pernille Rudebeck Mogensen
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark
- Department of Diabetes and Metabolism, University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Benjamin Ole Wolthers
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Ulrik Kristoffer Stoltze
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Ruta Tuckuviene
- Department of Pediatrics, Aalborg University Hospital, Aalborg, Denmark
| | - Thomas Frandsen
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark
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28
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Raja RA, Schmiegelow K, Sørensen DN, Frandsen TL. Asparaginase-associated pancreatitis is not predicted by hypertriglyceridemia or pancreatic enzyme levels in children with acute lymphoblastic leukemia. Pediatr Blood Cancer 2017; 64:32-38. [PMID: 27555294 DOI: 10.1002/pbc.26183] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Revised: 07/04/2016] [Accepted: 07/07/2016] [Indexed: 01/19/2023]
Abstract
BACKGROUND l-Asparaginase is an important drug for treatment of childhood acute lymphoblastic leukemia (ALL), but is associated with serious toxicities, including pancreatitis and hypertriglyceridemia (HTG). Asparaginase-associated pancreatitis (AAP) is a common reason for stopping asparaginase treatment. The aim of this study was to explore if HTG or early elevations in pancreatic enzymes were associated with the subsequent development of AAP. METHOD Children (1.0-17.9 years) diagnosed with ALL, treated with asparaginase for 30 weeks, according to the NOPHO ALL2008 protocol at the University Hospital Rigshospitalet, Copenhagen, Denmark, were eligible. Pancreatic enzymes, triglycerides, and cholesterol were measured regularly. RESULTS Thirty-one patients were included. Seven patients were diagnosed with AAP. HTG was most evident when PEG-asparaginase and dexamethasone were administered concomitantly. Overall, there was no significant difference in triglyceride levels in patients who experienced AAP and patients who did not. An increase in triglyceride levels during concomitant dexamethasone therapy in delayed intensification was significantly associated with an increase in pancreas-specific amylase levels two weeks later (P = 0.005). CONCLUSIONS AAP does not seem to be associated with HTG. Continuous monitoring of pancreas enzymes does not predict AAP.
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Affiliation(s)
- Raheel Altaf Raja
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Kjeld Schmiegelow
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.,Institute of Clinical Medicine, Faculty of Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Ditte Nørbo Sørensen
- Section of Biostatistics, Department of Public Health, University of Copenhagen, Denmark
| | - Thomas Leth Frandsen
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark
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29
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Raja RA, Schmiegelow K, Henriksen BM, Leth Frandsen T. Serial Ultrasound Monitoring for Early Recognition of Asparaginase Associated Pancreatitis in Children With Acute Lymphoblastic Leukemia. Pediatr Hematol Oncol 2016; 32:474-81. [PMID: 26270775 DOI: 10.3109/08880018.2015.1055868] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND Acute lymphoblastic leukemia (ALL) is the most common cancer in children and L-asparaginase is an essential component of the treatment. Cessation of L-asparaginase decreases event free survival. Acute pancreatitis is the toxicity that most commonly results in cessation of L-asparaginase. We tested whether serial ultrasound examinations could predict asparaginase-associated pancreatitis (AAP). METHODS Children (aged 1.0-17.9 years) with childhood ALL treated at the University Hospital Rigshopitalet, Copenhagen, according to the standard or intermediate risk arms of the NOPHO ALL2008 protocol, with PEG-asparaginase of 2 or 6 week intervals, for 30 weeks had their pancreas monitored using serial ultrasound in order to detect early signs of inflammation. RESULTS Nineteen of 31 eligible patients were included. Three of the included patients developed AAP. None of the patients, including the three patients that developed AAP, had signs of inflammatory edema or pancreas enzymes above three times the upper normal limit prior to AAP. CONCLUSION We found no signs of inflammatory edema within the pancreas on ultrasound during treatment with PEG-asparginase in our cohort prior to development of AAP or in patients that did not develop AAP.
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Affiliation(s)
- Raheel Altaf Raja
- a Department of Pediatrics and Adolescent Medicine , University Hospital Rigshospitalet , Copenhagen, Denmark
| | - Kjeld Schmiegelow
- a Department of Pediatrics and Adolescent Medicine , University Hospital Rigshospitalet , Copenhagen, Denmark.,b Institute of Clinical Medicine, Faculty of Medicine , University of Copenhagen , Copenhagen, Denmark
| | - Birthe Merethe Henriksen
- c Department of Diagnostic Radiology, Ultrasound section , University Hospital Rigshospitalet , Copenhagen, Denmark
| | - Thomas Leth Frandsen
- a Department of Pediatrics and Adolescent Medicine , University Hospital Rigshospitalet , Copenhagen, Denmark
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30
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Majbar AA, Cusick E, Johnson P, Lynn RM, Hunt LP, Shield JPH. Incidence and Clinical Associations of Childhood Acute Pancreatitis. Pediatrics 2016; 138:peds.2016-1198. [PMID: 27535145 DOI: 10.1542/peds.2016-1198] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/21/2016] [Indexed: 11/24/2022] Open
Abstract
OBJECTIVES To establish the UK incidence and clinical associations of acute pancreatitis (AP) in children aged 0 to 14 years. METHODS Monthly surveillance of new cases of AP in children under 15 years of age through the British Pediatric Surveillance Unit conducted from April 2013 to April 2014 (inclusive) followed by 1-year administrative follow-up for all valid cases. RESULTS Ninety-four cases (48 boys) fulfilled the diagnostic criteria. The median age at diagnosis was 11.2 years (range 1.3-14.9). White children accounted for 61% of the cases compared with 28% from Asian and 5% from African ethnicities. Pakistani children accounted for 18 of 26 (69%) Asian patients and 19% of the total cohort. The incidence of AP in children in the United Kingdom was 0.78 per 100 000/year (95% confidence interval [CI] 0.62-0.96). The incidence in Pakistani children (4.55; 95% CI 2.60-7.39) was sevenfold greater than white children (0.63; 95% CI 0.47-0.83). Of the 94 cases, 35 (37%) were idiopathic; other associations were: drug therapy, 18 (19%); gallstones, 12 (13%); hereditary, 7 (7%); organic acidemias, 7 (7%); anatomic anomalies, 5 (5%); viral infections, 3 (3%); systemic diseases, 2 (2%); and trauma 1 (1%). The most common drug associations were asparaginase (28%), azathioprine (17%), and sodium valproate (17%). CONCLUSIONS Although still relatively uncommon in the United Kingdom, on average there is >1 case of childhood AP diagnosed every week. The associations of AP have changed significantly since the 1970-80s. Overrepresentation of Pakistani children is worthy of further investigation.
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Affiliation(s)
- Abdalmonem A Majbar
- National Institute for Health Research, Bristol Biomedical Research Unit in Nutrition and University of Bristol, United Kingdom; Bristol Royal Hospital for Children, Bristol, United Kingdom;
| | - Eleri Cusick
- Bristol Royal Hospital for Children, Bristol, United Kingdom
| | - Paul Johnson
- Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom; and
| | - Richard M Lynn
- British Paediatric Surveillance Unit, Royal College of Paediatrics and Child Health, London, United Kingdom
| | - Linda P Hunt
- Musculoskeletal Research Unit, University of Bristol, United Kingdom
| | - Julian P H Shield
- National Institute for Health Research, Bristol Biomedical Research Unit in Nutrition and University of Bristol, United Kingdom; Bristol Royal Hospital for Children, Bristol, United Kingdom
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31
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Wolthers BO, Frandsen TL, Abrahamsson J, Albertsen BK, Helt LR, Heyman M, Jónsson ÓG, Kõrgvee LT, Lund B, Raja RA, Rasmussen KK, Taskinen M, Tulstrup M, Vaitkevičienė GE, Yadav R, Gupta R, Schmiegelow K. Asparaginase-associated pancreatitis: a study on phenotype and genotype in the NOPHO ALL2008 protocol. Leukemia 2016; 31:325-332. [PMID: 27451978 DOI: 10.1038/leu.2016.203] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2016] [Revised: 06/12/2016] [Accepted: 06/15/2016] [Indexed: 12/17/2022]
Abstract
Asparaginase (ASP)-associated pancreatitis (AAP) occurs during acute lymphoblastic leukemia treatment. Among 1285 children (1.0-17.9 years) diagnosed during July 2008-December 2014 and treated according to the Nordic/Baltic ALL2008 protocol, 86 (cumulative incidence=6.8%) developed AAP. Seventy-three cases were severe (diagnostic AAP criteria persisting >72 h) and 13 mild. Cases were older than controls (median: 6.5 vs 4.5 years; P=0.001). Pseudocysts developed in 28%. Of the 20 re-exposed to ASP, 9 (45%) developed a second AAP. After a median follow-up of 2.3 years, 8% needed permanent insulin therapy, and 7% had recurrent abdominal pain. Germline DNA on 62 cases and 638 controls was genotyped on Omni2.5exome-8-v1.2 BeadChip arrays. Overall, the ULK2 variant rs281366 showed the strongest association with AAP (P=5.8 × 10-7; odds ratio (OR)=6.7). Cases with the rs281366 variant were younger (4.3 vs 8 years; P=0.015) and had lower risk of AAP-related complications (15% vs 43%; P=0.13) compared with cases without this variant. Among 45 cases and 517 controls <10 years, the strongest associations with AAP were found for RGS6 variant rs17179470 (P=9.8 × 10-9; OR=7.3). Rs281366 is located in the ULK2 gene involved in autophagy, and RGS6 regulates G-protein signaling regulating cell dynamics. More than 50% of AAP cases <10 years carried one or both risk alleles.
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Affiliation(s)
- B O Wolthers
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark
| | - T L Frandsen
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark
| | - J Abrahamsson
- Department of Clinical Sciences, Queen Silvia's Children's Hospital, Gothenburg, Sweden
| | - B K Albertsen
- Department of Paediatrics, Aarhus University Hospital Skejby, Aarhus, Denmark
| | - L R Helt
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark
| | - M Heyman
- Department of Pediatrics, Astrid Lindgrens Hospital, Stockholm, Sweden
| | - Ó G Jónsson
- Children's Hospital, Landspitali University Hospital, Reykjavík, Iceland
| | | | - B Lund
- Department of Paediatrics, St Olavs University Hospital, Trondheim, Norway.,Department of Laboratory Medicine, Children's and Women's Health, Medical Faculty, The Norwegian University of Science and Technology, Trondheim, Norway
| | - R A Raja
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark
| | - K K Rasmussen
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark
| | - M Taskinen
- Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland
| | - M Tulstrup
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark
| | - G E Vaitkevičienė
- Clinic of Children's Diseases, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - R Yadav
- Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark
| | - R Gupta
- Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark
| | - K Schmiegelow
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.,Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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32
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Phillipson-Weiner L, Mirek ET, Wang Y, McAuliffe WG, Wek RC, Anthony TG. General control nonderepressible 2 deletion predisposes to asparaginase-associated pancreatitis in mice. Am J Physiol Gastrointest Liver Physiol 2016; 310:G1061-70. [PMID: 26968207 PMCID: PMC4935488 DOI: 10.1152/ajpgi.00052.2016] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Accepted: 03/07/2016] [Indexed: 01/31/2023]
Abstract
Treatment with the antileukemic agent asparaginase can induce acute pancreatitis, but the pathophysiology remains obscure. In the liver of mice, eukaryotic initiation factor 2 (eIF2) kinase general control nonderepressible 2 (GCN2) is essential for mitigating metabolic stress caused by asparaginase. We determined the consequences of asparaginase treatment on the pancreata of wild-type (WT, GCN2-intact) and GCN2-deleted (ΔGcn2) mice. Mean pancreas weights in ΔGcn2 mice treated with asparaginase for 8 days were increased (P < 0.05) above all other groups. Histological examination revealed acinar cell swelling and altered staining of zymogen granules in ΔGcn2, but not WT, mice. Oil Red O staining and measurement of pancreas triglycerides excluded lipid accumulation as a contributor to acini appearance. Instead, transmission electron microscopy revealed dilatation of the endoplasmic reticulum (ER) and accumulation of autophagic vacuoles in the pancreas of ΔGcn2 mice treated with asparaginase. Consistent with the idea that loss of GCN2 in a pancreas exposed to asparaginase induced ER stress, phosphorylation of protein kinase R-like ER kinase (PERK) and its substrate eIF2 was increased in the pancreas of asparaginase-treated ΔGcn2 mice. In addition, mRNA expression of PERK target genes, activating transcription factors 4, 3, and 6 (Atf4, Atf3, and Atf6), fibroblast growth factor 21 (Fgf21), heat shock 70-kDa protein 5 (Hspa5), and spliced Xbp1 (sXbp1), as well as pancreas mass, was elevated in the pancreas of asparaginase-treated ΔGcn2 mice. Furthermore, genetic markers of oxidative stress [sirtuin (Sirt1)], inflammation [tumor necrosis factor-α (Tnfα)], and pancreatic injury [pancreatitis-associated protein (Pap)] were elevated in asparaginase-treated ΔGcn2, but not WT, mice. These data indicate that loss of GCN2 predisposes the exocrine pancreas to a maladaptive ER stress response and autophagy during asparaginase treatment and represent a genetic basis for development of asparaginase-associated pancreatitis.
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Affiliation(s)
- Lindsey Phillipson-Weiner
- 1Department of Nutritional Sciences, Rutgers, The State University of New Jersey, New Brunswick, New Jersey;
| | - Emily T. Mirek
- 1Department of Nutritional Sciences, Rutgers, The State University of New Jersey, New Brunswick, New Jersey;
| | - Yongping Wang
- 1Department of Nutritional Sciences, Rutgers, The State University of New Jersey, New Brunswick, New Jersey;
| | - W. Geoffrey McAuliffe
- 4Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, New Jersey; and
| | - Ronald C. Wek
- 5Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Tracy G. Anthony
- 1Department of Nutritional Sciences, Rutgers, The State University of New Jersey, New Brunswick, New Jersey; ,2Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, New Jersey; ,3New Jersey Institute for Food, Nutrition, and Health, Rutgers, The State University of New Jersey, New Brunswick, New Jersey;
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33
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Liu C, Yang W, Devidas M, Cheng C, Pei D, Smith C, Carroll WL, Raetz EA, Bowman WP, Larsen EC, Maloney KW, Martin PL, Mattano LA, Winick NJ, Mardis ER, Fulton RS, Bhojwani D, Howard SC, Jeha S, Pui CH, Hunger SP, Evans WE, Loh ML, Relling MV. Clinical and Genetic Risk Factors for Acute Pancreatitis in Patients With Acute Lymphoblastic Leukemia. J Clin Oncol 2016; 34:2133-40. [PMID: 27114598 DOI: 10.1200/jco.2015.64.5812] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
PURPOSE Acute pancreatitis is one of the common causes of asparaginase intolerance. The mechanism is unknown, and genetic predisposition to asparaginase-induced pancreatitis has not been previously identified. METHODS To determine clinical risk factors for asparaginase-induced pancreatitis, we studied a cohort of 5,185 children and young adults with acute lymphoblastic leukemia, including 117 (2.3%) who were diagnosed with at least one episode of acute pancreatitis during therapy. A genome-wide association study was performed in the cohort and in an independent case-control group of 213 patients to identify genetic risk factors. RESULTS Risk factors associated with pancreatitis included genetically defined Native American ancestry (P < .001), older age (P < .001), and higher cumulative dose of asparaginase (P < .001). No common variants reached genome-wide significance in the genome-wide association study, but a rare nonsense variant rs199695765 in CPA2, encoding carboxypeptidase A2, was highly associated with pancreatitis (hazard ratio, 587; 95% CI, 66.8 to 5166; P = 9.0 × 10(-9)). A gene-level analysis showed an excess of additional CPA2 variants in patients who did versus those who did not develop pancreatitis (P = .001). Sixteen CPA2 single-nucleotide polymorphisms were associated (P < .05) with pancreatitis, and 13 of 24 patients who carried at least one of these variants developed pancreatitis. Biologic functions that were overrepresented by common variants modestly associated with pancreatitis included purine metabolism and cytoskeleton regulation. CONCLUSION Older age, higher exposure to asparaginase, and higher Native American ancestry were independent risk factors for pancreatitis in patients with acute lymphoblastic leukemia. Those who inherit a nonsense rare variant in the CPA2 gene had a markedly increased risk of asparaginase-induced pancreatitis.
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Affiliation(s)
- Chengcheng Liu
- Chengcheng Liu, Wenjian Yang, Cheng Cheng, Deqing Pei, Colton Smith, Sima Jeha, Ching-Hon Pui, William E. Evans, and Mary V. Relling, St Jude Children's Research Hospital; Scott C. Howard, University of Memphis, Memphis, TN; Meenakshi Devidas, University of Florida, Gainesville, FL; William L. Carroll, New York University Langone Medical Center, New York, NY; Elizabeth A. Raetz, University of Utah, Salt Lake City, UT; W. Paul Bowman, Cook Children's Hospital, Ft Worth; Naomi J. Winick, University of Texas Southwestern Medical Center, Dallas, TX; Eric C. Larsen, Maine Children's Cancer Program, Scarborough, ME; Kelly W. Maloney, University of Colorado Denver, Aurora, CO; Paul L. Martin, Duke University, Durham, NC; Leonard A. Mattano Jr, HARP Pharma Consulting, Mystic, CT; Elaine R. Mardis and Robert S. Fulton, The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO; Deepa Bhojwani, Children's Hospital of Los Angeles, Los Angeles; Mignon L. Loh, University of California San Francisco Medical Center-Parnassus, San Francisco, CA; and Stephen P. Hunger, Children's Hospital of Philadelphia, Philadelphia, PA
| | - Wenjian Yang
- Chengcheng Liu, Wenjian Yang, Cheng Cheng, Deqing Pei, Colton Smith, Sima Jeha, Ching-Hon Pui, William E. Evans, and Mary V. Relling, St Jude Children's Research Hospital; Scott C. Howard, University of Memphis, Memphis, TN; Meenakshi Devidas, University of Florida, Gainesville, FL; William L. Carroll, New York University Langone Medical Center, New York, NY; Elizabeth A. Raetz, University of Utah, Salt Lake City, UT; W. Paul Bowman, Cook Children's Hospital, Ft Worth; Naomi J. Winick, University of Texas Southwestern Medical Center, Dallas, TX; Eric C. Larsen, Maine Children's Cancer Program, Scarborough, ME; Kelly W. Maloney, University of Colorado Denver, Aurora, CO; Paul L. Martin, Duke University, Durham, NC; Leonard A. Mattano Jr, HARP Pharma Consulting, Mystic, CT; Elaine R. Mardis and Robert S. Fulton, The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO; Deepa Bhojwani, Children's Hospital of Los Angeles, Los Angeles; Mignon L. Loh, University of California San Francisco Medical Center-Parnassus, San Francisco, CA; and Stephen P. Hunger, Children's Hospital of Philadelphia, Philadelphia, PA
| | - Meenakshi Devidas
- Chengcheng Liu, Wenjian Yang, Cheng Cheng, Deqing Pei, Colton Smith, Sima Jeha, Ching-Hon Pui, William E. Evans, and Mary V. Relling, St Jude Children's Research Hospital; Scott C. Howard, University of Memphis, Memphis, TN; Meenakshi Devidas, University of Florida, Gainesville, FL; William L. Carroll, New York University Langone Medical Center, New York, NY; Elizabeth A. Raetz, University of Utah, Salt Lake City, UT; W. Paul Bowman, Cook Children's Hospital, Ft Worth; Naomi J. Winick, University of Texas Southwestern Medical Center, Dallas, TX; Eric C. Larsen, Maine Children's Cancer Program, Scarborough, ME; Kelly W. Maloney, University of Colorado Denver, Aurora, CO; Paul L. Martin, Duke University, Durham, NC; Leonard A. Mattano Jr, HARP Pharma Consulting, Mystic, CT; Elaine R. Mardis and Robert S. Fulton, The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO; Deepa Bhojwani, Children's Hospital of Los Angeles, Los Angeles; Mignon L. Loh, University of California San Francisco Medical Center-Parnassus, San Francisco, CA; and Stephen P. Hunger, Children's Hospital of Philadelphia, Philadelphia, PA
| | - Cheng Cheng
- Chengcheng Liu, Wenjian Yang, Cheng Cheng, Deqing Pei, Colton Smith, Sima Jeha, Ching-Hon Pui, William E. Evans, and Mary V. Relling, St Jude Children's Research Hospital; Scott C. Howard, University of Memphis, Memphis, TN; Meenakshi Devidas, University of Florida, Gainesville, FL; William L. Carroll, New York University Langone Medical Center, New York, NY; Elizabeth A. Raetz, University of Utah, Salt Lake City, UT; W. Paul Bowman, Cook Children's Hospital, Ft Worth; Naomi J. Winick, University of Texas Southwestern Medical Center, Dallas, TX; Eric C. Larsen, Maine Children's Cancer Program, Scarborough, ME; Kelly W. Maloney, University of Colorado Denver, Aurora, CO; Paul L. Martin, Duke University, Durham, NC; Leonard A. Mattano Jr, HARP Pharma Consulting, Mystic, CT; Elaine R. Mardis and Robert S. Fulton, The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO; Deepa Bhojwani, Children's Hospital of Los Angeles, Los Angeles; Mignon L. Loh, University of California San Francisco Medical Center-Parnassus, San Francisco, CA; and Stephen P. Hunger, Children's Hospital of Philadelphia, Philadelphia, PA
| | - Deqing Pei
- Chengcheng Liu, Wenjian Yang, Cheng Cheng, Deqing Pei, Colton Smith, Sima Jeha, Ching-Hon Pui, William E. Evans, and Mary V. Relling, St Jude Children's Research Hospital; Scott C. Howard, University of Memphis, Memphis, TN; Meenakshi Devidas, University of Florida, Gainesville, FL; William L. Carroll, New York University Langone Medical Center, New York, NY; Elizabeth A. Raetz, University of Utah, Salt Lake City, UT; W. Paul Bowman, Cook Children's Hospital, Ft Worth; Naomi J. Winick, University of Texas Southwestern Medical Center, Dallas, TX; Eric C. Larsen, Maine Children's Cancer Program, Scarborough, ME; Kelly W. Maloney, University of Colorado Denver, Aurora, CO; Paul L. Martin, Duke University, Durham, NC; Leonard A. Mattano Jr, HARP Pharma Consulting, Mystic, CT; Elaine R. Mardis and Robert S. Fulton, The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO; Deepa Bhojwani, Children's Hospital of Los Angeles, Los Angeles; Mignon L. Loh, University of California San Francisco Medical Center-Parnassus, San Francisco, CA; and Stephen P. Hunger, Children's Hospital of Philadelphia, Philadelphia, PA
| | - Colton Smith
- Chengcheng Liu, Wenjian Yang, Cheng Cheng, Deqing Pei, Colton Smith, Sima Jeha, Ching-Hon Pui, William E. Evans, and Mary V. Relling, St Jude Children's Research Hospital; Scott C. Howard, University of Memphis, Memphis, TN; Meenakshi Devidas, University of Florida, Gainesville, FL; William L. Carroll, New York University Langone Medical Center, New York, NY; Elizabeth A. Raetz, University of Utah, Salt Lake City, UT; W. Paul Bowman, Cook Children's Hospital, Ft Worth; Naomi J. Winick, University of Texas Southwestern Medical Center, Dallas, TX; Eric C. Larsen, Maine Children's Cancer Program, Scarborough, ME; Kelly W. Maloney, University of Colorado Denver, Aurora, CO; Paul L. Martin, Duke University, Durham, NC; Leonard A. Mattano Jr, HARP Pharma Consulting, Mystic, CT; Elaine R. Mardis and Robert S. Fulton, The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO; Deepa Bhojwani, Children's Hospital of Los Angeles, Los Angeles; Mignon L. Loh, University of California San Francisco Medical Center-Parnassus, San Francisco, CA; and Stephen P. Hunger, Children's Hospital of Philadelphia, Philadelphia, PA
| | - William L Carroll
- Chengcheng Liu, Wenjian Yang, Cheng Cheng, Deqing Pei, Colton Smith, Sima Jeha, Ching-Hon Pui, William E. Evans, and Mary V. Relling, St Jude Children's Research Hospital; Scott C. Howard, University of Memphis, Memphis, TN; Meenakshi Devidas, University of Florida, Gainesville, FL; William L. Carroll, New York University Langone Medical Center, New York, NY; Elizabeth A. Raetz, University of Utah, Salt Lake City, UT; W. Paul Bowman, Cook Children's Hospital, Ft Worth; Naomi J. Winick, University of Texas Southwestern Medical Center, Dallas, TX; Eric C. Larsen, Maine Children's Cancer Program, Scarborough, ME; Kelly W. Maloney, University of Colorado Denver, Aurora, CO; Paul L. Martin, Duke University, Durham, NC; Leonard A. Mattano Jr, HARP Pharma Consulting, Mystic, CT; Elaine R. Mardis and Robert S. Fulton, The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO; Deepa Bhojwani, Children's Hospital of Los Angeles, Los Angeles; Mignon L. Loh, University of California San Francisco Medical Center-Parnassus, San Francisco, CA; and Stephen P. Hunger, Children's Hospital of Philadelphia, Philadelphia, PA
| | - Elizabeth A Raetz
- Chengcheng Liu, Wenjian Yang, Cheng Cheng, Deqing Pei, Colton Smith, Sima Jeha, Ching-Hon Pui, William E. Evans, and Mary V. Relling, St Jude Children's Research Hospital; Scott C. Howard, University of Memphis, Memphis, TN; Meenakshi Devidas, University of Florida, Gainesville, FL; William L. Carroll, New York University Langone Medical Center, New York, NY; Elizabeth A. Raetz, University of Utah, Salt Lake City, UT; W. Paul Bowman, Cook Children's Hospital, Ft Worth; Naomi J. Winick, University of Texas Southwestern Medical Center, Dallas, TX; Eric C. Larsen, Maine Children's Cancer Program, Scarborough, ME; Kelly W. Maloney, University of Colorado Denver, Aurora, CO; Paul L. Martin, Duke University, Durham, NC; Leonard A. Mattano Jr, HARP Pharma Consulting, Mystic, CT; Elaine R. Mardis and Robert S. Fulton, The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO; Deepa Bhojwani, Children's Hospital of Los Angeles, Los Angeles; Mignon L. Loh, University of California San Francisco Medical Center-Parnassus, San Francisco, CA; and Stephen P. Hunger, Children's Hospital of Philadelphia, Philadelphia, PA
| | - W Paul Bowman
- Chengcheng Liu, Wenjian Yang, Cheng Cheng, Deqing Pei, Colton Smith, Sima Jeha, Ching-Hon Pui, William E. Evans, and Mary V. Relling, St Jude Children's Research Hospital; Scott C. Howard, University of Memphis, Memphis, TN; Meenakshi Devidas, University of Florida, Gainesville, FL; William L. Carroll, New York University Langone Medical Center, New York, NY; Elizabeth A. Raetz, University of Utah, Salt Lake City, UT; W. Paul Bowman, Cook Children's Hospital, Ft Worth; Naomi J. Winick, University of Texas Southwestern Medical Center, Dallas, TX; Eric C. Larsen, Maine Children's Cancer Program, Scarborough, ME; Kelly W. Maloney, University of Colorado Denver, Aurora, CO; Paul L. Martin, Duke University, Durham, NC; Leonard A. Mattano Jr, HARP Pharma Consulting, Mystic, CT; Elaine R. Mardis and Robert S. Fulton, The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO; Deepa Bhojwani, Children's Hospital of Los Angeles, Los Angeles; Mignon L. Loh, University of California San Francisco Medical Center-Parnassus, San Francisco, CA; and Stephen P. Hunger, Children's Hospital of Philadelphia, Philadelphia, PA
| | - Eric C Larsen
- Chengcheng Liu, Wenjian Yang, Cheng Cheng, Deqing Pei, Colton Smith, Sima Jeha, Ching-Hon Pui, William E. Evans, and Mary V. Relling, St Jude Children's Research Hospital; Scott C. Howard, University of Memphis, Memphis, TN; Meenakshi Devidas, University of Florida, Gainesville, FL; William L. Carroll, New York University Langone Medical Center, New York, NY; Elizabeth A. Raetz, University of Utah, Salt Lake City, UT; W. Paul Bowman, Cook Children's Hospital, Ft Worth; Naomi J. Winick, University of Texas Southwestern Medical Center, Dallas, TX; Eric C. Larsen, Maine Children's Cancer Program, Scarborough, ME; Kelly W. Maloney, University of Colorado Denver, Aurora, CO; Paul L. Martin, Duke University, Durham, NC; Leonard A. Mattano Jr, HARP Pharma Consulting, Mystic, CT; Elaine R. Mardis and Robert S. Fulton, The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO; Deepa Bhojwani, Children's Hospital of Los Angeles, Los Angeles; Mignon L. Loh, University of California San Francisco Medical Center-Parnassus, San Francisco, CA; and Stephen P. Hunger, Children's Hospital of Philadelphia, Philadelphia, PA
| | - Kelly W Maloney
- Chengcheng Liu, Wenjian Yang, Cheng Cheng, Deqing Pei, Colton Smith, Sima Jeha, Ching-Hon Pui, William E. Evans, and Mary V. Relling, St Jude Children's Research Hospital; Scott C. Howard, University of Memphis, Memphis, TN; Meenakshi Devidas, University of Florida, Gainesville, FL; William L. Carroll, New York University Langone Medical Center, New York, NY; Elizabeth A. Raetz, University of Utah, Salt Lake City, UT; W. Paul Bowman, Cook Children's Hospital, Ft Worth; Naomi J. Winick, University of Texas Southwestern Medical Center, Dallas, TX; Eric C. Larsen, Maine Children's Cancer Program, Scarborough, ME; Kelly W. Maloney, University of Colorado Denver, Aurora, CO; Paul L. Martin, Duke University, Durham, NC; Leonard A. Mattano Jr, HARP Pharma Consulting, Mystic, CT; Elaine R. Mardis and Robert S. Fulton, The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO; Deepa Bhojwani, Children's Hospital of Los Angeles, Los Angeles; Mignon L. Loh, University of California San Francisco Medical Center-Parnassus, San Francisco, CA; and Stephen P. Hunger, Children's Hospital of Philadelphia, Philadelphia, PA
| | - Paul L Martin
- Chengcheng Liu, Wenjian Yang, Cheng Cheng, Deqing Pei, Colton Smith, Sima Jeha, Ching-Hon Pui, William E. Evans, and Mary V. Relling, St Jude Children's Research Hospital; Scott C. Howard, University of Memphis, Memphis, TN; Meenakshi Devidas, University of Florida, Gainesville, FL; William L. Carroll, New York University Langone Medical Center, New York, NY; Elizabeth A. Raetz, University of Utah, Salt Lake City, UT; W. Paul Bowman, Cook Children's Hospital, Ft Worth; Naomi J. Winick, University of Texas Southwestern Medical Center, Dallas, TX; Eric C. Larsen, Maine Children's Cancer Program, Scarborough, ME; Kelly W. Maloney, University of Colorado Denver, Aurora, CO; Paul L. Martin, Duke University, Durham, NC; Leonard A. Mattano Jr, HARP Pharma Consulting, Mystic, CT; Elaine R. Mardis and Robert S. Fulton, The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO; Deepa Bhojwani, Children's Hospital of Los Angeles, Los Angeles; Mignon L. Loh, University of California San Francisco Medical Center-Parnassus, San Francisco, CA; and Stephen P. Hunger, Children's Hospital of Philadelphia, Philadelphia, PA
| | - Leonard A Mattano
- Chengcheng Liu, Wenjian Yang, Cheng Cheng, Deqing Pei, Colton Smith, Sima Jeha, Ching-Hon Pui, William E. Evans, and Mary V. Relling, St Jude Children's Research Hospital; Scott C. Howard, University of Memphis, Memphis, TN; Meenakshi Devidas, University of Florida, Gainesville, FL; William L. Carroll, New York University Langone Medical Center, New York, NY; Elizabeth A. Raetz, University of Utah, Salt Lake City, UT; W. Paul Bowman, Cook Children's Hospital, Ft Worth; Naomi J. Winick, University of Texas Southwestern Medical Center, Dallas, TX; Eric C. Larsen, Maine Children's Cancer Program, Scarborough, ME; Kelly W. Maloney, University of Colorado Denver, Aurora, CO; Paul L. Martin, Duke University, Durham, NC; Leonard A. Mattano Jr, HARP Pharma Consulting, Mystic, CT; Elaine R. Mardis and Robert S. Fulton, The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO; Deepa Bhojwani, Children's Hospital of Los Angeles, Los Angeles; Mignon L. Loh, University of California San Francisco Medical Center-Parnassus, San Francisco, CA; and Stephen P. Hunger, Children's Hospital of Philadelphia, Philadelphia, PA
| | - Naomi J Winick
- Chengcheng Liu, Wenjian Yang, Cheng Cheng, Deqing Pei, Colton Smith, Sima Jeha, Ching-Hon Pui, William E. Evans, and Mary V. Relling, St Jude Children's Research Hospital; Scott C. Howard, University of Memphis, Memphis, TN; Meenakshi Devidas, University of Florida, Gainesville, FL; William L. Carroll, New York University Langone Medical Center, New York, NY; Elizabeth A. Raetz, University of Utah, Salt Lake City, UT; W. Paul Bowman, Cook Children's Hospital, Ft Worth; Naomi J. Winick, University of Texas Southwestern Medical Center, Dallas, TX; Eric C. Larsen, Maine Children's Cancer Program, Scarborough, ME; Kelly W. Maloney, University of Colorado Denver, Aurora, CO; Paul L. Martin, Duke University, Durham, NC; Leonard A. Mattano Jr, HARP Pharma Consulting, Mystic, CT; Elaine R. Mardis and Robert S. Fulton, The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO; Deepa Bhojwani, Children's Hospital of Los Angeles, Los Angeles; Mignon L. Loh, University of California San Francisco Medical Center-Parnassus, San Francisco, CA; and Stephen P. Hunger, Children's Hospital of Philadelphia, Philadelphia, PA
| | - Elaine R Mardis
- Chengcheng Liu, Wenjian Yang, Cheng Cheng, Deqing Pei, Colton Smith, Sima Jeha, Ching-Hon Pui, William E. Evans, and Mary V. Relling, St Jude Children's Research Hospital; Scott C. Howard, University of Memphis, Memphis, TN; Meenakshi Devidas, University of Florida, Gainesville, FL; William L. Carroll, New York University Langone Medical Center, New York, NY; Elizabeth A. Raetz, University of Utah, Salt Lake City, UT; W. Paul Bowman, Cook Children's Hospital, Ft Worth; Naomi J. Winick, University of Texas Southwestern Medical Center, Dallas, TX; Eric C. Larsen, Maine Children's Cancer Program, Scarborough, ME; Kelly W. Maloney, University of Colorado Denver, Aurora, CO; Paul L. Martin, Duke University, Durham, NC; Leonard A. Mattano Jr, HARP Pharma Consulting, Mystic, CT; Elaine R. Mardis and Robert S. Fulton, The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO; Deepa Bhojwani, Children's Hospital of Los Angeles, Los Angeles; Mignon L. Loh, University of California San Francisco Medical Center-Parnassus, San Francisco, CA; and Stephen P. Hunger, Children's Hospital of Philadelphia, Philadelphia, PA
| | - Robert S Fulton
- Chengcheng Liu, Wenjian Yang, Cheng Cheng, Deqing Pei, Colton Smith, Sima Jeha, Ching-Hon Pui, William E. Evans, and Mary V. Relling, St Jude Children's Research Hospital; Scott C. Howard, University of Memphis, Memphis, TN; Meenakshi Devidas, University of Florida, Gainesville, FL; William L. Carroll, New York University Langone Medical Center, New York, NY; Elizabeth A. Raetz, University of Utah, Salt Lake City, UT; W. Paul Bowman, Cook Children's Hospital, Ft Worth; Naomi J. Winick, University of Texas Southwestern Medical Center, Dallas, TX; Eric C. Larsen, Maine Children's Cancer Program, Scarborough, ME; Kelly W. Maloney, University of Colorado Denver, Aurora, CO; Paul L. Martin, Duke University, Durham, NC; Leonard A. Mattano Jr, HARP Pharma Consulting, Mystic, CT; Elaine R. Mardis and Robert S. Fulton, The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO; Deepa Bhojwani, Children's Hospital of Los Angeles, Los Angeles; Mignon L. Loh, University of California San Francisco Medical Center-Parnassus, San Francisco, CA; and Stephen P. Hunger, Children's Hospital of Philadelphia, Philadelphia, PA
| | - Deepa Bhojwani
- Chengcheng Liu, Wenjian Yang, Cheng Cheng, Deqing Pei, Colton Smith, Sima Jeha, Ching-Hon Pui, William E. Evans, and Mary V. Relling, St Jude Children's Research Hospital; Scott C. Howard, University of Memphis, Memphis, TN; Meenakshi Devidas, University of Florida, Gainesville, FL; William L. Carroll, New York University Langone Medical Center, New York, NY; Elizabeth A. Raetz, University of Utah, Salt Lake City, UT; W. Paul Bowman, Cook Children's Hospital, Ft Worth; Naomi J. Winick, University of Texas Southwestern Medical Center, Dallas, TX; Eric C. Larsen, Maine Children's Cancer Program, Scarborough, ME; Kelly W. Maloney, University of Colorado Denver, Aurora, CO; Paul L. Martin, Duke University, Durham, NC; Leonard A. Mattano Jr, HARP Pharma Consulting, Mystic, CT; Elaine R. Mardis and Robert S. Fulton, The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO; Deepa Bhojwani, Children's Hospital of Los Angeles, Los Angeles; Mignon L. Loh, University of California San Francisco Medical Center-Parnassus, San Francisco, CA; and Stephen P. Hunger, Children's Hospital of Philadelphia, Philadelphia, PA
| | - Scott C Howard
- Chengcheng Liu, Wenjian Yang, Cheng Cheng, Deqing Pei, Colton Smith, Sima Jeha, Ching-Hon Pui, William E. Evans, and Mary V. Relling, St Jude Children's Research Hospital; Scott C. Howard, University of Memphis, Memphis, TN; Meenakshi Devidas, University of Florida, Gainesville, FL; William L. Carroll, New York University Langone Medical Center, New York, NY; Elizabeth A. Raetz, University of Utah, Salt Lake City, UT; W. Paul Bowman, Cook Children's Hospital, Ft Worth; Naomi J. Winick, University of Texas Southwestern Medical Center, Dallas, TX; Eric C. Larsen, Maine Children's Cancer Program, Scarborough, ME; Kelly W. Maloney, University of Colorado Denver, Aurora, CO; Paul L. Martin, Duke University, Durham, NC; Leonard A. Mattano Jr, HARP Pharma Consulting, Mystic, CT; Elaine R. Mardis and Robert S. Fulton, The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO; Deepa Bhojwani, Children's Hospital of Los Angeles, Los Angeles; Mignon L. Loh, University of California San Francisco Medical Center-Parnassus, San Francisco, CA; and Stephen P. Hunger, Children's Hospital of Philadelphia, Philadelphia, PA
| | - Sima Jeha
- Chengcheng Liu, Wenjian Yang, Cheng Cheng, Deqing Pei, Colton Smith, Sima Jeha, Ching-Hon Pui, William E. Evans, and Mary V. Relling, St Jude Children's Research Hospital; Scott C. Howard, University of Memphis, Memphis, TN; Meenakshi Devidas, University of Florida, Gainesville, FL; William L. Carroll, New York University Langone Medical Center, New York, NY; Elizabeth A. Raetz, University of Utah, Salt Lake City, UT; W. Paul Bowman, Cook Children's Hospital, Ft Worth; Naomi J. Winick, University of Texas Southwestern Medical Center, Dallas, TX; Eric C. Larsen, Maine Children's Cancer Program, Scarborough, ME; Kelly W. Maloney, University of Colorado Denver, Aurora, CO; Paul L. Martin, Duke University, Durham, NC; Leonard A. Mattano Jr, HARP Pharma Consulting, Mystic, CT; Elaine R. Mardis and Robert S. Fulton, The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO; Deepa Bhojwani, Children's Hospital of Los Angeles, Los Angeles; Mignon L. Loh, University of California San Francisco Medical Center-Parnassus, San Francisco, CA; and Stephen P. Hunger, Children's Hospital of Philadelphia, Philadelphia, PA
| | - Ching-Hon Pui
- Chengcheng Liu, Wenjian Yang, Cheng Cheng, Deqing Pei, Colton Smith, Sima Jeha, Ching-Hon Pui, William E. Evans, and Mary V. Relling, St Jude Children's Research Hospital; Scott C. Howard, University of Memphis, Memphis, TN; Meenakshi Devidas, University of Florida, Gainesville, FL; William L. Carroll, New York University Langone Medical Center, New York, NY; Elizabeth A. Raetz, University of Utah, Salt Lake City, UT; W. Paul Bowman, Cook Children's Hospital, Ft Worth; Naomi J. Winick, University of Texas Southwestern Medical Center, Dallas, TX; Eric C. Larsen, Maine Children's Cancer Program, Scarborough, ME; Kelly W. Maloney, University of Colorado Denver, Aurora, CO; Paul L. Martin, Duke University, Durham, NC; Leonard A. Mattano Jr, HARP Pharma Consulting, Mystic, CT; Elaine R. Mardis and Robert S. Fulton, The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO; Deepa Bhojwani, Children's Hospital of Los Angeles, Los Angeles; Mignon L. Loh, University of California San Francisco Medical Center-Parnassus, San Francisco, CA; and Stephen P. Hunger, Children's Hospital of Philadelphia, Philadelphia, PA
| | - Stephen P Hunger
- Chengcheng Liu, Wenjian Yang, Cheng Cheng, Deqing Pei, Colton Smith, Sima Jeha, Ching-Hon Pui, William E. Evans, and Mary V. Relling, St Jude Children's Research Hospital; Scott C. Howard, University of Memphis, Memphis, TN; Meenakshi Devidas, University of Florida, Gainesville, FL; William L. Carroll, New York University Langone Medical Center, New York, NY; Elizabeth A. Raetz, University of Utah, Salt Lake City, UT; W. Paul Bowman, Cook Children's Hospital, Ft Worth; Naomi J. Winick, University of Texas Southwestern Medical Center, Dallas, TX; Eric C. Larsen, Maine Children's Cancer Program, Scarborough, ME; Kelly W. Maloney, University of Colorado Denver, Aurora, CO; Paul L. Martin, Duke University, Durham, NC; Leonard A. Mattano Jr, HARP Pharma Consulting, Mystic, CT; Elaine R. Mardis and Robert S. Fulton, The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO; Deepa Bhojwani, Children's Hospital of Los Angeles, Los Angeles; Mignon L. Loh, University of California San Francisco Medical Center-Parnassus, San Francisco, CA; and Stephen P. Hunger, Children's Hospital of Philadelphia, Philadelphia, PA
| | - William E Evans
- Chengcheng Liu, Wenjian Yang, Cheng Cheng, Deqing Pei, Colton Smith, Sima Jeha, Ching-Hon Pui, William E. Evans, and Mary V. Relling, St Jude Children's Research Hospital; Scott C. Howard, University of Memphis, Memphis, TN; Meenakshi Devidas, University of Florida, Gainesville, FL; William L. Carroll, New York University Langone Medical Center, New York, NY; Elizabeth A. Raetz, University of Utah, Salt Lake City, UT; W. Paul Bowman, Cook Children's Hospital, Ft Worth; Naomi J. Winick, University of Texas Southwestern Medical Center, Dallas, TX; Eric C. Larsen, Maine Children's Cancer Program, Scarborough, ME; Kelly W. Maloney, University of Colorado Denver, Aurora, CO; Paul L. Martin, Duke University, Durham, NC; Leonard A. Mattano Jr, HARP Pharma Consulting, Mystic, CT; Elaine R. Mardis and Robert S. Fulton, The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO; Deepa Bhojwani, Children's Hospital of Los Angeles, Los Angeles; Mignon L. Loh, University of California San Francisco Medical Center-Parnassus, San Francisco, CA; and Stephen P. Hunger, Children's Hospital of Philadelphia, Philadelphia, PA
| | - Mignon L Loh
- Chengcheng Liu, Wenjian Yang, Cheng Cheng, Deqing Pei, Colton Smith, Sima Jeha, Ching-Hon Pui, William E. Evans, and Mary V. Relling, St Jude Children's Research Hospital; Scott C. Howard, University of Memphis, Memphis, TN; Meenakshi Devidas, University of Florida, Gainesville, FL; William L. Carroll, New York University Langone Medical Center, New York, NY; Elizabeth A. Raetz, University of Utah, Salt Lake City, UT; W. Paul Bowman, Cook Children's Hospital, Ft Worth; Naomi J. Winick, University of Texas Southwestern Medical Center, Dallas, TX; Eric C. Larsen, Maine Children's Cancer Program, Scarborough, ME; Kelly W. Maloney, University of Colorado Denver, Aurora, CO; Paul L. Martin, Duke University, Durham, NC; Leonard A. Mattano Jr, HARP Pharma Consulting, Mystic, CT; Elaine R. Mardis and Robert S. Fulton, The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO; Deepa Bhojwani, Children's Hospital of Los Angeles, Los Angeles; Mignon L. Loh, University of California San Francisco Medical Center-Parnassus, San Francisco, CA; and Stephen P. Hunger, Children's Hospital of Philadelphia, Philadelphia, PA
| | - Mary V Relling
- Chengcheng Liu, Wenjian Yang, Cheng Cheng, Deqing Pei, Colton Smith, Sima Jeha, Ching-Hon Pui, William E. Evans, and Mary V. Relling, St Jude Children's Research Hospital; Scott C. Howard, University of Memphis, Memphis, TN; Meenakshi Devidas, University of Florida, Gainesville, FL; William L. Carroll, New York University Langone Medical Center, New York, NY; Elizabeth A. Raetz, University of Utah, Salt Lake City, UT; W. Paul Bowman, Cook Children's Hospital, Ft Worth; Naomi J. Winick, University of Texas Southwestern Medical Center, Dallas, TX; Eric C. Larsen, Maine Children's Cancer Program, Scarborough, ME; Kelly W. Maloney, University of Colorado Denver, Aurora, CO; Paul L. Martin, Duke University, Durham, NC; Leonard A. Mattano Jr, HARP Pharma Consulting, Mystic, CT; Elaine R. Mardis and Robert S. Fulton, The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO; Deepa Bhojwani, Children's Hospital of Los Angeles, Los Angeles; Mignon L. Loh, University of California San Francisco Medical Center-Parnassus, San Francisco, CA; and Stephen P. Hunger, Children's Hospital of Philadelphia, Philadelphia, PA.
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Pui CH. Is Erwinase Necessary for all Children With ALL and Allergic Reactions to E. coli Asparaginase? Pediatr Blood Cancer 2016; 63:587-8. [PMID: 26739648 PMCID: PMC4755852 DOI: 10.1002/pbc.25876] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Accepted: 11/30/2015] [Indexed: 11/05/2022]
Affiliation(s)
- Ching-Hon Pui
- Departments of Oncology and Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee,Department of Pediatrics, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee,Correspondence to: Ching-Hon Pui, MD, Department of Oncology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-3678.
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Hijiya N, van der Sluis IM. Asparaginase-associated toxicity in children with acute lymphoblastic leukemia. Leuk Lymphoma 2015; 57:748-57. [PMID: 26457414 PMCID: PMC4819847 DOI: 10.3109/10428194.2015.1101098] [Citation(s) in RCA: 152] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Asparaginase is an integral component of multiagent chemotherapy regimens for the treatment of children with acute lymphoblastic leukemia. Positive outcomes are seen in patients who are able to complete their entire prescribed course of asparaginase therapy. Toxicities associated with asparaginase use include hypersensitivity (clinical and subclinical), pancreatitis, thrombosis, encephalopathy, and liver dysfunction. Depending on the nature and severity of the toxicity, asparaginase therapy may be altered or discontinued in some patients. Clinical hypersensitivity is the most common asparaginase-associated toxicity requiring treatment discontinuation, occurring in up to 30% of patients receiving Escherichia coli-derived asparaginase. The ability to rapidly identify and manage asparaginase-associated toxicity will help ensure patients receive the maximal benefit from asparaginase therapy. This review will provide an overview of the common toxicities associated with asparaginase use and recommendations for treatment management.
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Affiliation(s)
- Nobuko Hijiya
- a Division of Hematology/Oncology/Stem Cell Transplant, Ann & Robert H. Lurie Children's Hospital of Chicago and Department of Pediatrics, Feinberg School of Medicine , Northwestern University , Chicago , IL , USA
| | - Inge M van der Sluis
- b Department of Pediatric Oncology/Hematology , Erasmus MC-Sophia Children's Hospital , Rotterdam , The Netherlands
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Ko RH, Jones TL, Radvinsky D, Robison N, Gaynon PS, Panosyan EH, Avramis IA, Avramis VI, Rubin J, Ettinger LJ, Seibel NL, Dhall G. Allergic reactions and antiasparaginase antibodies in children with high-risk acute lymphoblastic leukemia: A children's oncology group report. Cancer 2015; 121:4205-11. [PMID: 26308766 DOI: 10.1002/cncr.29641] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Revised: 07/17/2015] [Accepted: 07/21/2015] [Indexed: 11/05/2022]
Abstract
BACKGROUND The objectives of this study were to assess the incidence of clinical allergy and end-induction antiasparaginase (anti-ASNase) antibodies in children with high-risk acute lymphoblastic leukemia treated with pegylated (PEG) Escherichia coli ASNase and to determine whether they carry any prognostic significance. METHODS Of 2057 eligible patients, 1155 were allocated to augmented arms in which PEG ASNase replaced native ASNase postinduction. Erwinia chrysanthemi (Erwinia) ASNase could be used to replace native ASNase after allergy, if available. Allergy and survival data were complete for 990 patients. End-induction antibody titers were available for 600 patients. RESULTS During the consolidation phase, 289 of 990 patients (29.2%) had an allergic reaction. There were fewer allergic reactions to Erwinia ASNase than to native ASNase (odds ratio, 4.33; P < .0001) or PEG ASNase (odds ratio, 3.08; P < .0001) only during phase 1 of interim maintenance. There was no significant difference in 5-year event-free survival (EFS) between patients who received PEG ASNase throughout the entire study postinduction versus those who developed an allergic reaction to PEG ASNase during consolidation phase and subsequently received Erwinia ASNase (80.8% ± 2.8% and 81.6% ± 3.8%, respectively; P = .66). Patients who had positive antibody titers postinduction were more likely to have an allergic reaction to PEG ASNase (odds ratio, 2.4; P < .001). The 5-year EFS rate between patients who had negative versus positive antibody titers (80% ± 2.6% and 77.7% ± 4.3%, respectively; P = .68) and between patients who did not receive any ASNase postconsolidation and those who received PEG ASNase throughout the study (P = .22) were significantly different. CONCLUSIONS The current results demonstrate differences in the incidence rates of toxicity between ASNase preparations but not in EFS. The presence of anti-ASNase antibodies did not affect EFS.
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Affiliation(s)
- Richard H Ko
- Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, California.,Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Tamekia L Jones
- Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, Tennessee
| | - David Radvinsky
- State University of New York of New York Downstate Medical Center, Brooklyn New York
| | - Nathan Robison
- Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, California.,Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Paul S Gaynon
- Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, California.,Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Eduard H Panosyan
- Division of Pediatric Hematology and Oncology, Harbor-University of California Los Angeles Medical Center, Torrance, California
| | - Ioannis A Avramis
- Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, California
| | - Vassilios I Avramis
- Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, California.,Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Joan Rubin
- Department of Pediatrics, St. Peter's University Hospital, New Brunswick, New Jersey
| | | | - Nita L Seibel
- Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland
| | - Girish Dhall
- Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, California.,Keck School of Medicine, University of Southern California, Los Angeles, California
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Bhojwani D, Darbandi R, Pei D, Ramsey LB, Chemaitilly W, Sandlund JT, Cheng C, Pui CH, Relling MV, Jeha S, Metzger ML. Severe hypertriglyceridaemia during therapy for childhood acute lymphoblastic leukaemia. Eur J Cancer 2014; 50:2685-94. [PMID: 25087182 DOI: 10.1016/j.ejca.2014.06.023] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2014] [Revised: 06/07/2014] [Accepted: 06/30/2014] [Indexed: 01/19/2023]
Abstract
BACKGROUND Asparaginase and steroids can cause hypertriglyceridaemia in children with acute lymphoblastic leukaemia (ALL). There are no guidelines for screening or management of patients with severe hypertriglyceridaemia (>1000mg/dL) during ALL therapy. PATIENTS AND METHODS Fasting lipid profiles were obtained prospectively at four time-points for 257 children consecutively enrolled on a frontline ALL study. Risk factors were evaluated by the exact chi-square test. Details of adverse events and management of hypertriglyceridaemia were extracted retrospectively. RESULTS Eighteen of 257 (7%) patients developed severe hypertriglyceridaemia. Older age and treatment with higher doses of asparaginase and steroids on the standard/high-risk arm were significant risk factors. Severe hypertriglyceridaemia was not associated with pancreatitis after adjustment for age and treatment arm or with osteonecrosis after adjustment for age. However, patients with severe hypertriglyceridaemia had a 2.5-3 times higher risk of thrombosis compared to patients without, albeit the difference was not statistically significant. Of the 30 episodes of severe hypertriglyceridaemia in 18 patients, seven were managed conservatively while the others with pharmacotherapy. Seventeen of 18 patients continued to receive asparaginase and steroids. Triglyceride levels normalised after completion of ALL therapy in all 12 patients with available measurements. CONCLUSION Asparaginase- and steroid-induced transient hypertriglyceridaemia can be adequately managed with dietary modifications and close monitoring without altering chemotherapy. Patients with severe hypertriglyceridaemia were not at increased risk of adverse events, with a possible exception of thrombosis. The benefit of pharmacotherapy in decreasing symptoms and potential complications requires further investigation.
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Affiliation(s)
- Deepa Bhojwani
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA; Department of Pediatrics, University of Tennessee Health Sciences Center, Memphis, TN, USA.
| | - Rashid Darbandi
- Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Deqing Pei
- Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Laura B Ramsey
- Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Wassim Chemaitilly
- Department of Pediatrics, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - John T Sandlund
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA; Department of Pediatrics, University of Tennessee Health Sciences Center, Memphis, TN, USA
| | - Cheng Cheng
- Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Ching-Hon Pui
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA; Department of Pediatrics, University of Tennessee Health Sciences Center, Memphis, TN, USA
| | - Mary V Relling
- Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Sima Jeha
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA; Department of Pediatrics, University of Tennessee Health Sciences Center, Memphis, TN, USA
| | - Monika L Metzger
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA; Department of Pediatrics, University of Tennessee Health Sciences Center, Memphis, TN, USA
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38
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Masurekar A, Fong C, Hussein A, Revesz T, Hoogerbrugge PM, Love S, Ciria C, Parker C, Krishnan S, Saha V. The optimal use of PEG-asparaginase in relapsed ALL--lessons from the ALLR3 Clinical Trial. Blood Cancer J 2014; 4:e203. [PMID: 24769644 PMCID: PMC4003420 DOI: 10.1038/bcj.2014.26] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Affiliation(s)
- A Masurekar
- Children's Cancer Group, Manchester Academic Health Sciences Centre, Institute of Cancer, University of Manchester, Manchester, UK
| | - C Fong
- Children's Cancer Group, Manchester Academic Health Sciences Centre, Institute of Cancer, University of Manchester, Manchester, UK
| | - A Hussein
- Children's Cancer Group, Manchester Academic Health Sciences Centre, Institute of Cancer, University of Manchester, Manchester, UK
| | - T Revesz
- Department of Haematology-Oncology, SA Pathology at Women's and Children's Hospital and University of Adelaide, Adelaide, South Australia, Australia
| | - P M Hoogerbrugge
- Childrens Hospital, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
- Dutch 17 Childhood Oncology Group, The Hague, The Netherlands
| | - S Love
- Centre for Statistics in Medicine, University of Oxford, Oxford, UK
| | - C Ciria
- Centre for Statistics in Medicine, University of Oxford, Oxford, UK
| | - C Parker
- Children's Cancer Group, Manchester Academic Health Sciences Centre, Institute of Cancer, University of Manchester, Manchester, UK
| | - S Krishnan
- Children's Cancer Group, Manchester Academic Health Sciences Centre, Institute of Cancer, University of Manchester, Manchester, UK
- Department of Paediatric Oncology, Tata Translational Cancer Research Centre, Kolkata, India
| | - V Saha
- Children's Cancer Group, Manchester Academic Health Sciences Centre, Institute of Cancer, University of Manchester, Manchester, UK
- Department of Paediatric Oncology, Tata Translational Cancer Research Centre, Kolkata, India
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39
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Raja RA, Schmiegelow K, Albertsen BK, Prunsild K, Zeller B, Vaitkeviciene G, Abrahamsson J, Heyman M, Taskinen M, Harila-Saari A, Kanerva J, Frandsen TL. Asparaginase-associated pancreatitis in children with acute lymphoblastic leukaemia in the NOPHO ALL2008 protocol. Br J Haematol 2014; 165:126-33. [PMID: 24428625 DOI: 10.1111/bjh.12733] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2013] [Accepted: 12/02/2013] [Indexed: 01/12/2023]
Abstract
L-asparaginase is an important drug in the treatment of childhood acute lymphoblastic leukaemia (ALL). Treatment is associated with several toxicities, including acute pancreatitis. Clinical course, presentation, re-exposure to L-asparginase after pancreatitis and risk of recurrent pancreatitis within an asparaginase-intensive protocol has been poorly reported. Children (1-17 years) on the ongoing Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol with asparaginase-associated pancreatitis (AAP) diagnosed between 2008 and 2012 were identified through the online NOPHO ALL toxicity registry. NOPHO ALL2008 includes eight or 15 doses of intramuscular pegylated L-asparginase (PEG-asparaginase) 1000 iu/m(2) /dose at 2-6 weeks intervals, with a total of 30 weeks of exposure to PEG-asparaginase (clinicaltrials.gov no: NCT00819351). Of 786 children, 45 were diagnosed with AAP with a cumulative risk of AAP of 5·9%. AAP occurred after a median of five doses (range 1-13), and 11 d (median) from the latest administration of PEG-Asparaginase. Thirteen patients developed pseudocysts (30%) and 11 patients developed necrosis (25%). One patient died from pancreatitis. Twelve AAP patients were re-exposed to L-asparginase, two of whom developed mild AAP once more, after four and six doses respectively. In conclusion, re-exposure to PEG-asparaginase in ALL patients with mild AAP seems safe.
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Affiliation(s)
- Raheel A Raja
- Department of Paediatric and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark
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