Genetic predisposition to <scp>PEG</scp>‐asparaginase hypersensitivity in children treated according to <scp>NOPHO ALL</scp>2008

Højfeldt, Sofie Gottschalk; Wolthers, Benjamin Ole; Tulstrup, Morten; Abrahamsson, Jonas; Gupta, Ramneek; Harila‐Saari, Arja; Heyman, Mats; Henriksen, Louise Tram; Jónsson, Òlafur G.; Lähteenmäki, Päivi; Lund, Bendik; Pruunsild, Kaie; Vaitkevičienė, Goda; Schmiegelow, Kjeld; Albertsen, Birgitte Klug

doi:10.1111/bjh.15660

Cited by 34 publications

(26 citation statements)

References 48 publications

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“…63 Additionally, NOPHO ALL2008, through a genome-wide association study (GWAS), correlated several genetic variants to an increased incidence of pegaspargase hypersensitivity. 64 The Dutch Childhood Oncology Group (DCOG) ALL-10 study enrolled children ages 1-18 years with newly diagnosed ALL from 2009-2012. 65 Patients were stratified into 3 risk groups after induction therapy (standard, medium and high) and all received 8 doses of native E. coli asparaginase (5000 IU/m 2 per dose) every 3 days in induction.…”

Section: Hypersensitivity To Pegaspargasementioning

confidence: 99%

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

Bender¹,

Maese²,

Carter-Febres³

et al. 2021

BLCTT

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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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Section: Hypersensitivity To Pegaspargasementioning

confidence: 99%

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

Bender¹,

Maese²,

Carter-Febres³

et al. 2021

BLCTT

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“…Studies included in this review added new knowledge to genes and polymorphisms that could play a role in asparaginase toxicity. Previous studies found associations between polymorphisms in asparagine synthase (ASNS gene), human leukocyte antigens (HLA gene) (Abaji and Krajinovic, 2016) and the glutamate receptor (GRIA1 gene) and asparaginase toxicity (Lee and Yang, 2017;Lopez-Santillan et al, 2017;Hojfeldt et al, 2019).…”

Section: Genetic Variances and Toxicitymentioning

confidence: 99%

“…A GWAS by Højfeldt et al. (2019) found a significant higher risk of hypersensitivity with CCR4-NOT Transcription Complex Subunit 3 ( CNOT3) (rs73062673).…”

Section: Role Of Pharmacogenetic Variations In Chemotherapeutic Relatmentioning

confidence: 99%

Pharmacogenomics as a Tool to Limit Acute and Long-Term Adverse Effects of Chemotherapeutics: An Update in Pediatric Oncology

et al. 2020

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“…In 2019, Højfeldt and collaborators performed a GWAS on a cohort of ALL pediatric patients treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol: they analyzed 59 cases and 772 controls. Authors found an association between the intronic variant rs73062673 (T > C) in CCR4‐NOT transcription complex subunit 3 ( CNOT3 ) and asparaginase hypersensitivity (OR = 3.7, 95% CI, 2.33–5.98, p = 4.68 × 10 −8 ) (Højfeldt et al, 2019). Although they did not find the genetic contribution of HLA‐DRB1 rs17885382, this GWAS result supported the hypothesis that the regulation of HLA genes could play an important role in the development of asparaginase hypersensitivity.…”

Section: Asparaginase Induced Adverse Effectsmentioning

confidence: 99%

Genome wide association studies for treatment‐related adverse effects of pediatric acute lymphoblastic leukemia

Franca

Zudeh

Lucafò

et al. 2020

WIREs Mechanisms of Disease

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Acute lymphoblastic leukemia (ALL) is the most common pediatric hematological malignancy; notwithstanding the success of ALL therapy, severe adverse drugs effects represent a serious issue in pediatric oncology, because they could be both an additional life threatening condition for ALL patients per se and a reason to therapy delay or discontinuation with important fallouts on final outcome. Cancer treatment‐related toxicities have generated a significant need of finding predictive pharmacogenomic markers for the a priori identification of at risk patients. In the era of precision medicine, high throughput genomic screening such as genome wide association studies (GWAS) might provide useful markers to tailor therapy intensity on patients' genetic profile. Furthermore, these findings could be useful in basic research for better understanding the mechanistic and regulatory pathways of the biological functions associated with ALL treatment toxicities. The purpose of this review is to give an overview of high throughput genomic screening of the last 10 years that had investigated the landscape of ALL treatment‐associated toxicities. This article is categorized under: Cancer > Genetics/Genomics/Epigenetics

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Genetic predisposition to PEG‐asparaginase hypersensitivity in children treated according to NOPHO ALL2008

Abstract: a Shared last co-authorship to identify PEG-asparaginase hypersensitivity.

Cited by 34 publications

References 48 publications

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

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

Pharmacogenomics as a Tool to Limit Acute and Long-Term Adverse Effects of Chemotherapeutics: An Update in Pediatric Oncology

Genome wide association studies for treatment‐related adverse effects of pediatric acute lymphoblastic leukemia

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