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Pegaspargase: A Review in Acute Lymphoblastic Leukaemia.

ABSTRACT: Pegaspargase (Oncaspar^®), a pegylated form of native Escherichia coli-derived L-asparaginase (hereafter referred as E. coliL-asparaginase), is indicated in the USA and EU for the treatment of acute lymphoblastic leukaemia (ALL) as a component of multi-agent chemotherapy in paediatric and adult patients. Relative to E. coliL-asparaginase, pegaspargase has a prolonged circulation time, thereby offering less frequent administration. Moreover, pegylation of E. coliL-asparaginase may diminish the immunogenicity of the enzyme. Based on extensive evidence, intramuscular (IM) or intravenous (IV) administration of pegaspargase as a component of a multi-agent chemotherapy is an effective first-line treatment for paediatric and adult patients with ALL, as well as for the treatment of paediatric and adult patients with ALL and hypersensitivity to E. coliL-asparaginase. Pegaspargase had a manageable tolerability profile in paediatric and adult patients with newly diagnosed ALL, with the most commonly occurring adverse events being generally consistent to that seen with E. coliL-asparaginase. Pegaspargase treatment in patients with relapsed ALL and hypersensitivity to E. coliL-asparaginase had a similar tolerability profile to that observed in patients with newly diagnosed ALL. Given the potentially reduced immunogenicity and more convenient dosage regimen over E. coliL-asparaginase, pegaspargase remains an important and effective treatment option for paediatric and adult patients with ALL, including those with hypersensitivity to E. coliL-asparaginase.

SUBMITTER: Heo YA

PROVIDER: S-EPMC6531401 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Pegaspargase: A Review in Acute Lymphoblastic Leukaemia.

Heo Young-A YA Syed Yahiya Y YY Keam Susan J SJ

Drugs 20190501 7

Pegaspargase (Oncaspar<sup>®</sup>), a pegylated form of native Escherichia coli-derived L-asparaginase (hereafter referred as E. coliL-asparaginase), is indicated in the USA and EU for the treatment of acute lymphoblastic leukaemia (ALL) as a component of multi-agent chemotherapy in paediatric and adult patients. Relative to E. coliL-asparaginase, pegaspargase has a prolonged circulation time, thereby offering less frequent administration. Moreover, pegylation of E. coliL-asparaginase may dimin ...[more]

PMID: 31030380

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Project description:Relapsed acute lymphoblastic leukaemia (ALL) is a leading cause of death due to disease in young people, but the biological determinants of treatment failure remain poorly understood. Recent genome-wide profiling of structural DNA alterations in ALL have identified multiple submicroscopic somatic mutations targeting key cellular pathways, and have demonstrated substantial evolution in genetic alterations from diagnosis to relapse. However, DNA sequence mutations in ALL have not been analysed in detail. To identify novel mutations in relapsed ALL, we resequenced 300 genes in matched diagnosis and relapse samples from 23 patients with ALL. This identified 52 somatic non-synonymous mutations in 32 genes, many of which were novel, including the transcriptional coactivators CREBBP and NCOR1, the transcription factors ERG, SPI1, TCF4 and TCF7L2, components of the Ras signalling pathway, histone genes, genes involved in histone modification (CREBBP and CTCF), and genes previously shown to be targets of recurring DNA copy number alteration in ALL. Analysis of an extended cohort of 71 diagnosis-relapse cases and 270 acute leukaemia cases that did not relapse found that 18.3% of relapse cases had sequence or deletion mutations of CREBBP, which encodes the transcriptional coactivator and histone acetyltransferase CREB-binding protein (CREBBP, also known as CBP). The mutations were either present at diagnosis or acquired at relapse, and resulted in truncated alleles or deleterious substitutions in conserved residues of the histone acetyltransferase domain. Functionally, the mutations impaired histone acetylation and transcriptional regulation of CREBBP targets, including glucocorticoid responsive genes. Several mutations acquired at relapse were detected in subclones at diagnosis, suggesting that the mutations may confer resistance to therapy. These results extend the landscape of genetic alterations in leukaemia, and identify mutations targeting transcriptional and epigenetic regulation as a mechanism of resistance in ALL.

Dataset Information

Pegaspargase: A Review in Acute Lymphoblastic Leukaemia.

Publications

Pegaspargase: A Review in Acute Lymphoblastic Leukaemia.

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