Toxicity profile of repeated doses of <scp>PEG</scp>‐asparaginase incorporated into a pediatric‐type regimen for adult acute lymphoblastic leukemia

Aldoss, Ibrahim; Douer, Dan; Behrendt, Carolyn E.; Chaudhary, Preeti; Mohrbacher, Ann; Vrona, Janice; Pullarkat, Vinod

doi:10.1111/ejh.12600

Cited by 69 publications

(86 citation statements)

References 15 publications

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“…[44,45] Within the last 15 years, reported rates of hypersensitivity in clinical trials have varied across studies using different routes of administration and asparaginases (Table 2). [14,[23][24][25]34,38,42,[46][47][48][49][50][51][52][53][54][55][56][57][58][59][60] Recently, a number of retrospective reports have compared the incidence of hypersensitivity between IV and IM PEG-asparaginase (Table 3). [8,34,[60][61][62][63][64] In a pediatric study of 318 patients, Petersen et al reported a 9% greater incidence of hypersensitivity following IV administration of PEG-asparaginase compared with IM PEG-asparaginase (p ¼ .028).…”

Section: Asparaginase Pharmacokineticsmentioning

confidence: 99%

Differentiating hypersensitivity versus infusion-related reactions in pediatric patients receiving intravenous asparaginase therapy for acute lymphoblastic leukemia

Burke

Rheingold

2016

Leukemia & Lymphoma

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Asparaginase is a key component of therapy for acute lymphoblastic leukemia (ALL). Traditionally, asparaginase was administered intramuscularly but is now commonly given intravenously. Although intravenous administration is less painful, it can be challenging to differentiate hypersensitivity versus infusion-related reactions. The ability to distinguish between asparaginase-mediated reactions is critical to ensure optimal asparaginase treatment. In this paper, we will review the differences in pharmacokinetics and toxicities, when asparaginase is administered intravenously versus intramuscularly in pediatric patients with ALL. Differences between antibody-mediated hypersensitivity events and nonantibody-mediated infusion reactions will be addressed to assist practitioners in distinguishing between these clinically similar asparaginase-associated toxicities.ARTICLE HISTORY

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Section: Asparaginase Pharmacokineticsmentioning

confidence: 99%

Differentiating hypersensitivity versus infusion-related reactions in pediatric patients receiving intravenous asparaginase therapy for acute lymphoblastic leukemia

Burke

Rheingold

2016

Leukemia & Lymphoma

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“…The L-glutaminase activity of these bacterial L-asparaginases is significant, ϳ2% of the EcA activity and as high as 10% for ErA (3). Of note, the L-glutaminase activity of the clinically used L-asparaginases has been implicated in many of the side effects of this treatment, which include immunosuppression (2, 6, 7), hepatotoxicity (8), pancreatitis (9), and coagulation dysfunction (9,10). Many of the side effects are believed to be due to the disruption of protein synthesis induced by the L-glutaminase activity of L-asparaginase drugs (2,7,8,11,12).…”

mentioning

confidence: 99%

Design and Characterization of Erwinia Chrysanthemi l-Asparaginase Variants with Diminished l-Glutaminase Activity

Nguyen

Lavie

2016

Journal of Biological Chemistry

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Current FDA-approved L-asparaginases also possess significant L-glutaminase activity, which correlates with many of the toxic side effects of these drugs. Therefore, L-asparaginases with reduced L-glutaminase activity are predicted to be safer. We exploited our recently described structures of the Erwinia chrysanthemi L-asparaginase (ErA) to inform the design of mutants with diminished ability to hydrolyze L-glutamine. Structural analysis of these variants provides insight into the molecular basis for the increased L-asparagine specificity. A primary role is attributed to the E63Q mutation that acts to hinder the correct positioning of L-glutamine but not L-asparagine. The substitution of Ser-254 with either an asparagine or a glutamine increases the L-asparagine specificity but only when combined with the E63Q mutation. The A31I mutation reduces the substrate K m value; this is a key property to allow the required therapeutic L-asparagine depletion. Significantly, an ultra-low L-glutaminase ErA variant maintained its cell killing ability. By diminishing the L-glutaminase activity of these highly active L-asparaginases, our engineered ErA variants hold promise as L-asparaginases with fewer side effects.L-Asparaginases are amidohydrolases that catalyze the hydrolysis of the amino acid L-asparagine (Asn) 2 to L-aspartate (Asp) and ammonia. Currently, the Food and Drug Administration has approved the L-asparaginase from Escherichia coli (EcA) and Erwinia chrysanthemi (ErA) for treatment of select blood cancers. These enzyme drugs function by depleting Asn from the blood, thereby affecting certain blood cancers that are dependent on exogenous Asn. Sensitivity to L-asparaginase has been attributed to a reduced ability of those cancers to synthesize this amino acid de novo (1). Because the concentration of Asn in human blood is ϳ50 M (2), for an L-asparaginase to be clinically useful, its Asn K m value must be in the low micromolar range. This property is present in EcA (K m ϭ 15 M) and ErAPatients treated with L-asparaginase often confront two types of adverse effects. The first is due to an immune response against the bacterial enzymes. To decrease the immunogenicity, the current standard of care in the United States employs a PEGylated version of EcA (3, 4). If immunogenicity still arises, ErA is used as second line treatment (5).The second source of adverse effects of L-asparaginase treatment relates to the enzyme's ability to hydrolyze the amino acid L-glutamine (Glu). That is, in addition to catalyzing the hydrolysis of Asn (L-asparaginase activity), both EcA and ErA also catalyze the hydrolysis of Gln to L-glutamate (Glu) and ammonia (L-glutaminase activity). L-Glutamine is the most abundant amino acid in the blood with a concentration range of 400 -650 M (2). The L-glutaminase activity of these bacterial L-asparaginases is significant, ϳ2% of the EcA activity and as high as 10% for ErA (3). Of note, the L-glutaminase activity of the clinically used L-asparaginases has been implicated in many of the side effe...

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“…While different forms of the drug offer multiple options for patients who experience allergic reactions, all forms are associated with metabolic complications that are difficult to predict, yet intensify with age (1,2,13,16,22,28,31,50,52,62).…”

mentioning

confidence: 99%

General control nonderepressible 2 deletion predisposes to asparaginase-associated pancreatitis in mice

Phillipson-Weiner

Mirek

Wang

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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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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Toxicity profile of repeated doses of PEG‐asparaginase incorporated into a pediatric‐type regimen for adult acute lymphoblastic leukemia

Cited by 69 publications

References 15 publications

Differentiating hypersensitivity versus infusion-related reactions in pediatric patients receiving intravenous asparaginase therapy for acute lymphoblastic leukemia

Differentiating hypersensitivity versus infusion-related reactions in pediatric patients receiving intravenous asparaginase therapy for acute lymphoblastic leukemia

Design and Characterization of Erwinia Chrysanthemi l-Asparaginase Variants with Diminished l-Glutaminase Activity

General control nonderepressible 2 deletion predisposes to asparaginase-associated pancreatitis in mice

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