Asparaginase-associated toxicity in children with acute lymphoblastic leukemia

Hijiya, Nobuko; Sluis, Inge M. van der

doi:10.3109/10428194.2015.1101098

Cited by 210 publications

(204 citation statements)

References 108 publications

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“…In this study, 8.7% of patients exposed to L-asparaginase had documented clinical hypersensitivity reactions, which is consistent with reported incidence rates with native E. coli L-asparaginase (0%-45%) or PEG-L-asparaginase (3%-24%). 27 This relative low incidence could be explained in part by the concomitant use of steroids because immune-suppressive therapy decreases the risk of hypersensitivity reactions by a reduction of high titer antibodies. 28,29 Detection of antibodies was not performed in this study, but it has been previously reported that silent inactivation occurs in 8% to 29% of patients with ALL receiving L-asparaginase.…”

Section: Discussionmentioning

confidence: 99%

Antithrombin and fibrinogen levels as predictors for plasma L‐asparaginase activity in children with acute lymphoblastic leukemia

Merlen

Bonnefoy

Afeich

et al. 2019

Pediatric Blood & Cancer

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Background L‐asparaginase is a cornerstone treatment for children with acute lymphoblastic leukemia (ALL). However, immune reaction to the drug may increase the clearance or impair the function of L‐asparaginase and reduces its therapeutic efficacy. The objective of this study was to identify potential plasma proteins that could be used as proxies for L‐asparaginase activity. Methods Fibrinogen, von Willebrand factor antigen (VWF:Ag), total protein, and albumin levels as well as antithrombin (AT) and L‐asparaginase activities were measured in 97 children with ALL treated for prolonged period of time with L‐asparaginase. Binary logistic regression and a receiver operating characteristic (ROC) curve analysis were performed to evaluate the predictive value of plasma proteins for L‐asparaginase activity. Results Median E. coli L‐asparaginase activity was 220 IU/L (range, 0–1308) throughout the treatment period. L‐asparaginase activity was below 100 IU/L in 23% of measured samples. L‐asparaginase activity was inversely associated with AT activity, fibrinogen, total protein, and albumin levels (r = −0.63, −0.62, −0.57, and −0.45, respectively; P < 0.0001), but not with VWF:Ag. ROC curve analyses showed an intermediate accuracy of AT activity (area under the ROC curve [AUC] = 0.77) to detect specimens with subtherapeutic level of L‐asparaginase. An optimal accuracy was found when AT and fibrinogen were combined (AUC = 0.82; sensitivity = 75%; specificity = 82%; positive predictive value = 55%; negative predictive value = 92%) with cutoff values of 0.73 IU/mL and 1.85 g/L, respectively. Conclusions AT combined with fibrinogen levels could be used as a proxy to identify patients with therapeutic level of L‐asparaginase activity in the absence of real‐time asparaginase measurement during prolonged exposure to L‐asparaginase.

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Section: Discussionmentioning

confidence: 99%

Antithrombin and fibrinogen levels as predictors for plasma L‐asparaginase activity in children with acute lymphoblastic leukemia

Merlen

Bonnefoy

Afeich

et al. 2019

Pediatric Blood & Cancer

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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).…”

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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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“…However, the results of clinical trials, in which prednisone and dexamethasone were administered simultaneously with 6-mercaptopurine and methotrexate, suggest hepatotoxicity and increased activity of liver enzymes, most likely as a consequence of the application of cytostatics [12]. Th e increase in activity of ALT, AST and GGT obtained in this study, are not typical side effects of antineoplastic drugs used according to the protocol [18][19][20][21], but could be explained as result of their concomitant application and interaction with prednisone and dexamethasone, as published in another studies [22,23]. Information in the literature suggest that glucocorticoids may cause disorders of the values of urea and uric acid [9].…”

Section: Discussionmentioning

confidence: 71%

Safety and tolerability of high doses of glucocorticoides

Rakić¹,

Kolarovic²,

Konstantinidis³

et al. 2016

Hosp Pharm Int Multi J

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SUMMARYIntroduction: Treatment of acute lymphoblastic leukemia includes the use of high doses of glucocorticoides (prednisone and dexamethasone), which signifi cantly increase the success of therapy due to lymphocytolitic eff ect. The aim: The aim of the study was to determine tolerability of high doses of prednisone and dexamethasone in children with acute lymphoblastic leukemia and the structure and the intensity of adverse eff ects, occurred after application of these medicines. Subjects and methods:In a prospective study, we analyzed adverse eff ects of high doses of glucocorticoides in children suff ering acute lymphoblastic leukemia treated in the Institute for Child and Youth Health Care of Vojvodina, since December 2010. until October 2014, were analyzed. This study included 18 patients, aged from 2 to 15 years. Results: Hyperglycemia appeared in 89% of patients treated with prednisone and in 61% of patients treated with dexamethasone. In order to control the high blood glucose level (above 10 mmol /L), in 11% of patients insulin was used. Hypertension appeared in 28% patients treated with prednisone and dexamethasone. Antihypertensives were needed for regulation in 17% patients. Hypopotassemia and hypocalcaemia were signifi cantly more expressed after the use of prednisone in comparison to dexamethasone. In 11% of patients, the treatment with dexamethasone caused depressive behavior, followed by agitation. Conclusion: Adverse eff ects of dexamethasone and prednisone, administered in high doses in children with ALL were known, expected and reversible. Adverse reactions usually disappeared spontaneously or after short-term symptomatic therapy.

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Asparaginase-associated toxicity in children with acute lymphoblastic leukemia

Cited by 210 publications

References 108 publications

Antithrombin and fibrinogen levels as predictors for plasma L‐asparaginase activity in children with acute lymphoblastic leukemia

Antithrombin and fibrinogen levels as predictors for plasma L‐asparaginase activity in children with acute lymphoblastic leukemia

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

Safety and tolerability of high doses of glucocorticoides

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