The toxicity of very prolonged courses of PEGasparaginase or Erwinia asparaginase in relation to asparaginase activity, with a special focus on dyslipidemia

Tong, Wing H.; Pieters, Rob; Groot-Kruseman, Hester A. de; Hop, Wim C. J.; Boos, Joachim; Tissing, Wim J. E.; Sluis, Inge M. van der

doi:10.3324/haematol.2014.109413

Cited by 67 publications

(120 citation statements)

References 16 publications

(15 reference statements)

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“…The incidence rates of hyperglycemia and hypertriglyceridemia in both groups were also similar with some previous studies174344. Furthermore, two endocrine complications were commonly observed in induction regimen (data not shown), which included a large dose of prednisone.…”

Section: Discussionsupporting

confidence: 89%

Use of PEG-asparaginase in newly diagnosed adults with standard-risk acute lymphoblastic leukemia compared with E. coli-asparaginase: a retrospective single-center study

Liu

Wang²,

Wang³

et al. 2016

Sci Rep

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Acute lymphoblastic leukemia (ALL) is a heterogeneous disease, and the long-term survival varies with different ages. We performed a retrospective analysis of 122 newly diagnosed adults with standard-risk ALL treated with Escherichia coli asparaginase (E. coli-asparaginase, n = 50) and polyethylene glycol-conjugated asparaginase (PEG-asparaginase, n = 72). No treatment-related mortality (TRM) occurred in the E. coli-asparaginase group, and 3 TRM events occurred in the PEG-asparaginase group without relation to asparaginase. In addition, 22 (44.0%) and 48 (66.7%) patients achieved a complete response (CR) on day 14 in the E. coli-asparaginase and PEG-asparaginase groups, respectively (P = 0.032). No different 5-year event-free survival (EFS) or overall survival (OS) rate (P = 0.632 and 0.769) was observed. Multivariate analysis revealed later CR (P = 0.008) and older age (P = 0.049) as adverse prognostic factors for both EFS and OS. In addition, we specifically monitored the known adverse effects of asparaginase, and no asparaginase-related death was observed. Allergy occurred in 9 patients using E. coli-asparaginase, and no patient in the PEG-asparaginase group suffered from allergies (P < 0.001). The incidence of other asparaginase-related toxicities was similar. We conclude that PEG-asparaginase can be safely and effectively used as asparaginase in adults with newly diagnosed standard-risk ALL.

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Section: Discussionsupporting

confidence: 89%

Use of PEG-asparaginase in newly diagnosed adults with standard-risk acute lymphoblastic leukemia compared with E. coli-asparaginase: a retrospective single-center study

Liu

Wang²,

Wang³

et al. 2016

Sci Rep

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“…Dexamethasone treatment was reduced from 12 to 8 mg/m 2 /day in SHR patients at week 7 (beginning of reinduction I) in both protocols, implicating high‐dose PEG‐asparaginase as the driver in the development of hypertriglyceridemia. As has been shown previously in a small subset of TXVI, no patients on Erwinia asparaginase developed grade 4 hypertriglyceridemia. Patients on SHR therapy maintained a persistent increase in triglycerides as compared to LR patients.…”

Section: Discussionsupporting

confidence: 58%

“…However, there are few large‐scale studies to support hypertriglyceridemia as an independent risk factor. In the general population, triglycerides >1000 mg/dL have been associated with pancreatitis, but this has not been confirmed for patients with ALL …”

Section: Introductionmentioning

confidence: 99%

Asparaginase formulation impacts hypertriglyceridemia during therapy for acute lymphoblastic leukemia

Finch

Smith

Yang

et al. 2019

Pediatric Blood & Cancer

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Background Glucocorticoids and asparaginase, used to treat acute lymphoblastic leukemia (ALL), can cause hypertriglyceridemia. We compared triglyceride levels, risk factors, and associated toxicities in two ALL trials at St. Jude Children's Research Hospital with identical glucocorticoid regimens, but different asparaginase formulations. In Total XV (TXV), native Escherichia coli l‐asparaginase was front‐line therapy versus the pegylated formulation (PEG‐asparaginase) in Total XVI (TXVI). Procedure Patients enrolled on TXV (n = 498) and TXVI (n = 598) were assigned to low‐risk (LR) or standard/high‐risk (SHR) treatment arms (ClinicalTrials.gov identifiers: NCT00137111 and NCT00549848). Triglycerides were measured four times and were evaluable in 925 patients (TXV: n = 362; TXVI: n = 563). The genetic contribution was assessed using a triglyceride polygenic risk score (triglyceride‐PRS). Osteonecrosis, thrombosis, and pancreatitis were prospectively graded. Results The largest increase in triglycerides occurred in TXVI SHR patients treated with dexamethasone and PEG‐asparaginase (4.5‐fold increase; P <1 × 10−15). SHR patients treated with PEG‐asparaginase (TXVI) had more severe hypertriglyceridemia (>1000 mg/dL) compared to native l‐asparaginase (TXV): 10.5% versus 5.5%, respectively (P = .007). At week 7, triglycerides did not increase with dexamethasone treatment alone (LR patients) but did increase with dexamethasone plus asparaginase (SHR patients). The variability in triglycerides explained by the triglyceride‐PRS was highest at baseline and declined with therapy. Hypertriglyceridemia was associated with osteonecrosis (P = .0006) and thrombosis (P = .005), but not pancreatitis (P = .4). Conclusion Triglycerides were affected more by PEG‐asparaginase than native l‐asparaginase, by asparaginase more than dexamethasone, and by drug effects more than genetics. It is not clear whether triglycerides contribute to thrombosis and osteonecrosis or are biomarkers of the toxicities.

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“…[82] Asparaginase therapy has also been associated with nonantibody-mediated infusion reactions that may result from spikes in serum ammonia levels. [83][84][85][86] Ammonia accumulation occurs as asparaginase facilitates the rapid conversion of asparagine and glutamine to aspartic acid and glutamic acid, with ammonia as the shared by-product of both reactions. [10] Symptoms of hyperammonemia are often transient in nature and can include nausea, vomiting, headache, dizziness, and rash.…”

Section: Infusion-related Adverse Eventsmentioning

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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The toxicity of very prolonged courses of PEGasparaginase or Erwinia asparaginase in relation to asparaginase activity, with a special focus on dyslipidemia

Cited by 67 publications

References 16 publications

Use of PEG-asparaginase in newly diagnosed adults with standard-risk acute lymphoblastic leukemia compared with E. coli-asparaginase: a retrospective single-center study

Use of PEG-asparaginase in newly diagnosed adults with standard-risk acute lymphoblastic leukemia compared with E. coli-asparaginase: a retrospective single-center study

Asparaginase formulation impacts hypertriglyceridemia during therapy for acute lymphoblastic leukemia

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

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