Reactions related to asparaginase infusion in a 10-year retrospective cohort

Santos, Amanda Cabral dos; Land, Marcelo Gerardin Poirot; Silva, Nathalia Peroni da; Santos, Kelly Oliveira; Lima, Elisângela da Costa

doi:10.1016/j.bjhh.2017.08.002

Cited by 16 publications

(22 citation statements)

References 21 publications

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“…Finally, high-risk classification of ALL and younger age were found to be risk factors for the development of hypersensitivity reactions in a recent study on 72 children treated according to the German ALL-BFM-IC protocol. 40 These data suggest that further investigation is required to determine whether factors such as age, risk stratification, or ALL subtypes would influence these findings.…”

Section: Ta B L E 1 Diagnostic Accuracy Of Plasma Proteins For L-aspamentioning

confidence: 96%

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: Ta B L E 1 Diagnostic Accuracy Of Plasma Proteins For L-aspamentioning

confidence: 96%

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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“…The predicted allergenic T-cell epitopes are summarized in Supplementary Table B.2. Hypersensitivity reactions caused by E. coli ASNase have been widely studied in vivo due to their high incidence [100][101][102][103]. However, fungal ASNase has not been explored in this regard.…”

Section: Resultsmentioning

confidence: 99%

Immunogenicity assessment of fungal l-asparaginases: an in silico approach

et al. 2020

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Acute lymphoblastic leukemia is the most common cancer among children worldwide, characterized by an overproduction of undifferentiated lymphoblasts in the bone marrow. The enzyme l-asparaginase isolated from Escherichia coli and Dickeya chrysanthemi is a key factor in multiple therapies against this disease. Regardless of their effectiveness, these formulations present well-known adverse effects, highlighting the immunogenicity and allergenicity they cause. Some strategies have been adopted in this regard, such as PEGylation and modification by bioengineering as well as the search for new non-bacterial microorganisms producing the enzyme. Fungi have been shown to be asparaginase producers with high antitumor activity; however, little is known about the immunological features of fungal asparaginase. In this work, we developed the first immunoinformatics study focused on revealing the antigenic determinants that contribute to the immunogenicity of nine asparaginases of filamentous fungi experimentally tested, and compared them with the enzyme from E. coli. We were able to predict that the fungal asparaginases evaluated have a high degree of immunogenicity, which is an important result to consider if the aim is to produce clinical l-asparaginase from a fungal source. Likewise, for the first time, a bioinformatics-based approach was used to predict the immunogenic and allergenic epitopes present in fungal asparaginases.

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“…[2][3][4] On the other hand, the costs of ammonia dosage at the study site were US$1,50. 5 We did not propose the use of ammonia level for silent inactivation, only in the context of an infusion reaction.…”

Section: Response To Comment On Ammonia Level As a Proxy Of Asparaginase Inactivation In Children: A Strategy For Classification Of Infusmentioning

confidence: 98%

“…Unfortunately, infusions reactions to native E. coli asparaginase are frequent and severe in some cases. 5 Even though there is a gold standard for identifying inactivation, especially the silent one, the discussion of asparaginase monitoring alternatives in the pharmacovigilance scope keeps relevant to oncology practice.…”

Section: Response To Comment On Ammonia Level As a Proxy Of Asparaginase Inactivation In Children: A Strategy For Classification Of Infusmentioning

confidence: 99%

Response to comment on Ammonia level as a proxy of asparaginase inactivation in children: A strategy for classification of infusion reactions

Santos

Land

Lima

2021

J Oncol Pharm Pract

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effect. The characteristic points different from the patient treated by Pamp ın-Sa´nchez et al. were: 1) an EGFR mutation-positive patient, 2) relapse after the long-term control, and 3) re-response to EGFR-TKI. Although the efficacy of immune checkpoint inhibitors in EGFR mutation-positive patients has been limited, 2 our patient responded to nivolumab. We evaluated that it is desirable to refrain from high-dose corticosteroid administration in order to sustain the effects of immune checkpoint inhibitors. We do agree with the conclusion by Pamp ın-Sa´nchez et al. 1 that suspension of treatment with close monitoring of these patients until progression may be an alternative, since immune-related toxicities could be related to a greater clinical benefit and a durable response to nivolumab.

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Reactions related to asparaginase infusion in a 10-year retrospective cohort

Cited by 16 publications

References 21 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

Immunogenicity assessment of fungal l-asparaginases: an in silico approach

Response to comment on Ammonia level as a proxy of asparaginase inactivation in children: A strategy for classification of infusion reactions

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