Influence of two different e.coli asparaginase preparations on coagulation and fibrinolysis: A randomized trial

Nowak‐Göttl, Ulrike; Boos, Joachim; Wolff, Johannes; Werber, G.; Ahlke, E.; Pollmann, H.; Jürgens, H.

doi:10.1016/0268-9499(94)90249-6

Cited by 23 publications

(27 citation statements)

References 11 publications

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“…These data are consistent with the notion that the risk of thrombosis may be higher in those with highest exposure to active asparaginase. 26,27 These data support our practice to substitute Erwinia asparaginase in patients who develop clinical hypersensitivity to native E. coli, asparaginase, and raise the concern of using PEG asparaginase (at the currently recommended dose) in this situation. It remains uncertain whether patients with subclinical hypersensitivity should receive an alternative asparaginase preparation even in the absence of clinical allergy.…”

Section: Discussionmentioning

confidence: 73%

Asparaginase pharmacodynamics differ by formulation among children with newly diagnosed acute lymphoblastic leukemia

Chen

et al. 2004

Leukemia

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Polyethylene glycol-conjugated (PEG) asparaginase is approved for use in patients who develop allergy to other forms of asparaginase, although its ability to deplete asparagine systemically in patients with hypersensitivity has not been well elucidated. In 53 children with newly diagnosed acute lymphoblastic leukemia, we serially assessed asparagine concentrations in cerebrospinal fluid (CSF) and plasma as well as serum anti-asparaginase antibodies. All patients received native Escherichia coli (Elspar) asparaginase during induction therapy; patients received PEG asparaginase during reinductions when available, and those who developed allergy received Erwinia asparaginase. All eight patients who developed clinical evidence of allergy to asparaginase had anti-asparaginase antibodies. Among patients who had no antibodies, those who received E. coli had lower mean (7s.d.) CSF asparagine (0.2970.63, n ¼ 9) than those who received PEG (0.7770.82, n ¼ 4) (P ¼ 0.007). Results were similar for plasma asparagine. There was no situation where asparagine concentrations were more effectively depleted by PEG than by other preparations. None of the five patients who developed thrombosis had an allergy or antibodies to asparaginase at the time of the thrombosis. We conclude that asparagine concentrations were less effectively depleted by PEG than by E. coli asparaginase at the doses commonly used. The risk of thrombosis may be affected by the intensity of asparaginase exposure.

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Section: Discussionmentioning

confidence: 73%

Asparaginase pharmacodynamics differ by formulation among children with newly diagnosed acute lymphoblastic leukemia

Chen

et al. 2004

Leukemia

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“…When evaluating only studies using E coli-ASP Medac, [73][74][75][76][77]82,83 IR of thrombosis did not change with different daily dosages of the drug.…”

Section: Subgroup Analysesmentioning

confidence: 99%

“…It has been previously observed in laboratory studies that Erwinase-ASP and some E coli-ASP preparations, such as L-ASP Crasnitin, only partially deplete the asparagine pool and are associated with fewer thrombotic complications, but also with a reduced antineoplastic efficacy. 3,47,59,83,85 As the degree of coagulation abnormalities correlates with ASP activity, 59,83,85 ASPrelated thrombotic risk appears to be a "price" to be paid to guarantee an effective treatment to ALL patients.…”

Section: Lower Doses Of Asp Given For a Longer Period Of Time Increasmentioning

confidence: 99%

Thrombotic complications in childhood acute lymphoblastic leukemia: a meta-analysis of 17 prospective studies comprising 1752 pediatric patients

Caruso

Iacoviello

Castelnuovo

et al. 2006

Blood

340

350

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The risk of thrombosis in children with acute lymphoblastic leukemia (ALL) reportedly ranges between 1% and 37%. Epidemiologic studies have usually been hampered by small numbers, making accurate estimates of thrombosis risk in ALL patients very difficult. The aim of this study was to better estimate the frequency of this complication and to define how the disease, its treatment, and the host contribute to its occurrence. We made an attempt to combine and analyze all published data on the association between pediatric ALL and thrombosis, by using a meta-analytic method. The rate of thrombosis in 1752 children from 17 prospective studies was 5.2% (95% CI: 4.2-6.4). The risk varies depending on several factors. Most of the events occurred during the induction phase of therapy. Lower doses of asparaginase (ASP) for long periods were associated with the highest incidence of thrombosis, as were anthracyclines and prednisone (instead of dexamethasone). The presence of central lines and of thrombophilic genetic abnormalities also appeared to be frequently associated with thrombosis. In conclusion, the overall thrombotic risk in ALL children was significant, and the subgroup analysis was able to identify high-risk individuals, a finding that will hopefully guide future prospective studies aimed at decreasing this risk. IntroductionAcute lymphoblastic leukemia (ALL) is more frequent in children than in adults; indeed, two thirds of all cases occur at pediatric age. 1 The risk of thrombosis is increased in ALL patients, 2 and its occurrence may complicate the treatment course with a negative prognostic impact. Its frequency reportedly ranges between 1.1% and 36.7%, a quite large variation related to several factors, such as different definitions of thrombosis (symptomatic vs asymptomatic), diagnostic methods for its detection, study design (prospective vs retrospective), and differences in treatment protocols. 2 The pathogenesis of this increased thrombotic risk is not fully understood, but includes a combination of variables related to the disease itself, its treatment, and the host. [3][4][5] Although many clinical and epidemiologic studies were performed in this field, the majority were either retrospective or prospective observations on small numbers of subjects. Thus, the results are contradictory and inconclusive, mainly due to lack of statistical power. However, a careful assessment of risk factors would be useful to improve the quality of treatment and to identify subgroups in which prophylactic interventions would be beneficial.The objective of the present study was to quantitatively combine and analyze the available data, by a meta-analytic approach, to obtain accurate estimates of the thrombotic risk in pediatric patients with ALL.Several subgroup analyses were carried out to control for possible biases arising from heterogeneous pieces of information and to sort out subpopulations at higher risk of thrombosis. Materials and methods Meta-analysisIn the PubMed database, all available articles were searched usin...

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“…48 Fibrinolytic parameters have been studied in L-Asp-treated ALL patients, with reduced fibrinogen levels being consistently reported. 41,42,47,55 There is uncertainty whether depletion of fibrinogen is due to lack of production, generation of dysfibrinogenaemia and/or excessive fibrinolytic activity, compounded by increased consumption during thrombotic episodes. Plasminogen and a2-antiplasmin levels have also been shown to decline following L-Asp and again it is uncertain whether this reflects lack of production by the liver, increased consumption, or both.…”

Section: Physiological Anticoagulantsmentioning

confidence: 99%

The coagulopathy and thrombotic risk associated with L-Asparaginase treatment in adults with acute lymphoblastic leukaemia

2012

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Influence of two different e.coli asparaginase preparations on coagulation and fibrinolysis: A randomized trial

Cited by 23 publications

References 11 publications

Asparaginase pharmacodynamics differ by formulation among children with newly diagnosed acute lymphoblastic leukemia

Asparaginase pharmacodynamics differ by formulation among children with newly diagnosed acute lymphoblastic leukemia

Thrombotic complications in childhood acute lymphoblastic leukemia: a meta-analysis of 17 prospective studies comprising 1752 pediatric patients

The coagulopathy and thrombotic risk associated with L-Asparaginase treatment in adults with acute lymphoblastic leukaemia

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