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

Truelove, Edward; Fielding, Adele K.; Hunt, Beverley J.

doi:10.1038/leu.2012.290

Cited by 108 publications

(76 citation statements)

References 61 publications

(89 reference statements)

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“…Compelling evidence (2,8,12,20,21) suggests that the thromboembolic coagulopathy (10,(22)(23)(24)(25), pancreatitis (26,27), and liver dysfunction (8,28) are direct results of the L-glutaminase side activity present in the Food and Drug Administration-approved bacterial L-asparaginases and not from the cancer-killing L-asparaginase activity. Therefore, an enzyme with high L-asparaginase activity (and here a low Asn K m value is critical) and low L-glutaminase activity may be advantageous clinically.…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

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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“…Asparaginase is associated with an increased risk of vte 9,10 that is largely related to inhibition of hepatic protein synthesis, leading to decreased plasma levels of antithrombin and proteins C and S 11,12 . In all, increased age has been identified as a risk factor for vte, the incidence being 34% in adults compared with 5% in pediatric patients treated with asparaginase-containing regimens 13 .…”

Section: Introductionmentioning

confidence: 99%

Venous Thromboembolism Prevention During Asparaginase-Based Therapy for Acute Lymphoblastic Leukemia

et al. 2016

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“…Cerebral sinus venous thrombosis has been frequently associated with PEG-ASP, especially if combined with steroids, cerebral hemorrhages, and PRES. 1,7,8 Cerebral vasospasm has never been reported in the context of PEG-ASP. Vincristine is mainly related to peripheral neuropathies.…”

Section: Discussionmentioning

confidence: 99%

Severe Cerebral Vasospasm and Childhood Arterial Ischemic Stroke After Intrathecal Cytarabine

et al. 2016

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We report on 2 patients who developed widespread cerebral vasospasm and arterial ischemic strokes (AIS) after application of intrathecal (IT) cytarabine. In a 3-year-old child with acute lymphoblastic leukemia (ALL), left leg weakness, hyperreflexia, and clonus were noted 4 days after her first dose of IT cytarabine during the induction phase of her chemotherapy. Cerebral MRI revealed multiple acute cerebral ischemic infarcts and widespread cerebral vasospasm. A 5-year-old girl complained of right arm and leg pain and began limping 11 days after IT cytarabine. Symptoms progressed to right dense hemiplegia, left gaze deviation, headache, and speech arrest. MRI revealed 2 large cortical areas of diffusion restriction in the right frontal and left parietal lobes. Cerebral magnetic resonance angiography (MRA) showed irregular narrowing affecting much of the intracranial arterial circulation. Although the first child fully recovered from her neurologic symptoms, the second patient had persistent hemiplegia on follow-up. Including this report, there are now 4 pediatric ALL cases of severe cerebral vasospasm and AIS in the context of IT cytarabine administration, strongly suggesting a true association. Differential diagnosis and management issues are discussed. Along with the more widespread use of MRI and MRA, the true frequency of this severe adverse effect will become clearer in future. For any child with neurologic symptoms within hours or days of receiving IT cytarabine, a low threshold for cerebral imaging with MRI and MRA is recommended.

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

Cited by 108 publications

References 61 publications

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

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

Venous Thromboembolism Prevention During Asparaginase-Based Therapy for Acute Lymphoblastic Leukemia

Severe Cerebral Vasospasm and Childhood Arterial Ischemic Stroke After Intrathecal Cytarabine

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