Efficacy and toxicity of reduced vs. standard dose pegylated asparaginase in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia

Derman, Benjamin A.; Streck, Mitchell; Wynne, Joseph; Christ, Trevor N; Curran, Emily; Stock, Wendy; Knoebel, Randall W

doi:10.1080/10428194.2019.1680839

Cited by 31 publications

(27 citation statements)

References 32 publications

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“…The uptake of glutamine by its major transporter SLC1A5 (ACST2) is required for leucine import by the glutamine/leucine antiporter (see below) and mTORC1 activation (Nicklin et al, 2009), thereby promoting CD4 + T-cell differentiation into Th1 and Th17 cells (Nakaya et al, 2014). The bacterial enzyme asparaginase, commonly used as an anticancer agent in lymphoblastic leukemia, catalyzes the deamination of asparagine and, to a lesser extent, glutamine, to aspartic acid and glutamic acid, respectively (Derman et al, 2020). The absence of asparagine affects T-cell activation and IL-2 production through inhibition of the mTORC1 pathway (Torres et al, 2016).…”

Section: Other Amino Acids Important For T-cell Signaling and Activationmentioning

confidence: 99%

Control of T-Cell Activation and Signaling by Amino-Acid Catabolizing Enzymes

Castellano

Molinier‐Frenkel

2020

Front. Cell Dev. Biol.

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Amino acids are essential for protein synthesis, epigenetic modification through the methylation of histones, and the maintenance of a controlled balance of oxidoreduction via the production of glutathione and are precursors of certain neurotransmitters. T lymphocytes are particularly sensitive to fluctuations in amino acid levels. During evolution, the production of amino-acid catabolizing enzymes by mainly antigen-presenting cells has become a physiological mechanism to control T-cell activation and polarization. The action of these enzymes interferes with TCR and co-stimulation signaling, allowing tuning of the T-cell response. These capacities can be altered in certain pathological conditions, with relevant consequences for the development of disease.

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Section: Other Amino Acids Important For T-cell Signaling and Activationmentioning

confidence: 99%

Control of T-Cell Activation and Signaling by Amino-Acid Catabolizing Enzymes

Castellano

Molinier‐Frenkel

2020

Front. Cell Dev. Biol.

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“…In a pediatric study using a more sensitive technique, an effective serum asparagine depletion was obtained with an enzymatic activity as low as 0.02 IU/ml [65]; also, in adult patients, 80-90% of the cases receiving Peg-ASP 500-1000 IU/m 2 reached drug levels > 0.1 IU/ml, that persisted for 14 days in 77% with 1000 IU/m 2 and for 7 days in 59% with 500 IU/m 2 [66]. Finally, a recent study reported that adults with comorbidities receiving a reduced dose of PEG-ASP < 1000 IU/m 2 experienced fewer toxicities while still attaining therapeutic activity levels > 0.1 IU/ mL [67]. The final consensus of the panel against the utility of routinely searching anti-asparaginase antibodies reflects the data mentioned above.…”

Section: Discussionmentioning

confidence: 95%

National Italian Delphi panel consensus: which measures are indicated to minimize pegylated-asparaginase associated toxicity during treatment of adult acute lymphoblastic leukemia?

et al. 2020

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Background L-asparaginase (L-ASP) is a key component of acute lymphoblastic leukemia (ALL) treatment, but its use in clinical practice raises challenges to clinicians due to a relatively high incidence of drug-related adverse events, mainly in adult patients. In the past years the use of ASP in adult population has been mainly limited due to a poor knowledge of its safety profile and to an approximate management of ASP-related toxicity. Recently the development of pediatric-inspired treatment protocols for adult ALL has led to a wider use of ASP and since 2010 in Italy three national treatment protocols including Pegylated asparaginase (Peg-ASP) have been sequentially developed for adolescents, young adults and adults with Philadelphia-negative (Ph-) ALL. Methods With the aim to better understand the approach adopted in Italian centers for the management and prevention of Peg-ASP toxicity in adult ALL and to provide practical, consensus-based recommendations, a board of 6 Italian clinicians, with known expertise in adult ALL, designed 41 consensus statements on current challenges on the management of Peg-ASP associated toxicity. A group of 19 clinical experts in the field then rated these statements using the 5-point Likert-type scale (1 = strongly disagree; 5 = strongly agree). Results The main Peg-ASP related issues identified by the board included: 1) clinician’s attitudes; 2) toxicity profile; 3) hypersensitivity reactions; 4) hepatic toxicity; 5) hepatic and/or metabolic toxicity; 6) hemorrhagic/thrombotic toxicity; 7) pancreatitis; 8) metabolic toxicity management and prevention; 9) activity levels monitoring. Overall, participants agreed on most statements, except those addressing the potential contraindications to the treatment with Peg-ASP, such as patients with a diagnosis of chronic liver disease or the subsequent administrations of the drug in patients who had previously developed chemical pancreatitis or severe metabolic toxicity. Participants agreed that adult patients with ALL should receive Peg-Asp because this drug is essential to improve treatment results. Conclusions The panel agreed that a critical evaluation of specific risk factors for each patient is crucial in order to reduce the risk of adverse events and specific advices in the management of Peg-ASP toxicities are reported.

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“…However, alternate doses and dosing schedules of peg-asparaginase have also been explored in an effort to reduce toxicities. Derman and colleagues were able to show, retrospectively, that patients who were treated per the CALGB 10403 regimen, off trial, with reduced doses of peg-asparaginase (≤1000 IU/m 2 ) were able to achieve adequate asparagine depletion and fewer total grade 3 or 4 toxicities, compared with patients who received standard dose peg-asparaginase (doses ≥1000 IU/m 2 ), without compromising RFS or OS [ 30 ]. However, rates of new VTE between the reduced dose peg-asparaginase group and the standard dose group were, essentially unchanged (20 vs 15.4%, p = 0.726).…”

Section: Discussionmentioning

confidence: 99%