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Official websites use. Share sensitive information only on official, secure websites. Correspondence to Professor Patrick W Burke; pwburke med. With recent prospective clinical trials that used paediatric regimens with multiple doses of pegylated form of asparaginase PEG asparaginase in adults reporting significantly improved survival compared with historical data with regimens that used less asparaginase, PEG asparaginase is increasingly being used in the treatment of adult acute lymphoblastic leukaemia ALL. However, administering asparaginase still comes with its challenges, especially in adult patients. Therefore, it is important to understand how to manage its toxicities properly. An expert group met in November in London to discuss recent data of paediatric as well as adult studies using paediatric regimens with regard to the best management of several key toxicities that can occur in adults treated with asparaginase including hepatotoxicity, pancreatitis, hypertriglyceridaemia, thrombosis and hypersensitivity. Several recommendations were made for each one of these toxicities, with the goal of safe administration of the drug and to educate clinicians when the drug can be continued despite side effects. Keywords: asparaginase, acute lymphoblastic leukaemia, toxicities, hypersensitivity, therapeutic drug monitoring, pancreatitis, thrombosis. Download video stream. Despite its use in the treatment of acute lymphoblastic leukaemia ALL for more than four decades, administering asparaginase still comes with its challenges, especially in adult patients. There are several reasons for this. The drug has a unique toxicity profile, different from any other chemotherapy drug. Adult oncologists are less familiar with asparaginase and its side effects, as the drug is predominantly used in ALL which is rare in adults. The toxicities can be serious; however, early discontinuation or dosing changes of the drug are often not necessary and could result in losing the improved reported outcome from multiple doses of asparaginase. Currently, the long-acting pegylated form of asparaginase PEG asparaginase is used more often than the short-acting native Escherichia coli derived form. Due to their success in the treatment of childhood ALL, paediatric or paediatric-inspired regimens with multiple doses of PEG asparaginase are increasingly being used in the treatment of newly diagnosed adult ALL. Prospective clinical trials using paediatric or paediatric-inspired regimens have shown a higher cure rate among adults compared with historic regimens with much less asparaginase. Of note, asparaginase is also particularly important in improving the outcome of childhood T-cell ALL. Taken together, as PEG asparaginase is increasingly being used in the treatment of adult ALL including T-ALL, it is important to understand how to manage its toxicities in adults properly. Doctors who use paediatric-inspired regimens that include multiple doses of PEG asparaginase have several management dilemmas when faced with hyperbilirubinaemia, and it is important to be familiar with its characteristics. First, the morbidity of asparaginase-related hepatotoxicity is generally low, transitory and without hepatic failure. High-grade hepatotoxicity may last for a month from onset to recovery and may cause delay of subsequent chemotherapy cycles. Second, high-grade hyperbilirubinaemia mostly occurs after the first asparaginase dose during induction and less often in subsequent cycles, 5 6 18 24 that is, perhaps at a time when patients are likely to have leukaemic infiltration of the liver. Third, when patients did not discontinue asparaginase, nor underwent dose reduction due to hepatotoxicity , and then were re-challenged with the drug, high-grade hepatotoxicity generally did not recur. Asparaginase, a key drug in all paediatric regimens, is not myelosuppressive. In fact, paediatric regimens typically use more non-myelosuppressive drugs such as vincristine and steroids; myelosuppressive drugs such as daunorubicin are minimised and are mostly used in induction. During induction it is important to synchronise the timing of the myelosuppressive drug with that of PEG asparaginase. The protocol was amended: PEG asparaginase was given only on day 18 and the dose of daunorubicin was reduced, resulting in a significantly lower 2. Hepatic steatosis can be seen post-PEG asparaginase, often in patients with high-grade hyperbilirubinaemia. In one small study, all eight patients with high-grade hyperbilirubinaemia had hepatic steatosis. However, no evidence of liver failure was reported in patients with hepatic steatosis. Others perform liver ultrasound and detected steatosis leads to a lower dose of PEG asparaginase. Single case observations and small case-series reported that L-carnitine can result in rapid amelioration of PEG asparaginase-induced hyperbilirubinaemia. Another common asparaginase-related adverse event is clinical pancreatitis which in adults should always lead to discontinuation of any form of asparaginase. It should be distinguished from chemical pancreatitis high amylase and lipase without clinical symptoms of pancreatitis in which asparaginase should be continued. Doctors should be aware and anticipate this side effect, as pancreatitis may easily be misinterpreted as other abdominal complications or sepsis. It is important to educate the patient to be aware of pancreatitis symptoms and alert their treating physicians at the onset of these symptoms. Diagnostic tests should include imaging as well as both lipase and amylase. It is a general understanding that there is a higher risk of recurrent pancreatitis with re-exposure to asparaginase following an initial diagnosis of pancreatitis. Since a second AAP did not involve an increased risk of complications and since the second episode occurred after a median of several additional doses of PEG asparaginase, the authors carefully argued that asparaginase re-exposure should be determined mainly by the anticipated need for asparaginase for antileukaemic efficacy. Educate the patient to report any symptoms for an early diagnosis of pancreatitis and obtain imaging on suspicion of pancreatitis. Immediately on the diagnosis of clinical pancreatitis start treatment with no oral intake, hydration as well as antibiotic and analgesic medication. Adjustments or discontinuation of asparaginase therapy are generally not necessary. Several treatment approaches have been reported for patients with hypertriglyceridaemia. Strong evidence for any specific option is lacking, and there is currently no standard treatment for hypertriglyceridaemia. Elevated lipids have been associated with risk of osteonecrosis in children, 37 but similar studies are lacking for adults. Both hypertriglyceridaemia and pancreatitis occur with PEG asparaginase, however early discontinuation of asparaginase or overtreating hypertriglyceridaemia can be avoided since no correlation was found between the two toxicities. Adjustments or discontinuation of asparaginase therapy in case of hypertriglyceridaemia are not necessary. Several interventions, including fibrates, may reduce hypertriglyceridaemia, but data are lacking to support that this reduces the risk of thromboembolism TE , osteonecrosis or pancreatitis. Monitoring of lipids is recommended in a research setting and can be considered in clinical practice. With the recent increased use of asparaginase and intensified use of dexamethasone partly due to paediatric-inspired therapy among adults with ALL, 10 TE has become a frequent and serious treatment-related toxicity challenging protocol adherence and cure rates. Adjusted HR HRa were associated with greater age Compared with younger patients, those aged Five deaths were attributable to TE. Genome-wide association studies have so far not identified significant single nucleotide polymorphisms SNPs associated with TE in children. F11 rs was significantly associated with TE HR 1. Importantly, the association was significant for adolescents aged TE may lead to truncation of asparaginase therapy, which in several studies have been associated with increased risk of relapse. Continuation of asparaginase therapy is thus generally recommended after TE with co-administration of low molecular weight heparin LMWH. Randomised trials on TE prophylaxis are also lacking in adults, although a recent paediatric randomisation gave support to prophylactic use of LMWH during induction therapy. Hypofibrinogenaemia often occurs after PEG asparaginase administration but bleeding is rare. Its administration was reported to be associated with a higher rate of thrombosis. A recent paediatric randomisation gave support to prophylactic use of LMWH but in adults prophylactic LMWH is controversial and is not routinely applied. One notable asparaginase adverse effect is hypersensitivity. This is because asparaginase is a foreign protein synthesised by either E. Hypersensitivity can pose symptom management challenges and significant long-term clinical outcome ramifications since enzymatic inactivation of the drug can occur with hypersensitivity. Asparaginase can provoke symptomatic ie, overt or clinical hypersensitivity or silent hypersensitivity through asparaginase antibody formation. Silent asparaginase antibodies may complicate therapy via enzymatic pharmacokinetic and pharmacodynamic effects. Several confounding factors may complicate adult hypersensitivity management. First, while the constellation of symptoms that may accompany clinical hypersensitivity are well described, different grading systems exist, which may render if difficult to compare data across agents and across clinical trials. Second, considerable overlap exists between low-grade clinical hypersensitivity, an immune-mediated process, and symptomatic hyperammonaemia, a function of rapid ammonia liberation—from the hydrolytic enzymatic activity—during and shortly after asparaginase administration. Clinical hypersensitivity presents with anaphylaxis or symptoms that include dyspnoea, pruritus, oedema, rash, cough and vomiting, which often lead to discontinuation of treatment. Anaphylaxis and other severe forms of clinical hypersensitivity is an indication for asparaginase infusion interruption and parenteral medication eg, antihistamines, glucocorticoids, acetaminophen and when necessary epinephrine. Silent inactivation is particularly relevant, as the decreased asparaginase activity is asymptomatic and will stay undetected if asparaginase activity is not monitored. In the case of diagnosed silent inactivation, the standard step of management is the prompt switch to Erwinia asparaginase therapy 71 73 ; although in some patients treated with PEG asparaginase, the inactivating antibodies may be directed towards the PEG moiety rather than asparaginase. With similar symptoms to those of real allergic hypersensitivity reactions, non-allergic infusion reactions are becoming more common with the use of intravenous PEG asparaginase. These non-allergic infusion reactions often occur shortly into the infusion. In suspected hypersensitivity, it may be helpful to measure the activity of asparaginase through therapeutic drug monitoring TDM. In addition to the identification of patients with silent inactivation, TDM of asparaginase may help distinguish between clinical hypersensitivity and non-allergic infusion reactions. TDM can also be used for adjusting asparaginase doses, but there is no sufficiently vetted algorithm to support this approach yet and this is not performed routinely outside of clinical trials. There are different ways to undertake TDM of asparaginase therapy, yet expert consensus recommends the monitoring of serum asparaginase activity SAA , which is now most used in practice. To provide recommendations for measurement of asparaginase activity, Salzer et al 74 propose a treatment algorithm to guide the use of activity monitoring in patients receiving PEG asparaginase therapy for ALL figure 1. Algorithm for pegylated form of asparaginase PEG asparaginase activity monitoring administration. There is not a standardisation of TDM for adults, however adult prospective clinical studies should incorporate TDM and report on it. A recent single-institution retrospective study of paediatric patients with ALL analysed hypersensitivity data from two cohorts 76 : one group of patients who were treated prior to the institution performing asparaginase premedication and a second later cohort who received standard premedication. Premedication with histamine antagonists, acetaminophen and in some cases corticosteroids was associated with both a lower rate of substitutions of PEG asparaginase to Erwinia asparaginase and lower acute adverse event rates. Also, a substantial financial saving was achieved in the premedication cohort, as fewer patients required Erwinia asparaginase. Importantly, if premedication is administered, TDM should become mandatory in order not to miss silent inactivation, although the yield of finding inactivation would be low even if done after every dose. Systematic and standardised TDM detects silent inactivation, distinguishes between true hypersensitivity versus other infusion reactions, and allows premedication, thus permitting more patients to benefit from asparaginase. If hypersensitivity occurs, all subsequent doses of PEG asparaginase including the dose that caused the reaction should be switched to Erwinia asparaginase. Discontinuation of PEG asparaginase for hypersensitivity without replacing all subsequent scheduled PEG asparaginase doses with Erwinia asparaginase was associated with inferior disease-free survival. Prolonged postremission asparaginase is a key component of a multiagent chemotherapy regimen for patients with newly diagnosed ALL, as confirmed in children by several randomised clinical trials. A recent study in children reported that discontinuation of asparaginase doses is often associated with inferior outcome. However, since asparaginase is almost exclusively used in ALL, clinicians who treat adults are less familiar with the drug and may be reluctant to use it or discontinue it prematurely. The expert panel reviewed the most common toxicities of asparaginase ie, hepatoxicity, pancreatitis, hypertriglyceridaemia, thrombosis and hypersensitivity and how to manage them. With the recent studies showing clinical benefit of paediatric regimens in adults with ALL, this information will help clinicians who use such regimens in this patient population. Table 1 summarises prevention and management of the discussed PEG asparaginase toxicities. Others continue after recovery without dose modification. We suggest that clinicians follow the approach of the protocol they use. However, it is not widely practised and currently the panel cannot make a specific recommendation on pre-PEG asparaginase liver ultrasound. Funding: The project is supported by an unrestricted educational grant from Servier. DD: speaker and consultant for Servier, Amgen and Jazz. As a library, NLM provides access to scientific literature. ESMO Open. Find articles by Patrick W Burke. Find articles by Dieter Hoelzer. Find articles by Jae H Park. Find articles by Kjeld Schmiegelow. Find articles by Dan Douer. No commercial re-use. Download video file Open in a new tab. Pegylated form of asparaginase PEG asparaginase toxicities prevention and management. Contributors: All authors have contributed to and reviewed the manuscript. Provenance and peer review: Commissioned; externally peer reviewed. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel. De-synchronisation of the administration of PEG asparaginase and myelosuppressive drugs. Try to avoid giving PEG asparaginase concomitantly with myelosupressive drugs. Synchronisation of PEG asparaginase and myelosuppressive drugs. Avoid after clinical PEG asparaginase-associated pancreatitis. Early recognition and treatment Permanent discontinuation. Possible low molecular weight heparin controversial Possible antithrombin III controversial Minimise cryoprecipitate for hypofibrinogenaemia. Continue dosing with co-administration of low molecular weight heparin Possible antithrombin III needs more study. Premedication with hydrocortisone, antihistamine and acetaminophen before each dose. Distinguish between allergic and non-allergic infusion reaction with the use of postdosing therapeutic drug monitoring Allergic reaction—switch to Erwinia asparaginase Non-allergic reaction—no switch, continue all doses of PEG asparaginase.

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