Asparaginase use for the treatment of acute lymphoblastic leukemia

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It can be considered in cases of very severe reaction and if the formulation cannot be changed and/or if the planned treatment has been almost completed." ] ] ] "textoCompleto" => "IntroductionAcute lymphoblastic leukaemia (ALL) is a rare neoplastic disease whose peak of incidence ranges between 2 and 5 years of age.<a class="elsevierStyleCrossRef" href="#bib0155">1</a> Asparaginase (L-ASA) is considered an essential drug in its treatment. It is an enzyme from cultures of Escherichia coli (E. coli) and of Chrysantemii Erwinia (E. chrysantemii) with the ability to hydrolyse L-asparagine converting it into aspartic acid and ammonium.<a class="elsevierStyleCrossRef" href="#bib0160">2</a> Normal cells are able to synthesize this amino acid de novo, but in leukemic cells, L-asparagine extracellular depletion causes cell cycle arrest and inhibition of protein synthesis by inducing cell apoptosis.<a class="elsevierStyleCrossRef" href="#bib0165">3</a> Depletion of L-asparagine is also associated with decreased synthesis of other proteins as albumin, insulin, fibrinogen and clotting factors, resulting in L-ASA-specific homeostatic abnormalities.<a class="elsevierStyleCrossRefs" href="#bib0170">4,5</a> Despite its strong anti-leukemic efficacy, especially demonstrated in childhood ALL,<a class="elsevierStyleCrossRefs" href="#bib0180">6,7</a> this drug has been used less frequently in adult ALL protocols, because its specific toxic effects increase with age.<a class="elsevierStyleCrossRefs" href="#bib0190">8,9</a> The use of L-ASA in adults is also limited by the lower tolerability of conventional multidrug therapy regimens, especially in older patients. Therefore, L-ASA is a little-known drug, especially in among haematologists who treat adult patients, in whom the disease is less prevalent.Methodology and objectivesFour Spanish doctors with extensive experience in the treatment of ALL in paediatric patients (JLD and SR) and adults (PB and PM) participated in the design and development of this article. A comprehensive literature search of the most relevant aspects of asparaginase in the treatment of ALL was performed. The authors shared their clinical experience and therapeutic approaches, discussed algorithms and recommendations and participated in drafting and revising the manuscript in various face-to-face and virtual meetings.Types of asparaginaseL-ASA is marketed in 3 forms (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>):<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">-Derived from native E. coli. It is the most commonly used formulation.</li><li class="elsevierStyleListItem" id="lsti0010">-Derived from the E. chrysanthemi bacteria. It is used in patients who have developed hypersensitivity to native E. coli L-ASA and Peg-asparaginase (PEG-ASP).</li><li class="elsevierStyleListItem" id="lsti0015">-E. coli asparaginase conjugated with polyethylene glycol (PEG-ASP). Indicated as part of the ALL combined cytostatic treatment in paediatric and adult patients.</li></ul><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Dose, dose equivalence, frequency and route of administrationL-ASA can be used intravenously (IV) or intramuscularly (IM). The plasma concentration of L-ASA depends on the dose administered, obtaining the peak plasma concentration with IM, half of what is obtained IV. Abbott et al.<a class="elsevierStyleCrossRef" href="#bib0200">10</a> allergic reactions evaluated PEG-ASP according to the route used, observing an increased frequency of allergic reactions in patients using the IV route. Petersen et al.,<a class="elsevierStyleCrossRef" href="#bib0205">11</a> in a similar study, showed that intravenous administration was associated with a higher incidence of reactions and an earlier onset of the same, although with a similar severity profile. In another study with PEG-ASP, more local reactions were observed using the IM route, while with IV these were more systemic, although less severe.<a class="elsevierStyleCrossRef" href="#bib0210">12</a>Regarding PEG-ASP's action duration, it has a longer half-life, providing a longer asparagine depletion period after a single dose.<a class="elsevierStyleCrossRef" href="#bib0215">13</a> L-ASA of native E. coli and Erwinia have a much shorter half-life and must be administered more frequently to maintain asparagine depletion (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).The recommended doses for native E. coli L-ASA are 5000–10,000IU/m2/48–72h, for Erwinia L-ASA 20,000IU/m2/48h (3 times/week), and PEG-ASP 1000–2500IU/m2 every 2 weeks. In general, each dose of 10,000IU/m2 of native E. coli L-ASA should be replaced by 20,000–25,000IU/m2 of Erwinia L-ASA. The replacement dose of Erwinia L-ASA in patients suffering from hypersensitivity to PEG-ASP would be 25,000IU/m2 administered IV or IM (mon-wed-fri) for 2 weeks, per dose of PEG-ASP.Using asparaginase according to current protocolsThe Spanish protocol for childhood ALL (LAL/SEHOP-PETHEMA 2013) differentiates 3 risk groups, each with a different adapted treatment. The treatment is less intensive in low risk patients, with 2 inductions, one consolidation, one re-induction and a prolonged maintenance. Both phases of induction and re-induction contain native L-ASA (12 doses of 10,000IU/m2 IM). In the cases of intermediate-risk children, their maintenance also contains 10 doses of 1000IU/m2 of PEG-ASP IM. In those with high risk, an additional dose of 1000IU/m2 of PEG-ASP IM is administered in each of the three intensifications and 2 equal doses of PEG-ASP in each of the three re-inductions, without PEG-ASP during maintenance.Regarding adult ALL, the PETHEMA group offers protocols adapted to the risk of relapse, age and ALL subtype. Teenagers and young adults (up to 30 years) receive a protocol based on paediatric regimens (ALL-RI-2008). This protocol contains 8 doses of 10,000IU/m2 of native IV L-ASA for induction and consolidation, and up to 6 doses of 20,000IU/m2 during re-inductions. For patients with very high risk, generally over 30 years of age, the ALL-AR-2011 protocol contains IV native L-ASA (4 doses of 10,000IU/m2 in induction and 6 doses of 20,000IU/m2 in consolidation, it is omitted at re-induction and maintenance) or IV PEG-ASP (a dose of 2000IU/m2 in induction and up to 6 doses 2000IU/m2 in consolidation). It is recommended to administer 50% of the native L-ASA and PEG-ASP doses in patients over 50 years of age. The protocol for those over 55 years of age (ALL-Old-2007) only contains 6 doses of 10,000IU/m2 native L-ASA, all in consolidation.One of the features in the PETHEMA and SEHOP protocols is the role of E. chrysantemii, L-ASA which would be indicated as the first alternative to native L-ASA and PEG-ASP in case of allergic reaction or prior hypersensitivity.Drug interactionsBecause of its effect on liver function, L-ASA can cause increased toxicity of hepatotoxic drugs with hepatic metabolism or attached to plasma proteins.<a class="elsevierStyleCrossRef" href="#bib0165">3</a> Therefore, these recommendations should be observed when using the following drugs commonly used in ALL:<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0020">-Vincristine: should not be administered together with L-ASA, as it may increase its toxicity (neurotoxicity) and the risk of allergic reactions (administer it 3–24h before L-ASA).</li><li class="elsevierStyleListItem" id="lsti0025">-Glucocorticoids and/or anticoagulants: its concomitant use increases the risk of clotting disorders, favouring a tendency to bleed (anticoagulants) or to develop thrombotic disorders (glucocorticoids).</li><li class="elsevierStyleListItem" id="lsti0030">-Methotrexate (MTX): inhibition of protein synthesis secondary to L-ASA-induced asparagine concentration decrease attenuates the cytotoxic effect of MTX, as cell replication is necessary for the antineoplastic activity of this drug. This antagonism occurs if L-ASA is administered prior to or in combination with MTX. In contrast, the antitumor effects of MTX increase when L-ASA is administered 24h after treatment with MTX.</li><li class="elsevierStyleListItem" id="lsti0035">-Cytarabine: in vitro and in vivo data indicate that the efficacy of cytarabine at high-doses decreases when administered before L-ASA. However, a synergistic effect was observed when L-ASA was administered after cytarabine.</li><li class="elsevierStyleListItem" id="lsti0040">-Oral contraceptives are not recommended to be used as L-ASA hepatotoxicity can affect the hepatic clearance of these.</li><li class="elsevierStyleListItem" id="lsti0045">-Avoid concomitant administration of PEG-ASP with live virus vaccines, BCG, belimumab, natalizumab, pimecrolimus or tacrolimus (topical). Patients should be carefully monitored if PEG-ASP is administered concomitantly with attenuated virus vaccines, denosumab or trastuzumab.</li><li class="elsevierStyleListItem" id="lsti0050">-Thyroxine: L-ASA produces a decrease in serum thyroxine.</li></ul>However, many of these drugs are commonly used in the treatment of ALL and co-administration may be inevitable. It is therefore important to follow the directions about the drugs’ order of administration and be attentive to their potential toxicities.Adverse effectsHypersensitivityHypersensitivity is one of the most common adverse reactions associated with the use of L-ASA. It is one of the most important complications due to the potential severity and therapeutic and prognostic implications involved in its development.The incidence ranges from 0 to 50%<a class="elsevierStyleCrossRefs" href="#bib0180">6,14</a> in children and around 15% in adults.<a class="elsevierStyleCrossRef" href="#bib0190">8</a> The incidence is higher with native L-ASA, while PEG-ASP and Erwinia L-ASA have shown a lower incidence.<a class="elsevierStyleCrossRef" href="#bib0225">15</a>Hypersensitivity reactions have been associated with the generation of antibodies against bacterial proteins. Most episodes occur during re-exposure, with consolidation and maintenance being the phases where these most frequently occur. The IV route has been associated classically with increased risk, although recent studies have not confirmed it.<a class="elsevierStyleCrossRefs" href="#bib0225">15,16</a>The severity of hypersensitivity reactions range from grade 1, with isolated hives or hypotension that does not require fluids to grade 4, with hypotension and anaphylactic shock (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). The vast majority are grade 1–2 and often appear as local reactions at the puncture site when administered intramuscularly.<a class="elsevierStyleCrossRef" href="#bib0230">16</a><elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Patient monitoring during the 2h after administration of L-ASA is recommended. Most reactions occur within the first hour, although IM route and the use of PEG-ASP can cause delayed reactions. It is therefore advisable to instruct the patient and his/her companions on delayed reaction detection.The use of premedication to prevent the development of hypersensitivity reactions is widespread, although there is little scientific evidence to support it. In addition, their use could mask reactions that would highlight the presence of inactivated antibodies. Since glucocorticoids are part of the treatment of ALL, it seems advisable to administer L-ASA after the glucocorticoid dose.The treatment will vary depending on severity and presentation. IV fluid therapy or fast-acting glucocorticoids (hydrocortisone) may be useful in most cases of grade 3–4. More intensive measures and transfer to an ICU may be needed in more severe situations.Prognostic implications, changes and suspension of asparaginaseSeveral studies have shown the importance of L-ASA as an essential part of the treatment of ALL, and how patients that can complete treatment with L-ASA have better survival than those who have to stop treatment. Two studies have shown that, if after a hypersensitivity reaction to native or PEGylated L-ASA, patients received Erwinia L-ASA, these had a similar survival to those who never developed hypersensitivity.<a class="elsevierStyleCrossRefs" href="#bib0190">8,17</a> It is therefore advisable to maintain the treatment with L-ASA, either using the same or different formulation (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Patients developing a grade 2–4 hypersensitivity should continue treatment with a different L-ASA. Erwinia L-ASA would be recommended if the L-ASA used as first-line was the native E. coli. If Erwinia L-ASA is not available, it could be switched to PEG-ASP, but, in these cases, it is recommended to measure the levels of activity due to the possibility of cross-reactivity. If the reaction occurs because of PEG-ASP, it is advisable to use Erwinia L-ASA, as there would be a high risk of developing a reaction of hypersensitivity with native E. coli L-ASA. As for the time of administration of the new formulation, it seems advisable to start early (24–48h after the reaction), providing the patient has recovered.In grade 1 hypersensitivity reactions, an infusion reaction must be ruled out. The L-ASA activity test determination would distinguish between a hypersensitivity reaction, which often leads to a decrease in the activity of L-ASA below the minimum level of activity (1.00IU/l), and an infusion reaction that would not mean a decrease in activity and would allow us to continue with the same treatment. In case of grade 2–4 hypersensitivity, the L-ASA formulation should be changed. If this change is not viable, a method which is underused and does not solve the silent inactivation, would be a desensitization with increasing doses of L-ASA.<a class="elsevierStyleCrossRef" href="#bib0240">18</a>Due to all these implications, it is essential to confirm that the reaction was due to the use of L-ASA and rule out any other cause, especially of infectious origin.Recommendations:<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0055">1.Monitor the patient during the first hour after administration of L-ASA in the native form and during 2h in the case of PEG-ASP.</li><li class="elsevierStyleListItem" id="lsti0060">2.Instruct the patient and their companions on the detection of delayed reactions.</li><li class="elsevierStyleListItem" id="lsti0065">3.Perform a L-ASA activity test after the hypersensitivity episode to rule out the inactivation of the drug.</li><li class="elsevierStyleListItem" id="lsti0070">4.Schedule the administration of L-ASA following the dose of glucocorticoids.</li><li class="elsevierStyleListItem" id="lsti0075">5.Do not use additional premedication with antihistamines and glucocorticoids.</li><li class="elsevierStyleListItem" id="lsti0080">6.L-ASA should be maintained whenever possible, either with the same formulation or a different one.</li><li class="elsevierStyleListItem" id="lsti0085">7.Change formulation in the case of a grade 2–4 hypersensitivity reaction.</li><li class="elsevierStyleListItem" id="lsti0090">8.Switch to Erwinia L-ASA if the L-ASA used in first line was native or PEGylated, according to equivalent doses (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). If Erwinia L-ASA is not available, it could be changed to PEG-ASP after a hypersensitivity reaction to native E. coli L-ASA.</li></ul>Silent inactivationL-ASA frequently causes the formation of antibodies that can inactivate it. These antibodies are not associated with hypersensitivity reaction in 8–33% of cases, but cause L-ASA inactivation which is associated with reduced efficacy.<a class="elsevierStyleCrossRef" href="#bib0250">20</a>Silent inactivation can be detected by:<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0095">1)Determination of asparagine concentration in plasma. Technically difficult because the enzyme still acts ex vivo if the blood sample is not kept on ice and processed immediately.</li><li class="elsevierStyleListItem" id="lsti0100">2)Detection of antibodies against L-ASA. Sensitive but unspecific, since not all antibodies have neutralizing activity.<a class="elsevierStyleCrossRef" href="#bib0165">3</a></li><li class="elsevierStyleListItem" id="lsti0105">3)Measurement of the enzymatic activity of L-ASA. It correlates with the level of asparagine depletion and is reliable. With L-ASA serum activity levels above 100IU/l, asparagine depletion is achieved below the quantification levels.<a class="elsevierStyleCrossRefs" href="#bib0160">2,20</a> Monitoring the activity of L-ASA allows to detect silent inactivation and individualize the dose to achieve the therapeutic range.</li></ul>RecommendationsIn cases of silent inactivation:<ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0110">1.Monitor L-ASA's enzymatic activity levels, whenever possible, which should be ≥100IU/l.</li><li class="elsevierStyleListItem" id="lsti0115">2.Change L-ASA's formulation for another without cross reactivity. There is no cross-reaction between native L-ASA or E. coli PEG-ASP with Erwinia L-ASA, so, in these cases, it would be of choice.</li></ul>ThrombosisBoth thrombosis and haemorrhage associated with L-ASA occur in 90% of cases during the induction phase,<a class="elsevierStyleCrossRef" href="#bib0170">4</a> probably due to multiple factors such as concomitant use of central venous catheter, glucocorticoid treatment and the neoplastic growth itself. Although the effects of L-ASA occur in procoagulant factors (hypofibrinogenemia, decreased factor IX, X and plasminogen) and anticoagulants (decreased antithrombin III, protein C and S), clinical manifestations usually reflect a prothrombotic state. Antithrombin III deficiency favours the generation of thrombin and fibrinogen and, secondarily, an increase of fibrinogen degradation products and factor consumption. The reported incidence of thrombosis ranges between 1% and 36%.Age is a risk factor and children have a lower predisposition. The presence of at least one inherited thrombophilic factor has been associated with an increased risk of thrombosis in children.According to a meta-analysis in the paediatric population,<a class="elsevierStyleCrossRef" href="#bib0255">21</a> thrombotic episodes were associated more frequently with the use of low doses of L-ASA in longer periods of time. Other factors were the use of prednisone (instead of dexamethasone) and anthracyclines.Recommendations<ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0120">1.The use of L-ASA should be discontinued temporarily in the case of clinically significant bleeding or thrombotic episodes.</li><li class="elsevierStyleListItem" id="lsti0125">2.L-ASA should be discontinued in the acute phase of venous thrombosis.</li><li class="elsevierStyleListItem" id="lsti0130">3.Patients with deep venous thrombosis should receive anticoagulant therapy, preferably with low molecular weight heparin (LMWH).</li><li class="elsevierStyleListItem" id="lsti0135">4.Once the symptoms and the thrombus are resolved, re-exposure to L-ASA under prophylaxis with LMWH may be feasible and safe. LMWH should be administered at anticoagulant doses during the first 3–6 months and if the thrombus is resolved, move on to prophylactic doses each time the patient receives L-ASA from the day before until 15 days after the last dose of L-ASA.</li><li class="elsevierStyleListItem" id="lsti0140">5.Primary prophylaxis with LMWH should be performed in patients with increased risk of thrombosis until the risk period is over (from one day before the start of treatment with L-ASA until 15 days later). Repeat every time L-ASA is administered.</li></ul>HaemorrhageThe incidence of bleeding complications by L-ASA is estimated to be between 5% (children) and 40% (in adults). The incidence of intracranial haemorrhage is less than 0.5% in both adults and paediatric patients. The same ALL can lead to an initial coagulopathy unrelated to chemotherapy which may increase the risk of bleeding and thrombotic episodes.<a class="elsevierStyleCrossRef" href="#bib0185">7</a> In these cases, in addition to starting chemotherapy treatment as early as possible, we must establish measures to prevent bleeding in the cytoreduction or debulking phase (transfusions of platelets and plasma correction times).Haemorrhagic complications of L-ASA are rare despite the high frequency of hypofibrinogenemia induced by this drug. The attitude towards hypofibrinogenemia is not clearly established: in children, fibrinogen determination is not usually done; in adults, some authors recommend fibrinogen or cryoprecipitate transfusion whenever serum levels are lower than 50–150mg/dl, while others only indicate replacement when bleeding occurs, monitoring fibrinogen levels weekly.Recommendations<ul class="elsevierStyleList" id="lis0035"><li class="elsevierStyleListItem" id="lsti0145">1.Fibrinogen levels should be monitored at least weekly in adult patients receiving L-ASA.</li><li class="elsevierStyleListItem" id="lsti0150">2.Do not replace plasma factors through transfusions of fresh frozen plasma as this product could reverse L-ASA-induced asparagine depletion, and thus reduce the antileukemic efficacy.</li><li class="elsevierStyleListItem" id="lsti0155">3.In case of cerebral thrombosis, administer anticoagulation effectively and correct coagulation disorders that favour haemorrhagic transformation, such as severe thrombocytopenia or hypofibrinogenemia.</li><li class="elsevierStyleListItem" id="lsti0160">4.Whenever any grade 3–4 bleeding event occurs, such as a cerebral haemorrhage, discontinue L-ASA administration. This would be final if the causal relationship is clearly established.</li></ul>PancreatitisThe incidence of pancreatitis is around 5–10%.<a class="elsevierStyleCrossRefs" href="#bib0155">1,22</a> Diagnosis is based on clinical criteria (abdominal pain, nausea and vomiting) associated with laboratory (elevated amylase and lipase) and/or radiological criteria. In most patients, it is mild or moderate, although severe in some, with pseudocysts or multiple organ failure that can be fatal. It can occur without a significant elevation of both pancreatic enzymes in up to a quarter of patients with pancreatitis.<a class="elsevierStyleCrossRef" href="#bib0155">1</a> It has been suggested that there might be a genetic predisposition for its development,<a class="elsevierStyleCrossRef" href="#bib0260">22</a> and polymorphisms have been described involving L-ASA's action pathway genes.<a class="elsevierStyleCrossRef" href="#bib0265">23</a>RecommendationsPancreatitis should be suspected in all patients receiving L-ASA who develop abdominal and/or back pain.<ul class="elsevierStyleList" id="lis0040"><li class="elsevierStyleListItem" id="lsti0165">1.When an asymptomatic elevation of amylase and lipase occurs, a temporary suspension of L-ASA is recommended, restarting after normalization.</li><li class="elsevierStyleListItem" id="lsti0170">2.Analgesia and supportive treatment should be administered (nutritional support, haemodynamic stabilization in severe forms and antibiotics in cases where infection cannot be ruled out).</li><li class="elsevierStyleListItem" id="lsti0175">3.Octreotide may be administered, although its role is not well defined.</li><li class="elsevierStyleListItem" id="lsti0180">4.Drug suspension until complete resolution of symptoms and laboratory abnormalities, reintroducing it in mild to moderate cases (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>), after individual assessment of risks versus benefits.<elsevierMultimedia ident="fig0010"></elsevierMultimedia></li><li class="elsevierStyleListItem" id="lsti0185">5.In severe cases, it should be suspended indefinitely.<a class="elsevierStyleCrossRef" href="#bib0270">24</a></li></ul>HepatotoxicityIt is difficult to establish the frequency of L-ASA-induced hepatotoxicity, since multiple concurrent causes can contribute, although it is a common complication associated with the use of this drug. The diagnosis of L-ASA-induced hepatotoxicity should be strengthened if there is liver involvement with a pattern of cholestasis accompanied by some grade of hypoalbuminemia, hypertriglyceridemia, hypoglycaemia, hyperammonemia, or hypofibrinogenemia. In paediatric series, the incidence of any grade of L-ASA-induced hepatotoxicity is between 30% and 60%, while the frequency of grades 3–4 is between 3% and 7%, with either L-native ASA, Erwinia or PEG-ASP.<a class="elsevierStyleCrossRef" href="#bib0275">25</a> In adults, the frequency of grade 3–4 hepatotoxicity may be between 14 and 52%.<a class="elsevierStyleCrossRef" href="#bib0195">9</a>Recommendations<ul class="elsevierStyleList" id="lis0045"><li class="elsevierStyleListItem" id="lsti0190">1.Rule out other treatable causes of liver disease and avoid concomitant hepatotoxic drugs.</li><li class="elsevierStyleListItem" id="lsti0195">2.Close monitoring of liver, metabolic and coagulation function.</li><li class="elsevierStyleListItem" id="lsti0200">3.When administering PEG-ASP, as its half-life is 6 days, its toxic effect can last up to 15 days from time of administration, so hepatotoxicity could be more frequent, and perhaps more serious, at least in adult patients who are more susceptible and have less hepatic reserve.</li><li class="elsevierStyleListItem" id="lsti0205">4.Suspend the remaining doses of L-ASA if grade 3–4 hepatotoxicity occurs, until the biochemical parameters of liver function are normalized. Patients with signs and symptoms of hepatic encephalopathy or with very pronounced toxicities (bilirubin >10–15mg/dl) should be hospitalized.</li><li class="elsevierStyleListItem" id="lsti0210">5.If toxicity was caused by Erwinia or native L-ASA, both with short half-life, it would be reasonable to reintroduce L-ASA at protocol-specified doses under close monitoring, resuspending if grade 3–4 hepatotoxicity reoccur. If hepatotoxicity was PEG-ASP-induced, it seems reasonable not to administer this drug and, instead, offer the patient a short half-life L-ASA form.</li></ul>Neurological toxicityThe incidence of nonvascular neurological complications appears to be higher in adult patients compared to paediatric, although it is below 10% in both cases.<a class="elsevierStyleCrossRef" href="#bib0280">26</a> Visual abnormalities, seizures, lethargy and coma are among the most common forms. The development of reversible posterior leukoencephalopathy syndrome has also been described, which has a characteristic radiologic translation in the occipital region of the MRI's T2 sequence.<a class="elsevierStyleCrossRef" href="#bib0285">27</a>The development of hyperammonemia associated with L-ASA has been suggested as a possible mechanism.<a class="elsevierStyleCrossRef" href="#bib0290">28</a> Notably, the high risk of neurological complications with other drugs used for the treatment of ALL (MTX, vincristine, glucocorticoids) makes it difficult to attribute the cause of the neurological disorder only to L-ASA.Recommendations<ul class="elsevierStyleList" id="lis0050"><li class="elsevierStyleListItem" id="lsti0215">1.Assess the risk–benefit of continuing treatment for each patient, considering the characteristics of the complication, the risk of disease and the L-ASA's administered/pending doses.</li><li class="elsevierStyleListItem" id="lsti0220">2.In severe complications, such as reversible posterior leukoencephalopathy syndrome or generalized seizures temporary or permanent discontinuation of L-ASA should be considered.</li></ul>HyperglycaemiaL-ASA-induced hyperglycaemia is caused by a decrease in insulin production.<a class="elsevierStyleCrossRef" href="#bib0295">29</a> Hyperglycaemia occurs in up to 23% of paediatric patients and in up to 76% of adults, although grade 3–4 affects to less than a quarter and can be linked to glucocorticoids.<a class="elsevierStyleCrossRef" href="#bib0300">30</a> A short insulin treatment may be required for some of these patients, although the vast majority of them normalize blood glucose levels after treatment with L-ASA is completed. The incidence of serious complications associated with hyperglycaemia (such as ketoacidosis) is very rare.Recommendations<ul class="elsevierStyleList" id="lis0055"><li class="elsevierStyleListItem" id="lsti0225">1.Frequent determination of blood glucose in patients receiving L-ASA.</li><li class="elsevierStyleListItem" id="lsti0230">2.Maintaining treatment with L-ASA with an adequate dietary and pharmacological control of blood glucose is generally safe.</li><li class="elsevierStyleListItem" id="lsti0235">3.In cases of ketoacidosis it may be necessary to temporarily or permanently suspend the administration of L-ASA.</li></ul>AuthorshipAll authors have contributed equally to the completion of this work.Conflict of interestsPB, JLD, PM and SR have participated in consultancy activities for Jazz Pharmaceuticals Inc. and Shire-Baxalta." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Methodology and objectives" ] 2 => array:3 [ "identificador" => "sec0015" "titulo" => "Types of asparaginase" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Dose, dose equivalence, frequency and route of administration" ] ] ] 3 => array:2 [ "identificador" => "sec0025" "titulo" => "Using asparaginase according to current protocols" ] 4 => array:2 [ "identificador" => "sec0030" "titulo" => "Drug interactions" ] 5 => array:3 [ "identificador" => "sec0035" "titulo" => "Adverse effects" "secciones" => array:1 [ 0 => array:3 [ "identificador" => "sec0040" "titulo" => "Hypersensitivity" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "Prognostic implications, changes and suspension of asparaginase" ] ] ] ] ] 6 => array:3 [ "identificador" => "sec0050" "titulo" => "Silent inactivation" "secciones" => array:7 [ 0 => array:2 [ "identificador" => "sec0055" "titulo" => "Thrombosis" ] 1 => array:2 [ "identificador" => "sec0060" "titulo" => "Haemorrhage" ] 2 => array:2 [ "identificador" => "sec0065" "titulo" => "Pancreatitis" ] 3 => array:2 [ "identificador" => "sec0070" "titulo" => "Hepatotoxicity" ] 4 => array:2 [ "identificador" => "sec0075" "titulo" => "Neurological toxicity" ] 5 => array:2 [ "identificador" => "sec0080" "titulo" => "Hyperglycaemia" ] 6 => array:2 [ "identificador" => "sec0085" "titulo" => "Recommendations" ] ] ] 7 => array:2 [ "identificador" => "sec0090" "titulo" => "Authorship" ] 8 => array:2 [ "identificador" => "sec0095" "titulo" => "Conflict of interests" ] 9 => array:2 [ "identificador" => "xack276262" "titulo" => "Acknowledgements" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-11-22" "fechaAceptado" => "2016-12-04" "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Barba P, Dapena JL, Montesinos P, Rives S. Asparaginasas en el tratamiento de la leucemia linfoblástica aguda. Med Clin (Barc). 2017;148:225–231." ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1802 "Ancho" => 2841 "Tamanyo" => 151029 ] ] "descripcion" => array:1 [ "en" => "Management algorithm for asparaginase hypersensitivity reactions. aIf an asparaginase activity test cannot be performed, and differentiation between an infusional or a hypersensitivity reaction is not possible, a formulation change is recommended, either to PEG-asparaginase or to Erwinia asparaginase. bMainly, a change to Erwinia L-ASA to avoid cross-reactivity. cNot recommended. It can be considered in cases of very severe reaction and if the formulation cannot be changed and/or if the planned treatment has been almost completed." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2035 "Ancho" => 2986 "Tamanyo" => 357015 ] ] "descripcion" => array:1 [ "en" => "Management algorithm in case of pancreatitis." ] ] 2 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "SD: standard deviation; IM: intramuscular; IV: intravenous; PEG asparaginase: E. coli asparaginase conjugated with polyethylene glycol." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Erwinia chrysanthemi asparaginase One IM dose of 25,000IU/m2 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Erwinia chrysanthemi asparaginase One IV dose of 25,000IU/m2 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Native Escherichia coli asparaginase One IM dose of 25,000IU/m2 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">PEG-asparaginase One IM dose of 2500IU/m2 \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Half-life, days (mean±SD) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.65±0.13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.31±1.79 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.28±0.35 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5.73±3.24 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Equivalent doses \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">20,000–25,000IU/m2 every 2 days \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">20,000–25,000IU/m2 every 2 days \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6000–10,000IU/m2 every 2–3 days \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2500–3500IU/m2 every 2 weeks 1000IU/m2 every 2 weeks<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1384838.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "In some protocols 1000IU/m2 every 2 weeks has been considered sufficient." ] ] ] "descripcion" => array:1 [ "en" => "Half-life and equivalent doses of the three asparaginase formulations." ] ] 3 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "NSAIDs: non-steroidal anti-inflammatory drugs; CTCAE: Common Terminology Criteria for Adverse Events.Source: Dueck et al.<a class="elsevierStyleCrossRef" href="#bib0245">19</a>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Grade \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Reaction \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Transient erythema or rash, fever <38°C; intervention not indicated \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Intervention or interruption of the infusion are indicated; responds quickly to symptomatic treatment (e.g. antihistamines, NSAIDs, opioids, etc.); prophylactic drugs indicated ≤24h \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Extended (e.g. do not respond quickly to symptomatic medication and/or a brief interruption of the infusion); recurrence of symptoms after initial improvement; hospitalization indicated by clinical sequelae (e.g. renal failure, pulmonary infiltrates) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Life threatening episodes; urgent intervention indicated \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Death \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1384837.png" ] ] ] ] "descripcion" => array:1 [ "en" => "CTCAE criteria for toxicity in hypersensitivity reactions." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:30 [ 0 => array:3 [ "identificador" => "bib0155" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Asparaginase-associated pancreatitis in children with acute lymphoblastic leukaemia in the NOPHO ALL2008 protocol" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R.A. Raja" 1 => "K. Schmiegelow" 2 => "B.K. Albertsen" 3 => "K. Prunsild" 4 => "B. Zeller" 5 => "G. Vaitkeviciene" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/bjh.12733" "Revista" => array:6 [ "tituloSerie" => "Br J Haematol" "fecha" => "2014" "volumen" => "165" "paginaInicial" => "126" "paginaFinal" => "133" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24428625" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0160" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pharmacokinetics, pharmacodynamics, efficacy, and safety of a new recombinant asparaginase preparation in children with previously untreated acute lymphoblastic leukemia: a randomized phase 2 clinical trial" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R. Pieters" 1 => "I. Appel" 2 => "H.J. Kuehnel" 3 => "I. Tetzlaff-Fohr" 4 => "U. Pichlmeier" 5 => "I. van der Vaart" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2008-04-149443" "Revista" => array:6 [ "tituloSerie" => "Blood" "fecha" => "2008" "volumen" => "112" "paginaInicial" => "4832" "paginaFinal" => "4838" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18805963" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0165" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Asparaginase pharmacokinetics and implications of therapeutic drug monitoring" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "B. Asselin" 1 => "C. Rizzari" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3109/10428194.2014.1003056" "Revista" => array:6 [ "tituloSerie" => "Leuk Lymphoma" "fecha" => "2015" "volumen" => "56" "paginaInicial" => "2273" "paginaFinal" => "2280" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25586605" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0170" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Thrombotic complications in childhood acute lymphoblastic leukemia: a meta-analysis of 17 prospective studies comprising 1752 pediatric patients" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "V. Caruso" 1 => "L. Iacoviello" 2 => "A. di Castelnuovo" 3 => "S. Storti" 4 => "G. Mariani" 5 => "G. de Gaetano" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2006-04-015511" "Revista" => array:6 [ "tituloSerie" => "Blood" "fecha" => "2006" "volumen" => "108" "paginaInicial" => "2216" "paginaFinal" => "2222" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16804111" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0175" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Changes in antithrombin and fibrinogen levels during induction chemotherapy with L-asparaginase in adult patients with acute lymphoblastic leukemia or lymphoblastic lymphoma. Use of supportive coagulation therapy and clinical outcome: the CAPELAL study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. Hunault-Berger" 1 => "P. Chevallier" 2 => "M. Delain" 3 => "C.E. Bulabois" 4 => "S. Bologna" 5 => "M. Bernard" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3324/haematol.12948" "Revista" => array:6 [ "tituloSerie" => "Haematologica" "fecha" => "2008" "volumen" => "93" "paginaInicial" => "1488" "paginaFinal" => "1494" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18728028" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0180" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Early postinduction intensification therapy improves survival for children and adolescents with high-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "N.L. Seibel" 1 => "P.G. Steinherz" 2 => "H.N. Sather" 3 => "J.B. Nachman" 4 => "C. Delaat" 5 => "L.J. Ettinger" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2007-02-070342" "Revista" => array:6 [ "tituloSerie" => "Blood" "fecha" => "2008" "volumen" => "111" "paginaInicial" => "2548" "paginaFinal" => "2555" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18039957" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0185" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Best practices in adolescent and young adult patients with acute lymphoblastic leukemia: a focus on asparaginase" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "N. Boissel" 1 => "L.S. Sender" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1089/jayao.2015.0014" "Revista" => array:6 [ "tituloSerie" => "J Adolesc Young Adult Oncol" "fecha" => "2015" "volumen" => "4" "paginaInicial" => "118" "paginaFinal" => "128" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26421220" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0190" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hypersensitivity reactions to L-asparaginase do not impact on the remission duration of adults with acute lymphoblastic leukemia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "R.A. Larson" 1 => "M.H. Fretzin" 2 => "R.K. Dodge" 3 => "C.A. Schiffer" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Leukemia" "fecha" => "1998" "volumen" => "12" "paginaInicial" => "660" "paginaFinal" => "665" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9593262" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0195" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Prevention and management of asparaginase/pegasparaginase-associated toxicities in adults and older adolescents: recommendations of an expert panel" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "W. Stock" 1 => "D. Douer" 2 => "D.J. DeAngelo" 3 => "M. Arellano" 4 => "A. Advani" 5 => "L. Damon" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3109/10428194.2011.596963" "Revista" => array:6 [ "tituloSerie" => "Leuk Lymphoma" "fecha" => "2011" "volumen" => "52" "paginaInicial" => "2237" "paginaFinal" => "2253" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21827361" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0200" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Allergic reactions associated with intravenous versus intramuscular pegaspargase: a retrospective chart review" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "L.S. Abbott" 1 => "M. Zakova" 2 => "F. Shaikh" 3 => "N. Shewaramani" 4 => "A. Punnett" 5 => "L.L. Dupuis" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s40272-015-0129-1" "Revista" => array:6 [ "tituloSerie" => "Paediatr Drugs" "fecha" => "2015" "volumen" => "17" "paginaInicial" => "315" "paginaFinal" => "321" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25862348" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0205" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Comparison of allergic reactions to intravenous and intramuscular pegaspargase in children with acute lymphoblastic leukemia" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "W.C. Petersen" 1 => "D. Clark" 2 => "S.L. Senn" 3 => "W.T. Cash" 4 => "S.E. Gillespie" 5 => "C.E. McCracken" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3109/08880018.2013.876134" "Revista" => array:6 [ "tituloSerie" => "Pediatr Hematol Oncol" "fecha" => "2014" "volumen" => "31" "paginaInicial" => "311" "paginaFinal" => "317" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24498943" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0210" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Comparison of allergic reactions to pegasparaginase given intravenously versus intramuscularly" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "M. Pidaparti" 1 => "B. Bostrom" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/pbc.23380" "Revista" => array:6 [ "tituloSerie" => "Pediatr Blood Cancer" "fecha" => "2012" "volumen" => "59" "paginaInicial" => "436" "paginaFinal" => "439" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22021170" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0215" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Comparative pharmacokinetic studies of three asparaginase preparations" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "B.L. Asselin" 1 => "J.C. Whitin" 2 => "D.J. Coppola" 3 => "I.P. Rupp" 4 => "S.E. Sallan" 5 => "H.J. Cohen" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.1993.11.9.1780" "Revista" => array:6 [ "tituloSerie" => "J Clin Oncol" "fecha" => "1993" "volumen" => "11" "paginaInicial" => "1780" "paginaFinal" => "1786" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8355045" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0220" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pegylated asparaginase (Oncaspar) in children with ALL: drug monitoring in reinduction according to the ALL/NHL-BFM 95 protocols" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "H.J. Müller" 1 => "L. Löning" 2 => "A. Horn" 3 => "D. Schwabe" 4 => "M. Gunkel" 5 => "M. Schrappe" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Br J Haematol" "fecha" => "2000" "volumen" => "110" "paginaInicial" => "379" "paginaFinal" => "384" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10971395" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0225" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A randomized comparison of native Escherichia coli asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: a Children's Cancer Group study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "V.I. Avramis" 1 => "S. Sencer" 2 => "A.P. Periclou" 3 => "H. Sather" 4 => "B.C. Bostrom" 5 => "L.J. Cohen" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Blood" "fecha" => "2002" "volumen" => "99" "paginaInicial" => "1986" "paginaFinal" => "1994" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11877270" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0230" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Comparison of intramuscular therapy with Erwinia asparaginase and asparaginase Medac: pharmacokinetics, pharmacodynamics, formation of antibodies and influence on the coagulation system" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "B.K. Albertsen" 1 => "H. Schrøder" 2 => "J. Ingerslev" 3 => "P. Jakobsen" 4 => "V.I. Avramis" 5 => "H.J. Müller" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Br J Haematol" "fecha" => "2001" "volumen" => "115" "paginaInicial" => "983" "paginaFinal" => "990" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11843837" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0235" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hypersensitivity or development of antibodies to asparaginase does not impact treatment outcome of childhood acute lymphoblastic leukemia" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M.H. Woo" 1 => "L.J. Hak" 2 => "M.C. Storm" 3 => "J.T. Sandlund" 4 => "R.C. Ribeiro" 5 => "G.K. Rivera" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.2000.18.7.1525" "Revista" => array:6 [ "tituloSerie" => "J Clin Oncol" "fecha" => "2000" "volumen" => "18" "paginaInicial" => "1525" "paginaFinal" => "1532" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10735901" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0240" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A desensitization protocol in children with L-asparaginase hypersensitivity" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "S. Akbayram" 1 => "M. Doğan" 2 => "C. Akgün" 3 => "H. Caksen" 4 => "A.F. Oner" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/MPH.0b013e3181e003c7" "Revista" => array:6 [ "tituloSerie" => "J Pediatr Hematol Oncol" "fecha" => "2010" "volumen" => "32" "paginaInicial" => "e187" "paginaFinal" => "e191" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20505537" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0245" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Validity and reliability of the US National Cancer Institute's Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A.C. Dueck" 1 => "T.R. Mendoza" 2 => "S.A. Mitchell" 3 => "B.B. Reeve" 4 => "K.M. Castro" 5 => "L.J. Rogak" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1001/jamaoncol.2015.2639" "Revista" => array:6 [ "tituloSerie" => "JAMA Oncol" "fecha" => "2015" "volumen" => "1" "paginaInicial" => "1051" "paginaFinal" => "1059" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26270597" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0250" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Optimizing asparaginase therapy for acute lymphoblastic leukemia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "C. Rizzari" 1 => "V. Conter" 2 => "J. Starý" 3 => "A. Colombini" 4 => "A. Moericke" 5 => "M. Schrappe" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/CCO.0000000000000017" "Revista" => array:7 [ "tituloSerie" => "Curr Opin Oncol" "fecha" => "2013" "volumen" => "25" "numero" => "Suppl. 1" "paginaInicial" => "S1" "paginaFinal" => "S9" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24305505" "web" => "Medline" ] ] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0255" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Venous thrombotic complications in adults undergoing induction treatment for acute lymphoblastic leukemia: results from a meta-analysis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "V. Caruso" 1 => "L. Iacoviello" 2 => "A. di Castelnuovo" 3 => "S. Storti" 4 => "M.B. Donati" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "J Thromb Haemost" "fecha" => "2007" "paginaInicial" => "621" "paginaFinal" => "623" ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0260" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Predicting asparaginase-associated pancreatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "H.M. Knoderer" 1 => "J. Robarge" 2 => "D.A. Flockhart" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/pbc.21037" "Revista" => array:6 [ "tituloSerie" => "Pediatr Blood Cancer" "fecha" => "2007" "volumen" => "49" "paginaInicial" => "634" "paginaFinal" => "639" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16937362" "web" => "Medline" ] ] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0265" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Polymorphisms of asparaginase pathway and asparaginase-related complications in children with acute lymphoblastic leukemia" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. Ben Tanfous" 1 => "B. Sharif-Askari" 2 => "F. Ceppi" 3 => "H. Laaribi" 4 => "V. Gagné" 5 => "J. Rousseau" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1158/1078-0432.CCR-14-0508" "Revista" => array:6 [ "tituloSerie" => "Clin Cancer Res" "fecha" => "2015" "volumen" => "21" "paginaInicial" => "329" "paginaFinal" => "334" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24907114" "web" => "Medline" ] ] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0270" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical course and outcome in children with acute lymphoblastic leukemia and asparaginase-associated pancreatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "S.L. Kearney" 1 => "S.E. Dahlberg" 2 => "D.E. Levy" 3 => "S.D. Voss" 4 => "S.E. Sallan" 5 => "L.B. Silverman" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/pbc.22076" "Revista" => array:6 [ "tituloSerie" => "Pediatr Blood Cancer" "fecha" => "2009" "volumen" => "53" "paginaInicial" => "162" "paginaFinal" => "167" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19405141" "web" => "Medline" ] ] ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0275" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Comparison of Escherichia coli-asparaginase with Erwinia-asparaginase in the treatment of childhood lymphoid malignancies: results of a randomized European Organisation for Research and Treatment of Cancer-Children's Leukemia Group phase 3 trial" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. Duval" 1 => "S. Suciu" 2 => "A. Ferster" 3 => "X. Rialland" 4 => "B. Nelken" 5 => "P. 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Asparaginase use for the treatment of acute lymphoblastic leukemia

Asparaginasas en el tratamiento de la leucemia linfoblástica aguda

Pere Barbaa,

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pebarba@vhebron.net

Corresponding author.

, José Luis Dapenab, Pau Montesinosc, Susana Rivesd

a Servicio de Hematología, Hospital Universitari Vall d’Hebrón, Universidad Autònoma de Barcelona, Barcelona, Spain

b Servicio de Oncología y Hematología pediátricas, Hospital Universitari Vall d’Hebrón, Barcelona, Spain

c Hospital Universitari i Politècnic la Fe, València, Spain

d Hospital Universitari Sant Joan de Déu, Barcelona, Spain

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            "entidad" => "Hospital Universitari i Polit&#232;cnic la Fe&#44; Val&#232;ncia&#44; Spain"
            "etiqueta" => "c"
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          ]
          3 => array:3 [
            "entidad" => "Hospital Universitari Sant Joan de D&#233;u&#44; Barcelona&#44; Spain"
            "etiqueta" => "d"
            "identificador" => "aff0020"
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        "titulo" => "Asparaginasas en el tratamiento de la leucemia linfobl&#225;stica aguda"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Management algorithm for asparaginase hypersensitivity reactions&#46; <span class="elsevierStyleSup">a</span>If an asparaginase activity test cannot be performed&#44; and differentiation between an infusional or a hypersensitivity reaction is not possible&#44; a formulation change is recommended&#44; either to PEG-asparaginase or to <span class="elsevierStyleItalic">Erwinia</span> asparaginase&#46; <span class="elsevierStyleSup">b</span>Mainly&#44; a change to <span class="elsevierStyleItalic">Erwinia</span> L-ASA to avoid cross-reactivity&#46; <span class="elsevierStyleSup">c</span>Not recommended&#46; It can be considered in cases of very severe reaction and if the formulation cannot be changed and&#47;or if the planned treatment has been almost completed&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Acute lymphoblastic leukaemia &#40;ALL&#41; is a rare neoplastic disease whose peak of incidence ranges between 2 and 5 years of age&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">1</span></a> Asparaginase &#40;L-ASA&#41; is considered an essential drug in its treatment&#46; It is an enzyme from cultures of <span class="elsevierStyleItalic">Escherichia coli &#40;E&#46; coli&#41;</span> and of <span class="elsevierStyleItalic">Chrysantemii Erwinia &#40;E&#46; chrysantemii&#41;</span> with the ability to hydrolyse L-asparagine converting it into aspartic acid and ammonium&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">2</span></a> Normal cells are able to synthesize this amino acid <span class="elsevierStyleItalic">de novo</span>&#44; but in leukemic cells&#44; L-asparagine extracellular depletion causes cell cycle arrest and inhibition of protein synthesis by inducing cell apoptosis&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">3</span></a> Depletion of L-asparagine is also associated with decreased synthesis of other proteins as albumin&#44; insulin&#44; fibrinogen and clotting factors&#44; resulting in L-ASA-specific homeostatic abnormalities&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">4&#44;5</span></a> Despite its strong anti-leukemic efficacy&#44; especially demonstrated in childhood ALL&#44;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">6&#44;7</span></a> this drug has been used less frequently in adult ALL protocols&#44; because its specific toxic effects increase with age&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">8&#44;9</span></a> The use of L-ASA in adults is also limited by the lower tolerability of conventional multidrug therapy regimens&#44; especially in older patients&#46; Therefore&#44; L-ASA is a little-known drug&#44; especially in among haematologists who treat adult patients&#44; in whom the disease is less prevalent&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Methodology and objectives</span><p id="par0010" class="elsevierStylePara elsevierViewall">Four Spanish doctors with extensive experience in the treatment of ALL in paediatric patients &#40;JLD and SR&#41; and adults &#40;PB and PM&#41; participated in the design and development of this article&#46; A comprehensive literature search of the most relevant aspects of asparaginase in the treatment of ALL was performed&#46; The authors shared their clinical experience and therapeutic approaches&#44; discussed algorithms and recommendations and participated in drafting and revising the manuscript in various face-to-face and virtual meetings&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Types of asparaginase</span><p id="par0015" class="elsevierStylePara elsevierViewall">L-ASA is marketed in 3 forms &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0020" class="elsevierStylePara elsevierViewall">Derived from native <span class="elsevierStyleItalic">E&#46; coli&#46;</span> It is the most commonly used formulation&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0025" class="elsevierStylePara elsevierViewall">Derived from the <span class="elsevierStyleItalic">E&#46; chrysanthemi bacteria&#46;</span> It is used in patients who have developed hypersensitivity to native <span class="elsevierStyleItalic">E&#46; coli</span> L-ASA and Peg-asparaginase &#40;PEG-ASP&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">-</span><p id="par0030" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">E&#46; coli</span> asparaginase conjugated with polyethylene glycol &#40;PEG-ASP&#41;&#46; Indicated as part of the ALL combined cytostatic treatment in paediatric and adult patients&#46;</p></li></ul></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Dose&#44; dose equivalence&#44; frequency and route of administration</span><p id="par0035" class="elsevierStylePara elsevierViewall">L-ASA can be used intravenously &#40;IV&#41; or intramuscularly &#40;IM&#41;&#46; The plasma concentration of L-ASA depends on the dose administered&#44; obtaining the peak plasma concentration with IM&#44; half of what is obtained IV&#46; Abbott et al&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">10</span></a> allergic reactions evaluated PEG-ASP according to the route used&#44; observing an increased frequency of allergic reactions in patients using the IV route&#46; Petersen et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">11</span></a> in a similar study&#44; showed that intravenous administration was associated with a higher incidence of reactions and an earlier onset of the same&#44; although with a similar severity profile&#46; In another study with PEG-ASP&#44; more local reactions were observed using the IM route&#44; while with IV these were more systemic&#44; although less severe&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">12</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Regarding PEG-ASP&#39;s action duration&#44; it has a longer half-life&#44; providing a longer asparagine depletion period after a single dose&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">13</span></a> L-ASA of native <span class="elsevierStyleItalic">E&#46; coli</span> and <span class="elsevierStyleItalic">Erwinia</span> have a much shorter half-life and must be administered more frequently to maintain asparagine depletion &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">The recommended doses for native <span class="elsevierStyleItalic">E&#46; coli</span> L-ASA are 5000&#8211;10&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span>&#47;48&#8211;72<span class="elsevierStyleHsp" style=""></span>h&#44; for <span class="elsevierStyleItalic">Erwinia</span> L-ASA 20&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span>&#47;48<span class="elsevierStyleHsp" style=""></span>h &#40;3 times&#47;week&#41;&#44; and PEG-ASP 1000&#8211;2500<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> every 2 weeks&#46; In general&#44; each dose of 10&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> of native <span class="elsevierStyleItalic">E&#46; coli</span> L-ASA should be replaced by 20&#44;000&#8211;25&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> of <span class="elsevierStyleItalic">Erwinia L-ASA&#46;</span> The replacement dose of <span class="elsevierStyleItalic">Erwinia</span> L-ASA in patients suffering from hypersensitivity to PEG-ASP would be 25&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> administered IV or IM &#40;mon-wed-fri&#41; for 2 weeks&#44; per dose of PEG-ASP&#46;</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Using asparaginase according to current protocols</span><p id="par0050" class="elsevierStylePara elsevierViewall">The Spanish protocol for childhood ALL &#40;LAL&#47;SEHOP-PETHEMA 2013&#41; differentiates 3 risk groups&#44; each with a different adapted treatment&#46; The treatment is less intensive in low risk patients&#44; with 2 inductions&#44; one consolidation&#44; one re-induction and a prolonged maintenance&#46; Both phases of induction and re-induction contain native L-ASA &#40;12 doses of 10&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> IM&#41;&#46; In the cases of intermediate-risk children&#44; their maintenance also contains 10 doses of 1000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> of PEG-ASP IM&#46; In those with high risk&#44; an additional dose of 1000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> of PEG-ASP IM is administered in each of the three intensifications and 2 equal doses of PEG-ASP in each of the three re-inductions&#44; without PEG-ASP during maintenance&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Regarding adult ALL&#44; the PETHEMA group offers protocols adapted to the risk of relapse&#44; age and ALL subtype&#46; Teenagers and young adults &#40;up to 30 years&#41; receive a protocol based on paediatric regimens &#40;ALL-RI-2008&#41;&#46; This protocol contains 8 doses of 10&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> of native IV L-ASA for induction and consolidation&#44; and up to 6 doses of 20&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> during re-inductions&#46; For patients with very high risk&#44; generally over 30 years of age&#44; the ALL-AR-2011 protocol contains IV native L-ASA &#40;4 doses of 10&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> in induction and 6 doses of 20&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> in consolidation&#44; it is omitted at re-induction and maintenance&#41; or IV PEG-ASP &#40;a dose of 2000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> in induction and up to 6 doses 2000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> in consolidation&#41;&#46; It is recommended to administer 50&#37; of the native L-ASA and PEG-ASP doses in patients over 50 years of age&#46; The protocol for those over 55 years of age &#40;ALL-Old-2007&#41; only contains 6 doses of 10&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> native L-ASA&#44; all in consolidation&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">One of the features in the PETHEMA and SEHOP protocols is the role of <span class="elsevierStyleItalic">E&#46; chrysantemii</span>&#44; L-ASA which would be indicated as the first alternative to native L-ASA and PEG-ASP in case of allergic reaction or prior hypersensitivity&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Drug interactions</span><p id="par0065" class="elsevierStylePara elsevierViewall">Because of its effect on liver function&#44; L-ASA can cause increased toxicity of hepatotoxic drugs with hepatic metabolism or attached to plasma proteins&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">3</span></a> Therefore&#44; these recommendations should be observed when using the following drugs commonly used in ALL&#58;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">-</span><p id="par0070" class="elsevierStylePara elsevierViewall">Vincristine&#58; should not be administered together with L-ASA&#44; as it may increase its toxicity &#40;neurotoxicity&#41; and the risk of allergic reactions &#40;administer it 3&#8211;24<span class="elsevierStyleHsp" style=""></span>h before L-ASA&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">-</span><p id="par0075" class="elsevierStylePara elsevierViewall">Glucocorticoids and&#47;or anticoagulants&#58; its concomitant use increases the risk of clotting disorders&#44; favouring a tendency to bleed &#40;anticoagulants&#41; or to develop thrombotic disorders &#40;glucocorticoids&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">-</span><p id="par0080" class="elsevierStylePara elsevierViewall">Methotrexate &#40;MTX&#41;&#58; inhibition of protein synthesis secondary to L-ASA-induced asparagine concentration decrease attenuates the cytotoxic effect of MTX&#44; as cell replication is necessary for the antineoplastic activity of this drug&#46; This antagonism occurs if L-ASA is administered prior to or in combination with MTX&#46; In contrast&#44; the antitumor effects of MTX increase when L-ASA is administered 24<span class="elsevierStyleHsp" style=""></span>h after treatment with MTX&#46;</p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">-</span><p id="par0085" class="elsevierStylePara elsevierViewall">Cytarabine&#58; <span class="elsevierStyleItalic">in vitro</span> and <span class="elsevierStyleItalic">in vivo</span> data indicate that the efficacy of cytarabine at high-doses decreases when administered before L-ASA&#46; However&#44; a synergistic effect was observed when L-ASA was administered after cytarabine&#46;</p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">-</span><p id="par0090" class="elsevierStylePara elsevierViewall">Oral contraceptives are not recommended to be used as L-ASA hepatotoxicity can affect the hepatic clearance of these&#46;</p></li><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">-</span><p id="par0095" class="elsevierStylePara elsevierViewall">Avoid concomitant administration of PEG-ASP with live virus vaccines&#44; BCG&#44; belimumab&#44; natalizumab&#44; pimecrolimus or tacrolimus &#40;topical&#41;&#46; Patients should be carefully monitored if PEG-ASP is administered concomitantly with attenuated virus vaccines&#44; denosumab or trastuzumab&#46;</p></li><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">-</span><p id="par0100" class="elsevierStylePara elsevierViewall">Thyroxine&#58; L-ASA produces a decrease in serum thyroxine&#46;</p></li></ul></p><p id="par0105" class="elsevierStylePara elsevierViewall">However&#44; many of these drugs are commonly used in the treatment of ALL and co-administration may be inevitable&#46; It is therefore important to follow the directions about the drugs&#8217; order of administration and be attentive to their potential toxicities&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Adverse effects</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Hypersensitivity</span><p id="par0110" class="elsevierStylePara elsevierViewall">Hypersensitivity is one of the most common adverse reactions associated with the use of L-ASA&#46; It is one of the most important complications due to the potential severity and therapeutic and prognostic implications involved in its development&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">The incidence ranges from 0 to 50&#37;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">6&#44;14</span></a> in children and around 15&#37; in adults&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">8</span></a> The incidence is higher with native L-ASA&#44; while PEG-ASP and <span class="elsevierStyleItalic">Erwinia</span> L-ASA have shown a lower incidence&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">15</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">Hypersensitivity reactions have been associated with the generation of antibodies against bacterial proteins&#46; Most episodes occur during re-exposure&#44; with consolidation and maintenance being the phases where these most frequently occur&#46; The IV route has been associated classically with increased risk&#44; although recent studies have not confirmed it&#46;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">15&#44;16</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">The severity of hypersensitivity reactions range from grade 1&#44; with isolated hives or hypotension that does not require fluids to grade 4&#44; with hypotension and anaphylactic shock &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; The vast majority are grade 1&#8211;2 and often appear as local reactions at the puncture site when administered intramuscularly&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">16</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0130" class="elsevierStylePara elsevierViewall">Patient monitoring during the 2<span class="elsevierStyleHsp" style=""></span>h after administration of L-ASA is recommended&#46; Most reactions occur within the first hour&#44; although IM route and the use of PEG-ASP can cause delayed reactions&#46; It is therefore advisable to instruct the patient and his&#47;her companions on delayed reaction detection&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">The use of premedication to prevent the development of hypersensitivity reactions is widespread&#44; although there is little scientific evidence to support it&#46; In addition&#44; their use could mask reactions that would highlight the presence of inactivated antibodies&#46; Since glucocorticoids are part of the treatment of ALL&#44; it seems advisable to administer L-ASA after the glucocorticoid dose&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">The treatment will vary depending on severity and presentation&#46; IV fluid therapy or fast-acting glucocorticoids &#40;hydrocortisone&#41; may be useful in most cases of grade 3&#8211;4&#46; More intensive measures and transfer to an ICU may be needed in more severe situations&#46;</p><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Prognostic implications&#44; changes and suspension of asparaginase</span><p id="par0145" class="elsevierStylePara elsevierViewall">Several studies have shown the importance of L-ASA as an essential part of the treatment of ALL&#44; and how patients that can complete treatment with L-ASA have better survival than those who have to stop treatment&#46; Two studies have shown that&#44; if after a hypersensitivity reaction to native or PEGylated L-ASA&#44; patients received <span class="elsevierStyleItalic">Erwinia</span> L-ASA&#44; these had a similar survival to those who never developed hypersensitivity&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">8&#44;17</span></a> It is therefore advisable to maintain the treatment with L-ASA&#44; either using the same or different formulation &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0150" class="elsevierStylePara elsevierViewall">Patients developing a grade 2&#8211;4 hypersensitivity should continue treatment with a different L-ASA&#46; <span class="elsevierStyleItalic">Erwinia</span> L-ASA would be recommended if the L-ASA used as first-line was the native <span class="elsevierStyleItalic">E&#46; coli</span>&#46; If <span class="elsevierStyleItalic">Erwinia</span> L-ASA is not available&#44; it could be switched to PEG-ASP&#44; but&#44; in these cases&#44; it is recommended to measure the levels of activity due to the possibility of cross-reactivity&#46; If the reaction occurs because of PEG-ASP&#44; it is advisable to use <span class="elsevierStyleItalic">Erwinia</span> L-ASA&#44; as there would be a high risk of developing a reaction of hypersensitivity with native <span class="elsevierStyleItalic">E&#46; coli</span> L-ASA&#46; As for the time of administration of the new formulation&#44; it seems advisable to start early &#40;24&#8211;48<span class="elsevierStyleHsp" style=""></span>h after the reaction&#41;&#44; providing the patient has recovered&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">In grade 1 hypersensitivity reactions&#44; an infusion reaction must be ruled out&#46; The L-ASA activity test determination would distinguish between a hypersensitivity reaction&#44; which often leads to a decrease in the activity of L-ASA below the minimum level of activity &#40;1&#46;00<span class="elsevierStyleHsp" style=""></span>IU&#47;l&#41;&#44; and an infusion reaction that would not mean a decrease in activity and would allow us to continue with the same treatment&#46; In case of grade 2&#8211;4 hypersensitivity&#44; the L-ASA formulation should be changed&#46; If this change is not viable&#44; a method which is underused and does not solve the silent inactivation&#44; would be a desensitization with increasing doses of L-ASA&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">18</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">Due to all these implications&#44; it is essential to confirm that the reaction was due to the use of L-ASA and rule out any other cause&#44; especially of infectious origin&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Recommendations&#58;</span><ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">1&#46;</span><p id="par0170" class="elsevierStylePara elsevierViewall">Monitor the patient during the first hour after administration of L-ASA in the native form and during 2<span class="elsevierStyleHsp" style=""></span>h in the case of PEG-ASP&#46;</p></li><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel">2&#46;</span><p id="par0175" class="elsevierStylePara elsevierViewall">Instruct the patient and their companions on the detection of delayed reactions&#46;</p></li><li class="elsevierStyleListItem" id="lsti0065"><span class="elsevierStyleLabel">3&#46;</span><p id="par0180" class="elsevierStylePara elsevierViewall">Perform a L-ASA activity test after the hypersensitivity episode to rule out the inactivation of the drug&#46;</p></li><li class="elsevierStyleListItem" id="lsti0070"><span class="elsevierStyleLabel">4&#46;</span><p id="par0185" class="elsevierStylePara elsevierViewall">Schedule the administration of L-ASA following the dose of glucocorticoids&#46;</p></li><li class="elsevierStyleListItem" id="lsti0075"><span class="elsevierStyleLabel">5&#46;</span><p id="par0190" class="elsevierStylePara elsevierViewall">Do not use additional premedication with antihistamines and glucocorticoids&#46;</p></li><li class="elsevierStyleListItem" id="lsti0080"><span class="elsevierStyleLabel">6&#46;</span><p id="par0195" class="elsevierStylePara elsevierViewall">L-ASA should be maintained whenever possible&#44; either with the same formulation or a different one&#46;</p></li><li class="elsevierStyleListItem" id="lsti0085"><span class="elsevierStyleLabel">7&#46;</span><p id="par0200" class="elsevierStylePara elsevierViewall">Change formulation in the case of a grade 2&#8211;4 hypersensitivity reaction&#46;</p></li><li class="elsevierStyleListItem" id="lsti0090"><span class="elsevierStyleLabel">8&#46;</span><p id="par0205" class="elsevierStylePara elsevierViewall">Switch to <span class="elsevierStyleItalic">Erwinia</span> L-ASA if the L-ASA used in first line was native or PEGylated&#44; according to equivalent doses &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; If <span class="elsevierStyleItalic">Erwinia</span> L-ASA is not available&#44; it could be changed to PEG-ASP after a hypersensitivity reaction to native <span class="elsevierStyleItalic">E&#46; coli</span> L-ASA&#46;</p></li></ul></p></span></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Silent inactivation</span><p id="par0210" class="elsevierStylePara elsevierViewall">L-ASA frequently causes the formation of antibodies that can inactivate it&#46; These antibodies are not associated with hypersensitivity reaction in 8&#8211;33&#37; of cases&#44; but cause L-ASA inactivation which is associated with reduced efficacy&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">20</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">Silent inactivation can be detected by&#58;<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0095"><span class="elsevierStyleLabel">1&#41;</span><p id="par0220" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Determination of asparagine concentration in plasma</span>&#46; Technically difficult because the enzyme still acts <span class="elsevierStyleItalic">ex vivo</span> if the blood sample is not kept on ice and processed immediately&#46;</p></li><li class="elsevierStyleListItem" id="lsti0100"><span class="elsevierStyleLabel">2&#41;</span><p id="par0225" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Detection of antibodies against L-ASA</span>&#46; Sensitive but unspecific&#44; since not all antibodies have neutralizing activity&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">3</span></a></p></li><li class="elsevierStyleListItem" id="lsti0105"><span class="elsevierStyleLabel">3&#41;</span><p id="par0230" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Measurement of the enzymatic activity of L-ASA</span>&#46; It correlates with the level of asparagine depletion and is reliable&#46; With L-ASA serum activity levels above 100<span class="elsevierStyleHsp" style=""></span>IU&#47;l&#44; asparagine depletion is achieved below the quantification levels&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">2&#44;20</span></a> Monitoring the activity of L-ASA allows to detect silent inactivation and individualize the dose to achieve the therapeutic range&#46;</p></li></ul></p><p id="par0235" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Recommendations</span></p><p id="par0240" class="elsevierStylePara elsevierViewall">In cases of silent inactivation&#58;<ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0110"><span class="elsevierStyleLabel">1&#46;</span><p id="par0245" class="elsevierStylePara elsevierViewall">Monitor L-ASA&#39;s enzymatic activity levels&#44; whenever possible&#44; which should be &#8805;100<span class="elsevierStyleHsp" style=""></span>IU&#47;l&#46;</p></li><li class="elsevierStyleListItem" id="lsti0115"><span class="elsevierStyleLabel">2&#46;</span><p id="par0250" class="elsevierStylePara elsevierViewall">Change L-ASA&#39;s formulation for another without cross reactivity&#46; There is no cross-reaction between native L-ASA or <span class="elsevierStyleItalic">E&#46; coli</span> PEG-ASP with <span class="elsevierStyleItalic">Erwinia</span> L-ASA&#44; so&#44; in these cases&#44; it would be of choice&#46;</p></li></ul></p><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Thrombosis</span><p id="par0255" class="elsevierStylePara elsevierViewall">Both thrombosis and haemorrhage associated with L-ASA occur in 90&#37; of cases during the induction phase&#44;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">4</span></a> probably due to multiple factors such as concomitant use of central venous catheter&#44; glucocorticoid treatment and the neoplastic growth itself&#46; Although the effects of L-ASA occur in procoagulant factors &#40;hypofibrinogenemia&#44; decreased factor IX&#44; X and plasminogen&#41; and anticoagulants &#40;decreased antithrombin III&#44; protein C and S&#41;&#44; clinical manifestations usually reflect a prothrombotic state&#46; Antithrombin III deficiency favours the generation of thrombin and fibrinogen and&#44; secondarily&#44; an increase of fibrinogen degradation products and factor consumption&#46; The reported incidence of thrombosis ranges between 1&#37; and 36&#37;&#46;</p><p id="par0260" class="elsevierStylePara elsevierViewall">Age is a risk factor and children have a lower predisposition&#46; The presence of at least one inherited thrombophilic factor has been associated with an increased risk of thrombosis in children&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall">According to a meta-analysis in the paediatric population&#44;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">21</span></a> thrombotic episodes were associated more frequently with the use of low doses of L-ASA in longer periods of time&#46; Other factors were the use of prednisone &#40;instead of dexamethasone&#41; and anthracyclines&#46;</p><p id="par0270" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Recommendations</span><ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0120"><span class="elsevierStyleLabel">1&#46;</span><p id="par0275" class="elsevierStylePara elsevierViewall">The use of L-ASA should be discontinued temporarily in the case of clinically significant bleeding or thrombotic episodes&#46;</p></li><li class="elsevierStyleListItem" id="lsti0125"><span class="elsevierStyleLabel">2&#46;</span><p id="par0280" class="elsevierStylePara elsevierViewall">L-ASA should be discontinued in the acute phase of venous thrombosis&#46;</p></li><li class="elsevierStyleListItem" id="lsti0130"><span class="elsevierStyleLabel">3&#46;</span><p id="par0285" class="elsevierStylePara elsevierViewall">Patients with deep venous thrombosis should receive anticoagulant therapy&#44; preferably with low molecular weight heparin &#40;LMWH&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0135"><span class="elsevierStyleLabel">4&#46;</span><p id="par0290" class="elsevierStylePara elsevierViewall">Once the symptoms and the thrombus are resolved&#44; re-exposure to L-ASA under prophylaxis with LMWH may be feasible and safe&#46; LMWH should be administered at anticoagulant doses during the first 3&#8211;6 months and if the thrombus is resolved&#44; move on to prophylactic doses each time the patient receives L-ASA from the day before until 15 days after the last dose of L-ASA&#46;</p></li><li class="elsevierStyleListItem" id="lsti0140"><span class="elsevierStyleLabel">5&#46;</span><p id="par0295" class="elsevierStylePara elsevierViewall">Primary prophylaxis with LMWH should be performed in patients with increased risk of thrombosis until the risk period is over &#40;from one day before the start of treatment with L-ASA until 15 days later&#41;&#46; Repeat every time L-ASA is administered&#46;</p></li></ul></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Haemorrhage</span><p id="par0300" class="elsevierStylePara elsevierViewall">The incidence of bleeding complications by L-ASA is estimated to be between 5&#37; &#40;children&#41; and 40&#37; &#40;in adults&#41;&#46; The incidence of intracranial haemorrhage is less than 0&#46;5&#37; in both adults and paediatric patients&#46; The same ALL can lead to an initial coagulopathy unrelated to chemotherapy which may increase the risk of bleeding and thrombotic episodes&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">7</span></a> In these cases&#44; in addition to starting chemotherapy treatment as early as possible&#44; we must establish measures to prevent bleeding in the cytoreduction or debulking phase &#40;transfusions of platelets and plasma correction times&#41;&#46;</p><p id="par0305" class="elsevierStylePara elsevierViewall">Haemorrhagic complications of L-ASA are rare despite the high frequency of hypofibrinogenemia induced by this drug&#46; The attitude towards hypofibrinogenemia is not clearly established&#58; in children&#44; fibrinogen determination is not usually done&#59; in adults&#44; some authors recommend fibrinogen or cryoprecipitate transfusion whenever serum levels are lower than 50&#8211;150<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#44; while others only indicate replacement when bleeding occurs&#44; monitoring fibrinogen levels weekly&#46;</p><p id="par0310" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Recommendations</span><ul class="elsevierStyleList" id="lis0035"><li class="elsevierStyleListItem" id="lsti0145"><span class="elsevierStyleLabel">1&#46;</span><p id="par0315" class="elsevierStylePara elsevierViewall">Fibrinogen levels should be monitored at least weekly in adult patients receiving L-ASA&#46;</p></li><li class="elsevierStyleListItem" id="lsti0150"><span class="elsevierStyleLabel">2&#46;</span><p id="par0320" class="elsevierStylePara elsevierViewall">Do not replace plasma factors through transfusions of fresh frozen plasma as this product could reverse L-ASA-induced asparagine depletion&#44; and thus reduce the antileukemic efficacy&#46;</p></li><li class="elsevierStyleListItem" id="lsti0155"><span class="elsevierStyleLabel">3&#46;</span><p id="par0325" class="elsevierStylePara elsevierViewall">In case of cerebral thrombosis&#44; administer anticoagulation effectively and correct coagulation disorders that favour haemorrhagic transformation&#44; such as severe thrombocytopenia or hypofibrinogenemia&#46;</p></li><li class="elsevierStyleListItem" id="lsti0160"><span class="elsevierStyleLabel">4&#46;</span><p id="par0330" class="elsevierStylePara elsevierViewall">Whenever any grade 3&#8211;4 bleeding event occurs&#44; such as a cerebral haemorrhage&#44; discontinue L-ASA administration&#46; This would be final if the causal relationship is clearly established&#46;</p></li></ul></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Pancreatitis</span><p id="par0335" class="elsevierStylePara elsevierViewall">The incidence of pancreatitis is around 5&#8211;10&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">1&#44;22</span></a> Diagnosis is based on clinical criteria &#40;abdominal pain&#44; nausea and vomiting&#41; associated with laboratory &#40;elevated amylase and lipase&#41; and&#47;or radiological criteria&#46; In most patients&#44; it is mild or moderate&#44; although severe in some&#44; with pseudocysts or multiple organ failure that can be fatal&#46; It can occur without a significant elevation of both pancreatic enzymes in up to a quarter of patients with pancreatitis&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">1</span></a> It has been suggested that there might be a genetic predisposition for its development&#44;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">22</span></a> and polymorphisms have been described involving L-ASA&#39;s action pathway genes&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">23</span></a></p><p id="par0340" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Recommendations</span></p><p id="par0345" class="elsevierStylePara elsevierViewall">Pancreatitis should be suspected in all patients receiving L-ASA who develop abdominal and&#47;or back pain&#46;<ul class="elsevierStyleList" id="lis0040"><li class="elsevierStyleListItem" id="lsti0165"><span class="elsevierStyleLabel">1&#46;</span><p id="par0350" class="elsevierStylePara elsevierViewall">When an asymptomatic elevation of amylase and lipase occurs&#44; a temporary suspension of L-ASA is recommended&#44; restarting after normalization&#46;</p></li><li class="elsevierStyleListItem" id="lsti0170"><span class="elsevierStyleLabel">2&#46;</span><p id="par0355" class="elsevierStylePara elsevierViewall">Analgesia and supportive treatment should be administered &#40;nutritional support&#44; haemodynamic stabilization in severe forms and antibiotics in cases where infection cannot be ruled out&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0175"><span class="elsevierStyleLabel">3&#46;</span><p id="par0360" class="elsevierStylePara elsevierViewall">Octreotide may be administered&#44; although its role is not well defined&#46;</p></li><li class="elsevierStyleListItem" id="lsti0180"><span class="elsevierStyleLabel">4&#46;</span><p id="par0365" class="elsevierStylePara elsevierViewall">Drug suspension until complete resolution of symptoms and laboratory abnormalities&#44; reintroducing it in mild to moderate cases &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#44; after individual assessment of risks <span class="elsevierStyleItalic">versus</span> benefits&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></li><li class="elsevierStyleListItem" id="lsti0185"><span class="elsevierStyleLabel">5&#46;</span><p id="par0370" class="elsevierStylePara elsevierViewall">In severe cases&#44; it should be suspended indefinitely&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">24</span></a></p></li></ul></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Hepatotoxicity</span><p id="par0375" class="elsevierStylePara elsevierViewall">It is difficult to establish the frequency of L-ASA-induced hepatotoxicity&#44; since multiple concurrent causes can contribute&#44; although it is a common complication associated with the use of this drug&#46; The diagnosis of L-ASA-induced hepatotoxicity should be strengthened if there is liver involvement with a pattern of cholestasis accompanied by some grade of hypoalbuminemia&#44; hypertriglyceridemia&#44; hypoglycaemia&#44; hyperammonemia&#44; or hypofibrinogenemia&#46; In paediatric series&#44; the incidence of any grade of L-ASA-induced hepatotoxicity is between 30&#37; and 60&#37;&#44; while the frequency of grades 3&#8211;4 is between 3&#37; and 7&#37;&#44; with either L-native ASA&#44; <span class="elsevierStyleItalic">Erwinia</span> or PEG-ASP&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">25</span></a> In adults&#44; the frequency of grade 3&#8211;4 hepatotoxicity may be between 14 and 52&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">9</span></a></p><p id="par0380" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Recommendations</span><ul class="elsevierStyleList" id="lis0045"><li class="elsevierStyleListItem" id="lsti0190"><span class="elsevierStyleLabel">1&#46;</span><p id="par0385" class="elsevierStylePara elsevierViewall">Rule out other treatable causes of liver disease and avoid concomitant hepatotoxic drugs&#46;</p></li><li class="elsevierStyleListItem" id="lsti0195"><span class="elsevierStyleLabel">2&#46;</span><p id="par0390" class="elsevierStylePara elsevierViewall">Close monitoring of liver&#44; metabolic and coagulation function&#46;</p></li><li class="elsevierStyleListItem" id="lsti0200"><span class="elsevierStyleLabel">3&#46;</span><p id="par0395" class="elsevierStylePara elsevierViewall">When administering PEG-ASP&#44; as its half-life is 6 days&#44; its toxic effect can last up to 15 days from time of administration&#44; so hepatotoxicity could be more frequent&#44; and perhaps more serious&#44; at least in adult patients who are more susceptible and have less hepatic reserve&#46;</p></li><li class="elsevierStyleListItem" id="lsti0205"><span class="elsevierStyleLabel">4&#46;</span><p id="par0400" class="elsevierStylePara elsevierViewall">Suspend the remaining doses of L-ASA if grade 3&#8211;4 hepatotoxicity occurs&#44; until the biochemical parameters of liver function are normalized&#46; Patients with signs and symptoms of hepatic encephalopathy or with very pronounced toxicities &#40;bilirubin &#62;10&#8211;15<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#41; should be hospitalized&#46;</p></li><li class="elsevierStyleListItem" id="lsti0210"><span class="elsevierStyleLabel">5&#46;</span><p id="par0405" class="elsevierStylePara elsevierViewall">If toxicity was caused by <span class="elsevierStyleItalic">Erwinia</span> or native L-ASA&#44; both with short half-life&#44; it would be reasonable to reintroduce L-ASA at protocol-specified doses under close monitoring&#44; resuspending if grade 3&#8211;4 hepatotoxicity reoccur&#46; If hepatotoxicity was PEG-ASP-induced&#44; it seems reasonable not to administer this drug and&#44; instead&#44; offer the patient a short half-life L-ASA form&#46;</p></li></ul></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Neurological toxicity</span><p id="par0410" class="elsevierStylePara elsevierViewall">The incidence of nonvascular neurological complications appears to be higher in adult patients compared to paediatric&#44; although it is below 10&#37; in both cases&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">26</span></a> Visual abnormalities&#44; seizures&#44; lethargy and coma are among the most common forms&#46; The development of reversible posterior leukoencephalopathy syndrome has also been described&#44; which has a characteristic radiologic translation in the occipital region of the MRI&#39;s T2 sequence&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">27</span></a></p><p id="par0415" class="elsevierStylePara elsevierViewall">The development of hyperammonemia associated with L-ASA has been suggested as a possible mechanism&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">28</span></a> Notably&#44; the high risk of neurological complications with other drugs used for the treatment of ALL &#40;MTX&#44; vincristine&#44; glucocorticoids&#41; makes it difficult to attribute the cause of the neurological disorder only to L-ASA&#46;</p><p id="par0420" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Recommendations</span><ul class="elsevierStyleList" id="lis0050"><li class="elsevierStyleListItem" id="lsti0215"><span class="elsevierStyleLabel">1&#46;</span><p id="par0425" class="elsevierStylePara elsevierViewall">Assess the risk&#8211;benefit of continuing treatment for each patient&#44; considering the characteristics of the complication&#44; the risk of disease and the L-ASA&#39;s administered&#47;pending doses&#46;</p></li><li class="elsevierStyleListItem" id="lsti0220"><span class="elsevierStyleLabel">2&#46;</span><p id="par0430" class="elsevierStylePara elsevierViewall">In severe complications&#44; such as reversible posterior leukoencephalopathy syndrome or generalized seizures temporary or permanent discontinuation of L-ASA should be considered&#46;</p></li></ul></p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Hyperglycaemia</span><p id="par0435" class="elsevierStylePara elsevierViewall">L-ASA-induced hyperglycaemia is caused by a decrease in insulin production&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">29</span></a> Hyperglycaemia occurs in up to 23&#37; of paediatric patients and in up to 76&#37; of adults&#44; although grade 3&#8211;4 affects to less than a quarter and can be linked to glucocorticoids&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">30</span></a> A short insulin treatment may be required for some of these patients&#44; although the vast majority of them normalize blood glucose levels after treatment with L-ASA is completed&#46; The incidence of serious complications associated with hyperglycaemia &#40;such as ketoacidosis&#41; is very rare&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Recommendations</span><p id="par0440" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0055"><li class="elsevierStyleListItem" id="lsti0225"><span class="elsevierStyleLabel">1&#46;</span><p id="par0445" class="elsevierStylePara elsevierViewall">Frequent determination of blood glucose in patients receiving L-ASA&#46;</p></li><li class="elsevierStyleListItem" id="lsti0230"><span class="elsevierStyleLabel">2&#46;</span><p id="par0450" class="elsevierStylePara elsevierViewall">Maintaining treatment with L-ASA with an adequate dietary and pharmacological control of blood glucose is generally safe&#46;</p></li><li class="elsevierStyleListItem" id="lsti0235"><span class="elsevierStyleLabel">3&#46;</span><p id="par0455" class="elsevierStylePara elsevierViewall">In cases of ketoacidosis it may be necessary to temporarily or permanently suspend the administration of L-ASA&#46;</p></li></ul></p></span></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Authorship</span><p id="par0460" class="elsevierStylePara elsevierViewall">All authors have contributed equally to the completion of this work&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Conflict of interests</span><p id="par0465" class="elsevierStylePara elsevierViewall">PB&#44; JLD&#44; PM and SR have participated in consultancy activities for Jazz Pharmaceuticals Inc&#46; and Shire-Baxalta&#46;</p></span></span>"
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        1 => array:2 [
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          "titulo" => "Methodology and objectives"
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          "identificador" => "sec0015"
          "titulo" => "Types of asparaginase"
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          "titulo" => "Using asparaginase according to current protocols"
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          "titulo" => "Silent inactivation"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as&#58; Barba P&#44; Dapena JL&#44; Montesinos P&#44; Rives S&#46; Asparaginasas en el tratamiento de la leucemia linfobl&#225;stica aguda&#46; Med Clin &#40;Barc&#41;&#46; 2017&#59;148&#58;225&#8211;231&#46;</p>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Management algorithm for asparaginase hypersensitivity reactions&#46; <span class="elsevierStyleSup">a</span>If an asparaginase activity test cannot be performed&#44; and differentiation between an infusional or a hypersensitivity reaction is not possible&#44; a formulation change is recommended&#44; either to PEG-asparaginase or to <span class="elsevierStyleItalic">Erwinia</span> asparaginase&#46; <span class="elsevierStyleSup">b</span>Mainly&#44; a change to <span class="elsevierStyleItalic">Erwinia</span> L-ASA to avoid cross-reactivity&#46; <span class="elsevierStyleSup">c</span>Not recommended&#46; It can be considered in cases of very severe reaction and if the formulation cannot be changed and&#47;or if the planned treatment has been almost completed&#46;</p>"
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          "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">SD&#58; standard deviation&#59; IM&#58; intramuscular&#59; IV&#58; intravenous&#59; PEG asparaginase&#58; <span class="elsevierStyleItalic">E&#46; coli</span> asparaginase conjugated with polyethylene glycol&#46;</p>"
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                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">Erwinia chrysanthemi</span> asparaginase<br>One IM dose of 25&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">Erwinia chrysanthemi</span> asparaginase<br>One IV dose of 25&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Native <span class="elsevierStyleItalic">Escherichia coli</span> asparaginase<br>One IM dose of 25&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">PEG-asparaginase<br>One IM dose of 2500<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Half-life&#44; days &#40;mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;65<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;13&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;28<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;35&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#46;73<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Equivalent doses&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20&#44;000&#8211;25&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> every 2 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20&#44;000&#8211;25&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> every 2 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6000&#8211;10&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> every 2&#8211;3 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2500&#8211;3500<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> every 2 weeks<br>1000<span class="elsevierStyleHsp" style=""></span>IU&#47;m<span class="elsevierStyleSup">2</span> every 2 weeks<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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          "leyenda" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">NSAIDs&#58; non-steroidal anti-inflammatory drugs&#59; CTCAE&#58; <span class="elsevierStyleItalic">Common Terminology Criteria for Adverse Events</span>&#46;</p><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Source</span>&#58; Dueck et al&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">19</span></a></p>"
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Transient erythema or rash&#44; fever &#60;38<span class="elsevierStyleHsp" style=""></span>&#176;C&#59; intervention not indicated&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Intervention or interruption of the infusion are indicated&#59; responds quickly to symptomatic treatment &#40;e&#46;g&#46; antihistamines&#44; NSAIDs&#44; opioids&#44; etc&#46;&#41;&#59; prophylactic drugs indicated &#8804;24<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">3&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Life threatening episodes&#59; urgent intervention indicated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Death&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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            0 => array:3 [
              "identificador" => "bib0155"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Asparaginase-associated pancreatitis in children with acute lymphoblastic leukaemia in the NOPHO ALL2008 protocol"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "R&#46;A&#46; Raja"
                            1 => "K&#46; Schmiegelow"
                            2 => "B&#46;K&#46; Albertsen"
                            3 => "K&#46; Prunsild"
                            4 => "B&#46; Zeller"
                            5 => "G&#46; Vaitkeviciene"
                          ]
                        ]
                      ]
                    ]
                  ]
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                    0 => array:2 [
                      "doi" => "10.1111/bjh.12733"
                      "Revista" => array:6 [
                        "tituloSerie" => "Br J Haematol"
                        "fecha" => "2014"
                        "volumen" => "165"
                        "paginaInicial" => "126"
                        "paginaFinal" => "133"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24428625"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0160"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pharmacokinetics&#44; pharmacodynamics&#44; efficacy&#44; and safety of a new recombinant asparaginase preparation in children with previously untreated acute lymphoblastic leukemia&#58; a randomized phase 2 clinical trial"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "R&#46; Pieters"
                            1 => "I&#46; Appel"
                            2 => "H&#46;J&#46; Kuehnel"
                            3 => "I&#46; Tetzlaff-Fohr"
                            4 => "U&#46; Pichlmeier"
                            5 => "I&#46; van der Vaart"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1182/blood-2008-04-149443"
                      "Revista" => array:6 [
                        "tituloSerie" => "Blood"
                        "fecha" => "2008"
                        "volumen" => "112"
                        "paginaInicial" => "4832"
                        "paginaFinal" => "4838"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18805963"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0165"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Asparaginase pharmacokinetics and implications of therapeutic drug monitoring"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "B&#46; Asselin"
                            1 => "C&#46; Rizzari"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3109/10428194.2014.1003056"
                      "Revista" => array:6 [
                        "tituloSerie" => "Leuk Lymphoma"
                        "fecha" => "2015"
                        "volumen" => "56"
                        "paginaInicial" => "2273"
                        "paginaFinal" => "2280"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25586605"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0170"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Thrombotic complications in childhood acute lymphoblastic leukemia&#58; a meta-analysis of 17 prospective studies comprising 1752 pediatric patients"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "V&#46; Caruso"
                            1 => "L&#46; Iacoviello"
                            2 => "A&#46; di Castelnuovo"
                            3 => "S&#46; Storti"
                            4 => "G&#46; Mariani"
                            5 => "G&#46; de Gaetano"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1182/blood-2006-04-015511"
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                        "tituloSerie" => "Blood"
                        "fecha" => "2006"
                        "volumen" => "108"
                        "paginaInicial" => "2216"
                        "paginaFinal" => "2222"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16804111"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0175"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Changes in antithrombin and fibrinogen levels during induction chemotherapy with L-asparaginase in adult patients with acute lymphoblastic leukemia or lymphoblastic lymphoma&#46; Use of supportive coagulation therapy and clinical outcome&#58; the CAPELAL study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; Hunault-Berger"
                            1 => "P&#46; Chevallier"
                            2 => "M&#46; Delain"
                            3 => "C&#46;E&#46; Bulabois"
                            4 => "S&#46; Bologna"
                            5 => "M&#46; Bernard"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3324/haematol.12948"
                      "Revista" => array:6 [
                        "tituloSerie" => "Haematologica"
                        "fecha" => "2008"
                        "volumen" => "93"
                        "paginaInicial" => "1488"
                        "paginaFinal" => "1494"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18728028"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0180"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Early postinduction intensification therapy improves survival for children and adolescents with high-risk acute lymphoblastic leukemia&#58; a report from the Children&#39;s Oncology Group"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "N&#46;L&#46; Seibel"
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                            3 => "J&#46;B&#46; Nachman"
                            4 => "C&#46; Delaat"
                            5 => "L&#46;J&#46; Ettinger"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1182/blood-2007-02-070342"
                      "Revista" => array:6 [
                        "tituloSerie" => "Blood"
                        "fecha" => "2008"
                        "volumen" => "111"
                        "paginaInicial" => "2548"
                        "paginaFinal" => "2555"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18039957"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0185"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Best practices in adolescent and young adult patients with acute lymphoblastic leukemia&#58; a focus on asparaginase"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "N&#46; Boissel"
                            1 => "L&#46;S&#46; Sender"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1089/jayao.2015.0014"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Adolesc Young Adult Oncol"
                        "fecha" => "2015"
                        "volumen" => "4"
                        "paginaInicial" => "118"
                        "paginaFinal" => "128"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26421220"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0190"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hypersensitivity reactions to L-asparaginase do not impact on the remission duration of adults with acute lymphoblastic leukemia"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "R&#46;A&#46; Larson"
                            1 => "M&#46;H&#46; Fretzin"
                            2 => "R&#46;K&#46; Dodge"
                            3 => "C&#46;A&#46; Schiffer"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Leukemia"
                        "fecha" => "1998"
                        "volumen" => "12"
                        "paginaInicial" => "660"
                        "paginaFinal" => "665"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9593262"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0195"
              "etiqueta" => "9"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Prevention and management of asparaginase&#47;pegasparaginase-associated toxicities in adults and older adolescents&#58; recommendations of an expert panel"
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                        0 => array:2 [
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                            0 => "W&#46; Stock"
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                            3 => "M&#46; Arellano"
                            4 => "A&#46; Advani"
                            5 => "L&#46; Damon"
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                        ]
                      ]
                    ]
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                    0 => array:2 [
                      "doi" => "10.3109/10428194.2011.596963"
                      "Revista" => array:6 [
                        "tituloSerie" => "Leuk Lymphoma"
                        "fecha" => "2011"
                        "volumen" => "52"
                        "paginaInicial" => "2237"
                        "paginaFinal" => "2253"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21827361"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib0200"
              "etiqueta" => "10"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Allergic reactions associated with intravenous versus intramuscular pegaspargase&#58; a retrospective chart review"
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                        0 => array:2 [
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                            0 => "L&#46;S&#46; Abbott"
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                            3 => "N&#46; Shewaramani"
                            4 => "A&#46; Punnett"
                            5 => "L&#46;L&#46; Dupuis"
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                      "doi" => "10.1007/s40272-015-0129-1"
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                        "tituloSerie" => "Paediatr Drugs"
                        "fecha" => "2015"
                        "volumen" => "17"
                        "paginaInicial" => "315"
                        "paginaFinal" => "321"
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25862348"
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                    0 => array:2 [
                      "titulo" => "Comparison of allergic reactions to intravenous and intramuscular pegaspargase in children with acute lymphoblastic leukemia"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "W&#46;C&#46; Petersen"
                            1 => "D&#46; Clark"
                            2 => "S&#46;L&#46; Senn"
                            3 => "W&#46;T&#46; Cash"
                            4 => "S&#46;E&#46; Gillespie"
                            5 => "C&#46;E&#46; McCracken"
                          ]
                        ]
                      ]
                    ]
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                    0 => array:2 [
                      "doi" => "10.3109/08880018.2013.876134"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pediatr Hematol Oncol"
                        "fecha" => "2014"
                        "volumen" => "31"
                        "paginaInicial" => "311"
                        "paginaFinal" => "317"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24498943"
                            "web" => "Medline"
                          ]
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                    0 => array:2 [
                      "titulo" => "Comparison of allergic reactions to pegasparaginase given intravenously versus intramuscularly"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "M&#46; Pidaparti"
                            1 => "B&#46; Bostrom"
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/pbc.23380"
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                        "tituloSerie" => "Pediatr Blood Cancer"
                        "fecha" => "2012"
                        "volumen" => "59"
                        "paginaInicial" => "436"
                        "paginaFinal" => "439"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22021170"
                            "web" => "Medline"
                          ]
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                ]
              ]
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              "identificador" => "bib0215"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Comparative pharmacokinetic studies of three asparaginase preparations"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "B&#46;L&#46; Asselin"
                            1 => "J&#46;C&#46; Whitin"
                            2 => "D&#46;J&#46; Coppola"
                            3 => "I&#46;P&#46; Rupp"
                            4 => "S&#46;E&#46; Sallan"
                            5 => "H&#46;J&#46; Cohen"
                          ]
                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1200/JCO.1993.11.9.1780"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Oncol"
                        "fecha" => "1993"
                        "volumen" => "11"
                        "paginaInicial" => "1780"
                        "paginaFinal" => "1786"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8355045"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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            13 => array:3 [
              "identificador" => "bib0220"
              "etiqueta" => "14"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pegylated asparaginase &#40;Oncaspar&#41; in children with ALL&#58; drug monitoring in reinduction according to the ALL&#47;NHL-BFM 95 protocols"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "H&#46;J&#46; M&#252;ller"
                            1 => "L&#46; L&#246;ning"
                            2 => "A&#46; Horn"
                            3 => "D&#46; Schwabe"
                            4 => "M&#46; Gunkel"
                            5 => "M&#46; Schrappe"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Br J Haematol"
                        "fecha" => "2000"
                        "volumen" => "110"
                        "paginaInicial" => "379"
                        "paginaFinal" => "384"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10971395"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib0225"
              "etiqueta" => "15"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A randomized comparison of native <span class="elsevierStyleItalic">Escherichia coli</span> asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia&#58; a Children&#39;s Cancer Group study"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "V&#46;I&#46; Avramis"
                            1 => "S&#46; Sencer"
                            2 => "A&#46;P&#46; Periclou"
                            3 => "H&#46; Sather"
                            4 => "B&#46;C&#46; Bostrom"
                            5 => "L&#46;J&#46; Cohen"
                          ]
                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Blood"
                        "fecha" => "2002"
                        "volumen" => "99"
                        "paginaInicial" => "1986"
                        "paginaFinal" => "1994"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11877270"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0230"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Comparison of intramuscular therapy with Erwinia asparaginase and asparaginase Medac&#58; pharmacokinetics&#44; pharmacodynamics&#44; formation of antibodies and influence on the coagulation system"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "B&#46;K&#46; Albertsen"
                            1 => "H&#46; Schr&#248;der"
                            2 => "J&#46; Ingerslev"
                            3 => "P&#46; Jakobsen"
                            4 => "V&#46;I&#46; Avramis"
                            5 => "H&#46;J&#46; M&#252;ller"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Br J Haematol"
                        "fecha" => "2001"
                        "volumen" => "115"
                        "paginaInicial" => "983"
                        "paginaFinal" => "990"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11843837"
                            "web" => "Medline"
                          ]
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                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "etiqueta" => "17"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hypersensitivity or development of antibodies to asparaginase does not impact treatment outcome of childhood acute lymphoblastic leukemia"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46;H&#46; Woo"
                            1 => "L&#46;J&#46; Hak"
                            2 => "M&#46;C&#46; Storm"
                            3 => "J&#46;T&#46; Sandlund"
                            4 => "R&#46;C&#46; Ribeiro"
                            5 => "G&#46;K&#46; Rivera"
                          ]
                        ]
                      ]
                    ]
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                    0 => array:2 [
                      "doi" => "10.1200/JCO.2000.18.7.1525"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Oncol"
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                        "volumen" => "18"
                        "paginaInicial" => "1525"
                        "paginaFinal" => "1532"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10735901"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0240"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A desensitization protocol in children with L-asparaginase hypersensitivity"
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                          "etal" => false
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                            0 => "S&#46; Akbayram"
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                            2 => "C&#46; Akg&#252;n"
                            3 => "H&#46; Caksen"
                            4 => "A&#46;F&#46; Oner"
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                        "tituloSerie" => "J Pediatr Hematol Oncol"
                        "fecha" => "2010"
                        "volumen" => "32"
                        "paginaInicial" => "e187"
                        "paginaFinal" => "e191"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20505537"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Validity and reliability of the US National Cancer Institute&#39;s Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events &#40;PRO-CTCAE&#41;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
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                            1 => "T&#46;R&#46; Mendoza"
                            2 => "S&#46;A&#46; Mitchell"
                            3 => "B&#46;B&#46; Reeve"
                            4 => "K&#46;M&#46; Castro"
                            5 => "L&#46;J&#46; Rogak"
                          ]
                        ]
                      ]
                    ]
                  ]
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                    0 => array:2 [
                      "doi" => "10.1001/jamaoncol.2015.2639"
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                        "tituloSerie" => "JAMA Oncol"
                        "fecha" => "2015"
                        "volumen" => "1"
                        "paginaInicial" => "1051"
                        "paginaFinal" => "1059"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26270597"
                            "web" => "Medline"
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                      ]
                    ]
                  ]
                ]
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              "identificador" => "bib0250"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Optimizing asparaginase therapy for acute lymphoblastic leukemia"
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                          "etal" => false
                          "autores" => array:6 [
                            0 => "C&#46; Rizzari"
                            1 => "V&#46; Conter"
                            2 => "J&#46; Star&#253;"
                            3 => "A&#46; Colombini"
                            4 => "A&#46; Moericke"
                            5 => "M&#46; Schrappe"
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                      "doi" => "10.1097/CCO.0000000000000017"
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                        "tituloSerie" => "Curr Opin Oncol"
                        "fecha" => "2013"
                        "volumen" => "25"
                        "numero" => "Suppl&#46; 1"
                        "paginaInicial" => "S1"
                        "paginaFinal" => "S9"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24305505"
                            "web" => "Medline"
                          ]
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                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0255"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Venous thrombotic complications in adults undergoing induction treatment for acute lymphoblastic leukemia&#58; results from a meta-analysis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "V&#46; Caruso"
                            1 => "L&#46; Iacoviello"
                            2 => "A&#46; di Castelnuovo"
                            3 => "S&#46; Storti"
                            4 => "M&#46;B&#46; Donati"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "J Thromb Haemost"
                        "fecha" => "2007"
                        "paginaInicial" => "621"
                        "paginaFinal" => "623"
                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0260"
              "etiqueta" => "22"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Predicting asparaginase-associated pancreatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "H&#46;M&#46; Knoderer"
                            1 => "J&#46; Robarge"
                            2 => "D&#46;A&#46; Flockhart"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/pbc.21037"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pediatr Blood Cancer"
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                        "volumen" => "49"
                        "paginaInicial" => "634"
                        "paginaFinal" => "639"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16937362"
                            "web" => "Medline"
                          ]
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                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0265"
              "etiqueta" => "23"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Polymorphisms of asparaginase pathway and asparaginase-related complications in children with acute lymphoblastic leukemia"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
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                            4 => "V&#46; Gagn&#233;"
                            5 => "J&#46; Rousseau"
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                        ]
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                    ]
                  ]
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                    0 => array:2 [
                      "doi" => "10.1158/1078-0432.CCR-14-0508"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Cancer Res"
                        "fecha" => "2015"
                        "volumen" => "21"
                        "paginaInicial" => "329"
                        "paginaFinal" => "334"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24907114"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0270"
              "etiqueta" => "24"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Clinical course and outcome in children with acute lymphoblastic leukemia and asparaginase-associated pancreatitis"
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                        0 => array:2 [
                          "etal" => false
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                            3 => "S&#46;D&#46; Voss"
                            4 => "S&#46;E&#46; Sallan"
                            5 => "L&#46;B&#46; Silverman"
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                    0 => array:2 [
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                        "tituloSerie" => "Pediatr Blood Cancer"
                        "fecha" => "2009"
                        "volumen" => "53"
                        "paginaInicial" => "162"
                        "paginaFinal" => "167"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19405141"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Comparison of <span class="elsevierStyleItalic">Escherichia coli</span>-asparaginase with Erwinia-asparaginase in the treatment of childhood lymphoid malignancies&#58; results of a randomized European Organisation for Research and Treatment of Cancer-Children&#39;s Leukemia Group phase 3 trial"
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                            4 => "B&#46; Nelken"
                            5 => "P&#46; Lutz"
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                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Blood"
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                        "paginaInicial" => "2734"
                        "paginaFinal" => "2739"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11929760"
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                          ]
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                      ]
                    ]
                  ]
                ]
              ]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Central nervous system complications during treatment of acute lymphoblastic leukemia in a single pediatric institution"
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                          "etal" => true
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                            4 => "E&#46; Cianciulli"
                            5 => "S&#46; Buffardi"
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                        ]
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                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3109/10428191003754608"
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                        "tituloSerie" => "Leuk Lymphoma"
                        "fecha" => "2010"
                        "volumen" => "51"
                        "paginaInicial" => "1063"
                        "paginaFinal" => "1071"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20470218"
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                          ]
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                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0285"
              "etiqueta" => "27"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "L-asparaginase-induced reversible posterior leukoencephalopathy syndrome in a child with acute lymphoblastic leukemia"
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                        0 => array:2 [
                          "etal" => false
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                            4 => "V&#46; Sawlani"
                            5 => "R&#46;K&#46; Gupta"
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                        ]
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                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "65395"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pediatr Neurosurg"
                        "fecha" => "2002"
                        "volumen" => "37"
                        "paginaInicial" => "203"
                        "paginaFinal" => "205"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12372914"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib0290"
              "etiqueta" => "28"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hyperammonemic encephalopathy after induction chemotherapy for acute lymphoblastic leukemia"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "T&#46;H&#46; Jaing"
                            1 => "J&#46;L&#46; Lin"
                            2 => "Y&#46;P&#46; Lin"
                            3 => "S&#46;H&#46; Yang"
                            4 => "J&#46;J&#46; Lin"
                            5 => "S&#46;H&#46; Hsia"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/MPH.0b013e3181b8beb1"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Pediatr Hematol Oncol"
                        "fecha" => "2009"
                        "volumen" => "31"
                        "paginaInicial" => "955"
                        "paginaFinal" => "956"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19887962"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib0295"
              "etiqueta" => "29"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effect of L-asparaginase on carbohydrate metabolism"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "J&#46;P&#46; Whitecar"
                            1 => "G&#46;P&#46; Bodey"
                            2 => "C&#46;S&#46; Hill"
                            3 => "N&#46;A&#46; Samaan"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Metabolism"
                        "fecha" => "1970"
                        "volumen" => "19"
                        "paginaInicial" => "581"
                        "paginaFinal" => "586"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/4913910"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0300"
              "etiqueta" => "30"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Intensified PEG-L-asparaginase and antimetabolite-based therapy for treatment of higher risk precursor-B acute lymphoblastic leukemia&#58; a report from the Children&#39;s Oncology Group"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "W&#46;L&#46; Salzer"
                            1 => "M&#46; Devidas"
                            2 => "J&#46;J&#46; Shuster"
                            3 => "C&#46; Wang"
                            4 => "A&#46; Chauvenet"
                            5 => "B&#46;L&#46; Asselin"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/MPH.0b013e3180640d54"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Pediatr Hematol Oncol"
                        "fecha" => "2007"
                        "volumen" => "29"
                        "paginaInicial" => "369"
                        "paginaFinal" => "375"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17551397"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
          ]
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        "titulo" => "Acknowledgements"
        "texto" => "<p id="par0470" class="elsevierStylePara elsevierViewall">The authors wish to thank the invaluable assistance of Professor Josep Maria Ribera in the critical review of this work&#46; The recommendations contained in this article have the backing of the Spanish Society of Paediatric Haematology and Oncology &#40;SEHOP&#41; and the Spanish acute lymphocytic leukaemia group of the Haematological Malignancies Treatment Programme &#40;PETHEMA&#41;&#46; We also appreciate the logistical and technical support of Ms&#46; Marta Gonz&#225;lez&#46; This work has been supported by Jazz Pharmaceuticals Inc&#46;</p>"
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Article information

ISSN: 23870206
Original language: English

DOI:10.1016/j.medcle.2017.03.002

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