The risk of serious allergic reactions is higher in patients with known hypersensitivity to other forms of l asparaginase. Asparaginase, pharmacogenomics, hypersensitivity reactions, pancreatitis, relapse, acute lymphoblastic leukemia, adverse drug reactions asparaginase and acute lymphoblastic leukemia l asparaginase asnase is a key component in leukemias and lymphomas treatment strategies and is universally incorporated into major childhood acute lymphoblastic. Silent hypersensitivity reactions to this microbial enzyme need to be monitored accurately during treatment to avoid adverse effects of the drug and its silent inactivation. The specific route of asparaginase administration may lead to disparate rates of hsrs and other adverse events in. Since these trials included patients who had previous hypersensitivity reactions to the native asparaginase, the possibility exists that crosssensitivity played a role in the reported reactions. A desensitization protocol in children with lasparaginase. Because adequate erwinase treatment requires an onerous thrice weekly schedule, and as many as one. When intravenous iv infusion replaced intramuscular im injection as the standard route of administration, there were early reports suggested an increased hypersensitivity reactions hsrs rate with iv administration. Apr 27, 2014 asparaginase is an essential component of pediatric acute lymphoblastic leukemia all therapy. Hypersensitivity reactions are unexpected and excessive responses of the immune system to a foreign substance antigen that cause a cascade of symptoms. However, asparaginase induced hypersensitivity reactions can compromise its efficacy either by directly influencing the pharmacokinetics of asparaginase or by leading to a discontinuation of asparaginase treatment. Differentiating hypersensitivity versus infusionrelated. Sensitized mice developed high levels of anti asparaginase igg antibodies and had immediate hypersensitivity reactions to asparaginase upon challenge.
Asparaginase encapsulated in erythrocytes for patients with. Pdf severe allergic reactions occur to lasparaginase, an important chemotherapeutic agent in treatment of childhood leukaemia. Reactions can range from local reactions more common to anaphylactic reactions, including skin rash, erythema, swelling, urticaria, pruritus, arthralgia, bronchospasm, wheezing, laryngeal edema, hypotension, respiratory andor cardiovascular collapse and death. Differentiating hypersensitivity versus infusionrelated reactions in. Throughout the united states, nurses assume frontline responsibility for the assessment of asparaginaserelated hypersensitivity reactions. History of serious thrombosis with prior l asparaginase therapy history of serious hemorrhagic events with prior l asparaginase therapy 5 warnings and precautions 5. Allergic reactions and antiasparaginase antibodies in children. Hypersensitivity reactions to lasparaginase do not impact. A murine model was developed that recapitulates key features of clinical hypersensitivity to escherichia coli asparaginase.
History of serious hemorrhagic events with prior l asparaginase therapy. Proposal for the inclusion of pege coli asparaginase in. L asparaginase is effective in the treatment of malignant diseases, but it has been associated with hypersensitivity reactions in 5% to 45% of the patients. Rates of clinical hypersensitivity to e coli asparaginase generally range from 10% to 30%, and with pegasparaginase rates range from 3% to. Review of pharmacogenetics studies of lasparaginase. How to solve the problem of hypersensitivity to asparaginase. The goal of this activity is increased knowledge and competence of learners regarding the identification and management of asparaginase associated hypersensitivity reactions, including screening and management of silent inactivation, in pediatric and adolescent patients with acute lymphoblastic leukemia all. Polyethyleneglycolated peg asparaginase pegasp is a crucial component of pediatric acute lymphoblastic leukemia therapy.
The prevalence of clinical hypersensitivity with asparaginase therapy depends on a number of factors including the type of asparaginase used, treatment intensity and history, concurrent corticosteroid use, and patient age and genetics. Thus, it is required to search for serologically different asparaginase from new organisms for the. Anaphylaxis and serious hypersensitivity reactions can occur in patients receiving oncaspar. History of serious hypersensitivity reactions to asparaginase erwinia chrysanthemi, including anaphylaxis. Neutralising anti asparaginase antibodies can develop without a clinical allergic reaction and is known as silent hypersensitivity. Severe hsr of pegaspargase via iv or im route of administration necessitates substitution with antigenically distinct erwinia asparaginase. Information on asparaginase hypersensitivity in this patient population is limited.
Toxicity, other than hypersensitivity reactions, may be more severe when the drug is administered. Here, we report successful challenges using native escherichia coli asparaginase. The other 35% had no prior hypersensitivity reaction to native asparaginase. The native asparaginase, used in the pediatric studies, 1 was recently removed from the market. In these studies, concomitant medications and dosing schedules varied. Jan 02, 2020 options for patients after allergic reactions to pegaspargase include rechallenging with premedications, switching to erwinia asparaginase, or discontinuation of asparaginase therapy. There is an everincreasing number of therapeutics used to treat cancer. Managing hypersensitivity to asparaginase in pediatrics.
There were less allergic reactions to erwinia asnase than native asnase. Hypersensitivity reactions can range from mild rashes and flushing to lifethreatening airway compromise and car diovascular collapse. Comparison of hypersensitivity reactions to pegasparaginase. Consensus expert recommendations for identification and. Lasparaginase is effective in the treatment of malignant diseases, but it has been associated with hypersensitivity reactions in 5% to 45% of the patients. Serious hypersensitivity reactions, including anaphylaxis, reported. A recent publication listed 86 currently available antineoplastic medications. Inflammatory response local, eliminates antigen without extensively damaging the hosts tissue. Other effects in patients taking l asparaginase include the possibility of hepatitis, pancreatitis, and altered production of coagulation factors resulting in either increased bleeding or increased clotting risk. Patients receiving pegaspargase may experience hypersensitivity reactions including anaphylaxis, bronchospasm, hypotension, laryngeal oedema, local erythema or swelling, rash and urticaria and the risk of serious hypersensitivity reaction is particularly high in patients with known hypersensitivity to e. Pegasparaginase hypersensitivity reactions developed during a median of 3 iv infusions range. The risk of serious hypersensitivity reactions is higher in patients with known hypersensitivity to e. Reactions whose route of administration was iv were more severe than the im reactions, a statistically significant result. Rheingoldb adivision of pediatric oncology, medical college of wisconsin, milwaukee, wi, usa.
Asparaginase is a key component of therapy for acute lymphoblastic leukemia all. L asparaginase is an effective antineoplastic agent used in chemotherapy of all. Clinical hypersensitivity occurs frequently in post induction regimens when asparaginase has not been given for weeks or months, but reactions have been reported after the first dose. As a medication, l asparaginase is used to treat acute lymphoblastic leukemia all, acute myeloid leukemia aml, and nonhodgkins lymphoma. Purposeto determine whether a desensitization protocol in children with native escherichia coli l asparaginase hypersensitivity allows. Earn 1 contact hour free of charge the goal of this ce activity is to provide nurses and nurse practitioners with knowledge and skills to recognize and manage acute hypersensitivity reactions hsrs occurring as a result of medication administration. Sensitized mice developed high levels of antiasparaginase igg antibodies and had immediate hypersensitivity reactions to asparaginase upon challenge. Hypersensitivity reaction hsr rates with these agents are common, multifactorial, and treatmentaltering. Pharmacogenetics of asparaginase in acute lymphoblastic. We studied allergic reactions and serum antibodies to e. Hypersensitivity reactions to chemotherapeutic drugs have been documented for numerous cancer therapies. Asparaginase is an essential component of pediatric acute lymphoblastic leukemia all therapy.
Clinical hypersensitivity reactions to elspar in studies were common ranging from 32. Hypersensitivity is an immunologic response 5 hypersensitivity reactions are mediated by the immune system 5. Immune reactions in patients treated with asparaginase fall into two general categories. Backgroundl asparaginase is effective in the treatment of malignant diseases, but it has been associated with hypersensitivity reactions in 5% to 45% of the patients. Despite this large number, hypersensitivity reactions are not common except with platinum compound cisplatin, carboplatin, epipodophyllotoxins teniposide, etoposide, asparaginase, taxanes paclitaxel, and procarbazine. Coli asparaginase and substitution with erwinia asparaginase. The halflife of erwinia asparaginase is shorter than other forms of asparaginase, and the shorter halflife of erwinia asparaginase has demonstrated clinical implications, with the need for more frequent dosing every 23 days. Other hypersensitivity reactions can include angioedema, lip swelling, eye. Predicting success of desensitization after pegaspargase. Clinical hypersensitivity reactions appear to be less prevalent with pegasparaginase, with rates from 324% reported in clinical trials 3,7,24,26. Hypersensitivity reactions associated with lasparaginase. History of serious thrombosis with prior l asparaginase therapy. Subgroups of paediatric acute lymphoblastic leukaemia might. In those cases, discontinuation of treatment is usually needed and anti asparaginase antibody production may also attenuate asparaginase activity, compromising its antileukemic effect.
How to manage asparaginase hypersensitivity in acute. Asparaginase is an enzyme that is used as a medication and in food manufacturing. Managing asparaginaserelated toxicity in adult patients. An antigen, such as asparaginase, may trigger an immune response, which results in the proliferation of antibodyproducing plasma cells 5. Do not receive any kind of immunization or vaccination without your doctors approval while taking asparaginase. Throughout the united states, nurses assume frontline responsibility for the assessment of asparaginase related hypersensitivity reactions. A promising enzyme for treatment of acute lymphoblastic leukiemia richa jain, k. Antibodies may directly bind to the surface of the mast cell, thereby activating the mast cell 5. Hypersensitivity reactions to escherichia coli jaci. Asparaginase agents are vital in the treatment of acute lymphoblastic leukemia all and can be delivered via an intravenous iv or intramuscular im injection. Effect of premedications in a murine model of asparaginase. Nurses administering peg asparaginase play a critical role in the early identification and management of hypersensitivity reactions. Treatmentlimiting reactions occurred in 9% of all patients, 14% of patients who had an allergic reaction to asparaginase, and 26% of patients who had an allergic reaction to both asparaginase and erwinia asparaginase. Hypersensitivity was lower when native asparaginase was administered intramuscularly im compared with intravenous administration.
Reactions to a single administration are rare, but since native l asparaginase is isolated from e. Hypersensitivity reactions to chemotherapeutic drugs. The national cancer institute has developed common toxicity criteria that can be used by health care providers to classify the severity of hypersensitivity reactions. The alternative, pegylated asparaginase was developed for patients with allergic reactions to the native enzyme and is associated with allergic reactions to the pegylated moiety, 7 which exists in canned food and cosmetic products. Grade 2 or moderate hypersensitivity reactions mild bronchospasm. Because asparaginase is a large protein that is foreign to the human body, it is commonly associated with hypersensitivity reactions. Tracking silent hypersensitivity reactions to asparaginase. Clinical hypersensitivity reactions against commercially available asparaginase have resulted in failure of asparaginase in treatment of all in more than 60% of cases. Clinical utility and implications of asparaginase antibodies. For pegasp, a metaanalysis showed a reduction in hypersensitivity reactions when administration occurs by the im route, in comparison to the iv route, in. When intravenous iv infusion replaced intramuscular im injection as the standard route of administration, there were early reports suggested an increased hypersensitivity reactions hsrs rate.
Antibodies were absent in all but one patient with an allergiclike reaction while they were detected in all patients with a real allergy. Almost all chemotherapeutic agents can cause an allergic reaction. Managing asparaginase hypersensitivity in pediatric and. Asparaginase products may produce acute hypersensitivity reactions with hypotension, sweating, bronchospasm, and urticaria. Lasparaginase is a cancer chemotherapeutic agent derived from escherichia coli. Rates of clinical hypersensitivity to e coli asparaginase generally range from 10% to 30%, and with pegasparaginase rates range from 3% to 24% vrooman et al. May continue dosing for urticaria without bronchospasm, hypotension, edema, or need for parenteral intervention. Erwinaze asparaginase erwinia chrysanthemi is indicated as a component of a multiagent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia all who have developed hypersensitivity to e. History of serious pancreatitis with prior l asparaginase therapy. Samples were sent after changing treatment to another drug because of hypersensitivity reactions in an additional 276 patients. We describe associations of allergic reactions and antiasparaginase. L asparaginase asp is a key element in the treatment of paediatric acute lymphoblastic leukaemia all. History of serious hypersensitivity reactions to erwinaze, including anaphylaxis.
Aug 21, 2014 the story with asparaginase is somewhat different. Pharmacogenetics of asparaginase in acute lymphoblastic leukemia. Other hypersensitivity reactions can include angioedema, lip swelling, eye swelling. However, hypersensitivity reactions hsrs to asp are major challenges in paediatric patients.
Hypersensitivity reactions to asparaginase therapy can occur in 30% of children with acute lymphoblastic leukemia all, and silent inactivation with the formation of neutralizing antibodies and reduced asparaginase activity can occur in the absence of a clinically evident allergic reaction. Fatal hypersensitivity reactions hsrs occur in less than 1% of humans treated. Hypersensitivity hypersensitivity reactions to pegaspargase, including lifethreatening anaphylaxis, can occur during therapy, including in patients with known hypersensitivity to e. Those who react to erwinia asparaginase may switch to pegasparaginase and usually tolerate it well. Pdf genomewide analysis links nfatc2 with asparaginase. For pegasp, a metaanalysis showed a reduction in hypersensitivity reactions when administration occurs by the im route, in comparison to the iv route, in pediatric patients under treatment for all. Pegasparaginase may decrease, although not eliminate the risk for an hsr and reactions are often milder. Aug 30, 2017 asparaginase encapsulated in erythrocytes for patients with all and hypersensitivity to peg asparaginase the safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Pegaspargase is a mainstay in the treatment of acute lymphoblastic leukemia.
Clinical hypersensitivity to escherichia coli asparaginase has been reported to range from 0% to 75%. Asparaginaseassociated toxicity in children with acute. Toxicity, other than hypersensitivity reactions, may be more severe when the drug is administered daily rather than weekly. Pharmacokinetics of native escherichia coli asparaginase. Proposal for the inclusion of pege coli asparaginase in the. It is effective in treating acute lymphoblastic leukemia all and other related. Hypersensitivity rates in pediatric patients receiving. Observe patients for 1 hour after administration in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis. Among its multiple toxic effects, l asparaginase induces allergic reactions that may reduce its biological effect.
Clinical hypersensitivity reactions against commercially available asparaginase have resulted in failure of asparaginase in treatment of all in more. History of serious pancreatitis with prior lasparaginase therapy history of serious thrombosis with prior lasparaginase therapy history of serious hemorrhagic events with prior lasparaginase therapy. Guidelines on asparaginase hypersensitivity and silent. Sensitized mice had complete inhibition of plasma asparaginase activity p 4. Nov 22, 2017 because adequate erwinase treatment requires an onerous thrice weekly schedule, and as many as one. Asparaginase dosing, monitoring, and toxicity management. Clinical hypersensitivity ranges from a mild local injection site reaction. Hypersensitivity reactions to pegasparaginase are more common when patients have been previously exposed to native e. Although hypersensitivity reactions to pegasp occur less frequently than with other formulations, they are not uncommon and have an adverse impact on patient outcomes. Differentiating hypersensitivity versus infusionrelated reactions in pediatric patients receiving intravenous asparaginase therapy for acute lymphoblastic leukemia michael j.
There are two forms of hypersensitivity seen in clinical practice. The impact of hypersensitivity reactions on the duration of leukemiafree. The incidence of hypersensitivity reactions to pegylated asparaginase in children with all. Hypersensitivity reactions may necessitate the discontinuation of e. Asparaginase may be inadvisable if you have had a hypersensitivity allergic reaction to asparaginase.
Despite its indisputable indication, hypersensitivity reactions are common. To determine whether a desensitization protocol in children with native escherichia coli lasparaginase hypersensitivity allows subsequent safe administration of native e. Subgroups of paediatric acute lymphoblastic leukaemia. If wheezing or other symptomatic bronchospasm with or without urticaria, angioedema, hypotension, andor lifethreatening hypersensitivity reactions occur, discontinue asparaginase. It is given by injection into a vein, muscle, or under the skin.
Microbial asparaginase is an essential component of chemotherapy for the treatment of childhood acute lymphoblastic leukemia call. Hypersensitivity reactions types i, ii, iii, iv april 15, 2009. Grade 1 or mild hypersensitivity reactions transient rash. Clinical characteristics of intravenous pegasparaginase. Hypersensitivity reactions to lasparaginase do not impact on. Our aim was to investigate genetic variants that may influence the risk to escherichia coliderived asp hypersensitivity. Additional research is needed to safely guide peg asparaginase monitoring, hypersensitivity reaction management, and patientfamily education. It is essential that nurses educate themselves on the signs and symptoms of asparaginase related hypersensitivity reactions.
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