Recommendations for identification and management of asparaginase hypersensitivity and silent inactivation have been issued in consensus expert guidelines written by Dr. Inge M. van der Sluis of Sophia Children’s Hospital, Rotterdam, The Netherlands, and her colleagues.
The guidelines were published in Haematologica, the Journal of the European Hematology Association (Haematologica 2016 March;101:279-85).
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A Wright's stained bone marrow aspirate smear of patient with precursor B-cell acute lymphoblastic leukemia.
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. The guidelines seek to reduce the risk that patients will receive an inadequate course of asparaginase therapy due to either intolerable side effects or silent inactivation. The recommendations address therapeutic drug monitoring through serum asparaginase level assessment, indications for switching asparaginase preparations, and recommendations for monitoring after changes in asparaginase preparation.
The guidelines conclude that measures of serum asparaginase activity levels are the best and most reliable indicators of asparaginase efficacy. Trough asparaginase activity levels of at least 0.1 IU/mL appear to be a safe target level to ensure therapeutic benefit. Anti-asparaginase antibodies and asparagine measurements are not indicated for clinical decision making outside the context of a clinical trial.
Should clinical hypersensitivity occur, the patient has likely developed anti-asparaginase antibodies. Continued use of asparaginase of the same formulation will be ineffective in the treatment of leukemia and should be discouraged, even when it is clinically possible to administer the same preparation by using premedication such as steroids and antihistamines or by decreasing the infusion rate. Such measures reduce the symptoms of the allergy, but do not prevent asparaginase inactivation.
In patients with grade 1 allergic reactions (transient flushing or rash without need for intervention), the guideline writers recommend monitoring serum asparaginase level in real-time within 7 days to identify inactivation. In those with grade 2-4 reactions, the guideline writers recommend switching the asparaginase preparation, and there is no definite need to check asparaginase levels.
Screening for silent inactivation should be considered in all patients undergoing therapy for ALL with asparaginase, especially when there have been gaps in asparaginase therapy or in the setting of the treatment of relapsed leukemia.
“We recommend the testing of serum asparaginase activity level after the first dose of E. coli–derived asparaginase. With the use of pegaspargase, this should be done within 7 days of the dose. If the level is detectable but less than 0.1 IU/mL, activity should be rechecked at day 14,” according to the authors.
In patients who receive pegylated asparaginase every 14 days without a gap in dosing, it would be reasonable to confirm a low or undetectable level after a subsequent dose, and to change to an Erwinia preparation, for example, if two consecutive levels are undetectable.
“When there is a gap between asparaginase doses, we recommend checking a level after the first dose of asparaginase administered after the gap, with a gap defined as a period in which asparaginase activity level will have decreased to less than the [lower limit of quantification] between doses. In practice, this is usually the case when there is an interval of at least 4 weeks between pegylated asparaginase doses. With native E. coli asparaginase, we recommend measuring a trough level after the first dose and after every reintroduction of asparaginase,” the authors wrote.
When a limited number of asparaginase doses is planned or there are prolonged gaps between doses, the guidelines advise screening for silent inactivation after every asparaginase dose, and considering a switching in preparation based upon a single undetectable or low level.
The guidelines also recommend more insight into the costs of treatment with the various asparaginase preparations. In addition to the detection of silent inactivation, therapeutic drug monitoring can be used to individualize dosing based on activity levels and has the potential to reduce medication costs.
Several of the consensus writers have participated in advisory boards of companies involved in asparaginase, including Sigma-Tau, Medac, and Jazz Pharmaceuticals. Jazz Pharmaceuticals provided financial support for the investigator-initiated consensus meeting.
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