Managing asparaginase-related toxicity in adult patients
Managing asparaginase-related toxicity in adult patients
An increasing number of antineoplastic agents and complex treatment regimens challenge oncology nurses to stay well-versed on the specifics of drug administration and patient care management issues. One such agent is asparaginase (Elspar), which has the potential for life-threatening infusion-related reactions. In addition, serious adverse reactions can occur days to weeks after administration. However, asparaginase is an important component of many multidrug regimens used to treat acute lymphoblastic leukemia (ALL). This article focuses on what the oncology nurse needs to know to safely administer asparaginase in the adult oncology patient.
Asparaginase is an enzyme isolated from a number of natural sources. Two sources used in clinical practice are Escherichia coli (also called native asparaginase) and Erwinia carotovora (currently available in the United States through the National Cancer Institute [NCI] for compassionate use only). Asparaginase hydrolyzes the amino acid L-asparagine to aspartic acid and ammonia, eliminating the exogenous availability of asparagine needed for DNA and RNA synthesis during the G1 phase of cell division.1 This unique mechanism of action capitalizes on the defect in leukemia cells, which lack the ability to synthesize asparagine. Thus, asparagine becomes an essential amino acid for the leukemic cell, and depleting its exogenous availability results in cell death.2
A version with a molecular modification created with monomethoxypolyethylene glycol (mPEG) was developed because the immune system recognizes the foreign proteins E coli and E carotovora. Furthermore, the E coli and E carotovora preparations have a short half-life and require frequent dosing (Table 1). The pegylated version (pegaspargase [Oncaspar, PEG-l-asparaginase]) reduces hypersensitivity and prolongs interval dosing yet preserves clinical efficacy. One dose of pegaspargase can replace six to nine doses of native asparaginase. Table 2 lists frequently used dosages of the three asparaginase preparations.
Side effects associated with asparaginase are divided into two categories: hypersensitivity or immunologic reactions to E coli or E carotovora and protein synthesis inhibition resulting from asparagine depletion (Table 3). Asparaginase has little to no effect on bone marrow and is not cytotoxic to oral or intestinal mucosa, allowing for its use in combination therapy regimens. It also does not cause hair loss.
Immune reactions vary from mild erythema at the injection site to generalized urticaria, bronchospasm, laryngeal edema, hypotension, hypoxia, and full-blown anaphylaxis (rare). Acute lymphoblastic leukemia is uncommon in adults; therefore, the adult oncology nurse may be unfamiliar with administering asparaginase. Information on asparaginase hypersensitivity in this patient population is limited. For example, some reviews of management and preparedness for infusion and hypersensitivity reactions do not include asparaginase.3 In addition, the resources of a protocol and research staff usually are available only in clinical trials. Thus, even the most experienced oncology nurse may be uncomfortable administering asparaginase. An unfamiliarity of the risks of infusion-related reactions, including life-threatening anaphylaxis, is intimidating.
Hypersensitivity rates vary among the three forms of asparaginase. Severe (grade 3 or 4) acute allergic reactions were seen in an average of 24% and 29% of pediatric and adult patients, respectively, treated with native asparaginase,4 but in 3% to 14% of all patients treated with pegaspargase.4,5 The potential for a reaction increases with each dose because of the type 1 hypersensitivity mechanism of action of the immune response. Patients should be monitored frequently to ensure prompt recognition of a reaction and instructed to report any change in how they feel during and immediately following administration of the agent.
Patients should be observed for 1 hour following asparaginase administration in a setting with resuscitation equipment available.6 When administering intravenously, standing orders to stop the infusion and initiate corticosteroids, antihistamine, epinephrine, oxygen, and IV fluids as symptoms dictate can limit the severity of the reaction. Attempts to predict a significant immunologic reaction via an intradermal test dose are unreliable, producing both false-positive and false-negative results.7 The efficacy of premedication with a corticosteroid and/or antihistamine has not been studied. However, concomitant administration of high-dose corticosteroids during a treatment cycle has been anecdotally associated with lower rates of hypersensitivity, prompting some clinicians to include premedication when a patient is not taking high-dose corticosteroids.
The route of administration may play a role. Hypersensitivity was lower when native asparaginase was administered intramuscularly (IM) compared with intravenous administration.7 Increased rates of injection site reaction, notably induration and erythema, are seen when asparaginase is given subcutaneously. However, IV administration of pegaspargase is associated with comparable or lower rates of hypersensitivity compared with IM administration of pegaspargase.8,9 In cases of grade 3 or 4 hypersensitivity, asparaginase should be discontinued. Native asparaginase may be switched to pegaspargase. Approximately two-thirds of patients are able to tolerate pegaspargase. If hypersensitivity occurs, E carotovora asparaginase may be tolerated if available.
INHIBITION OF PROTEIN SYNTHESIS
Other significant side effects associated with asparaginase are related to the drug's inhibitory effect on protein synthesis. The incidence of this effect is similar among the three types of asparaginase; therefore, unlike for a hypersensitivity reaction, switching to another type of asparaginase preparation if protein synthesis inhibition occurs is not beneficial. Although these effects are normally transient and without clinical significance, symptoms may be severe enough to warrant discontinuation of therapy, and further dosing during future cycles of the current regimen or in the event of relapse is prohibited.