INTRODUCTION
All chemotherapeutic agents can cause hypersensitivity reactions (HSRs), but these reactions usually occur prominently when agents such as platinum compounds, epipodophyllotoxins, taxanes, procarbazine and L-asparaginase are administered [1, 2]. These may develop immunologically or non-immunologically, but the responsible mechanism in most of them is unknown [2, 3]. The clinical picture of the patients may vary from mild skin reactions to severe, life-threatening reactions [2].
Asparaginase is a chemotherapeutic used in the treatment of hematological malignancies. Hypersensitivity reactions due to L-asparaginase have been described in 60% of patients [4], in which case switching to alternative forms of asparaginase is recommended: PEG-asparaginase (PEG-ASP) is an easily available formulation [5]. Although PEG-asparaginase is thought to be hypoallergenic, allergic reactions are observed in approximately 25% of patients receiving this drug [6]. In hypersensitivity reactions to native E. coli asparaginase, premedication and desensitisation or substitution with Erwinia chrysanthemi (ERW) or PEG-ASP is the preferred treatment [7–9]. Premedication and desensitisation protocols may prevent the development of anaphylaxis in many cases [8, 9]. However, use of PEG-ASP despite premedication and desensitisation may not be sufficient to prevent severe hypersensitivity reactions.
When a patient reacts to a chemotherapeutic drug, management options include using an alternative drug, giving the same drug with premedication, or desensitisation. Changing drugs when the offending agent is necessary or the best treatment option can have a negative impact on the patient’s outcomes. In these cases, drug desensitisation is more appropriate [10, 11].
CASE REPORT
A 5-year and 8-month-old male patient who was being followed up due to recurrent B-ALL B-cell acute lymphoblastic leukemia (B-ALL) was given PEG-ASP treatment. In the 3rd cycle of treatment, a hypersensitivity reaction developed in the 5th minute of intravenous (i.v.) infusion of PEG-ASP. The patient had dyspnea, wheezing and a urticaria-like rash that faded with pressure. The patient’s blood pressure was measured as 85/55 mm Hg. It was in the normal range for his age. The infusion was terminated immediately upon development of the hypersensitivity reaction. Symptoms improved rapidly after a single dose of IM adrenaline. After adrenaline treatment, intravenous methylprednisolone (1 mg/kg/dose) and pheniramine (1 mg/kg/dose) were administered. At the time of the reaction, the patient was not receiving any other medication and was evaluated for other allergen sensitizations and allergen contact. According to the results, no other allergen sensitization was detected. Following this reaction, the patient’s treatment was changed to ERW. During the 6th cycle of this treatment, the patient developed urticarial rash, abdominal pain, nausea and vomiting. The treatment was terminated immediately, but the patient who described itching in the throat in the 3rd minute was evaluated as moderate anaphylaxis [12] and intramuscular (IM) adrenaline (0.01 mg/kg/dose), intravenous methylprednisolone (1 mg/kg/dose) and pheniramine (1 mg/kg/dose) were administered. The patient’s blood pressure was 90/60 mm Hg before adrenaline treatment. Desensitisation with ERW was planned for the patient who had no alternative treatment option and had a more severe hypersensitivity reaction (severe anaphylaxis) [12] with PEG-ASP. Chemotherapy and monoclonal antibodies by Castells protocol for antibiotic desensitisation can also be applied to different commonly used preparations is a current protocol (moderate/strong positive recommendation) [13]. For patients whose reference reaction is severe anaphylaxis, a 16-step protocol with four different concentrations is feasible. Since our patient had recently experienced anaphylaxis and treatment should be started as soon as possible, a 16-step protocol was applied. A total of 4 different concentrations of L-asparaginase were prepared (Table 1). A desensitisation protocol was designed starting with 0.25/100,000 of the total required dose calculated according to the patient’s weight. The patient was premedicated with montelukast (4 mg) 36 h before, hydroxyzine (1 mg/kg) and famotidine (0.5 mg/kg) 24 h before, and methylprednisolone (1 mg/kg) 12 h before. The 4-vial desensitisation protocol was administered every other day for 6 days without any complications (Table 1). The patient received the first dose of desensitisation in the pediatric intensive care unit and was followed up in the ward for subsequent doses. No hypersensitivity reaction was observed during desensitisation.
Table 1
Erwinia chrysanthemi desensitisation protocol
DISCUSSION
Hypersensitivity has been reported to develop to many chemotherapeutic agents which play a great role in increasing survival in cancer patients. The most frequently observed reactions are triggered by taxanes, platins, epipodophilins, procarbazine, asparaginase and methotrexate [11]. The underlying mechanism may be immunological or non-immunological [14]. Clinical findings may range from simple cutaneous reactions to life-threatening anaphylaxis and death.
Three L-asparaginase preparations are available for clinical use: an E. coli derivative, an ERW derivative and a PEG-bound form [11]. Asparaginase preparations derived from E. coli are the most commonly used forms; most HSRs develop with this form. In this case, switching to a different L-asparaginase preparation is an option for continued treatment. Therapeutic asparaginase activity can be achieved by using different asparaginase preparations [11, 15, 16]. ERW is antigenically different from E. coli asparaginase [11], but allergic reactions to ERW in children have been reported in up to 37% of patients who continued treatment with this preparation after clinical HSRs to E. coli asparaginase [15–17]. However, hypersensitivity reactions occur in 4.4% of children and adolescents treated with ALL following pegaspargase treatment [18]. Because of the risk of a second reaction and the development of anti-asparaginase antibodies, consensus guidelines recommend changing asparaginase treatment to ERW after a grade 2 or greater reaction [5]. When ERW is not available, the only option for patients experiencing a hypersensitivity reaction is to discontinue all asparaginase treatment or retry with pegaspargase [7]. Since our patient also showed signs of respiratory distress in the hypersensitivity reaction to PEG-ASP, desensitization with ERW was performed. Our patient developed severe hypersensitivity reactions to both PEG-ASP and ERW and clinical options for the use of alternative agents were exhausted. In this case, desensitization was considered as the only viable treatment option. As in our case, the case reported by Nguyen et al. [19] also developed HSR to PEG-ASP and ERW and desensitization was performed with calaspargase pegol-mknl (calaspargase), a second-generation PEGylated E coli-derived asparaginase product, since no alternative treatment was available.
CONCLUSIONS
When an HSR develops, discontinuation of treatment may lead to worse outcomes, but most patients are able to receive their planned dose through premedication, drug replacement or desensitisation. In our patient, the time required for desensitization after anaphylaxis could not be awaited due to the urgency of treatment of the patient’s B-ALL disease and desensitization was performed. It was completed without any reaction.
