Allergic-like reactions to asparaginase: Atypical allergies without asparaginase inactivation

Background: Asparaginase is an important component of pediatric acute lymphoblastic leukemia (ALL) therapy. Unfortunately, this treatment is hampered by hypersensitivity reactions. In general, allergies – regardless of severity – cause complete inactivation of the drug. However, we report atypical allergic reactions without inactivation of asparaginase, here called allergic-like reactions. Procedure: Patients with an allergic-like reaction, who were treated according to the Dutch Childhood Oncology Group ALL-11 or the CoALL 08–09 protocol, were described. The reactions were identified by continual measurement of asparaginase activity levels. Characteristics, including timing of occurrence, symptoms, grade, and the presence of antiasparaginase antibodies, were compared to those of real allergies. Results: Fourteen allergic-like reactions occurred in nine patients. Five reactions were to PEGasparaginase and nine to Erwinia asparaginase. Allergic-like reactions occurred relatively late after the start of infusion compared to real allergies. Antibodies were absent in all but one patient with an allergic-like reaction, while they were detected in all patients with a real allergy. Symptoms and grade did not differ between the groups. Asparaginase was continued with the same formulation in six patients of whom four finished treatment with adequate activity levels. Conclusions: In conclusion, allergic-like reactions occur relatively late after the start of infusion and without antibodies. Despite these clinical differences, allergic-like reactions can only be distinguished from real allergies by continually measuring asparaginase activity levels. If clinically tolerated, formulations should not be switched in case of allergic-like reactions. Moreover, failure to recognize these reactions may lead to a less favorable prognosis if asparaginase therapy is terminated unnecessarily

Acute lymphoblastic leukaemia patients treated with PEGasparaginase develop antibodies to PEG and the succinate linker

Polyethylene glycol (PEG) conjugated asparaginase (PEGasparaginase) is essential for treatment of paediatric acute lymphoblastic leukaemia. We developed an assay identifying antibodies against the PEG-moiety, the linker and the drug itself in patients experiencing hypersensitivity reactions to PEGasparaginase. Eighteen patients treated according to the DCOG ALL-11 protocol, with a neutralizing hypersensitivity reaction to PEGasparaginase to the first PEGasparaginase doses in induction (12 patients) or during intensification after interruption of several months (6 patients) were included. ELISA was used to measure antibodies, coating with the succinimidyl succinate linker conjugated to BSA, PEGfilgrastim and Escherichia coli asparaginase, and using hydrolysed PEGasparaginase and mPEG5,000 for competition. Anti-PEG antibodies were detected in all patients (IgG 100%; IgM 67%) of whom 39% had anti-PEG antibodies exclusively. Pre-existing anti-PEG antibodies were also detected in patients who not previously received a PEGylated therapeutic (58% IgG; 21% IgM). Antibodies against the SS-linker were predominantly detected during induction (50% IgG; 42% IgM). Anti-asparaginase antibodies were detected in only 11% during induction but 94% during intensification. In conclusion, anti-PEG and anti-SS-linker antibodies predominantly play a role in the immunogenic response to PEGasparaginase during induction. Thus, switching to native E. coli asparaginase would be an option for adequate asparaginase treatment

A cost-effectiveness analysis of Erwinia asparaginase therapy in children with acute lymphoblastic leukemia

Objectives: Erwinia asparaginase is used as a second-line formulation after a neutralizing hypersensitivity reaction to the first-line formulation of asparaginase. Here, we have performed a costeffectiveness analysis of Erwinia asparaginase treatment. Methods: Children with acute lymphoblastic leukemia treated according to the Dutch Childhood Oncology ALL-10 or ALL-11 protocol were included and initially treated with PEGasparaginase in the intensification phase. The total treatment costs of this treatment phase, quality of life (QoL), and life years saved (LYS) were studied for two scenarios: (a) patients were switched to Erwinia asparaginase treatment after a hypersensitivity reaction, or (b) asparaginase would have been permanently stopped. Results: Sixty-eight patients were included. There was no difference in QoL between patients with and without a hypersensitivity reaction. The mean costs of the intensification phase per patient were $40,925 if PEGasparaginase could be continued,$175,632 if patients had to switch to Erwinia asparaginase, and $21,190 if asparaginase would have been permanently stopped. An extrapolation of the literature suggests that the 5-year event-free survival would be 10.3 without intensive asparaginase treatment if asparaginase is stopped after a reaction. Thus, the costs per LYS were$1892 for scenario 1 and $872 for scenario 2. Conclusions: Switching to Erwinia asparaginase increases the costs per LYS by$1020, which is modest in view of the total costs. Moreover, when asparaginase treatment can be completed by switching to Erwinia asparaginase, relapses—and consequential costs—will be avoided. Therefore, from a cost perspective, we recommend a switch to Erwinia asparaginase to complete asparaginase treatment

The evaluation of red blood cell folate and methotrexate levels during protocol M in childhood acute lymphoblastic leukemia

Background: After High-Dose Methotrexate (HD-MTX), folinic acid rescue therapy (Leucovorin) is administered to reduce side effects in pediatric acute lymphoblastic leukemia (ALL) patients. Leucovorin and MTX are structural analogues, possibly competing for cellular transport and intracellular metabolism. We hypothesize that Leucovorin accumulates during consecutive courses, which might result in a lower MTX uptake. Methods: We prospectively measured red blood cell (RBC) folate and MTX levels during four HD-MTX and Leucovorin courses in 43 patients treated according the DCOG ALL-11 protocol with 2-weekly HD-MTX (5 g/m2 /dose) and Leucovorin (15 mg/m2 /dose) using LC-MS/MS. We estimated a linear mixed model to assess the relationship between these variables over time. Results: Both RBC MTX-PG and folate levels increased significantly during protocol M. MTX-PG2–5 levels increased most substantially after the first two HD-MTX courses (until median 113.0 nmol/L, IQR 76.8–165.2) after which levels plateaued during the 3d and 4th course (until median 141.3 nmol/L, IQR 100.2–190.2). In parallel, folate levels increased most substantially after the first two HD-MTX courses (until median 401.6 nmol/L, IQR 163.3–594.2) after which levels plateaued during the 3d and 4th course (until median 411.5 nmol/L, IQR 240.3–665.6). The ratio folate/MTX-PG decreased significantly over time, which was mostly due to the relatively higher increase (delta) of MTX-PG. Conclusion: These results suggest that the increase in RBC folate levels does not seem to have a large effect on RBC MTX levels. Future studies, assessing competition of Leucovorin and MTX on other cellular mechanisms which might negatively affect treatment efficacy, are necessary

Population pharmacokinetics of intravenous erwinia asparaginase in pediatric acute lymphoblastic leukemia patients

Erwinia asparaginase is an important component in the treatment of pediatric acute lymphoblastic leukemia. A large variability in serum concentrations has been observed after intravenous Erwinia asparaginase. Currently, Dutch Childhood Oncology Group protocols dose alterations are based on trough concentrations to ensure adequate asparaginase activity (≥100 IU/L). The aim of this study was to describe the population pharmacokinetics of intravenous Erwinia asparaginase to quantify and gather insight into inter-individual and inter-occasion variability. The starting dose was evaluated on the basis of the derived population pharmacokinetic parameters. In a multicenter prospective observational study, a total of 714 blood samples were collected from 51 children (age 1-17 years) with acute lymphoblastic leukemia. The starting dose was 20,000 IU/m2 three times a week and adjusted according to trough levels from week three onwards. A population pharmacokinetic model was developed using NONMEM®. A 2-compartment linear model with allometric scaling best described the data. Inter-individual and interoccasion variability of clearance were 33% and 13%, respectively. Clearance in the first month of treatment was 14% higher (P<0.01). Monte Carlo simulations with our pharmacokinetic model demonstrated that patients with a low weight might require higher doses to achieve similar concentrations compared to patients with high weight. The current starting dose of 20,000 IU/m2 might result in inadequate concentrations, especially for smaller, lower weight patients, hence dose adjustments based on individual clearance are recommended. The protocols were approved by the institutional review boards