Monitoring of treatment with L-asparaginase in children with acute lymphoblastic leukaemia, with a focus on silent inactivation and its influence on the treatment outcome.

Introduction: The aim of the study was to analyse the frequency of silent inactivation and allergic reaction to asparaginase (ASP) and its impact on treatment results in patients with lymphoblastic leukaemia. Material and methods: Seventy patients with acute lymphoblastic leukaemia treated with ASP were enrolled in the study. Asparaginase activity was monitored. The patients were switched to another ASP formulation after allergy or inactivation. The treatment results were analysed. Results: Silent inactivation of native E. coli ASP was diagnosed in 5 patients (7%) and allergy in 34 patients (49%), and these patients were switched to pegylated ASP (PEG-ASP). Silent inactivation of PEG-ASP occurred in 8 patients (23%) and allergy in 6 patients (17%). Eight children continued therapy with Erwinase, and 4 did not switch to Erwinase after inactivation of PEG-ASP. Allergy to Erwinase occurred in 2 patients (22%); there was no inactivation. No significant differences in outcome were found between the groups of patients with and without allergy or silent inactivation of ASP. Due to regular monitoring and switching to other ASP preparations after allergy or silent inactivation, therapeutic activity was ensured in almost all patients. Conclusions: Monitoring of ASP activity is crucial to recognize silent inactivation and to guarantee treatment effectiveness by switching to other ASP preparations.

Prospective, real-time monitoring of pegylated Escherichia coli and Erwinia asparaginase therapy in childhood acute lymphoblastic leukaemia and non-Hodgkin lymphoma in Belgium.

Asparaginase (ASNase) is an important anti-leukaemic drug in the treatment of childhood acute lymphoblastic leukaemia (ALL) and non-Hodgkin lymphoma (NHL). A substantial proportion of patients develop hypersensitivity reactions with anti-ASNase neutralising antibodies, resulting in allergic reactions or silent inactivation (SI), and characterised by inactivation and rapid clearance of ASNase. We report results of a prospective, real-time therapeutic drug monitoring of pegylated Escherichia coli (PEG-)ASNase and Erwinia ASNase in children treated for ALL and NHL in Belgium. Erwinia ASNase was given as second-line after hypersensitivity to PEG-ASNase. In total, 286 children were enrolled in the PEG-ASNase cohort. Allergy was seen in 11·2% and SI in 5·2% of patients. Of the 42 patients treated with Erwinia ASNase, 7·1% experienced allergy and 2·4% SI. The median trough PEG-ASNase activity was high in all patients without hypersensitivity. After Erwinia administration significantly more day 3 samples had activities <100 IU/l (62·5% vs. 10% at day 2 (D2)). The median D2 activity was significantly higher for intramuscular (IM; 347 IU/l) than for intravenous Erwinia administrations (159 IU/l). This prospective, multicentre study shows that monitoring of ASNase activity during treatment of children with ALL and NHL is feasible and informative. Treatment with Erwinia ASNase warrants close monitoring and optimally adherence to a 2-day interval of IM administrations.

Immunology of infusion reactions in the treatment of patients with acute lymphoblastic leukemia.

Infusion reactions are potentially dose-limiting adverse events associated with intravenous administration of several common agents used to treat patients with acute lymphoblastic leukemia. True clinical hypersensitivity reactions are antibody-mediated and can occur only after repeated exposure to an antigen. Conversely, anaphylactoid infusion reactions are nonantibody-mediated and often occur on the initial exposure to a drug. Cytokine-release syndrome comprises a subset of nonantibody-mediated infusion reactions associated with the use of monoclonal antibodies and immune therapies. Clinical symptoms of hypersensitivity reactions and nonantibody-mediated infusion reactions heavily overlap and can be difficult to distinguish in practice. Regardless of the underlying mechanism, any infusion reaction can negatively affect treatment efficacy and patient safety. These events require prompt response, and potentially, modification of subsequent therapy.

How to manage asparaginase hypersensitivity in acute lymphoblastic leukemia.

Outcomes for children with acute lymphoblastic leukemia (ALL) have improved significantly in recent decades, primarily due to dose-intensified, multi-agent chemotherapy regimens, of which asparaginase has played a prominent role. Despite this success, hypersensitivity remains a significant problem, often requiring the termination of asparaginase. Failure to complete the entire asparaginase therapy course due to clinical hypersensitivity, subclinical hypersensitivity (i.e., silent inactivation), or other treatment-related toxicity is associated with poor ALL outcomes. Thus, it is critical to rapidly identify patients who develop clinical/subclinical hypersensitivity and switch these patients to an alternate asparaginase formulation. This article provides an overview of asparaginase hypersensitivity, identification and management of hypersensitivity and subclinical hypersensitivity, and issues related to switching patients to asparaginase Erwinia chrysanthemi following hypersensitivity reaction.

Correlation of ex vivo and in vivo ammonia production with L-asparaginase biological activity in adults with lymphoid malignancies.

Silent inactivation of L-asparaginase (L-Asp) represents rapid clearance of L-Asp by anti-L-Asp IgG antibodies without clinical symptoms. Measurement of L-Asp activity is the gold standard for diagnosis of silent inactivation, but this test is not commercially available in Japan as of 2023. We evaluated ex vivo and in vivo ammonia production in relation to L-Asp activity. Blood samples from ten adult patients treated with L-Asp were collected to measure ammonia levels and L-Asp activity before the first dose and 24 h after the last dose of L-Asp, during each cycle of treatment. Plasma ammonia levels were analyzed immediately and 1 h after incubation at room temperature, and ex vivo ammonia production was defined as the increase in ammonia concentration. Ex vivo ammonia production correlated with L-Asp activity (R2 = 0.741), and ammonia levels measured immediately after blood collection were moderately correlated with L-Asp activity (R2 = 0.709). One patient with extranodal NK/T-cell lymphoma showed an increase in ammonia levels during the first cycle, but no increase in ammonia levels or L-Asp activity after L-Asp administration during the second cycle. Both ex vivo and in vivo ammonia production and surrogate markers are used for L-Asp biological activity.

Silent inactivation of asparaginase in Japan: results of the prospective ALL-ASP19 trial.

Silent inactivation (SI) of L-asparaginase (ASP) is a phenomenon by which a neutralizing antibody for ASP (AAA) decreases ASP activity (ASA) in patients without a clinical allergy to ASP. Acute lymphoblastic leukemia (ALL) has a poor prognosis in patients with SI. Therefore, measurement of ASA levels, not AAA levels, is needed to identify patients with SI. We herein report the results of the prospective clinical trial ALL-ASP19, the first study in Japan to measure ASA and AAA to identify patients with SI. A total of 110 newly diagnosed ALL patients were enrolled, and ASA levels were measured three times during ALL treatment. Besides the 12 patients who discontinued the study, 32 were excluded due to inappropriate frequency and timing of ASA measurements and inappropriate ASP dosing. The remaining 66 patients were analyzed, and 3 patients with SI (4.5%) were identified. The incidence of SI is lower in Japan than in other countries. AAA was detected in all patients with SI, but four of the seven patients with AAA did not develop SI. Clinical characteristics did not significantly differ between patients with and without SI. Therefore, ASA levels must be measured to identify patients receiving insufficient ASP treatment.

Our Experiences with Asparaginase Activity Measurements in Children with Lymphoblastic Diseases.

BACKGROUND: Asparaginase is a key component of chemotherapy protocols for the treatment of lymphoblastic malignancies among children. Adequate asparagine depletion is an important factor to achieve optimal therapeutic outcomes. METHODS: Over a 3.5 year period, 106 patients were monitored for asparaginase activity (329 samples) in a single center of the Hungarian Pediatric Oncology-Hematology Group. In Hungary, three asparaginase products are available: native E. coli ASNase (Kidrolase), a pegylated form of this enzyme (Pegaspargase) and another native product from Erwinia chrysanthemi (Erwinase). A retrospective data analysis was performed. RESULTS: In 81% (268/329) of our patients, AEA levels were in the optimal therapeutic range of over 100 IU/L. Of 106 patients, 13 (12%) were diagnosed with 'silent inactivation'. CONCLUSIONS: Monitoring of AEA can help to identify patients with 'silent inactivation' and their asparaginase therapy can thus be optimized.

Efficacy of a Standardized Premedication and Therapeutic Drug Monitoring Protocol for Pegaspargase to Prevent Hypersensitivity Reactions.

OBJECTIVE: The purpose of this study was to evaluate the efficacy of a standardized premedication and therapeutic drug monitoring (TDM) protocol to prevent hypersensitivity reactions from pegaspargase infusions. Pegaspargase is an essential therapeutic agent used for the treatment of acute lymphoblastic leukemia (ALL) in pediatric patients. METHODS: This study was a retrospective cohort study conducted at Wolfson Children's Hospital, Jacksonville, Florida, and included pediatric ALL patients 0 to 21 years old. Patients were excluded if they had not received the appropriate premedication after protocol implementation or had received premedication before protocol implementation. Patients were separated into 2 groups: those who received premedication before pegaspargase infusion and those who did not. The primary endpoint was the incidence of documented hypersensitivity reactions. Observational data endpoints included incidence of silent inactivation and cost savings from reducing complicated drug substitutions. RESULTS: A total of 38 patients (50 doses in no premedication group; 80 doses in premedication group) were evaluated. There was not a significant reduction in the incidence of hypersensitivity reactions for patients receiving premedication and TDM (5.3% vs 6.4%, p = 1.0). A trend towards patients reacting earlier with more severe reactions in the post-implementation group was observed. There were no incidences of silent inactivation. Observational cost analysis predicts potential drug cost savings of $106,550.45. CONCLUSIONS: A standardized premedication protocol did not reduce the incidence of hypersensitivity reactions. Premedication to prevent hypersensitivity reactions may provide a potential drug cost savings. Further investigation is warranted to assess the efficacy of a standardized premedication and TDM protocol to prevent hypersensitivity reactions.

A Pharmacokinetic Study of Native E.coli Asparaginase for Acute Lymphoblastic Leukemia Treated with ThaiPOG Protocol.

BACKGROUND: Asparaginase is one of the essential chemotherapies used to treat acute lymphoblastic leukemia (ALL). Asparaginase antibody production may cause a subtherapeutic level and result in an inferior outcome. The aim of this study was to prove the efficacy of current native E.coli asparaginase-based protocol. Moreover, does subtherapeutic result appeared in small group of the trial?. METHODS: A prospective study of asparaginase activity among patients who received native E.coli asparaginase 10,000 IU/m2 intramuscularly according to The Thai Pediatric Oncology Group (ThaiPOG) protocol was done. The plasma asparaginase activity was measured by the coupled enzymatic reaction. Pharmacokinetic data including peak activity (Cmax), time to maximum concentration (Tmax), area under the curve (AUC0-48h) being elucidated. RESULTS: Eight patients (five males and three females), median age 9.5 years, were enrolled. The median asparaginase activity of seven cases who were eligible for calculation reached Tmax within 24 hours (range 6-48 hours) with mean±SD of Cmax 3.60±0.34 (range 3.02-4.11) IU/ml. Mean±SD of AUC0-48h is 143.23±36.94 IU.h/mL (range 71.07 - 180.12 IU.h/mL). The post-48-hour activity showed a mean±SD of 3.19±0.24 IU/ml (range 2.77-3.51 IU/ml) which implied an adequacy of activity over 48 hours and proper for the 12-day period. One relapsed ALL patient showed an extremely low AUC of asparaginase activity which coincided with urticaria after asparaginase injection. Subsequently, the asparaginase antibody was demonstrated in this patient. CONCLUSION: Native E. coli asparaginase-based protocol provides a compelling pharmacokinetic effect. Asparaginase activity and/or antibody testing is recommended for all cases especially in a relapsed patient, history of high accumulative dose of asparaginase or suspected allergic reaction. Patients with low asparaginase activity or allergy may benefit from switching to an alternative form of asparaginase to maintain treatment efficacy.

Asparaginase: an old drug with new questions.

The long-term outcome of acute lymphoblastic leukemia has improved dramatically due to the development of more effective treatment strategies. L-asparaginase (ASNase) is one of the main drugs used and causes death of leukemic cells by systematically depleting the non-essential amino acid asparagine. Three main types of ASNase have been used so far: native ASNase derived from Escherichia coli, an enzyme isolated from Erwinia chrysanthemi and a pegylated form of the native E. coli ASNase, the ASNase PEG. Hypersensitivity reactions are the main complication related to this drug. Although clinical allergies may be important, a major concern is that antibodies produced in response to ASNase may cause rapid inactivation of ASNase, leading to a worse prognosis. This reaction is commonly referred to as "silent hypersensitivity" or "silent inactivation". We are able to analyze hypersensitivity and inactivation processes by the measurement of the ASNase activity. The ability to individualize the ASNase therapy in patients, adjusting the dose or switching patients with silent inactivation to an alternate ASNase preparation may help improve outcomes in those patients. This review article aims to describe the pathophysiology of the inactivation process, how to diagnose it and finally how to manage it.

Retrospective cohort study monitoring PEG-asparaginase activity in acute lymphoblastic leukemia patients with and without premedication.

Background: PEG-L-asparaginase (pegaspargase) is a critical component of therapy for children and adults with acute lymphoblastic leukemia (ALL). Allergic reactions, which may occur in up to one third of patients, are the major cause for discontinuation. One study reported lower rates of allergic reactions with premedication. Besides allergy, an unknown number of patients develop silent neutralizing antibodies not associated with allergic reactions. The purpose of this retrospective cohort study was to determine the incidence of silent inactivation of pegasparaginase and compare incidence of allergic reactions with and without premedication. Methods: Using a commercial assay, asparaginase activity was monitored following pegaspargase (2500 units/m 2) in newly diagnosed children and young adults with B- and T-cell ALL from February 2013 to May 2017. The incidence of allergic reactions before and after initiation of premedication in May 2015 was compared. Results: One patient out of 59 (1.7%) had silent inactivation after the second dose. No patient had silent inactivation after the first pegaspargase dose and no standard risk B-cell ALL patients, who received only two pegaspargase doses in combination with oral dexamethasone, had silent inactivation. The incidence of grade 3 or 4 allergic reactions was 3.7% per dose with premedication (methylprednisolone, acetaminophen and diphenhydramine) versus 5.2% without.  The incidence per patient with premedication given for most of the doses was 8.3% versus 17% without. These values are not statistically significant. Premedication did not affect pegaspargase activity. Conclusions: Due to the low incidence of silent inactivation with intravenous pegaspargase and the unlikely event patients receiving only two doses of pegasparaginase would receive erwinase for this possible transient silent inactivation, we recommend routine monitoring of pegaspargase activity only in patients scheduled to receive more than two doses.

Asparaginase activity levels and monitoring in patients with acute lymphoblastic leukemia.

Asparaginase is an integral component of multiagent chemotherapy regimens for the treatment of acute lymphoblastic leukemia (ALL). Adequate asparagine depletion is believed to be an important factor in achieving optimal therapeutic outcomes. Measurement of asparaginase activity allows practitioners to evaluate the potential effectiveness of therapy in real time. Asparaginase activity levels can be used to identify patients with silent inactivation and modify therapy in these patients. Patients with silent inactivation to asparaginase who are switched to therapy with an immunologically distinct asparaginase exhibit outcomes similar to patients who never developed silent inactivation. Despite these benefits, there exists no universally agreed-upon guideline for treatment adjustments based on asparaginase activity levels. The goal of this manuscript is to review the clinical evidence linking asparaginase activity levels to outcomes in patients with ALL and to provide an overview of how asparaginase activity levels may be used to guide treatment.

Pegasparaginase silent inactivation during therapy for NK/T cell lymphoma.

Natural Killer/T cell (NK/T cell) lymphoma is a rare, yet aggressive T cell lymphoma, which often displays resistance to traditional chemotherapies. Asparagainse (ASNase), through its unique mechanism of action, has become a vital component in the treatment of NK/T cell lymphoma. However, because ASNase is of bacterial origin, antibody formation can render the therapy ineffective, even in the absence of clinical hypersensitivity, which has been coined 'silent inactivation.' While the phenomenon of silent inactivation of PEG-ASNase is well documented in the treatment of ALL, it has not been described in NK/T cell lymphoma patients. Herein, we report a case series of six patients treated for NK/T cell lymphoma with PEG-ASNase who subsequently developed silent inactivation identified using therapeutic drug monitoring (TDM). The goal of this manuscript is to alert clinicians of this phenomenon, and review the importance of TDM in NK/T cell lymphoma patients receiving ASNase.

Asparaginase: an old drug with new questions

ABSTRACT The long-term outcome of acute lymphoblastic leukemia has improved dramatically due to the development of more effective treatment strategies. L-asparaginase (ASNase) is one of the main drugs used and causes death of leukemic cells by systematically depleting the non-essential amino acid asparagine. Three main types of ASNase have been used so far: native ASNase derived from Escherichia coli, an enzyme isolated from Erwinia chrysanthemi and a pegylated form of the native E. coli ASNase, the ASNase PEG. Hypersensitivity reactions are the main complication related to this drug. Although clinical allergies may be important, a major concern is that antibodies produced in response to ASNase may cause rapid inactivation of ASNase, leading to a worse prognosis. This reaction is commonly referred to as "silent hypersensitivity" or "silent inactivation". We are able to analyze hypersensitivity and inactivation processes by the measurement of the ASNase activity. The ability to individualize the ASNase therapy in patients, adjusting the dose or switching patients with silent inactivation to an alternate ASNase preparation may help improve outcomes in those patients. This review article aims to describe the pathophysiology of the inactivation process, how to diagnose it and finally how to manage it.

Asparaginase pharmacokinetics and implications of therapeutic drug monitoring.

Asparaginase is widely used in chemotherapeutic regimens for the treatment of acute lymphoblastic leukemia (ALL) and has led to a substantial improvement in cure rates, especially in children. Optimal therapeutic effects depend on a complete and sustained depletion of serum asparagine. However, pronounced interpatient variability, differences in pharmacokinetic properties between asparaginases and the formation of asparaginase antibodies make it difficult to predict the degree of asparagine depletion that will result from a given dose of asparaginase. The pharmacological principles underlying asparaginase therapy in the treatment of ALL are summarized in this article. A better understanding of the many factors that influence asparaginase activity and subsequent asparagine depletion may allow physicians to tailor treatment to the individual, maximizing therapeutic effect and minimizing treatment-related toxicity. Therapeutic drug monitoring provides a means of assessing a patient's current depletion status and can be used to better evaluate the potential benefit of treatment adjustments.