Safety and Efficacy of Asparaginase Therapy in Pediatric Patients with Previous Associated Serious Adverse Reactions Under the Guidance of Asparagine Concentration Monitoring

Introduction:

Asparaginase (L-Asp) is a critical component in chemotherapy for Acute Lymphoblastic Leukemia (ALL).However, Antibodies to asparaginase affects the anti-tumor activity and adverse drug reactions restrict the clinical application. Monitoring plasma asparagine concentrations can identify patients with poor enzyme activity or insufficient depletion of asparagine, determine the individualized dosage to minimize toxicity while maintaining the anti-cancer activity of the drug.

Objective:

This retrospective study aims to observe the safety and efficacy of asparaginase therapy in pediatric patients who have experienced severe adverse drug reactions under the monitoring of plasma asparagine concentration.

Methods:

Data was collected from pediatric patients with ALL undergoing maintenance chemotherapy using regimens containing L-Asp at Beijing GoBroad Hospital since February 2024. Patients with a history of severe adverse reactions related to L-Asp/Pegaspargase chemotherapy were selected, patients without such medical history were compared. Both groups received intramuscular injection of asparaginase (Erwinia) at a dose of 10000 IU per injection,10 doses in total. If mild adverse reactions occur, the administration interval can be extended, in cases of moderate or severe adverse reactions, treatment should be discontinued. Based on the monitored asparagine concentration, the timing of resumption, dosage and frequency of asparaginase was adjusted to maintain asparagine levels below 0.4 μmol/L. Efficacy was assessed by proportion of patients completed maintenance chemotherapy and maintained asparagine concentrations complete depletion.

Results:

By July 10, 2024, 6 patients (3 males, 3 females, range: 5-13 years) with a history of severe adverse reactions to L-asp were enrolled, including severe allergic reactions in 3 patients, pancreatitis in 2 patients, and bleeding with thrombosis in one patient. The control group comprised of 18 patients (12 males, 6 females, range: 5-17 years) experienced no adverse reactions before.

Among the 6 patients with a history of adverse reactions, 2 completed the full course of 10 doses (33.3%), while the remaining 4 (66.7%) did not complete all 10 doses as prescribed (average dose per course was 7.67±2.25 units, with an interval of 4.33±0.52 days). In the control group of 18 patients, 8 (44.4%) completed the full course of 10 doses, another 8 (44.4%) did not complete all prescribed doses, and 2 (11.1%) completed more than 10 doses (average dose per course was 9±1.85 units, with an interval of 3.89±2.22 days).Under the monitoring of asparagine concentration, both groups successfully completed maintenance chemotherapy with asparaginase and maintained complete depletion of asparagine concentrations.

Coagulation abnormalities shows the most serious and common adverse reaction, primarily characterized by Fibrinogen decreased and Activated partial thromboplastin time prolonged. Patients with a history of adverse reactions compared with the control group exhibited the following incidence rates: Fibrinogen decreased [Grade 1: (1/6 (33.3%) vs 4/18 (22.2%)), Grade 2: (3/6 (50.0%) vs 6/18 (33.3%)), Grade 3: (2/6(33.3%) vs 6/18(33.3%))] and Activated partial thromboplastin time prolonged [Grade 1: (2/6(33.3%)vs7/18(38.9%)), Grade 2: (3/6(50%)vs7 /18(38 .9 %))]. Patients with a Fibrinogen decreased at the Grade 3 and Activated partial thromboplastin time prolonged at the Grade 2 required suspension of drug administration, no higher-level adverse reactions occurred. Other adverse reactions included: Blood bilirubin increased(Grade 1) (1/6 (16.7%) vs 2/18 (11.1%)), Dyspepsia (1/6 (16.7%)vs 1/18 (5.6%)), Nausea (0/6 (0%)vs 1/18 (5.6%)), and Allergic reaction to a specific batch of medication (1/6 [16.7%] vs 0/18 [0%]). Among the 24 patients monitored, no serious adverse events such as pancreatitis, bleeding, and thrombosis were observed.

Conclusion:

Personalized treatment incorporating asparagine concentration monitoring may enable these patients with prior asparaginase-related severe adverse reactions to achieve controlled adverse reactions while maintaining the drug's efficacy.

No relevant conflicts of interest to declare.