A Refined Population Pharmacokinetic Model–Based Guideline for Individualized PEGasparaginase Dosing in Pediatric Acute Lymphoblastic Leukemia

Abstract

Background: In the Dutch Childhood Oncology Group ALL11 protocol, PEGasparaginase dosing was individualized for standard-risk and medium-risk patients with acute lymphoblastic leukemia. After using our pragmatic old guideline, we aimed to improve individualized PEGasparaginase dosing by developing a population pharmacokinetic model–based dosing guideline. Method: After the 3 doses of 1500 IU/m2 administered in induction, standard-risk patients received 1 individualized dose and medium-risk patients 14, targeting trough activity levels between 100 and 250 IU/L. The effectiveness, adherence, and toxicity of our new dosing guideline was assessed and compared with the old guideline. Results: In total, 92 patients (714 samples) were included in the new dosing group and 509 patients (4539 samples) were included in the old dosing group. Comparing the effectiveness, we found that 32% (22/67) of patients in the new and 13% (47/354) of patients in the old dosing group were within the target range after the first individualized dose (P < 0.001). Among medium-risk patients, a median of 3 dose reductions was needed to reach and maintain levels within the target range in the new dosing group compared with 5 in the old dosing group (P < 0.001). With a continuous PEGasparaginase dosing schedule, target trough activity levels were reached after 2 dose reductions in the new group versus 4 in the old dosing group. The adherence to the new guideline was >99%, with 6/714 recommended doses deviating from the guideline. With exception of a lower proportion of patients with increased (≥grade 3) serum alanine transaminase (34% new vs 64% old, P < 0.05) in the new dosing group, toxicity was comparable between guidelines. Conclusions: With the new dosing guideline, fewer dose-reduction steps are necessary to reach and remain within the target. The high adherence rate emphasized its simplicity and practicality, confirming that it can be easily integrated into clinical practice.