RESUMO
L-asparaginase (L-Asp) is an essential enzyme in the treatment of patients with Acute Lymphoblastic Leukemia (ALL), commonly associated with adverse events (AE). Knowing the pharmacokinetic and pharmacodynamic (PK/PD) parameters of L-Asp as well as its relationship with the development of AE is an important strategy in the search to improve the efficacy and safety of the treatment. Seventy-four children with ALL that were being treated with L-Asp, were included. One to three blood samples were randomly obtained from each patient, at times from 0 to 30 hours, until completing a total of 211 samples. The L-Asp activity and the Asparagine (Asp) concentration were quantified, in addition, the presence of anti-L-Asp antibodies (Anb) was determined. A population PK/PD model of L-Asp was developed to determine the association of covariates with PK/PD parameters. The presence of Anb was associated with the increase in L-Asp clearance (CL) and with the decrease of volume of distribution 1 (V1). On the other hand, female sex was significantly associated with the increase of V1, while the age from 1 to 6 years was significantly associated with the increase of V1. The presence of Anb as well as the female sex were related to the increase IC50 (concentration-needed to deplete-50% of Asp). Patients who presented Asp depletion before the first 24 hours after administration presented pancreatitis, this could be a risk marker. Significant results were found in this study, use of these results may contribute to the safe and effective use of L-Asp.
RESUMO
Background and aims: Pediatric acute lymphoblastic leukemia (ALL) survival rates in low- and middle-income countries are lower due to deficiencies in multilevel factors, including access to timely diagnosis, risk-stratified therapy, and comprehensive supportive care. This retrospective study aimed to analyze outcomes for pediatric ALL at 16 centers in Mexico. Methods: Patients <18 years of age with newly diagnosed B- and T-cell ALL treated between January 2011 and December 2019 were included. Clinical and biological characteristics and their association with outcomes were examined. Results: Overall, 2,116 patients with a median age of 6.3 years were included. B-cell immunophenotype was identified in 1,889 (89.3%) patients. The median white blood cells at diagnosis were 11.2.5 × 103/mm3. CNS-1 status was reported in 1,810 (85.5%), CNS-2 in 67 (3.2%), and CNS-3 in 61 (2.9%). A total of 1,488 patients (70.4%) were classified as high-risk at diagnosis. However, in 52.5% (991/1,889) of patients with B-cell ALL, the reported risk group did not match the calculated risk group allocation based on National Cancer Institute (NCI) criteria. Fluorescence in situ hybridization (FISH) and PCR tests were performed for 407 (19.2%) and 736 (34.8%) patients, respectively. Minimal residual disease (MRD) during induction was performed in 1,158 patients (54.7%). The median follow-up was 3.7 years. During induction, 191 patients died (9.1%), and 45 patients (2.1%) experienced induction failure. A total of 365 deaths (17.3%) occurred, including 174 deaths after remission. Six percent (176) of patients abandoned treatment. The 5-year event-free survival (EFS) was 58.9% ± 1.7% for B-cell ALL and 47.4% ± 5.9% for T-cell ALL, while the 5-year overall survival (OS) was 67.5% ± 1.6% for B-cell ALL and 54.3% ± 0.6% for T-cell ALL. The 5-year cumulative incidence of central nervous system (CNS) relapse was 5.5% ± 0.6%. For the whole cohort, significantly higher outcomes were seen for patients aged 1-10 years, with DNA index >0.9, with hyperdiploid ALL, and without substantial treatment modifications. In multivariable analyses, age and Day 15 MRD continued to have a significant effect on EFS. Conclusion: Outcomes in this multi-institutional cohort describe poor outcomes, influenced by incomplete and inconsistent risk stratification, early toxic death, high on-treatment mortality, and high CNS relapse rate. Adopting comprehensive risk-stratification strategies, evidence-informed de-intensification for favorable-risk patients and optimized supportive care could improve outcomes.