Pharmacogenomic and Genetic Polymorphisms Associated with Drug Toxicity, Treatment Response, and Clinical Outcomes in Paediatric Acute Lymphoblastic Leukaemia Treated Under BFM-Based Protocols: A Systematic Review and Meta-Analysis

This is a systematic review and meta-analysis of germline pharmacogenomic and genetic polymorphisms affecting drug toxicity, treatment response, and clinical outcome in children and adolescent/young adult patients with acute lymphoblastic leukaemia receiving treatment on Berlin-Frankfurt-Munster based regimens. The main goal is to summarize the high-quality evidence published on the topic of inherited genetic variations in pharmacogenes involved in ALL therapeutics as predictors of adverse events related to chemotherapy, dose intensity requirements, pharmacokinetics/pharmacodynamics changes, and long-term clinical outcomes like event-free survival, overall survival, and risk of relapse. Paediatric acute lymphoblastic leukaemia is the most prevalent childhood malignancy in the world but in high-resource-based countries, with the use of modern multi-agent chemotherapy regimens, the survival rate is more than 90% in 5 years. However, treatment-associated toxicities cause 5-10% treatment-related mortality, dose (or time) reduction or delaying that affect efficacy, and high morbidity long-term survivors. Only clinical factors (age, nutrition, and co-morbidities) can partially explain inter-individual variation in toxicity and response, and emerging evidence suggests that host germline pharmacogenomic variation is a key factor. Alterations in NUDT15 have become some of the most proactive predictors of thiopurine intolerance and can necessitate a significant reduction in dose without impaired effectiveness. Although there are strong pharmacogenomic data about the cohort trials of the same on the basis of a protocol like the Children Oncology Group, St. Jude or the Asian consortia, there are significant differences in the cumulative doses of drugs, schedule and supportive care protocols in BerlinFrankfurtMunzer protocols which is the standard platform in other regions like Eastern Europe, Latin America, Russia, Middle East and Central Asia. There are apparently no published pharmacogenomic studies undertaken that have specifically measured, or validated predictors in pure Berlin-Frankfurt-Munster-treated groups, which are a critical translational deficit. In such environments, clinicians have no assurance in applying available guidelines based on non Berlin-Frankfurt-Münster cohorts, and new polygenic and ancestry-based models have not been tested on such populations. To address this gap, the review identifies and synthesises germline predictors of toxicity and outcomes in cohorts of children with paediatric acute lymphoblastic leukaemia all over the globe, (1) performing quantitative meta-analysis of the reproducible associations; (2) explicitly mapping the lack of Berlin-Frankfurt-Munster-specific pharmacogenomic evidence despite the presence of extensive clinical outcome data in over 15,000 Berlin-Frankfurt-Munster-treated children. The search is based on PRISMA 2020 guidelines, followed by citation chasing, with 87 studies found in PubMed/MEDLINE and Scopus, including 30 studies with primary pharmacogenomic data of 4847 patients [qualitative synthesis] and 87 studies assessed through the use of the Newcastle-Ottawa Scale and Joanna Briggs Institute tools [quality appraisal]. It is estimated that NUDT15 will be noted as the best global predictor of thiopurine toxicity, meta-estimates of weaker effects of methotrexate-associated variants will be provided, and polygenic models will be shown to be more predictive. Most importantly, the article demonstrates the necessity of large-scale, prospective pharmacogenomic research in regimens of Berlin-Frankfurt-Munster to enable safe, precision chemotherapy that is also tailored to individual needs in underrepresented populations. This registration (retrospective, as it has been previously performed on the review) guarantees complete transparency of predetermined means and allows it to be scrutinized, replicated, and incorporated into future work on evidence synthesis in paediatric oncology and pharmacogenomics.