Molecularly Targeted Small Molecule Inhibitor Therapy for Pediatric Acute Lymphoblastic Leukemia: A Comprehensive Review of Clinical Trials

In the past decades, significant advancements in the biological and genetic characterization of acute leukemias and optimization of risk-adapted multi-agent treatment protocols have dramatically improved cure rates and quality of life for children with acute lymphoblastic leukemia (ALL). Despite these optimal results, patients with relapsed or chemotherapy-refractory (R/R) disease or with high-risk genetic features still face unsatisfactory outcomes. Further intensification of conventional chemotherapy has reached its limits in achieving the desired efficacy without undue side effects, necessitating innovative approaches to improve cure rates while continuing to minimize the toxicities associated with chemotherapy and hematopoietic stem cell transplantation. In the era of precision medicine, two key therapeutic strategies have emerged in hemato-oncology: molecularly targeted therapies and immunotherapies. Antibody-based and cellular immunotherapies have undoubtedly reshaped the landscape of childhood ALL treatment and have significant potential to play leading roles in current and future frontline regimens; these important therapies are well delineated in recent reviews. Molecularly targeted small molecule inhibitor therapies remain a cornerstone of precision medicine, supported by recent advancements in next-generation sequencing, which have enabled the application of transcriptomic and genomic profiling data to risk stratification and therapy optimization. Clinical trials for children with ALL have been instrumental in refining therapies and improving outcomes, a paradigm that remains critical as treatment strategies become increasingly complex. This comprehensive review focuses upon molecularly targeted therapy approaches for childhood ALL and aims to summarize findings from completed clinical trials to highlight the current landscape of ongoing and upcoming trials and to provide insights into future directions for the precision-driven optimization of pediatric B-ALL and T-ALL treatment.