{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T23:10:23Z","timestamp":1785798623498,"version":"3.56.0"},"reference-count":143,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T00:00:00Z","timestamp":1760486400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health\/National Cancer Institute","award":["1U24OD038422"],"award-info":[{"award-number":["1U24OD038422"]}]},{"name":"National Institutes of Health\/National Cancer Institute","award":["R01CA293587"],"award-info":[{"award-number":["R01CA293587"]}]},{"name":"Pennsylvania Department of Health Commonwealth Universal Research Enhancement"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/cancers17203322","type":"journal-article","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T11:57:42Z","timestamp":1760529462000},"page":"3322","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Molecularly Targeted Small Molecule Inhibitor Therapy for Pediatric Acute Lymphoblastic Leukemia: A Comprehensive Review of Clinical Trials"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-9779-4165","authenticated-orcid":false,"given":"Nicol\u00f2","family":"Peccatori","sequence":"first","affiliation":[{"name":"Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy"},{"name":"School of Medicine and Surgery, University of Milano-Bicocca, 20126 Milan, Italy"},{"name":"Pediatric Hematology-Oncology Unit, Department of Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy"},{"name":"Princess M\u00e1xima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica","family":"Brivio","sequence":"additional","affiliation":[{"name":"Princess M\u00e1xima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrej","family":"Lissat","sequence":"additional","affiliation":[{"name":"Charit\u00e9 Universit\u00e4tsmedizin, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0421-8862","authenticated-orcid":false,"given":"Francisco","family":"Bautista Sirvent","sequence":"additional","affiliation":[{"name":"Princess M\u00e1xima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Salzer","sequence":"additional","affiliation":[{"name":"Willem Alexander Children\u2019s Hospital, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6757-6173","authenticated-orcid":false,"given":"Andrea","family":"Biondi","sequence":"additional","affiliation":[{"name":"Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy"},{"name":"School of Medicine and Surgery, University of Milano-Bicocca, 20126 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7077-8422","authenticated-orcid":false,"given":"Grazia","family":"Fazio","sequence":"additional","affiliation":[{"name":"Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy"},{"name":"School of Medicine and Surgery, University of Milano-Bicocca, 20126 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmelo","family":"Rizzari","sequence":"additional","affiliation":[{"name":"School of Medicine and Surgery, University of Milano-Bicocca, 20126 Milan, Italy"},{"name":"Pediatric Hematology-Oncology Unit, Department of Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah K.","family":"Tasian","sequence":"additional","affiliation":[{"name":"Princess M\u00e1xima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands"},{"name":"Division of Oncology and Center for Childhood Cancer Research, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA"},{"name":"Department of Pediatrics and Abramson Cancer Center, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian Michel","family":"Zwaan","sequence":"additional","affiliation":[{"name":"Princess M\u00e1xima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands"},{"name":"Department of Pediatric Oncology, Erasmus MC-Sophia Children\u2019s Hospital, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2524","DOI":"10.3324\/haematol.2020.247031","article-title":"Pediatric Acute Lymphoblastic Leukemia","volume":"105","author":"Inaba","year":"2020","journal-title":"Haematologica"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Inaba, H., and Pui, C.-H. 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