Precision medicine for high risk childhood leukemias

Therapeutic advances in pediatric acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) have been driven by improvements in genomic characterisation, risk-adapted therapy, and supportive care, which have engendered substantial gains in survival. Despite this progress, high-risk childhood leukemia subtypes continue to limit further outcome improvements and highlight the need for more precise and less toxic treatment strategies. This thesis synthesizes multiple PhD projects focused upon translational and clinical investigations aimed at advancing precision medicine approaches for children with biologically-relevant B-ALL or AML subtypes. A major focus of this work is Philadelphia chromosome-like (Ph-like) ALL, a high-risk leukemia characterised by various kinase-activating alterations, including CRLF2 rearrangements and ABL-class fusions. Comparative analyses of BCR::ABL1-rearranged and ABL-class ALL define key biological features, diagnostic considerations, and mechanisms of treatment resistance, while also highlighting emerging opportunities for targeted and/or immunotherapeutic intervention. Preclinical studies by our groups demonstrate that sensitivity to tyrosine kinase inhibitors (TKIs) is strongly dependent on the specific underlying fusion with PDGFRB-rearranged leukemias preferentially responsive to imatinib and ABL1 or ABL2-rearranged leukemias more sensitive to second-generation TKIs, such as dasatinib and bosutinib. These findings are corroborated in vivo using patient-derived xenograft models in which the third-generation TKI ponatinib induces broad and potent activity across ABL-class fusion subtypes, while asciminib activity is restricted to select molecular contexts. In parallel, clinical analyses of pediatric patients with CRLF2-rearranged B-ALL reveal notable geographic variability in survival outcomes between North American and European cohorts, underscoring the importance of treatment context, population differences, and study design in interpreting prognostic significance and guiding clinical trial development. In pediatric AML, therapeutic progress has been more limited with cure rates reliant on intensive multi-agent chemotherapy and frequent allogeneic hematopoietic stem cell transplantation that confers substantial toxicity. Efforts to reduce treatment burden remain constrained by the risk of relapse, emphasizing the importance of optimised supportive care to mitigate therapy-associated complications. Emerging precision medicine strategies targeting molecular vulnerabilities, including BCL-2 and menin inhibition, are under active investigation with augmented efficacy in combination with cytotoxic chemotherapy. However, immunotherapeutic approaches in AML have thus far shown limited clinical success, highlighting persistent biological and translational challenges. To address disease-specific complexities, international consensus guidelines have been established for the diagnosis and management of pediatric AML, integrating advances in genomic profiling and measurable residual disease assessment. Additionally, ‘real world’ evaluation of azacytidine/venetoclax therapy in children with relapsed/refractory AML demonstrates encouraging activity with manageable toxicity, supporting continued prospective investigation in clinical trials. Collectively, these PhD thesis studies emphasize the central role of biologically-informed precision-based therapeutic approaches in improving outcomes for children, adolescents, and young adults with high-risk leukemias. Ongoing integration of genomic insights, targeted therapies, and collaborative clinical trial efforts provides a strong foundation for future progress with the goal of maximising cure rates while minimising treatment-related toxicity.