Advancing Chemogenomic Strategies for Functional Precision Medicine in Relapsed/Refractory T-ALL and ETP-ALL: TheGimema ALL2720 Trial

Abstract Despite the vast amount of cancer genomic data, linking mutations to drug efficacy remains challenging. National efforts integrating ex vivo drug response profiling (DRP) with clinical genomics are rare. To address this gap, we designed the GIMEMA ALL2720 trial (NCT04582487), a multicenter study evaluating a chemogenomic-driven approach in T-cell acute lymphoblastic leukemia (T-ALL), a subtype still lacking effective salvage therapies. 29 patients with de novo or relapsed/refractory (R/R) T-ALL or ETP-ALL were enrolled in the study to receive genomic profiling and DRP. Integrated patient-specific reports were generated within a median of 7 days. DRP revealed recurrent vulnerabilities and four response clusters. Of 28 patients, 15 (53.6%) received chemogenomic-guided therapy, achieving an overall response rate of 60%. Four responders proceeded to transplantation. This prospective study demonstrates the nationwide feasibility and clinical relevance of integrating genomic and functional profiling in T-ALL, supporting chemogenomic-guided precision medicine as a promising strategy to broaden rescue options and improve outcomes.