DP087 | EARLY RESULTS FROM THE GIMEMA ALL2720 TRIAL: CHEMOGENOMIC STRATEGIES IN RELAPSED/REFRACTORY T-ALL AND ETP-ALL

Despite the increasing volume of cancer genomic data, linking mutations to drug efficacy remains challenging. National initiatives integrating drug response profiling (DRP) with clinical genomics are limited to a few cancer centers. To address this gap, we focused on T-cell Acute Lymphoblastic Leukemia (T-ALL), a leukemia subgroup that, despite new targets identified over the last two decades, still lacks effective salvage treatments. For this reason, we developed a chemogenomic platform to identify potential therapeutic alternatives to nelarabine, the only approved agent for relapsed or refractory (R/R) T-ALL. In the GIMEMA ALL2720 trial (NCT04582487), we evaluated the feasibility of a chemogenomic-driven approach for the clinical management of early T-cell precursor (ETP)-ALL and T-ALL by integrating DRP and genomic data into therapeutic decisions. We collected samples from 23 R/R patients (14 ETP-ALL, 9 T-ALL) and 6 de novo ETP-ALL. Samples underwent combined interphase (CI)-FISH analysis, SNP array, targeted NGS, and ex vivo DRP. A review board provided treatment recommendations for individual patients based on pharmacogenomics results. The median age was 55 (21-77); 18 were males and 11 were females. Oncogenic classification identified 21% HOXA, 10% TLX1, 3% each for TAL/LMO and TLX3, and 62% were “unclassified”. The most recurrent genetic aberrations were NOTCH1 mutations (67.8%) and CDKN2AB deletions (31%). A manually reviewed pharmacogenomics report was available for 28 patients. Top hits were BCL2 (24/28), proteasome (23/28), and HDAC (15/28). We assessed the impact of guided N-of-1 treatments on clinical outcomes while leaving final therapeutic decisions at the treating physician’s discretion, ensuring adaptability across national clinical settings. Fifteen patients (53.6%), including 12 ETP-ALL, received a chemogenomic-matched treatment after a median of 2 prior therapies (1-5). A composite complete response (CR+CRi) was achieved in 9/15 cases (60%), with 5 being MRD-negative. Nearly half (4/9; 44%) were bridged to alloHSCT, all with an ETP phenotype. In conclusion, we suggest that a coordinated, unified platform can address the needs of large, densely populated countries by delivering functional genomic data to guide “on-time” treatment decisions. Our results indicate that R/R T-ALL cases, especially ETP with unknown subtype-defining oncogenic lesions, can be rescued through a tandem DRP-alloHSCT, offering a long-term solution for this disease.