Drug sensitivity and resistance profiling: a platform to identify new therapeutic strategies in relapsed/refractory acute leukemia

Precision Medicine with N-of-1 personalized approach represents an intriguing tool to treat one patient at a time and can have interesting clinical applications in rare malignancies or relapsed/refractory (R/R) diseases. In this context, Drug Sensitivity and Resistance Profiling (DSRP) helps to detect compounds with selective effectiveness in a variety of diseases: preclinical studies on Acute Myeloid Leukemia (AML) and Acute Lympoblastic Leukemia (ALL) provided evidence of efficacy of this approach with potential of clinical translation. In our study, we have applied DSRP by performing ATP-cell viability assay on primary bone marrow blasts samples of AML and T-ALL patients aimed to obtain in AML a better selection of patients sensitive to alternative salvage therapies such as Venetoclax-containing regimen and in T-ALL a possible combinatorial strategy in high risk ETP-ALL category with R/R disease. In a small population of ETP-ALL our approach has been validated by a broader Drug Sensitivity Profile performed in collaboration with the laboratories of the Division of Pediatric/Oncology, University Children’s Hospital of Zurich and Hematology and Bone Marrow Unit of University of Perugia. The results have led to a clinical application with a DSRP-driven salvage strategy in 3 patients with chemorefractory disease. Our study supported the approval of a biological trial promoted by the GIMEMA group to providing a DSRP oriented approach to treat R/R T-ALL. Furthermore we expect that DSRP on large scale will generate information about mechanisms of drug resistance in leukemia and will identify personalized treatment based on ex vivo drugs sensitivity.