Genomic drivers of leukemia and blinatumomab response in adult acute lymphoblastic leukemia - the ECOG-ACRIN E1910 study

The bispecific CD19/CD3 T-cell engaging antibody blinatumomab is efficacious in front-line therapy in B-cell acute lymphoblastic leukemia (B-ALL) but the biological determinants of response and resistance are incompletely understood. To examine the genomic determinants of outcome, we analyzed genomic and clinical data of 569 adults registered to the ECOG-ACRIN E1910 study of blinatumomab in BCR::ABL1-negative B-ALL (ClinicalTrials.gov NCT02003222). We identified 23 molecular subtypes including the high-risk subtypes BCR::ABL1 (20%), BCR::ABL1-like (18%), low hypodiploid (14%) and KMT2A-R (12%), and 267 putative driver genes. We identified a subtype characterized by CEBPA overexpression or elevated CEBPB expression due to chromosomal translocation-mediated enhancer hijacking, or insertions downstream of CEBPA that generate neoenhancers. Attainment of MRD-negativity patients after induction and intensification chemotherapy was more common in PAX5alt, TCF3::PBX1 and ZNF384-R B-ALL, and less common in BCR::ABL1-like and KMT2A-R B-ALL. Integration of genomic and clinical data suggested that the addition of blinatumomab to chemotherapy was associated with improved relapse-free and overall survival for several B-ALL subtypes, including hyperdiploid, PAX5alt, PAX5 P80R, BCR::ABL1-like JAK-STAT and KMT2A-R B-ALL, although small sample sizes for several subtypes indicate that confirmation is required. Alteration of TP53 or mutations associated with myeloid clonal hematopoiesis of indeterminate potential (CHIP) were identified in 15.3% and 9.8% of patients, respectively. The presence of these mutations was associated with older age at diagnosis and inferior outcome to chemotherapy. In summary, we define the landscape of genomic alterations of adult B-ALL, and identify genomic subtypes that may influence the efficacy of blinatumomab when combined with chemotherapy.