Preferential Genetic Pathways Lead to Relapses in Adult B-Cell Acute Lymphoblastic Leukemia.

Adult B-cell acute lymphoblastic leukemia (B-ALL) is characterized by genetic heterogeneity and a high relapse rate, affecting over 40% of adults. However, the mechanisms leading to relapse in adults are poorly understood. Forty-four adult B-ALL patients were studied at both diagnosis and relapse by next-generation sequencing (NGS). Four main genetic pathways leading to relapse in adults were identified: genetic profile, mutations and alterations in Ph-negative B-ALL and acquisition of mutations in Ph-positive patients. The most frequently deleted gene at diagnosis was (52%), and 70% of these patients had profile. Notably, 88% of patients with at diagnosis retained this genetic profile at relapse. Conversely, the acquisition of mutations or the expansion of subclones (normalized variant allele frequency < 25%) present from diagnosis were observed in 24% of Ph-negative patients at relapse. In addition, 24% of relapses in the Ph-negative cohort could potentially be driven by alterations. Of these cases, five presented from diagnosis, and four emerged at relapse, mostly as "double-hit" events involving both deletion and mutation. In Ph-positive B-ALL, the main genetic finding at relapse was the acquisition of mutations (86%). Three clonal evolution patterns were identified: the persistent clone trajectory (25%), the expanding clone trajectory (11%) and the therapy-boosted trajectory (48%). Our results reveal the presence of preferential biological pathways leading to relapse in adult B-ALL. These findings underscore the need for personalized therapeutic strategies to improve clinical outcomes in adult patients with B-ALL.