High-risk features in adult patients with B-cell acute lymphoblastic leukemia: redefining risk in the era of targeted immunotherapy

The treatment landscape of adult B-cell acute lymphoblastic leukemia (B-ALL) has changed substantially with the introduction of targeted immunotherapeutic agents. Historically, high-risk disease was defined by clinical and cytogenetic features such as older age, elevated leukocyte count, and Philadelphia chromosome (Ph)-positive status. Advances in genomic profiling, together with the use of next-generation tyrosine kinase inhibitors, bispecific T-cell engagers, antibody–drug conjugates, and chimeric antigen receptor T-cell therapies, have altered both treatment outcomes and risk stratification. Outcomes for patients with Ph-positive B-ALL have improved markedly, particularly with ponatinib- and blinatumomab-based regimens, but several molecularly defined subgroups continue to have poor prognoses. These include IKZF1 plus Ph-positive B-ALL, TP53 -mutated and hypodiploid B-ALL, Ph-like B-ALL, and KMT2A -rearranged B-ALL. Emerging evidence indicates that introducing immunotherapeutic agents early in treatment can improve response quality and rates of measurable residual disease negativity, including in patients with high-risk disease. Relapse nevertheless remains a major challenge, and the optimal integration of novel agents, allogeneic hematopoietic cell transplantation, and cellular immunotherapy remains uncertain. This review summarizes the biological and clinical features of the major high-risk molecular subgroups of adult B-ALL and discusses how recent therapeutic advances are redefining risk assessment and treatment strategies in the era of targeted immunotherapy.