Hematology:

Cure rates for patients with acute lymphoblastic leukemia (ALL) have improved markedly in recent decades, in part because of risk stratification incorporating leukemia genomics, response to treatment, and clinical features to be able to determine at diagnosis which patients are more likely to relapse or have refractory disease. Although risk stratification is well developed for patients with B-lineage ALL, it remains challenging for those with T-lineage ALL (T-ALL). Prognostic factors validated across clinical trials and real-world data in T-ALL include age, central nervous system involvement, and measurable residual disease (MRD) response. Immunophenotype, including early T-cell precursor ALL, is widely used to classify T-ALL but is not consistently associated with outcome in multivariable risk models. Historically, few genetic alterations have been consistently associated with outcome, but recent comprehensive, large-scale genomic profiling has identified multiple genetic subtypes and alterations associated with outcome independent of MRD. This review highlights ongoing efforts to identify reliable prognostic biomarkers and underscores the potential of genomics-based classification to guide future T-ALL treatment strategies.

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Chimeric antigen receptor T-cell therapy (CAR-T) targeting CD19 has transformed the management of relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL), with the US Food and Drug Administration approval of tisagenlecleucel for pediatric/young adult patients and brexucabtagene autoleucel for adults. Efficacy is contingent upon several factors including disease burden. Emerging data suggest that bridging therapy, lymphodepletion, and, for some patients, consolidation therapy have an important role in the success of treatment. Furthermore, strategies to define and manage immunotoxic side effects including hematotoxicity is critical to safe delivery. Advancements in CAR-T design beyond CD19 represent an ongoing therapeutic evolution. Overall, CAR-T signifies a paradigm shift in B-ALL management, with the potential for improved remission and survival in a historically challenging patient population.

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