Optimization of upfront therapy for adult acute lymphoblastic leukemia: a paradigm shift toward immunotherapy.

Adult acute lymphoblastic leukemia (ALL) treatment protocols are evolving with frontline therapy now incorporates targeted immunotherapeutic agents. Targeted immune therapies like blinatumomab, inotuzumab ozogamicin (InO), rituximab, and nelarabine are being combined with traditional chemotherapy protocols to enhance remission rates and minimal residual disease (MRD) negativity while decreasing toxicities. The incorporation of blinatumomab into initial treatment protocols for both Philadelphia chromosome-negative (Ph -) and positive (Ph +) ALL patients results in notable early MRD elimination. The medical use of InO as an initial treatment has increased specifically for older or medically unfit patients. The addition of rituximab to chemotherapy treatment in CD20-positive B-ALL patients produces superior long-term results. Adding nelarabine to pediatric-inspired T-cell ALL treatment protocols in young adult and adolescent (AYA) patients resulted in decrease their risk of central nervous system (CNS) relapse. High-risk ALL subtypes including Ph + and Ph-like ALL now receive immunotherapeutic and molecularly targeted treatments. Ph + ALL patients receive standard treatment with multi-agent chemotherapy and TKIs dasatinib or ponatinib and blinatumomab as part of their frontline therapy to enhance molecular responses and minimize the requirement for allogeneic hematopoietic stem cell transplantation (allo-HCT). The combination of JAK inhibitors with ABL-class TKIs, chemotherapy, and immunotherapy represents current early-phase trial approaches for Ph-like ALL patients with kinase-activating alterations. The practice of testing MRD and genomic profiling at diagnosis revolutionized treatment approaches by allowing personalized curative strategies for all patients. Research on clinical trials aims to establish the best sequence of targeted therapies and CAR T-cell therapy for high-risk and MRD-positive patients to achieve longer survival rates with reduced toxicity and less dependence on allo-HCT in first remission.