The emerging role of immunotherapy in improving outcomes in Down syndrome - associated acute lymphoblastic leukemia: an insightful review

Down syndrome-associated acute lymphoblastic leukemia (DS-ALL) is a biologically distinct subtype with high rates of treatment-related mortality and relapse. Genomic profiling reveals frequent CRLF2 rearrangements, JAK-STAT pathway mutations, and high-risk subtypes such as BCR::ABL1-like disease. Conventional chemotherapy achieves remission but is limited by toxicity in DS patients. Recent advances in immunotherapy, including blinatumomab, inotuzumab ozogamicin, and CD19-directed CAR T-cell therapy, have shown significant efficacy and favorable tolerability in pediatric and adult DS-ALL. Blinatumomab and inotuzumab enable minimal residual disease clearance and serve as chemotherapy-sparing or bridging strategies, while CAR T-cell therapy offers curative potential and may reduce transplant reliance. Emerging approaches incorporating early immunotherapy, MRD-guided treatment, and chemotherapy-free regimens may improve survival and quality of life. Prospective DS-specific trials are essential to optimize therapy and close the outcome gap in this high-risk population.