Incorporating Immunotherapies into the Evolving Standard of Care for Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia

Survival for pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) exceeds 90% in high-income countries due to risk-adapted chemotherapy and measurable residual disease (MRD)-guided strategies. However, relapse remains a leading cause of death, and chemotherapy-related toxicities highlight the need for equally effective, less toxic approaches. B-cell–directed immunotherapies targeting CD19 and CD22 have emerged as transformative modalities. This review synthesizes clinical evidence for three major immunotherapeutic classes: CD19/CD3 T cell engagers (blinatumomab), CD22 antibody–drug conjugates (inotuzumab ozogamicin (InO)), and CD19-directed chimeric antigen receptor (CAR)-T cell therapies, evaluating their integration into frontline and relapsed treatment algorithms, safety, resistance mechanisms, and future directions. Randomized pediatric trials demonstrate that blinatumomab improves survival by reducing relapse and treatment-related mortality when incorporated into frontline and first-relapse therapy, primarily in consolidation. InO shows high induction response and MRD-negativity rates in relapsed disease but carries a risk of sinusoidal obstruction syndrome, particularly around hematopoietic stem cell transplantation (HSCT). CD19 CAR-T cell therapy induces MRD-negative remissions in 80–90% of heavily pretreated patients, with durable survival in 40–50% without mandatory HSCT consolidation. Emerging agents and combination strategies aim to overcome antigen escape and improve durability. Challenges remain regarding central nervous system (CNS) disease control, long-term immune effects, sequencing, regulatory disparities, and global access. Immunotherapies are reshaping pediatric BCP-ALL treatment, enabling chemotherapy reduction while maintaining or improving cure rates. Strategic integration and equitable global access are vital to achieving universal cures with reduced toxicity. Post-immunotherapy relapses may exhibit distinct disease characteristics requiring novel treatment approaches.