P1/2, N=83, Recruiting, AstraZeneca | Not yet recruiting --> Recruiting

Bispecific antibodies such as blinatumomab (anti-CD19), antibody-drug conjugates like inotuzumab ozogamicin (anti-CD22), and monoclonal antibodies such as daratumumab (anti-CD38) have demonstrated efficacy in relapsed or refractory disease with improved safety profiles. The integration of targeted and immune-based therapies into conventional regimens represents a decisive step toward precision medicine, aiming to enhance survival outcomes while reducing treatment-related toxicity and improving quality of life in ALL children. This review aims to provide a comprehensive overview of the current understanding of ALL pathobiology and therapeutic approaches, with particular emphasis on the expanding role of immunotherapeutic strategies in pediatric disease.

Blinatumomab and inotuzumab ozogamicin have become established treatments, enhancing remission rates, measurable residual disease clearance, and overall survival in relapsed/refractory disease, and these agents, are now increasingly incorporated into frontline therapy...In acute myeloid leukemia (AML), gemtuzumab ozogamicin has shown significant clinical benefits, particularly in molecularly defined subsets...This review highlights how immunotherapy has reshaped treatment paradigms across acute leukemias, underscoring successful experiences in B-ALL. These insights emphasize the need for continued innovation to overcome existing hurdles in AML and T-ALL, ultimately aiming to enhance patient outcomes and quality of life.

P4, N=44, Completed, Pfizer | Active, not recruiting --> Completed

CD24 therefore emerged as an effective target in BCP-ALL, and the combination of CD24 and CD123 as a potential effective double-targeting strategy. The combination of different recognition modalities (eg, a CAR and CD16) should be tested to determine whether it provides synergistic cytotoxic activity in triple targeting.

Patients ≥60 years with Ph-negative B-cell ALL and TP53 VAF ≥45% had poor outcomes, with 4-year event-free survival (EFS) and overall survival (OS) of 28%, driven primarily by increased relapse risk, even among patients treated with frontline inotuzumab ozogamicin (INO) and/or blinatumomab. TP53 persistence at remission occurred in 44% of tested patients and was associated with increased ALL relapse risk. These results demonstrate that TP53 VAF is prognostic in older patients with Ph-negative B-cell ALL; high VAF may increase relapse risk but is not independently associated with survival in younger patients.

P2, N=80, Recruiting, Children's Oncology Group | Trial completion date: Mar 2026 --> Dec 2026 | Trial primary completion date: Mar 2026 --> Dec 2026

P1/2, N=37, Terminated, M.D. Anderson Cancer Center | Active, not recruiting --> Terminated; <75% participation

P2, N=42, Recruiting, Sheng-Li Xue, MD | Trial completion date: Aug 2025 --> Aug 2026 | Trial primary completion date: Aug 2025 --> Aug 2026

P=N/A, N=102, Active, not recruiting, Ruijin Hospital

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. 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.

Further randomized studies are needed to validate these findings. https://www.crd.york.ac.uk/prospero/, identifier CRD42024619042.