Current status and future potential of CD123-based targeted therapies for acute leukemia

Acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and blastic plasmacytoid dendritic cell neoplasm (BPDCN) are aggressive hematologic malignancies with poor outcomes, particularly in relapsed/refractory settings. CD123, the interleukin-3 receptor alpha chain, is highly expressed on leukemic blasts and leukemia stem cells, making it an attractive therapeutic target with limited expression on normal hematopoietic cells. CD123-directed therapies - including antibody-drug conjugates (ADCs), bispecific T-cell engagers (BiTEs), and CAR T-cell therapies - are under active investigation.

This review details the preclinical rationale, clinical development, efficacy, and toxicity of CD123-targeted therapies. It discusses completed and ongoing clinical trials for agents such as tagraxofusp, pivekimab sunirine, flotetuzumab, vibecotamab, and investigational CAR T-cell therapies (e.g. MB-102, UCART123v1.2). Toxicities, including myelosuppression, cytokine release syndrome (CRS), and hepatotoxicity - are characterized in detail, with attention to mitigation strategies. Future directions highlight combination regimens, switchable CAR designs, and biomarker-driven personalization.

CD123-targeted therapy represents a promising yet challenging frontier in treating high-risk leukemias. While clinical activity has been demonstrated, especially in BPDCN, therapeutic durability and safety remain hurdles. Precision in antigen targeting, combination strategies, and toxicity management will be critical for successful integration of CD123-directed therapies into standard clinical practice.