From the Guidelines
CD123 is a crucial cell surface marker in the diagnosis and treatment of acute myeloid leukemia (AML) and other hematologic malignancies, with high expression associated with poorer prognosis and increased risk of relapse, and is targeted by therapies such as tagraxofusp and bispecific antibodies. The importance of CD123 in AML is highlighted by its role in identifying leukemic stem cells and its potential as a therapeutic target 1. In the context of AML, CD123 expression is used in flow cytometry panels to identify and quantify abnormal blast populations, particularly in minimal residual disease monitoring.
Several targeted therapies have been developed against CD123, including tagraxofusp, a CD123-directed cytotoxin approved for blastic plasmacytoid dendritic cell neoplasm, and bispecific antibodies such as flotetuzumab, which redirects T lymphocytes to attack CD123-expressing cells 2. These treatments work by binding to CD123 on malignant cells and triggering cell death through various mechanisms. CD123 is particularly valuable as a therapeutic target because it is minimally expressed on normal hematopoietic stem cells, potentially allowing for selective targeting of leukemic cells while sparing normal bone marrow function.
Key points about CD123 include:
- High expression in AML is associated with poorer prognosis and increased risk of relapse
- Used in flow cytometry panels for minimal residual disease monitoring
- Targeted by therapies such as tagraxofusp and bispecific antibodies
- Minimally expressed on normal hematopoietic stem cells, allowing for selective targeting of leukemic cells
- Important in the diagnosis and treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) and other hematologic malignancies 3, 1.
Overall, CD123 plays a critical role in the diagnosis and treatment of AML and other hematologic malignancies, and its targeting by therapies such as tagraxofusp and bispecific antibodies offers a promising approach for improving patient outcomes 2.
From the FDA Drug Label
Tagraxofusp-erzs is a CD123-directed cytotoxin composed of recombinant human interleukin-3 (IL-3) and truncated diphtheria toxin (DT) fusion protein that inhibits protein synthesis and causes cell death in CD123-expressing cells. The CD123 marker is the target of the drug tagraxofusp-erzs, which is a CD123-directed cytotoxin. This means that the drug is designed to bind to cells that express the CD123 marker and cause cell death.
From the Research
CD123 Marker Overview
- CD123, the α chain of the interleukin 3 receptor, is a cytokine receptor that is overexpressed in multiple hematolymphoid neoplasms, including acute myeloid leukemia, blastic plasmacytoid dendritic cell neoplasm, acute lymphoblastic leukemia, hairy cell leukemia, and systemic mastocytosis 7.
- CD123 expression is upregulated in leukemic stem cells relative to non-neoplastic hematopoietic stem cells, making it a useful diagnostic and therapeutic biomarker in hematologic malignancies 7, 8.
CD123-Targeted Therapies
- Varying levels of evidence have shown that CD123-targeted therapy represents a promising therapeutic approach in several cancers, including the use of tagraxofusp, an anti-CD123 antibody conjugated to a diphtheria toxin 7, 9, 10.
- Multiple clinical trials are investigating the use of various CD123-targeting agents, including chimeric antigen receptor-modified T cells (expressing CD123), monoclonal antibodies, combined CD3-CD123 dual-affinity retargeting antibody therapy, recombinant fusion proteins, and CD123-engager T cells 7, 8, 10.
- CD123-targeted CAR T cell therapy has exhibited potential in clinical trials for the treatment of acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm, but may cause endothelial damage, which can be aggravated by IFN-γ and TNF-α 11.
CD123 Expression and Diagnosis
- CD123 is highly expressed in leukemic stem cells (LSCs), while not in normal hematopoietic stem cells (HSCs), and associates with treatment response, minimal residual disease (MRD) detection, and prognosis 8.
- CD123 is an important marker for the identification and targeting of LSCs for refractory or relapsed leukemia 8.
- Diagnosis of blastic plasmacytoid dendritic cell neoplasm (BPDCN) is based on the presence of plasmacytoid dendritic cell precursors expressing CD123, and a distinct histologic appearance 9.