Researchers at the University of Texas MD Anderson Cancer Center have determined why some patients with a rare type of leukemia called blastic plasmacytoid dendritic cell neoplasm (BPDCN) eventually develop resistance to taglaxofusp, which the Food and Drug Administration approved as the first treatment for the disease.
This study leukemia, It was Co-leader: Dr. Hannah Bayard, Senior Researcher in Genomic Medicine, and Dr. Naveen Pemaraju, professor of leukemia. This discovery is the result of a molecular analysis of previously published results from the Phase 2 trial of Talaxofusp, which Pemaraju led.
Resistance was associated with severe mutations Tet 2 Consistently reduces levels of the TXNRD1 enzyme, which is required to control genes and activate the toxic components of drugs. The findings suggest that Tet 2 Mutations may serve as prognostic biomarkers to identify which patients are most likely to benefit from taglaxofusp. Additionally, monitoring TXNRD1 levels could alert clinicians to patients developing resistance.
Our findings show that by lowering the levels of key enzymes required for Talaxofusp to function, certain cancer cells can be effectively spared from destruction. With this information, we can predict which patients are less likely to respond, allowing us to design smarter, more personalized treatments to improve outcomes. ”
Dr. Hannah Beard, Senior Research Scientist in Genomic Medicine
What is BPDCN? How does tagraxofusp work?
BPDCN is a highly malignant type of acute leukemia that develops from rare immune cells normally found in the bone marrow. Treatment options for patients with BPDCN are limited and the prognosis is poor.
Tagraxofusp was the first approved treatment for BPDCN. As a front-line targeted therapy, it works by using a marker called IL-3, which specifically targets CD123, a surface marker overexpressed on BPDCN cells. Once bound, the drug enters the cell and releases a toxin that stops protein production and ultimately destroys the cell. However, not all patients respond to this treatment in the same way.
Approximately 10-25% of newly diagnosed patients may not initially respond to taglaxofusp treatment, prompting researchers to investigate potential underlying reasons.
What determines whether cancer cells respond to Taglaxofusp?
In this study, patients with normal or mild symptoms Tet 2 Mutations responded better than severe mutations Tet 2 mutation, it suggests Tet 2 Status may be a biomarker for prognosis.
Using single-cell sequencing of about 100,000 cells, the researchers also found that most tumor cell types were eliminated by the treatment, with the exception of one resistant group known as “cluster 22.”
These surviving cells consistently expressed low levels of TXNRD1 and exhibited severe symptoms. Tet 2 Mutations appear to promote this resistant state. TXNRD1 functions as a “release switch” that allows Talaxofusp toxin to be activated within cancer cells.
When TXNRD1 levels are low, toxins remain trapped and cancer cells can survive. Blocking TXNRD1 in preclinical models increased treatment resistance, while combining taglaxofusp with the hypomethylating agent azacytidine restored key pathways and improved outcomes.
What do these findings mean for patients?
Monitoring TXNRD1 levels can alert clinicians to patients developing resistance and allow testing. Tet 2 Mutations may help identify patients most likely to benefit from taglaxofusp. Additionally, combining taglaxofusp with other drugs, such as hypomethylating agents, could overcome this resistance and reduce the risk of relapse, potentially providing further insights to improve patient outcomes.
“This study highlights the importance of investigating rare and ultra-rare tumors to gain insights and breakthroughs that may be applicable to other, more common tumor types,” Professor Pemaraju said. “Molecular studies in rare blood cancers like this could provide a blueprint for new techniques and approaches for other cancers with similar resistance phenomena.”
sauce:
University of Texas MD Anderson Cancer Center
Reference magazines:
Beard HC, Others. (2026) Decreased TXNRD1 is associated with resistance to taglaxofusp in blastic plasmacytoid dendritic cell tumors as seen in phase II. leukemia. DOI: 10.1038/s41375-026-03022-0. https://www.nature.com/articles/s41375-026-03022-0
