Researchers at the University of Texas MD Anderson Cancer Center have discovered why some patients with a rare type of leukemia called basal plasmacytoid dendritic cell neoplasm (BPDCN) eventually develop resistance to tagraxofusp, the first Food and Drug Administration-approved treatment for the disease.
This study, published in Leukemia, it was led by Hannah Baird, Ph.D., Senior Research Scientist in Genomic Medicine, and Naveen Pemmaraju, MD, professor of Leukemia. The findings are the result of a molecular analysis of previously published results from a Phase 2 trial of tagraxofusp led by Pemmaraju.
Resistance was associated with severe mutations in TET2 gene and consistently lower levels of the TXNRD1 enzyme, which is required to activate the drug’s toxic component. The findings suggest that TET2 Mutations are potential prognostic biomarkers to identify patients most likely to benefit from tagraxofusp. Additionally, monitoring TXNRD1 levels could alert clinicians to patients developing resistance.
Our findings show that certain cancer cells can effectively escape destruction by typing key enzymes that tagraxofusp needs to work. Armed with this information, we can begin to predict which patients are less likely to respond and can design smarter, more personalized treatments to help improve outcomes.”
Hannah Baird, Ph.D., senior researcher in Genomic Medicine
What is BPDCN and how does tagraxofusp work?
BPDCN is an aggressive type of acute leukemia that usually arises from a rare immune cell found in the bone marrow. Patients with BPDCN have limited treatment options and a poor prognosis.
Tagraxofusp is the first approved treatment for BPDCN. As a first-line targeted therapy, it works by using a marker, called IL-3, that specifically targets CD123, a surface marker overexpressed on BPDCN cells. Once attached, the drug enters the cell and releases a toxin that shuts down protein production to eventually destroy the cell. However, not all patients respond in the same way to this treatment.
About 10 to 25% of newly diagnosed patients may not initially respond to tagraxofusp treatment, leading researchers to consider possible underlying causes.
What determines whether cancer cells respond to tagraxofusp?
This study found that patients with normal or mild TET2 mutations responded better than those with severe TET2 mutations, suggesting that TET2 condition could be a prognostic biomarker.
Using single-cell sequencing of nearly 100,000 cells, the researchers also found that most types of tumor cells were eliminated by treatment except for one resistant group, known as ‘cluster 22’.
These surviving cells consistently showed lower levels of TXNRD1 expression, with severe TET2 mutations that appear to promote this resistant state. TXNRD1 serves as a “release switch” that allows the tagraxofusp toxin to be activated inside cancer cells.
When TXNRD1 levels are low, the toxin remains trapped, allowing cancer cells to survive. Blockade of TXNRD1 in preclinical models increased treatment resistance, while combining tagraxofusp with the hypomethylating agent azacitidine restored key pathways and improved outcomes.
What do these findings mean for patients?
Monitoring TXNRD1 levels could alert clinicians to patients developing resistance and screen TET2 Mutations could identify patients most likely to benefit from tagraxofusp. Additionally, combining tagraxofusp with other drugs – such as hypomethylating agents – could help overcome this resistance and reduce the risk of relapse, providing further insights into improving patient outcomes.
“This study highlights the importance of investigating rare and ultra-rare tumors for insights and discoveries that may apply to other, even more common tumor types,” Pemmaraju said. “Molecular research in rare blood cancers such as this may serve as a blueprint for new techniques and approaches for other cancers with similar resistance phenomena.”
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