Scientists uncover why some patients with rare leukemia may not benefit from approved targeted therapy

UT MD Anderson Research News July 07, 2026

• Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive form of acute leukemia
• Tagraxofusp is the first approved therapy for BPDCN, but many patients eventually develop resistance
• Resistance was linked with certain genetic mutations and with levels of a key enzyme
• These findings could provide important prognostic information to guide personalized treatment strategies

Researchers at The University of Texas MD Anderson Cancer Center have identified why some patients with a rare type of leukemia, called blastic plasmacytoid dendritic cell neoplasm (BPDCN), eventually develop resistance to tagraxofusp, the first Food and Drug Administration-approved treatment for this disease.

This study, published in Leukemia, was co-led by Hannah Beird, Ph.D., senior research scientist in Genomic Medicine, and Naveen Pemmaraju, M.D., 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 linked to severe mutations in the TET2 gene and to consistently lower levels of the TXNRD1 enzyme, which is needed to activate the drug’s toxic component. The findings suggest that TET2 mutations are potential prognostic biomarkers to identify which patients are most likely to benefit from tagraxofusp. Further, monitoring TXNRD1 levels could alert clinicians to patients who are developing resistance.

“Our findings show that specific cancer cells can effectively escape destruction by dialing down key enzymes that tagraxofusp needs in order to work,” Beird said. “Armed with this information, we can begin to predict which patients are less likely to respond, and we can design smarter, more personalized treatments to help improve outcomes.”

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 bone marrow. Patients with BPDCN have limited treatment options and a poor prognosis.

Tagraxofusp is the first approved therapy for BPDCN. As a frontline targeted therapy, it works by using a marker, called IL-3, that specifically targets CD123, a surface marker that is overexpressed in BPDCN cells. Once bound, the drug enters the cell and releases a toxin that shuts down protein production to ultimately destroy the cell. However, not all patients respond the same way to this treatment.

Around 10 to 25% of newly diagnosed patients may not initially respond to tagraxofusp treatment, leading the researchers to examine potential underlying reasons.

What determines whether cancer cells respond to tagraxofusp?

This study discovered that patients with normal or mild TET2 mutations responded better than those with severe TET2 mutations, suggesting that TET2 status could be a prognostic biomarker.

Using single-cell sequencing of nearly 100,000 cells, the researchers also found that most tumor cell types were eliminated by treatment except for one resistant group, known as “cluster 22.”

These surviving cells consistently showed lower expression levels of TXNRD1, with severe TET2 mutations appearing to promote this resistant state. TXNRD1 serves as a “release switch” that allows tagraxofusp’s toxin to activate inside cancer cells.

When TXNRD1 levels are low, the toxin remains trapped, allowing cancer cells to survive. Blocking 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 who are developing resistance, and checking TET2 mutations could identify the patients who are most likely to benefit from tagraxofusp. Additionally, combining tagraxofusp with other drugs – such as hypomethylating agents – could help overcome this resistance and lower the risk of relapse, providing further insights to improve patient outcomes.

“This study highlights the importance of investigating rare and ultra-rare tumors for insights and breakthroughs that may potentially apply to other, even more common tumor types,” Pemmaraju said. “Molecular investigations in rare blood cancers, such as this, may serve as a blueprint for novel techniques and approaches for other cancers with similar resistance phenomena.”  

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This study was funded by Menarini Stemline, the U.S. Department of Defense, the UT MD Anderson Leukemia SPORE, the SagerStrong Foundation, the Cancer Prevention and Research Institute of Texas, the Sheikh Mohamed Bin Zayed Al Nahyan Distinguished University Chair in Cancer Research, and institutional funding. For a full list of collaborating authors, disclosures and funding sources, see the full paper in Leukemia.