New Biomarkers Predict Resistance to Targeted Therapy in Rare Blood Cancer

Although tagraxofusp is the first approved targeted therapy for BPDCN, some newly diagnosed patients fail to respond, while others develop resistance after an initial benefit. A new study identifies genetic and transcriptional features that may help explain this variability in treatment response.

The University of Texas MD Anderson Cancer Center (Houston, TX, USA) investigated clinical resistance to tagraxofusp and identified molecular determinants linked to treatment failure. The work, published in Leukemia, analyzed previously published phase 2 data and focused on features that distinguish responders from nonresponders. The findings address a significant diagnostic gap in anticipating which patients benefit from this therapy.

Tagraxofusp functions as a frontline targeted therapy that uses a marker called interleukin-3 (IL-3) to bind CD123, a surface marker overexpressed on BPDCN cells. After binding, the drug is internalized and releases a toxin that shuts down cellular protein synthesis, leading to cell death. Despite this targeted mechanism, approximately 10% to 25% of newly diagnosed patients may not initially respond to treatment.

Using single-cell sequencing of nearly 100,000 cells, researchers showed that most tumor cell populations were eliminated by therapy except for one resistant subset, termed “cluster 22.” Resistance was associated with severe mutations in the TET2 gene and with consistently lower expression of TXNRD1, an enzyme needed to activate tagraxofusp’s toxic payload. In preclinical models, blocking TXNRD1 increased resistance, whereas combining tagraxofusp with the hypomethylating agent azacitidine restored key pathways and improved outcomes.

The study indicates that TET2 mutation severity may serve as a prognostic biomarker for response to tagraxofusp, and that monitoring TXNRD1 expression could help identify emerging resistance. According to the authors, these molecular insights offer practical avenues for stratifying patients and refining combination strategies in BPDCN. The study was published in Leukemia on July 6, 2026.

“Our findings show that specific cancer cells can effectively escape destruction by dialing down key enzymes that tagraxofusp needs in order to work. 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,” said Hannah Beird, Ph.D., senior research scientist in Genomic Medicine at The University of Texas MD Anderson Cancer Center.

“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. 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,” said Naveen Pemmaraju, M.D., professor of Leukemia at The University of Texas MD Anderson Cancer Center.

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