Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive type of blood and bone marrow cancer. The first FDA approved targeted therapy for BPDCN is tagraxofusp (Elzonris), a CD123-directed cytotoxin. This therapy is an important treatment option for people with BPDCN. But, not everyone responds to tagraxofusp, and for some people, tagraxofusp eventually stops working to treat BPDCN.
A recent study out of The University of Texas MD Anderson Cancer Center looks more closely at what causes tagraxofusp resistance. Their findings can help doctors better understand who is most likely to benefit from tagraxofusp.
How does tagraxofusp treat BPDCN?
BPDCN cells typically have high levels of a protein called CD123 on their surface. Tagraxofusp is designed to target these cells. It delivers a toxin that eliminates the cells.
Even though tagraxofusp can be effective, treatment may not be effective in about 10% to 25% of people newly diagnosed with BPDCN. Others may respond at first but later develop resistance.
Researchers wanted to understand what makes some BPDCN cells more likely to survive treatment.
Read about different types of treatment for BPDCN.
TET2 mutations may affect treatment response
The researchers found an important connection between mutations in a gene called TET2 and response to tagraxofusp.
People whose BPDCN cells had normal TET2 or less severe TET2 mutations responded better to treatment than people with more severe TET2 mutations.
This shows that a person’s TET2 mutation status could potentially serve as a biomarker. A biomarker is a biological molecule that can give doctors information about a disease and how it may respond to treatment. Knowing a patient’s TET2 status may help doctors better predict how likely their BPDCN is to respond to tagraxofusp.
How some BPDCN cells survive treatment
Researchers also analyzed nearly 100,000 individual cells to see what happened during treatment. Most types of BPDCN cells were destroyed by tagraxofusp. However, one group of cancer cells, “cluster 22”, survived.
These cells had consistently lower levels of an enzyme called TXNRD1. This enzyme plays an important role in allowing the toxin carried by tagraxofusp to become active once it enters the cancer cell. When there is not enough TXNRD1, the toxin may not activate allowing the BPDCN cells to survive treatment.
Could combination treatment help?
Understanding how BPDCN cells resist tagraxofusp could also point researchers toward ways to overcome resistance.
Researchers also tested tagraxofusp with azacitidine. The combination helped improve the response to treatment.
More research is needed to understand how these findings could be used in clinical care. However, they provide another possible strategy for treating BPDCN that does not respond to tagraxofusp or becomes resistant.
What does this mean for people with BPDCN?
These findings could eventually help make BPDCN treatment more personalized.
Testing for TET2 mutations may help identify people who are more or less likely to respond to treatment. Monitoring TXNRD1 levels could also potentially help doctors recognize when BPDCN cells are developing resistance.
Understanding how cancer cells become resistant to treatment can help researchers develop new strategies to make treatments work better and potentially last longer.
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