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Thioridazine Under Study for Dopamine Receptor D2–Positive AML

By: Anna Nowogrodzki
Posted: Tuesday, March 30, 2021

Thioridazine reduces leukemic progenitor cells in patients with acute myeloid leukemia (AML) who are positive for dopamine receptor D2, according to a small phase I trial. Mickie Bhatia, MD, of McMaster University in Hamilton, Ontario, Canada, and colleagues published their results in Cell Reports Medicine.

“We have successfully understood the mechanism by which the drug benefited patients, and we are using this information to develop a new, more tolerable formulation of the drug that is likely to work in some of the patients,” Dr. Bhatia said in a McMaster University press release.

The phase I dose-escalation trial enrolled 13 patients, 11 of whom completed the initial 5-day lead-in phase testing thioridazine alone. After that, patients received thioridazine in combination with standard chemotherapy. The authors collected patient cells at baseline and after the initial 5 days. They then measured the number of leukemic progenitor colonies using in vitro assays and performed further tests using liquid culture and mouse xenograft studies.

Only patients who expressed abnormally high levels of dopamine receptor D2 experienced a rapid decrease in leukemic progenitor function from treatment with thioridazine. This was held across different experimental systems and in the clinical setting. The positive enantiomer of thioridazine appeared to be more effective than the negative one.

The authors noted that AML genetics vary considerably among patients. Consequently, the study’s small sample size is limiting, and further larger studies will be required to confirm their early findings. “We have established objective evidence to recommend that dopamine receptor D2–positive patients should be prioritized for subsequent trials in the future,” the authors wrote.

Disclosure: The study authors reported no conflicts of interest.


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