New Therapy Targets STAT3 in Chemotherapy-Resistant Leukemic Stem Cells in AML and MDS

Aditi Shastri, MBBS, Albert Einstein College of Medicine, Bronx, New York, and colleagues shared early data from a phase 1 study suggesting that danvatirsen, a selective antisense oligonucleotide inhibitor of signal transducer and activator of transcription 3 (STAT3), may have promise as a monotherapy and in combination with venetoclax for treating chemotherapy-resistant leukemic stem cells.¹

Acute myeloid leukemia (AML) remains a significant challenge in oncology, with only 30% of patients achieving long-term survival despite advances in targeted therapies. Relapse often occurs due to chemotherapy-resistant leukemic stem cells, which drive disease recurrence and represent a significant obstacle to cure. STAT3, a key transcription factor driving leukemogenesis, is often overactivated in AML and myelodysplastic syndromes (MDS), contributing to disease progression and resistance to therapy. Although targeting STAT3 holds great therapeutic potential, progress has been hindered by difficulties in developing safe and specific inhibitors.

Previous research demonstrated that danvatirsen effectively targets STAT3 in hematopoietic stem and progenitor cells, inducing apoptosis in malignant cells while sparing healthy ones. Prior work also showed a correlation between STAT3 and myeloid cell leukemia 1, a protein linked to resistance against the BCL2 inhibitor venetoclax.²

The ongoing phase 1 study presented by Dr. Shastri is evaluating the safety and efficacy of danvatirsen through two substudies. The first assesses danvatirsen as a monotherapy across three dose levels (1-3 mg/kg), and the second investigates the combination of danvatirsen with venetoclax. The treatment regimen begins with a loading dose followed by weekly infusions. Safety is the primary objective. Secondary objectives measuring efficacy include STAT3 inhibition in hematopoietic stem and progenitor cells, the correlation of response to STAT3 gene expression signature, duration of response, event-free survival, and overall survival. Biomarker analyses are also planned.

By combining targeted approaches, this strategy aims to overcome resistance mechanisms and enhance durability of response in this high-risk patient population. The results of the study will inform the recommended phase 2 dose. Recruitment is currently ongoing at the Montefiore Einstein Comprehensive Cancer Center, Bronx, New York and the M.D. Anderson Cancer Center, Houston, Texas.

Reference

1. Shastri A, Goldfinger M, Mantzaris I, et al. A phase 1 study investigating the safety and efficacy of danvatirsen as monotherapy followed by combination with venetoclax in patients with relapsed/refractory MDS and AML. Abstract #4265.5. Presented at the American Society of Hematology Annual Meeting; December 7-10, 2024; San Diego, California.
2. Shastri A, Choudhary G, Teixeira M, et al. Antisense STAT3 inhibitor decreases viability of myelodysplastic and leukemic stem cells. J Clin Invest. 2018;128:5479-5488. doi: 10.1172/JCI120156