Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS)—two related blood diseases that disproportionally strike older adults—are notoriously difficult to treat and associated with high relapse rates. Although new therapies have improved survival, treatment options remain limited, and the prognosis for the 50% of people who experience disease relapse remains poor. 

Researchers at the National Cancer Institute-designated Montefiore Einstein Comprehensive Cancer Center (MECCC) were recently awarded a four-year, $2.6 million grant from the U.S. Food and Drug Administration (FDA) to conduct an innovative phase 1 clinical trial of a new drug for patients with relapsed and treatment-resistant forms of AML and MDS. It is one of only 10 grants issued this year by the FDA through its Office of Orphan Products Development. 

“This is a tremendous opportunity to apply the knowledge we have developed in our MECCC labs over the past decade to develop a novel therapeutic strategy,” said Aditi Shastri, M.D., the principal investigator of the grant, a member of MECCC’s Stem Cell and & Cancer Biology Research Program and Blood Cancer Institute, and associate professor of oncology, medicine, and developmental and molecular biology at Albert Einstein College of Medicine. 

Drugs that initially work against AML are ineffective when the disease returns. Research suggests that those treatments leave behind leukemic stem cells that are resistant to existing medications and lead to relapsed and drug-resistant AML and MDS. 

“We have identified a molecular target in leukemic stem cells and a novel drug that performed well against those stem cells in pre-clinical studies,” Dr. Shastri said. “We are eager to see if this drug and its combinations can provide clinical benefit for our patients.” 

AML and MDS are rare diseases with among the worst prognoses of all cancers: most people who develop relapsed or treatment-resistant disease live for only another 4 to 10 months.  Since AML is so difficult to treat, most patients receive care at academic cancer centers. MECCC, with its Blood Cancer Institute and Stem Cell and Cancer Biology Research Program, is few institutions in the country specializing in AML and MDS. 

In 2018, Dr. Shastri and colleagues found that relapsed AML and MDS patients with the worst prognosis have leukemic stem cells that express excessive levels of the protein STAT3. In subsequent studies, her lab found that STAT3 does several things to help MDS and AML cancer cells survive; most importantly, STAT3 prevents cancer cells from undergoing apoptosis, known as programmed cell death—the goal of a major AML/MDS drug called venetoclax. Dr. Shastri hypothesized that blunting the impact of STAT3 could make venetoclax more effective and lead to better outcomes for patients. 

Dr. Shastri then looked for compounds that specifically targeted STAT3 and identified the novel targeted drug danvatirsen: a STAT3 inhibitor developed by Flamingo Therapeutics and Ionis Pharmaceuticals that is now being developed as a cancer treatment in early-phase clinical trials. After conducting preclinical tests indicating that danvatirsen shows promise against AML/MDS, Dr. Shastri is investigating the drug in a phase 1 clinical trial. 

The trial is slated to begin this month and will enroll patients with therapy-resistant MDS and AML at MECCC and MD Anderson Cancer Center in Houston, Texas. “Since this is a phase 1 trial, our first priority is to determine the safety of danvatirsen when used alone and in combination with venetoclax, as well as the optimal dosages for the two drugs,” Dr. Shastri said. “We will investigate the effect of danvatirsen, alone and in combination with venetoclax, on leukemic stem cells.” 

If the researchers find evidence that the experimental treatment has clinical activity, they will expand the study to a phase 2 trial to further assess the treatment’s effectiveness. The co-principal investigator of the clinical trial is Naval Daver, M.D., at the MD Anderson Cancer Center. MECCC co-investigators on this grant are Marina Konopleva, M.D., and Ulrich Steidl, M.D., Ph.D. 

The grant is titled “A phase 1 study investigating the safety & efficacy of danvatirsen as monotherapy followed by combination with venetoclax in patients with relapsed/refractory MDS & AML” (R01FD007836).

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About Montefiore Einstein Comprehensive Cancer Center
Montefiore Einstein Comprehensive Cancer Center (MECCC) is a National Cancer Institute (NCI)-designated comprehensive cancer center and a national leader in cancer research and clinical care located in the racially and ethnically diverse borough of the Bronx, N.Y. MECCC combines the exceptional science of Albert Einstein College of Medicine with the multidisciplinary and team-based approach to cancer clinical care at Montefiore Health System. Founded in 1971 and an NCI-designated cancer center since 1972, MECCC is redefining excellence in cancer research, clinical care, education and training, and community outreach and engagement. Its mission is to reduce the burden of cancer for all, especially people from historically underrepresented groups.