Michael Andreeff, MD, PhD, Paul and Mary Haas Chair of Genetics, professor of medicine, Department of Leukemia, director, Bone Marrow Aspiration Clinic, Department of Hematology, chief, Section of Molecular Hematology and Therapy, Division of Cancer Medicine, director, Flow Cytometry and Cellular Imaging Facility, The University of Texas MD Anderson Cancer Center, discusses the rationale for investigating uproleselan (GMI-1271) plus venetoclax (Venclexta) and azacitidine in patients with acute myeloid leukemia (AML).

Analysis of the tumor microenvironment for AML has shown overactivation of the CXCR4 G-protein–mediated signaling pathway, Andreeff begins. The signal is transmitted to leukemic cells through expression of the transcription factor Yin Yang 1 (YY1), which is located downstream from the CXCR4 binding site and is thought to regulate several cancer-related genes, Andreeff says.

Although E-selectin has a separate downstream activation site from YY1, dysregulation of the signal transduction pathway occurs through a similar process. This pathway is also known to trigger malignant cell growth and regeneration. Blocking E-selectin can detach the cell from the vascular niche and affect intercellular signaling, Andreeff states. Dual inhibition of CXCR4 and E-selectin could both cut off supply structures in the bone marrow and the vascular niche, he adds.

A single-center phase 1 trial (NCT04964505) is currently evaluating the addition of the E-selectin antagonist uproleselan to standard-of-care venetoclax and azacitidine in older or unfit patients with AML. Using uproleselan to target the tumor microenvironment could help patients overcome resistance to chemotherapy in AML. Inhibiting E-selectin and BCL2 expression with uproleselan and venetoclax, respectively, could help prevent the formation of cancerous growths.

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Michael Andreeff, MD, PhD, discusses the rationale for investigating uproleselan plus venetoclax and azacitidine in patients with acute myeloid leukemia.



Dr Andreeff on the Rationale for Investigating Uproleselan Plus Venetoclax and Azacitidine in AML

Michael Andreeff, MD, PhD, chair of genetics, professor of medicine, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses the promise of venetoclax (Venclexta) in the treatment of patients with acute myeloid leukemia (AML).

BCL2 is a survival factor for AML cells, particularly stem cells, Andreef says. For decades, this molecule was considered untargetable, but research over the last few years has proven otherwise. Recent data has suggested that the best established BCL2 inhibitor is venetoclax. In June 2018, venetoclax was granted full approval by the FDA for the treatment of patients with chronic lymphocytic leukemia or small lymphocytic leukemia, regardless of 17p deletion. The drug has shown promise even in patients with 

-mutant CLL, who are known to have a particularly poor prognosis.

Despite this success, when used in patients with AML, the agent had been largely ineffective and trials examining the use of venetoclax monotherapy had been negative. Combining the BCL2 inhibitor with chemotherapy agents like decitabine, however, has shown tremendous efficacy in elderly patients who previously had no effective options available to them. For example, results from a study conducted by The University of Texas MD Anderson Cancer Center and presented at the 2018 ASH Annual Meeting showed that the use of venetoclax in combination with demethylating agents resulted in response rates of up to 100% in this patient population.

Michael Andreeff, MD, PhD, chair of genetics, professor of medicine, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses the promise of venetoclax in acute myeloid leukemia.

Michael Andreeff, MD, PhD

Articles

Dr Andreeff on the Rationale for Investigating Uproleselan Plus Venetoclax and Azacitidine in AML

Dr. Andreeff Discusses Promise of Venetoclax in AML