Dr Daver on the Investigation of Uproleselan Plus Azacitidine and Venetoclax in AML

Naval G. Daver, MD, associate professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses the rationale for an ongoing phase 1 trial (NCT04964505) investigating uproleselan (GM-1271) in combination with azacitidine (Vidaza) and venetoclax (Venclexta) in patients with treatment-naïve acute myeloid leukemia (AML).

The combination of azacitidine plus venetoclax is frequently used in patients with AML who are older than 75 years of age as well as those who are between 60 years and 75 years of age, Daver says. Approximately 60% to 70% of patients with newly diagnosed AML receive azacitidine/venetoclax-based therapy in the front line, Daver notes. This is an ideal combination for many patients with AML because it generates good response rates, is tolerable, and allows patients to feasibly undergo subsequent allogeneic stem cell transplant, Daver explains.

The phase 3 VIALE-A trial (NCT02993523) evaluated the combination of azacitidine and venetoclax vs azacitidine alone in patients with treatment-naïve AML who were ineligible for standard induction therapy. At a median follow-up of 43.2 months, the median overall survival was 14.7 months (95% CI, 12.1-18.7) with the combination vs 9.6 months (95% CI, 7.4-12.7) with azacitidine alone. Although these data are encouraging, the efficacy of this combination may be enhanced with additional targeted therapies, such as inhibitors of FLT3, IDH, and CD123, according to Daver.

Brian Jonas, MD, PhD, of the University of California, Davis, is leading the phase 1 trial investigating the addition of the E-selectin inhibitor uproleselan to the azacitidine/venetoclax backbone in this patient population. Preclinical data have shown a synergy between venetoclax and uproleselan, Daver says. Furthermore, the addition of uproleselan to this combination does not seem to contribute significant cumulative toxicities, such as myelosuppression and neutropenia, Daver explains. For these reasons, the E-selectin inhibitor is a viable agent to explore in combination with venetoclax and azacitidine, and investigators await data readouts from this phase 1 study, Daver concludes.