Uproleselan (GMI-1271) is a new E-selectin antagonist that alters cell survival pathways, increases survival in xenograft and syngeneic mice models, and reduces chemotherapy toxicity in vivo. A phase 1/2 research compared uproleselan (5-20 mg/kg) to MEC (mitoxantrone, etoposide, and cytarabine) in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). No dose-limiting effects were found among the first 19 patients. About 10 mg/kg twice daily was the recommended phase 2 dosage (RP2D). At the RP2D plus MEC, uproleselan was administered to an additional 47 patients with R/R AML. 

The remission rate (complete response [CR]/CR with partial count recovery [CRi]) at the RP2D was 41% (CR, 35%), with a median overall survival (OS) of 8.8 months. In a second study, 25 newly diagnosed patients over the age of 60 were given uproleselan at the RP2D level, as well as cytarabine and idarubicin (7 + 3). The CR/CRi rate was 72% (CR, 52%), and the median OS was 12.6 months in these frontline patients. Low incidences of oral mucositis were related to the use of uproleselan. E-selectin ligand expression on leukemic blasts was greater in relapsed versus primary refractory patients with AML, as well as newly diagnosed older patients with high-risk cytogenetics and secondary AML. E-selectin expression of more than 10% in the R/R cohort was linked with a higher response rate and better survival.

Uproleselan was well tolerated in combination with chemotherapy, with high remission rates, low induction mortality, and low rates of mucositis, giving a solid basis for phase 3 randomized confirmatory investigations.