According to a report published in Blood, addition of the novel E-selectin inhibitor uproleselan to both an intensive chemotherapy-based salvage regimen and a standard intensive frontline regimen was safe, well tolerated, and active in patients with acute myeloid leukemia (AML).
Expression of E-selectin in the bone marrow microenvironment contributes to drug resistance and poor outcomes in patients with AML. In this multicenter, open-label phase 1/2 study (ClinicalTrials.gov Identifier: NCT02306291) the investigators evaluated the safety, tolerability, and anti-leukemic activity of uproleselan with chemotherapy among patients with relapsed/refractory (R/R) AML and among patients with newly diagnosed AML who were ≥60 years of age.
The primary endpoint was the frequency, severity, and relatedness of treatment emergent adverse events (TEAEs). The efficacy assessment included remission rate (rates of complete response [CR] and CR with incomplete count recovery [CRi]) and overall survival (OS).
The R/R AML cohort comprised 66 patients, with a median age of 59 years (range, 26-84). The first 19 patients were treated with mitoxantrone, etoposide, cytarabine (MEC) plus uproleselan (dose ranging from 5-20 mg/kg: 5 mg/kg, n=6; 10 mg/kg, n=7; and 20 mg/kg, n=6). No dose-limiting toxicities were observed and the recommended phase 2 dose (RP2D) was 10 mg/kg twice daily.
In the expansion phase of the study, an additional 47 patients with R/R AML were treated with MEC plus uproleselan at the RP2D. The remission rate was 41% with a CR rate of 35% and the median OS was 8.8 months.
In a separate newly diagnosed AML cohort, 25 patients, with a median age of 67 years (range, 60-79), received cytarabine and idarubicin (7+3) plus uproleselan at the RP2D. The remission rate was 72%, with a CR rate of 52%, and the median OS was 12.6 months.
The investigators also demonstrated that high E-selectin ligand expression levels (≥10%) on leukemic blasts were detected in patients with relapsed AML (66%) and those with high-risk cytogenetics (67%) in the R/R AML cohort and in patients with secondary AML (73%) and those with adverse cytogenetics (40%) in the newly diagnosed cohort.
None of the 66 patients with R/R AML discontinued treatment due to an AE. Most of the TEAEs observed were attributed to the chemotherapy, including grade 4 myelosuppression (thrombocytopenia, neutropenia, anemia). Uproleselan was associated with low rates of oral mucositis (grade 3; 2% of R/R AML cohort). Grade 3 or 4 TEAEs related to uproleselan with an incidence ≥10% were febrile neutropenia (17% and 12%) and thrombocytopenia (11% and 12%) among the R/R AML cohort and the newly diagnosed AML cohort, respectively.
“Taken together, these data suggest that E-selectin ligand expression contributes to chemotherapy resistance, which may be overcome with uproleselan and could be an important predictor of response and survival,” the authors wrote. “The results from this phase 1/2 clinical trial support the biological and clinical rationale for targeting E-selectin and support the need for a confirmatory randomized controlled trial to further evaluate the benefits of adding uproleselan to salvage chemotherapy regimens in R/R patients and anthracycline-based treatments in older patients with AML. Randomized trials are ongoing in both populations.”
Disclosure: This research was supported by GlycoMimetics Inc.. Please see the original reference for a full list of disclosures.
Reference
DeAngelo DJ, Jonas BA, Liesveld JL, et al. Phase 1/2 study of uproleselan added to chemotherapy in patients with relapsed or refractory acute myeloid leukemia. Blood. 2021; blood.2021010721. doi: https://doi.org/10.1182/blood.2021010721