Final Results of a Phase II Study of Uproleselan Combined with Cladribine and Low-Dose Cytarabine for Patients with Treated Secondary Acute Myeloid Leukemia (ts-AML)

Introduction: Patients with newly diagnosed AML arising from a previously treated myelodysplastic syndrome (treated-secondary AML, ts-AML) have particularly dismal outcomes, with an anticipated overall survival of less than 6 months. E-selectin (E-sel) is expressed throughout the bone marrow microenvironment, promotes myeloid blast sequestration and chemotherapy resistance. Uproleselan is a novel E-sel antagonist which disrupts cell survival pathway activation and increases susceptibility to chemotherapy. Studies have demonstrated that exposure of AML blasts to hypomethylating agents (HMAs) increases expression of E-sel ligand, providing the rationale for the addition of uproleselan to chemotherapy in this population. Here we report the final results of a prospective phase Ib/II study of uproleselan plus cladribine and low-dose cytarabine (LDAC) in patients with ts-AML (NCT04848974).

Methods: Patients with ts-AML arising from myelodysplastic syndrome (MDS) previously treated with HMA were enrolled. Induction was uproleselan 800 mg IV D1, followed by 800 mg Q12 hours D2-12, cladribine 5 mg/m² IV Days 1-5, LDAC 20 mg subcutaneous BID Days 1-10. Uproleselan was dosed once daily D1-12 and cladribine D1-3 during consolidation with LDAC as above. Cycles were 4 weeks long and patients could receive up to 6 cycles of therapy. E-sel ligand expression was assessed at baseline and soluble E-sel levels were evaluated prior to and on D1,5,10,12 of induction.

Results: A total of 37 patients were treated on study. The median age was 74 (range, 58-86) and 70% were male. Twenty-seven patients (73%) had prior MDS, 8 (22%) CMML, and 2 patients (5%) had MDS/MPN. Patients received a median of 1 line of therapy (range, 1-5) for their AHD, including HMA (100%), venetoclax (41%), and allogeneic SCT (16%). Complex karyotype was present in 12 patients (32%), diploid karyotype in 8 patients (22%), and 3 patients (8%) had -5/5q- and/or -7/7q-. The most common genetic mutations were ASXL1 in 13 patients (35%), TP53 in 12 (32%), TET2 in 11 (30%), SRSF2 in 10 (27%), RUNX1 in 8 (22%) and NRAS in 8 (22%). According to ELN 2022 criteria, 31 patients (84%) had adverse-risk and the remaining 6 (16%) had intermediate-risk disease.

Overall response rate (ORR) was 38% (14/37), including CR in 4 patients (11%), CRi in 6 (16%), and MLFS in 4 (11%). ORR in patients with 1 prior therapy was 42% (8/19). ORR in patients with prior venetoclax exposure was 60% (9/15). Among the 12 responders evaluated for MRD, 5 (42%) achieved MRD-negativity. Patients received a median of 2 cycles of therapy (range, 1-5). Median number of cycles to best response was 1 (range, 1-2). After achieving remission, 3 patients (21%) proceeded to allogeneic SCT. After a median follow up of 14.4 months, the median RFS was 2.9 months and OS was 4.2 months. Among the 3 patients who underwent SCT, the 1-year OS was 65% and the median OS has not been reached.

Seventeen patients were evaluable for E-sel ligand expression. Median E-sel ligand expression was 58% (range, 20.9%-98.9%) overall. Among responders, median expression was 72% compared to 45% in those who did not respond (p=0.097). Median E-sel plasma concentration decreased from 26.1 ng/mL to 9.3 ng/mL after treatment with uproleselan (p<0.01).

The most frequent grade 3 or higher adverse events were infection (46%), febrile neutropenia (8%), and hemorrhage (8%). Four patients (11%) died during induction due to pneumonia (n=2), intracranial hemorrhage (n=1), and sepsis (n=1).

Conclusion: The addition of uproleselan to cladribine and LDAC was found to be safe and tolerable in patients with ts-AML. Response rates and MRD negativity compare favorably to what is anticipated in this population, particularly in those who were less heavily treated for their MDS. There was no additional toxicity with the addition of uproleselan, and a trend toward better response among patients with higher E-sel ligand expression was observed. Randomized trials evaluating the role of uproleselan in patients with adverse-risk AML are ongoing.