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)

• Published in: Blood 2024-11, Vol.144 (Supplement 1), p.4262-4262
• Main Authors: Rausch, Caitlin R, Almanza-Huante, Emmanuel, Jen, Wei-Ying, Montalban-Bravo, Guillermo, Ravandi, Farhad, Chien, Kelly S., Short, Nicholas J., Daver, Naval, DiNardo, Courtney D., Maiti, Abhishek, Jabbour, Joseph E., Issa, Ghayas C., Garcia-Manero, Guillermo, Kantarjian, Hagop M., Kadia, Tapan M.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2024-203831

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