Uproleselan Added to Cladribine Plus Low-Dose Cytarabine (LDAC) In Patients with Treated Secondary Acute Myeloid Leukemia (TS-AML)

Background

• Treated secondary acute myeloid leukemia AML (TS-AML) that arises after prior treatment of MDS with hypomethylating agents (HMAs) is associated with very poor prognosis (complete remission [CR] rates, 15%-30%; median overall survival [OS], 6-8 months).
• E-selectin ligand is highly expressed on AML blasts in the leukemic microenvironment, and it may be a marker of cell survival and resistance to chemotherapy.
• Exposure of leukemic blasts to HMAs has been shown to increase their expression of the E-selectin ligand.
• Uproleselan is an E-selectin antagonist that overcomes resistance to chemotherapy in AML.
• We studied the combination of low-intensity chemotherapy with cladribine plus LDAC (CLAD/LDAC) with uproleselan to overcome local and microenvironmental resistance and improve outcomes in this difficult patient subset.

Methods

• This is Phase Ib/II clinical trial (NCT04848974) to evaluate the safety, tolerability, and explore the efficacy of Uproleselan added to Cladribine and LDAC.
• A 3+3 dose-escalation approach was implemented to evaluate 2 different dose levels for Cladribine (CLAD)+ LDAC; each 4-week cycle consists of Uproleselan (at a fixed dose of 800mg intravenously [IV]) added to IV CLAD 5 days (3.75mg/m2 and 5mg/m2; level -1 and 1, respectively) and subcutaneous LDAC twice daily 10 days (15mg, and 20mg; level -1 and 1, respectively) during induction; consolidation was similar except it was with 3-days of CLAD, for up to 6 cycles.
• Pts aged ≥18 years with a diagnosis of TS-AML with adequate organ function, who have not received therapy for their AML were enrolled. TS-AML is defined as AML arising from a previously treated myeloid neoplasm.
• Presence of the E-selectin ligand was assessed using Flow Cytometry (FC).

Results

• Ten patients have been treated, with 9 patients currently evaluable (gender, 6 men [67%]; median age, 68 years [range, 58-80 years]). At the start of therapy, the median concentration of bone marrow blasts was 33% (range, 1%-78%), median white blood count was 2.2 × 103/µL (range, 0.6-20.1 × 103/µL), median platelet count was 18 × 103/µL (4-305 × 103/µL), and median creatinine level was 0.98 mg/dL (range, 0.67-1.52 mg/dL).
• Patients had received a median of 1 treatment (range, 1-2 treatments) prior to AML transformation.

• Prior diagnoses were: therapy-related Myelodysplastic Syndrome (t-MDS), Chronic Myelomonocytic Leukemia (CMML), MDS and MDS/MPN in 3 (33%), 3 (33%), 2 (22%) and 1 (11%) respectively; all had received HMA, 5 (56%) additionally had Ven and 3 (33%) had stem cell transplantation (SCT) prior to enrolling.
• All pts had unfavorable features by ELN 2017.
• The most frequent mutations were: SXL1, TP53 and TET2 in 4 pts each (44%), SRSF2 and NRAS in 3 patients each (33%) and SETBP1, RUNX1 and EZH2 in 2 patients each (22%). 6 pts were evaluable for E-selectin ligand expression; the median expression was 59% (42%-95%) and median MFI was 20.5 (13-262).
• The most common SAEs were ≥ grade 3 neutropenic fever (70%), (including 2 grade 5 events), grade 3 bleeding (10%), and grade 2 thrombosis (5%)
• There were no dose-limiting toxicities observed on dose levels -1 or 1.
• Two pts treated on dose level -1 die during the study follow-up due to sepsis within the first 4-weeks during induction.
• Median time to 0.5x109/L neutrophil and 50x109/L platelets recovery was 29 (17-39) and 38 (33-48) days respectively.
• The median follow-up is 4+ months. 8 pts were evaluable for response at the time of analysis. The ORR was 62% (5/8), including 2 (25%) PR, 1 (13%) CRi, 1 (13%) CRp and 1 (13%) MLFS.
• There was a reduction in BM blasts in 6 pts (75%). 5 pts were taken off protocol due to progression, 2 for death, 1 for allogeneic SCT and 1 continued onto maintenance in remission.
• The one pt who achieved negative MRD, underwent SCT and is still alive. Median OS and EFS were 4.7 and 1.3 months respectively; 4-month RFS (CRi, CRp, and MLFS) was 67%.
• The median cycles received was 1 (1-3), median cycles at which the best response was achieved was 1 (1-2).
• The 4-month OS were 100% and 60% among responders vs. non-responders, respectively (p=0.27), and the 4-month EFS were 50% and 0% respectively (p=0.01). The ORR was 40% (2/5) (p=0.85) and 33% (1/3) (p=0.85) among pts who had prior Ven exposure or prior SCT, respectively.

Conclusions

• The combination of Cladribine + LDAC with Uproleselan was overall well tolerated with few treatment-related AEs.
• The combination produced an ORR of 62% in a high-risk, refractory population whose prognosis is very dismal.
• The relationship of E-selectin ligand expression, response to treatment, and outcomes is being analyzed.

Huante EA, Kantarjian H, Chien KS, et al. 1448 Uproleselan added to cladribine plus low-dose cytarabine (LDAC) in patients with treated secondary acute myeloid leukemia (TS-AML).Abstract presented at: 2022 American Society of Hematology, December 10, 2022; New Orleans, LA. Abstract 1448. Accessed December 14, 2022. https://ash.confex.com/ash/2022/webprogram/Paper169670.html