Infusion of UM171-Expanded Cord Blood Led to Excellent Survival in Patients with High-Risk Leukemias: Results from Two Independent Phase II Studies

Background: Cord blood transplant (CBT) recipients experience delayed hematopoietic recovery and an increased risk of non-relapse mortality (NRM). UM171 is a small molecule that expands hematopoietic stem and progenitor cells (HSPC). An initial phase I-II clinical trial of a single UM171-expanded CBT was associated with low NRM and excellent long-term outcomes. (S Cohen et al. Lancet Haematology 2020). With the primary goal of generating increased numbers of HSPC to supplement a conventional single cord blood (CB) graft, we tested the same approach exclusively in high and very high-risk patients with acute leukemias/myelodysplastic syndromes (MDS).Methods: Between 2019 and 2022, two single independent prospective phase II studies were conducted in Montreal, at the Maisonneuve Rosemont Hospital and in Seattle, at the Fred Hutchinson Cancer Center. Primary objectives were safety/NRM and progression free survival at 2-years post-transplant. Only patients with high and very-high risk acute myeloid leukemia (AML), acute lymphoid leukemia (ALL) and MDS were eligible. Patients were required to have adequate organ function and comorbidity index as defined by the transplant center. Patients received a single UM171 7-day expanded and cryopreserved CB after either a myeloablative or mid-intensity conditioning regimen. All patients received tacrolimus and mycophenolate mofetil for GVHD prophylaxis. Results: A total of 52 patients were enrolled (31 in Montreal and 21 in Seattle) with 2 patients not receiving the UM171 expanded product and therefore removed from the final analysis. Patient’s characteristics are shown in Table 1. The median age was 44 years (range 19-66) and weight 78 kg (range, 44-145). Twenty-eight patients (54%) were either in a no complete response (CR) status or in ≥CR2, ten (19%) were p53+ and 17 (33%) were second or third transplants. Forty patients (77%) received a 5/8 HLA-matched CB unit and the median of CD34+ cells infused was 4.7 10⁶/Kg (0.9-7.5). All patients engrafted (ANC >500 10^⁹/L for 2 consecutive days) at a median of 17 days (range, 9-39 days). The median time to platelet recovery (>20 x 10^⁹/L) was 37 days (range 24–116). With a median follow-up of 24 months (range 0.7 – 39), the probability of 2-year overall survival (OS) and progression-free survival (PFS) was 67% (95% CI, 54-82) and 63% (95% CI, 50-79). OS for second/third transplants and p53+ patients was 64% (95% CI, 43-96) and 40 (95% CI, 19-86), PFS was 51 % (95% CI, 29-87) and 40 (95% CI, 19-86), respectively. At 2 years, the cumulative incidence of NRM was 19% (95% CI, 8-31) while the incidence of relapse was 18% (95% CI, 6-29). The incidence of grade II-IV and III-IV acute GVHD was 69% (95% CI, 56−82%) and 16% (95% CI, 6−27%). The rate of moderate/severe chronic GVHD was 7% (95% CI,1−15%) and translated in an incidence of a chronic-relapse-free-survival of 55% (95% CI, 42−72%). Of note, Kaplan-Meier analysis of all clinical outcomes showed no difference for patients treated in Montreal and Seattle, and results were similar for both centers (Figure 1). Conclusions: The results of 2 independent Phase II clinical studies demonstrated that infusion of a UM171 single CBT led to excellent clinical outcomes in patients with high and very-high risk malignancies including patients with p53+ mutation. We also observed encouraging results for patients undergoing second/third transplants (33% of the entire cohort). Clinical outcomes were similar between the two Transplant Centers. Based on these positive results, a multicenter randomized clinical trial is currently in the planning stage.