UM171 Cord Blood Transplantation for TP53 Mutated and EVI1 Rearranged Myelodysplasia/Acute Myeloid Leukemia

Background: UM171 is a molecular glue (Fares et al, Science 2014) developed by our group which expands balanced-hematopoietic stem cells (B-HSCs) while enhancing their lymphoid differentiation potential (Dumont-Lagace et al, TCT, 2021) and generating cells in the graft with direct activity against acute myeloid leukemia (AML) blasts through a novel mechanism of action that involves degradation of CoREST1 (Chagraoui et al, Cell Stem Cell, 2012) and nuclear cMYC (Chagraoui et al, Blood 2024). Cord blood transplantation (CBT) has several advantages including lower risk of relapse in high risk hematologic diseases (Milano et al, NEJM 2016, Horgan et al, Blood Adv 2023). However CBT is hampered by high non relapse mortality (NRM) due to low cell dose and selection of poorly HLA matched cords. From 2016 to 2018, 22 patients with hematologic malignancies who lacked a donor were transplanted on a phase I-II clinical trial with a single UM171-expanded CB (Cohen S et al, Lancet Haematol 2019). The goal was to accelerate engraftment while selecting smaller, better HLA matched CBs to decrease NRM. Results demonstrated prompt neutrophil engraftment and lower NRM compared to controls (Cohen S et al, Blood Adv., 2023). Between 2019 and 2022, 30 additional patients with high and very high-risk myelodysplasia/acute leukemia underwent a single UM171 CBT on a phase II trial. Amongst these 52 patients on these 2 trials, there were patients with very high-risk myelodysplasia (MDS) or AML, defined as TP53 mutation/deletion or EVI1 rearrangement. Expected long term outcomes after a conventional allogeneic stem cell transplant for these diseases are dismal to the point that some transplant centers now exclude these patients from transplantation. The aim of this current analysis is to examine the outcome of patients with poor outcome TP53 or EVI1 anomalies who were transplanted with a single UM171 CBT during the course of these 2 clinical trials.

Methods: Data for this analysis were drawn from both trials listed above. Eligibility criteria for this analysis included patients with MDS or AML with TP53 mutation/deletion or EVI1 rearrangement who were transplanted with a single UM171 CB. Examined clinical outcomes included NRM, relapse, progression-free survival (PFS) and overall survival (OS) at 2- and 3-years post-transplant. PFS and OS were estimated by Kaplan-Meir method; relapse and NRM were calculated using cumulative incidence estimates.

Results: A total of 10 patients met inclusion criteria, 1 from the initial phase I-II trial and 9 from the phase II trial. Three patients had EVI1 rearrangements and 7 patients had TP53 mutation/deletion. One patient had MDS and 9 had AML. Patient characteristics included 9 men and 1 woman with a median age and weight of 50 years and 83kg, respectively. Median HCT-CI was 1(0-4). One patient (10%) had previously failed an allogeneic transplant. Conditioning regimen was myeloablative or reduced intensity. Median follow-up is 35 months. Three patients died from NRM (NRM was 11% for the entire group of 52 patients from both clinical trials). Cumulative incidence of relapse was 10% at 2 years and 22% at 3 years. OS and PFS at 2 years were both 60% (95%CI 36-99%) and at 3 years 48% (95%CI 25-94%).

Conclusion: We previously showed that UM171 expanded CBT permits the use of CB with a low NRM of 11% and that these grafts are highly effective in high/very high-risk malignancies. Subset analyses presented herein suggest that this technology has the potential to overcome the negative prognosis associated with TP53/EVI1 MDS/AML with OS and relapse at 24 months of 60% and 10%, respectively. These results compare quite favorably to previous publications with OS usually being reported at ≈20% at 2 years. The main limitation of our study is the low number of patients, and thus more patients are needed to confirm these results.