Long Term Follow up of UM171 Expanded Cord Blood Transplantation Patients Does Not Reveal Any Late Toxicity

Background: Cord blood (CB) transplantation (CBT) has several advantages compared with other graft sources including low rates of chronic graft-versus-host disease, improved donor availability, and lower risk of relapse in high risk leukemias. However, CBT has fallen into disfavor because of its low cell dose leading to higher risk of infections and non-relapse mortality (NRM). Furthermore, the need for large CBs leads to selection of poorly HLA matched CBs, further increasing NRM. UM171 is a small molecule that expands hematopoietic stem cells (HSC) while enhancing their lymphoid differentiation potential. 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 that indeed UM171 overcame slow neutrophil engraftment, increased T cell receptor repertoire diversity (Dumont-Lagace M et al, TCT 2021) and diminished NRM compared to controls (Cohen S et al, Blood Adv., 2023). Between 2019 and 2022, 30 patients with high and very high-risk myelodysplasia/acute leukemia underwent a single UM171 CBT on a phase II trial. As UM171 CBT includes graft manipulation there is always concern about potential long term complications associated with poor graft function or deficient immune reconstitution. The aim of this current analysis is to examine the long-term outcome of patients transplanted with a single UM171 CBT.

Methods: Data for this analysis were drawn from both trials listed above. Eligibility criteria included patients transplanted with a single UM171 CB and who engrafted with the UM171 CB. In addition, a minimum of 3 years from day of transplant to July 31, 2024 had to have elapsed in order to be able to analyze any late adverse events (AEs). Patients were followed on study until a maximum of 5 years post-transplant. Examined clinical outcomes included 2ary graft failure, relapse, ≥ grade 3 AEs between years 2-5 post transplant, CD4 counts at 2 years, late cytopenias, need for immunosuppressive therapy beyond 2 years, NRM, progression-free survival (PFS) and overall survival (OS).

Results: A total of 44 patients met inclusion criteria, 22 from the initial phase I-II trial and 22 from the phase II trial. Patient characteristics included 13 women and 31 men with a median age and weight of 48 years and 78kg, respectively. Twenty out of 44 CBs used were considered too small for use without expansion. Median HCT-CI was 2 (0-5). Eleven patients (25%) had previously failed an allogeneic transplant. Conditioning regimen was myeloablative or reduced intensity. Median follow-up is 60 months (range 36-60). There was no late graft failure. There were 12 relapses: 7 before 12 months, 2 between 12-24 months, and 5 between 24-36 months. NRM and progression at 5 years were 11% (95%CI 5-26%) and 32% (95%CI 21-49%), respectively. The last NRM occurred at 13 months post transplant. OS and PFS at 5 years were 61% (95%CI 47-76%) and 57% (95%CI 42-72%), respectively. At 24 months post-transplant, there were 31 patients alive without relapse. Amongst these 31 patients, ≥ grade 3 AEs after 24 months included: portal hypertension (liver disease present prior to transplant), EBV viremia, anxiety, cataracts, left ventricular systolic dysfunction, non-severe visceral shingles, autoimmune hemolytic anemia (resolved after short course of prednisone), increase in ALT (resolved spontaneously), pneumothorax, pneumonia and sinusitis. Median CD4 at 24 months was 512/µL (range 216-1279). Two out of 31 patients were taking a low dose of 1 immunosuppressant at 24 months. All patients at 36 months who were alive without relapse had a hemoglobin ≥ 110 g/L, platelets ≥ 110 x10⁹/L, neutrophils ≥ 2.5 x10⁹/L, and lymphocytes ≥1.3 x10⁹/L with one exception, a patient with portal hypertension and hypersplenism who had a platelet count of 27 with a normal bone marrow.

Conclusion: Long term follow-up of patients undergoing a single expanded UM171 CBT does not reveal any late toxicity and indeed there are few late AEs. There is no late cytopenia or graft failure and immune reconstitution is robust. In addition to the demonstrated efficacy of UM171 transplants in short term outcomes, these results confirm the long-term safety of UM171 expanded grafts, supporting its preferential effect on long-term HSCs.