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Hematopoietic stem cell transplantation using single UM171-expanded cord blood: a single-arm, phase 1–2 safety and feasibility study

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Background

Benefits of cord blood transplantation include low rates of relapse and chronic graft-versus-host
disease (GVHD). However, the use of cord blood is rapidly declining because of the
high incidence of infections, severe acute GVHD, and transplant-related mortality.
UM171, a haematopoietic stem cell self-renewal agonist, has been shown to expand cord
blood stem cells and enhance multilineage blood cell reconstitution in mice. We aimed
to investigate the safety and feasibility of single UM171-expanded cord blood transplantation
in patients with haematological malignancies who do not have a suitable HLA-matched
donor.

Methods

This single-arm, open-label, phase 1–2 safety and feasibility study was done at two
hospitals in Canada. The study had two parts. In part 1, patients received two cord
blood units (one expanded with UM171 and one unmanipulated cord blood) until UM171-expanded
cord blood demonstrated engraftment. Once engraftment was documented we initiated
part 2, reported here, in which patients received a single UM171-expanded cord blood
unit with a dose de-escalation design to determine the minimal cord blood unit cell
dose that achieved prompt engraftment. Eligible patients were aged 3–64 years, weighed
12 kg or more, had a haematological malignancy with an indication for allogeneic hematopoietic
stem cell transplant and did not have a suitable HLA-matched donor, and a had a Karnofsky
performance status score of 70% or more. Five clinical sites were planned to participate
in the study; however, only two study sites opened, both of which only treated adult
patients, thus no paediatric patients (aged 2, and 12 Gy total body irradiation) and patients aged older than 50 years and those
with comorbidities received a less myeloablative conditioning regimen (cyclophosphamide
50 mg/kg, thiotepa 10 mg/kg, fludarabine 150 mg/m
2, and 4 Gy total body irradiation). Patients were infused with the 7-day UM171-expanded
CD34-positive cells and the lymphocyte-containing CD34-negative fraction. The primary
endpoints were feasibility of UM171 expansion, safety of the transplant, kinetics
of hematopoietic reconstitution (time to neutrophil and platelet engraftment) of UM171-expanded
cord blood, and minimal pre-expansion cord blood unit cell dose that achieved prompt
engraftment. We analysed feasibility in all enrolled patients and all other primary
outcomes were analysed per protocol, in all patients who received single UM171-expanded
cord blood transplantation. This trial has been completed and was registered with

ClinicalTrials.gov,
NCT02668315.

Findings

Between Feb 17, 2016, and Nov 11, 2018, we enrolled 27 patients, four of whom received
two cord blood units for safety purposes in part 1 of the study. 23 patients were
subsequently enrolled in part 2 to receive a single UM171-expanded cord blood transplant
and 22 patients received a single UM171-expanded cord blood transplantation. At data
cutoff (Dec 31, 2018), median follow-up was 18 months (IQR 12–22). The minimal cord
blood unit cell dose at thaw that achieved prompt engraftment as a single cord transplant
after UM171 expansion was 0·52 × 10
5 CD34-positive cells. We successfully expanded 26 (96%) of 27 cord blood units with
UM171. Among the 22 patients who received single UM171-expanded cord blood transplantation,
median time to engraftment of 100 neutrophils per μL was 9·5 days (IQR 8–12), median
time to engraftment of 500 neutrophils per μL was 18 days (12·5–20·0), and no graft
failure occurred. Median time to platelet recovery was 42 days (IQR 35–47). The most
common non-haematological adverse events were grade 3 febrile neutropenia (16 [73%]
of 22 patients) and bacteraemia (nine [41%]). No unexpected adverse events were observed.
One (5%) of 22 patients died due to treatment-related diffuse alveolar haemorrhage.

Interpretation

Our preliminary findings suggest that UM171 cord blood stem cell expansion is feasible,
safe, and allows for the use of small single cords without compromising engraftment.
UM171-expanded cord blood might have the potential to overcome the disadvantages of
other cord blood transplants while maintaining the benefits of low risk of chronic
GVHD and relapse, and warrants further investigation in randomised trials.

Funding

Canadian Institutes of Health Research, Canadian Cancer Society and Stem Cell Network.

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