Promising Early Results From UM171-Expanded Cord-Blood Transplant

By Will Boggs MD

December 10, 2019

NEW YORK (Reuters Health) - Preliminary results suggest that hematopoietic-stem-cell transplantation (HSCT) using UM171-expanded cord blood is feasible and safe in patients with hematological malignancy.

The use of cord blood for transplantation has declined rapidly over the past decade because of its low cell dose, which has been associated with delayed neutrophil engraftment, graft failure, transplant-related mortality and high costs.

Ex vivo hematopoietic-stem-cell expansion of cord blood might circumvent the cell dose issue without altering its potent antitumor effect, low risk of virus transmission, and low incidence of chronic graft-versus-host disease (GVHD).

In a preclinical study, the small molecule UM171 expanded cord-blood hematopoietic stem cells, thereby enhancing multilineage human blood-cell reconstitution in immunocompromised mice.

Dr. Sandra Cohen from Maisonneuve-Rosemont Hospital, in Montreal, Canada, and colleagues investigated the safety and feasibility of single UM171-expanded cord-blood transplantation in an open-label phase 1-2 study of 27 patients with hematological malignancies who did not have a suitable HLA-matched donor.

Only one cord-blood unit did not meet release criteria because of poor expansion; the other 26 units were successfully expanded without technical hurdles.

All patients had neutrophil recovery, with a median time to engraftment of 9.5 days to 100 neutrophils/uL and 18 days to 500 neutrophils/uL. Median time to platelet recovery was 42 days, the researchers report in The Lancet Haematology, online November 5.

The minimal post-thaw CD34-positive cell dose that, when expanded, achieved prompt engraftment was 52,000 cells/kg. After the seven-day UM171 expansion, the median net CD34-positive cell dose was 28 times higher than that of the thawed cord-blood cell dose and 35 times higher than the number of cells placed into culture.

No patient developed late graft failure.

At one year, the cumulative incidence of chronic GVHD was 17%, and no patients had moderate to severe chronic GVHD. Systemic immunosuppressive therapy had been discontinued in 85% of patients.

The one-year incidence of transplant-related mortality was 5% and the incidence of relapse was 21%. Overall survival was 90%, progression-free survival was 74%, GVHD-free and relapse-free survival was 64%, and chronic GVHD-free relapse-free survival was 74%.

"The findings of this study highlight potential benefits of UM171 transplants with regard to severe acute GVHD and treatment related mortality, while preserving the low incidence of moderate to severe chronic GVHD and relapse associated with unexpanded cord blood transplants," the researchers conclude. "Dedicated phase 2 studies for niche indications (e.g., high-risk diseases) and randomized phase 3 trials will be required to adequately compare UM171-expanded cord blood with standards of care."

"On the basis of these findings, a randomized trial comparing the outcomes of expanded umbilical cord blood and mismatched related donor transplantation would be beneficial, although challenging to implement," writes Dr. Mary Eapen of the Medical College of Wisconsin, in Milwaukee, in a linked editorial. "Research assessing non-traditional outcomes such as costs (e.g., out-of-pocket expenses for the patient where applicable) and health-related quality of life are also required."

"The advantages of umbilical cord blood transplantation include the ability to select units that are HLA-matched or mismatched at one HLA-locus to the recipient; transplantation overcomes the cell dose barrier via one or more of the several strategies available; the cost of acquisition of the unit and its expansion is comparable to that of acquisition of a graft from an adult unrelated or mismatched related donor; and such transplantation improves immune reconstitution," she said.

Dr. Sofia Berglund of Karolinska Institutet and Karolinska University Hospital Solna, in Stockholm, who has researched various aspects of umbilical-cord-blood transplant (UCBT), told Reuters Health by email, "The method here reported is interesting, and continues a tradition in UCBT of trying to increase the number of stem cells and their engraftment capability to extend the applicability of UCBT to more patients than is at present possible. As UCBT has several attractive features, including the low risk of severe GVHD, this is worth further consideration."

"This is a rather labor-intensive method, and would require a GMP-classified lab with the capability to perform the culture," she said. "I do not know what the cost of clinical grade UM171 would be, but I would guess that it would be rather high. The usefulness in clinical practice of the findings presented is limited to a certain extent by the costliness and the highly specialized laboratory work required, and also by the increasing publication of studies indicating that good results can be obtained with haplo-identical SCT."

"I would personally like to see larger studies before I would change the standard practice from what is used today with regard to alternative donor grafts." Dr. Berglund said. "I have not worked with cord-blood transplantation for a while, as Swedish transplantation centers to a large extent have stopped performing UCBTs in favor of haplo-identical adult donor transplantation."

The study did not have commercial funding. Two of the 28 authors are co-authors of a patent related to this technology, and they and three other authors are officers and/or employees of ExCellThera, which owns an exclusive license to use UM171 for hematopoietic-stem-cell expansion. Three other authors have various relationships with ExCellThera and will receive royalties from the sales of UM171.

Dr. Cohen did not respond to a request for comments.

SOURCE: and The Lancet Haematology, online November 5, 2019.