Novel Molecule Opens Door to Wider Use of Cord Blood HSCT

Pam Harrison

January 15, 2020

A novel molecule has opened the door to wider use of banked umbilical cord blood as a source of stem cells for patients who need a hematopoietic stem-cell transplant (HSCT), a pilot study suggests.

The molecule, dubbed UM171, was discovered and synthesized by researchers at the University of Montreal, in Quebec, Canada, and has now been licensed to ExCellThera.

It has been used to expand umbilical cord blood so that one unit can provide enough stem cells to renew the bone marrow in a timely manner and facilitate engraftment as quickly as standard bone marrow transplant.

Results from a pilot study in 22 patients were published online November 5, 2019, in the Lancet Haematology.

"[U]se of cord blood for transplantation has rapidly declined in the past decade because of its low cell dose, which has been associated with delayed neutrophil engraftment, graft failure, frequent severe infections, transplant-related mortality, prolonged hospital stays, and high cost," the authors explain.

"Moreover," they add, "only 5% of cord blood units stored in public banks offer an adequate cell dose for a patient weighing 70 kg, forcing clinicians to select larger, poorly HLA-matched cord blood units of two cord bloods…leaving many unused units in cord blood banks."

Expands Volume of Cells in Single Unit

The new molecule expands the number of cells in a single unit of cord blood, explained lead author Sandra Cohen, MD, Maisonneuve-Rosemont Hospital in Montreal. It multiplied the CD34 cell content of the cord unit on average 35 times its baseline count, she noted in an interview with Medscape Medical News. CD34 cells are a marker of stem cells in cord blood, she explained.

"So now, instead of having access to only 5% of the cords in a bank, you have access to 50% with this expansion technique, because even the smaller cords are now acceptable in size to transplant in adults," Cohen observed.

UM171 is a hematopoetic stem-cell self-renewal agonist that not only increases the number of stem cells in cord blood but also changes the composition of the graft by multiplying the number of dendritic cells 600-fold and the number of mastocytes 8000-fold. Both types of cells have a vital role in the immune system, the authors note.

Use of UM171 would allow considerably more patients who require HSCT for the treatment of hematologic malignancies to receive a cord blood transplant. This source of stem cells has some inherent advantages, including potent antitumor effects, a low risk for virus transmission, and a low incidence of chronic graft-vs-host disease (GVHD), the authors point out. This latter point is particularly important, inasmuch as chronic GVHD is the main determinant of long-term morbidity and mortality in HSCT recipients, they add.

Clinical Trial Details

The results now being reported come from a single-arm, open-label, phase 1-2 safety and feasibility study that was carried out in two parts at two hospitals in Canada.

"In part 1, patients received two cord blood units (one expanded by UM171 and one unmanipulated cord blood) until UM171-expanded cord blood demonstrated engraftment," the researchers report.

Once engraftment of the UM171-expanded cord blood unit was confirmed, patients entered into part 2 of the study, essentially a dose deescalation analysis to determine the minimal cord blood unit cell dose that would facilitate prompt engraftment of a single cord unit transplant, they continue.

Twenty-seven patients were initially enrolled. Of those, 22 subsequently received a single UM171-expanded cord blood transplant in part 2 of the study.

Following a myeloablative conditioning regimen of varying intensity depending on the patients' age, a single cord unit was exposed to UM171 expansion for 7 days, following which UM171-expanded CD34 cells were infused in each of the 22 patients.

The primary endpoint of part 2 of the study was the feasibility of using UM171 to expand cell dose in a single cord blood unit and time to neutrophil and platelet engraftment of UM171-expanded cord blood.

The investigators also sought to determine the minimal cell dose in preexpansion cord blood units that would facilitate prompt engraftment.

Study Results

At a median follow-up of 18 months, the team had successfully expanded 96% of cord blood units with UM171 in both parts of the study.

"The cumulative incidence of neutrophil recovery was 100% with a median time to engraftment of 100 neutrophils/uL of 9.5 days...and a median time to 500 neutrophils/uL of 18 days," the investigators report.

Cohen explained that neutrophil recovery is usually defined as achieving 500 neutrophils/uL.

Even when patients in the study achieved only 100 neutrophils/uL, "that was when they seemed to have a clinical benefit," she observed.

The median time to platelet recovery was 42 days, the researchers note.

"No patients developed late graft failure," Cohen and colleagues point out, and only three patients had not achieved target levels of platelet or neutrophil counts or hemoglobin levels at 6 and at 12 months.

Almost three quarters of patients developed grade 3 febrile neutropenia following the transplant procedure; 41% developed bacteremia, and one patient died due to treatment-related diffuse alveolar hemorrhage.

GVHD at 1 Year

"At 1 year, the cumulative incidence of grade 2–4 acute GVHD was 64% and the cumulative incidence of grade 3–4 acute GVHD was 10%," the researchers report.

No patient developed steroid-refractory acute GVHD, they add.

Importantly, the cumulative incidence of chronic GVHD was low, at 17% at 1 year, they comment, and no patient in part 2 of the study developed moderate to severe chronic GVHD.

Some 85% of patients in the study had discontinued immunosuppressive drug therapy at 1 year.

At 12 months, 90% of patients were still alive, and 74% were free of disease progression.

At 13 months, "not a single patient needed immunosuppression treatment, whereas with normal transplants, 50% of patients require such treatment at that point," commented UM171 co-discoverer Guy Sauvageau, MD, PhD, University of Montreal, in a statement.

"No other biotechnology procedure has produced these kinds of results," he added.

Chemist Anne Marinier, PhD, also of the University of Montreal, was instrumental in synthesizing UM171 and is considered Sauvageau's co-discoverer of the molecule.

Advantages of Umbilical Cord as a Source of Stem Cell

One of the advantages of the use of umbilical cord as a source of stem cells for transplant is the ability to select units that are HLA-matched or mismatched at one HLA locus to the recipient, comments Mary Eapen, MD, Medical College of Wisconsin in Milwaukee, in an accompanying editorial.

Thus, "the true value of an expanded cord blood unit might be enhanced by focusing on the minimization of donor-recipient HLA mismatching to one HLA-locus or a fully matched unit which is the approach used when selecting an adult unrelated donor," she writes.

Eapen notes that the cost of acquiring the cord blood unit and its expansion is comparable to that of acquiring a graft from an unrelated adult donor or mismatched related donor.

She suggests that in the future, nontraditional outcomes, such as costs (eg, out-of-pocket expenses for the patient) and health-related quality of life should be assessed.

Cohen argues that instead considering the immediate costs of using expanded cord blood units vs the costs of standard bone marrow transplant, long-term costs should be taken into consideration.

"With the cord transplant, there are more problems within the first year, so cord blood costs more in the first year, but once you get over that first year, it is probably less costly because there are fewer complications than with an adult donor," she said.

"Cord blood [transplant] has half the risk of chronic GVHD as someone who has an adult donor [bone marrow] transplant, so if you get a stem cell transplant from your brother or sister, your risk of GVHD is double that of a cord blood transplant," Cohen emphasized.

"So you have to look at whether a person is back to work in 5 years, if they are still taking their immunosuppressive medication at that time, and what their quality of life is, which is why I say that if you want to compare costs, you have to look at the long-term costs of each procedure," she added.

The study was funded by the Canadian Institutes of Health Research, Canadian Cancer Society, and the Stem Cell Network. UM171 has been licensed to ExCellThera. Cohen is a consultant to ExCellThera. Eapen has disclosed no relevant financial relationships.

Lancet Haematol. Published online November 5, 2019. Abstract, Editorial

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