UM171-expanded cord blood safe for certain adults with hematologic malignancies
Single UM171-expanded cord blood transplantation appeared safe and feasible among a small cohort of patients with hematologic malignancies who lacked suitable HLA-matched donors, according to results of a phase 1/phase 2 study published in The Lancet Haematology.
“We decided to conduct this trial for several reasons,” Sandra Cohen, MD, FRCP, researcher in the division of hematology at Maisonneuve-Rosemont Hospital in Montreal, told Healio. “Other experts have been working on hematopoietic stem cells for at least 2 decades and have tried to understand how these cells work. When [Guy Sauvageau, MD, PhD, FRCP, and Anne Marinier, PhD] at University of Montreal discovered UM171, they were looking for an application. Cord blood is a great source of hematopoietic stem cells because of the low risk for chronic graft-versus-host disease and lower likelihood of relapse, and it allows for HLA mismatches.”
However, cord blood is associated with several limitations, including a low cell number that can result in prolonged duration of neutropenia after transplant.
“Consequently, these limitations translate into high rates for infections and transplant-associated mortality,” Cohen told Healio. “We thought that if we could get rid of the disadvantages of cord blood, we would be left with many advantages.”
A preclinical study showed UM171 (ECT-001, ExCellThera), a hematopoietic stem cell self-renewal agonist, expanded cord blood stem cells for improved reconstitution of multilineage blood cells in mice.
In the first phase of the study, four patients received one unmanipulated cord blood unit and one UM171-expanded cord blood unit until engraftment as a safety measure.
For the phase 2 analysis, 22 patients (median age, 45 years; 64% men) received one UM171-expanded cord blood unit with a dose de-escalation design to determine minimal cord blood unit cell dose that achieved prompt engraftment.
All patients had a hematologic malignancy with an indication for allogeneic HSCT and no adequate HLA-matched donor, as well as a Karnofsky performance status score of at least 70%. Five patients (23%) had undergone an unsuccessful allogeneic transplant and five patients (23%) had refractory or relapsed acute leukemia or aggressive lymphoma. Median HSCT comorbidity index was 2 (interquartile range [IQR], 0-3).
Patients received a myeloablative conditioning regimen, reduced for patients aged older than 50 years and those with comorbidities, and underwent infusion with the 7-day UM171-expanded CD34-positive cells and the lymphocyte-containing CD34-negative fraction.
Median follow-up was 18 months (IQR, 12-22).
Researchers successful expanded 26 of 27 cord blood units in the first and second parts of the study.
Median time to engraftment of 100 neutrophils/µL was 9.5 days (IQR, 8-12) and median time to engraftment of 500 neutrophils/µL was 18 days (IQR, 12.5-20). No graft failure occurred.
Engraftment of 100 neutrophils/µL and of platelets with UM171-expanded cord blood occurred independent of CD34-positive cells dose and CD34-positive CD45RA-negative cell dose, according to the researchers.
Researchers observed a negative association between engraftment of 500 neutrophils/µL and CD34-positive cell dose (r = 0.4224; P = .05) and CD34-positive CD45RA-negative cell dose (r = 0.4861; P = .022).
Median time to platelet recovery was 42 days (IQR, 35-47).
Common grade 3 nonhematologic adverse events included febrile neutropenia in 16 patients (73%) and bacteremia in nine patients (41%). One patient died of treatment-related diffuse alveolar hemorrhage.
“This trial showed UM171-expanded cord blood is feasible, and results in these 22 patients suggest that it is safe — transplant-related mortality was low,” Cohen told Healio. “Results are impressive enough to move on to other trials to confirm safety and to look a bit more at efficacy. Several trials are now underway looking at patients with high-risk acute leukemia to see if preliminary results in a first trial of low relapse in high-risk patients will be confirmed. We would also like to confirm that transplant-associated mortality is low in additional patients. Further down the line, we would like to have a trial of UM171 cord blood compared with standard 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, albeit challenging to implement, Mary Eapen, MD, associate professor in the division of hematology and oncology in the department of medicine at Medical College of Wisconsin, wrote in an accompanying editorial.
“Research assessing nontraditional outcomes such as costs (eg, out-of-pocket expenses for the patient where applicable) and health-related quality of life are also required,” Eapen wrote. – by Jennifer Southall
For more information:
Sandra Cohen, MD, FRCP, can be reached at Maisonneuve-Rosemont Hospital, University of Montreal, 5415 Boulevard Assomption, Montreal, QC H1T 2M4, Canada; email: email@example.com.
Disclosures: The study was funded by the Canadian Institutes of Health Research, Canadian Cancer Society and Stem Cell Network. Cohen reports consultant fees from ExCellThera and grants from Canadian Cancer Society Research Institute and Stem Cell Network. Please see the study for all other authors’ relevant financial disclosures. Eapen reports no relevant financial disclosures.