UM171-expanded cord blood safe for certain adults with hematologic malignancies
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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: sandra.cohen@umontreal.ca.
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.
Perspective
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Gerhard C. Hildebrandt, MD
More than 2 decades ago, the first umbilical cord blood transplant (UCBT) marked a milestone toward optimizing donor availability for patients needing a hematopoietic stem cell transplant. Since then, the concept of UCBT as an alternative transplant option led to the development of public cord blood banks that store more than 800,000 cord blood units and resulted in access to a life-saving donor cell source for numerous children and adults. The times of plenty seemed near, yet infections, treatment-related mortality and costs of UCBT and the development of novel strategies, like haploidentical transplant with post-transplant cyclophosphamide, drove famine upon UCBT.
Cohen and colleagues now present their early-phase data on single UM171-expanded UCBT with promising results. UM171 is a pyrimidoindole derivative that not only drives the expansion of CD34-positive CD45RA cells within the long-term repopulating stem cell population, but also leads to expansion of natural killer cell progenitors and mast cells. Treatment of single cord blood units with UM171 resulted in successful expansion of cord blood units in 96% of cases. Neutrophil engraftment and platelet recovery appeared similar to other previously published expansion strategies, whereas the more striking observations in this (limited) patient cohort were the low 1-year transplant related mortality of 5% (95% CI, 1-31), the 1-year PFS rate of 74% (95% CI, 44-88) and 1-year OS rate of 90% (95% CI, 67-98), the low incidence of grade 3 to grade 4 acute GVHD, and the moderate-to-severe chronic GVHD incidence of 0% at 12 months. A 7-day course of UM171 induced expansion of cord blood cells and, therefore, seems to provide an approach that allows for promising approximation of the best of two worlds: GVHD-free survival and RFS, as demonstrated by the 12-month GVHD-free RFS rate of 64% and chronic GVHD-free RFS rate of 74% in a high-risk patient population. These findings are very promising, and further studies are needed to directly compare UM171-expanded UCBT with other transplant and GVHD prophylaxis strategies, like post-transplantation cyclophosphamide in mismatched/haploidentical HSCT, where a donor is urgently needed or hard to be found.
For now, the times of famine of UCBT seem over, with UM171 and other expansion strategies currently being explored. Future studies will define whether there may be sustained plenty again.
References:
Fares I, et al. Science. 2014; doi:10.1126/science.1256337.
Gluckman E, et al. N Engl J Med. 1989;doi:10.1056/NEJM198910263211707.
Mesquitta WT, et al. Sci Rep. 2019;doi:10.1038/s41598-019-43054-4.
Shearer WT, et al. Pediatrics. 2017;doi:10.1542/peds.2017-2695.
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