Partially matched double umbilical cord blood (dUCB) transplants may be a viable alternative for patients with hematologic cancer who do not have a related or unrelated hematopoietic stem cell donor, according to a study now available online ahead of print in Blood.
This paper shows that “double cord transplantation is definitely an alternative to offer allogeneic transplantation patients who don't have a more conventional donor such as sibling or matched unrelated,” said the study's lead author, Claudio G. Brunstein, MD, PhD, Medical Director of Unrelated Donor Transplantation at the University of Minnesota Blood and Marrow Transplant Program. “Otherwise, they may have to wait for weeks to months and may relapse.”
The problem with single-unit UCB is that it often does not have a sufficient number of cells for adults, preventing them from receiving this type of graft, Dr. Brunstein explained. Moreover, the risk of nonengraftment, when the cell dose is suboptimal, is greater.
Asked for his opinion for this article, Willis Navarro, MD, Medical Director of Transplant Services at the National Marrow Donor Program, said that based on the Brunstein et al research data, he agreed that double umbilical cord blood transplants appear to be a viable option in people without related or unrelated donors. The paper also presented some interesting findings on lower rates of five-year relapse in dUBC patients, he added.
For the study, researchers from Fred Hutchinson Cancer Research Center and the University of Minnesota conducted a retrospective analysis of 536 patients aged 10 years and older with a hematologic malignancy and who were undergoing allogeneic hematopoietic cell transplant (HCT) between 2001 and 2008.
The investigators compared outcomes of patients with an HLA 8/8 allele, or perfectly matched, related donor (n=204), an HLA perfectly matched unrelated donor (n=152), a 1-allele mismatched unrelated donor (n=52), or an HLA 4-6/6 matched dUCB donor (n=128).
All patients underwent myeloablative conditioning with cyclophosphamide and high-dose total body irradiation. Patients in the dUBC group also received fludarabine.
Dr. Brunstein said that he and his colleagues were encouraged by the rates of disease-free survival in the dUCB transplant patients. Leukemia-free survival at five years was similar among all groups.
Specifically, the rates were:
* 51% (95% CI, 41%-59%) in the dUCB group.
* 33% (95% CI, 26%-41%) in the matched related donor group.
* 48% [95% CI, 40%-56%) in matched unrelated patients.
* 38% (95% CI, 25%-51%) in the mismatched unrelated donor group.
The risk of relapse at five years was only 15% (95% CI, 9%-22%) in dUCB transplant patients, compared with 43% (95% CI, 35%-52%) in matched related donor recipients, 37% (95% CI, 29%-46%) in matched unrelated patients, and 35% (95% CI, 21%-48%) in the mismatched unrelated donor group.
Non-relapse mortality at two years was higher in patients who underwent dUCB transplant:
* 34% (95% CI, 25%-42%) in the dUCB group.
* 24% (95% CI, 17%-39%) in the matched related donor group.
* 14% (95% CI, 9%-20%) in the matched unrelated group.
* 27% (95% CI,15%-39%) in the mismatched unrelated patients.
The incidence of acute Grade II-IV graft versus host disease (GvHD) at 100 days was lowest in dUCB patients. The rates were:
* 60% (95% CI, 50%-70%) in dUCB patients.
* 65% (95% CI, 57%-73%) in the matched related donor group.
* 80% (95% CI, 70%-90%) in matched unrelated patients.
* 85% (95% CI, 68%-100%) in mismatched unrelated patients.
Additionally, the cumulative incidence of chronic GVHD at two years was lowest in the dUCB group.
“Acute GVHD in double cord transplant is mostly Grade II and is not life threatening due to naiveté of immune cells,” Dr. Brunstein said. Compared with other transplant types in this study, dUCB patients experienced reduced chronic GVHD, which may impact quality of life, he added.
Lower Relapse in dUCB Transplant Patients Intriguing
Researchers don't yet understand the mechanisms for why the cumulative incidence of relapse at five years was lower in dUCB transplant recipients than in other groups, Dr. Brunstein noted.
Reduced relapse risk may be inherent to the type of transplant or it may be an artifact of the experience of the two centers, which have been performing the procedure for several years, he explained, adding that this outcome needs to be confirmed in a proper randomized trial.
What is intriguing about this study is that transplanting two cord blood units that are both mismatched appears to be associated with less relapse than a living related or unrelated transplant, although this is not yet proven, said Patrick J. Stiff, MD, Division Director and Coleman Professor of Oncology in the Division of Hematology/Oncology at Loyola University Chicago Stritch School of Medicine and Director of the Cardinal Bernardin Cancer Center at Loyola University Health System.
Theoretically, the unit with the better antileukemic impact may be more readily engrafted by the patient, he said.
The lower relapse rate at five years in dUCB transplant recipients was mysterious, especially when considering the lower rate of chronic GVHD in these individuals, Dr. Navarro said. A lower rate of chronic GVHD is not unexpected due to the naiveté of T cells in umbilical cord blood. However, this, in addition to a lower rate of relapse “is quite surprising,” he said.
“I can't think of a paper where these don't correlate inversely. To see less GVHD and less relapse is an intriguing finding.”
One explanation may be that immunological interaction between the two cord blood units results in an antileukemic effect, he said. Additionally, mismatching of the KIR ligand may be playing a role, although this is not usually seen in patients with acute lymphoblastic leukemia.
“If we were to understand the immunological basis of this interaction, it might be very helpful for all transplant patients,” Dr. Navarro continued. “We're always trying to disassociate GVHD and graft-versus-leukemia in patients.”
Higher Non-relapse Mortality in dUBC Patients Due to Delayed Engraftment
The reason for a higher rate of non-relapse mortality in dUBC transplant patients is better understood, Dr. Brunstein noted. The outcome is related to the delay in engraftment that occurs in this group of patients—those who experienced longer time to neutrophil recovery (26 or more days) had a higher risk of non-relapse mortality, he explained, and those in the dUBC group who achieved earlier neutrophil recovery did just as well as patients with other donor types.
“If we can shorten the time to engraftment, with, for example, ex vivo expansion, non-relapse mortality would at least, in part, improve.”
Stimulated cord blood expansion, using notch ligand- or MSC-stimulated units, may provide more rapid engraftment, Dr. Navarro said.
And Dr. Stiff explained that non-relapse mortality may also have been higher in dUCB transplant patients due to a less robust immune system leading to more opportunistic viral infections.
Double vs Single Cord May Need to Be Addressed
“This study was a retrospective comparison between double cord and traditional transplant from living sibling or unrelated donors, not a comparison between single and double umbilical cord blood transplant,” he said.
“The question to ask is whether two UBC units are needed in these patients. We don't necessarily know if two are better than one. But if you have patients with leukemia and no siblings or no unrelated matched donors, then they are candidates for cord blood, whether this is a single cord transplant, single with ex vivo cord blood expansion, or double cord blood transplant. All are viable options and better than standard chemotherapy alone in most cases.”
Loyola performs single cord blood transplants and is working on growing UCB outside of the body, Dr. Stiff said. “The rationale is that engraftment times for dual are no different than what we find in giving a single cord blood unit.” Additionally, the costs of two UCB units may be prohibitive for some patients.
However, if a dual transplant is associated with a higher cure rate, this approach would be worth pursuing, Dr. Stiff continued. Consequently, a randomized trial comparing single to double cord transplant is needed. “Maybe the end point should be not how fast we see counts come in but whether we are seeing improvements in survival.”
Trial of One vs Two Not Practical
A randomized trial of one and two cord transplants in adults is not practical, Dr. Navarro noted. A single unit doesn't provide sufficient cell dose for engraftment in patients who are physically large, and while ex vivo expansion of a single cord blood unit is interesting, it still requires more data before being used as the sole cell source in a randomized study, he said.
However, he added, for children with leukemia or myelodysplastic syndrome, a single cord versus double cord study is currently under way (BMT CTN 0501).
Dr. Brunstein added that although that trial may provide some interesting answers about relapse, the situation for transplants in adults and children is somewhat different.