Mismatched human leukocyte antigen (HLA) donor umbilical cord blood (UCB) transplants offer adults with acute leukemia similar leukemia-free survival as HLA-matched bone marrow or peripheral blood progenitor cell (PBPC) transplants do, according to a new study—the first to come to such a conclusion.
“Based on the fact that leukemia-free survival rates are similar with HLA mismatched UCB, we no longer have to think of UCB as a second-line source,” said the corresponding author, John E. Wagner, MD, Professor of Pediatrics and Director of the Division of Pediatric Hematology/Oncology and Bone Marrow Transplantation and Co-director of the Center for Translational Medicine at the University of Minnesota Medical School.
“And, with lower risks of graft-versus-host disease, UCB may at some point become the preferred unrelated donor stem cell source, particularly if we can fix the slow rate of recovery.”
The study is published in the July issue of Lancet Oncology (2010;11:653-660).
Asked for his opinion for this article, Fred Appelbaum, MD, Director of the Clinical Research Division at Fred Hutchinson Cancer Research Center and Head of the Division of Medical Oncology at the University of Washington, said the findings are important because, according to donor registries, only about one third of patients will have a matched sibling donor, meaning that the remaining two thirds have to look for alternative donors.
Moreover, 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 of Loyola University Health System, donor registries indicate that appropriate unrelated HLA-matched donors can be found for only about 50% of Caucasians and 20% to 25% of minorities, meaning that many people cannot have transplants.
Use of umbilical cord blood may help achieve the goal of hematopoietic stem cells being universally available to all patients because tissue-typing requirements are not as stringent as with traditional sources, and HLA mismatch appears to relatively tolerable, said Dr. Appelbaum.
Dr. Wagner and his colleagues evaluated data from 1525 acute leukemia patients, age 16 and older, who received unrelated donor hematopoietic stem-cell transplant at 216 centers worldwide between 2002 and 2006. These patients had received umbilical cord blood (165 patients), bone marrow (472 patients) or PBPCs (888 patients).
Umbilical cord blood was perfectly matched for all antigens, or 6/6 HLA-matched (n=10), and mismatched at one or two antigens, 5/6 HLA-matched (n=40) or 4/6 HLA-matched (n=115), respectively. Bone marrow and PBPC recipients were 8/8 HLA-matched (332 and 632, respectively) and 7/8 HLA-matched (140 and 256, respectively).
Leukemia-Free Survival and Transplant-Related Death
At two years, the leukemia-free survival rate in the 4-6/6 matched UCB groups was comparable to that in the 7/8 and 8/8 HLA matched bone marrow and PBPC groups. However, patients who were not in complete remission had significantly higher treatment failure than those in complete remission.
Additionally, transplant-related mortality was significantly higher after 4-6/6 HLA-matched UCB transplants than with perfectly matched bone-marrow or PBPC transplants. Most deaths in the UCB group occurred less than six months after transplantation.
While early mortality after UCB transplant may be partially explained by delayed recovery and infection, early and late mortality after 8/8 HLA-matched bone marrow or PBPC is more often due to acute and chronic GvHD, Dr. Wagner said.
In this study, the incidence of acute graft-versus-host disease (GvHD) in UCB 4-6/6 HLA matched recipients was lower when compared with perfectly matched PBPC patients. This was also true for chronic GvHD in the same sets of patients.
The incidence of chronic GvHD was also significantly lower after UCB transplant versus perfectly matched bone-marrow recipients; this did not hold true for acute GvHD.
Rates of GvHD may be lower with umbilical cord blood because of immunological naiveté and the preponderance of suppressor cell populations, Dr. Wagner said, adding that neonate blood would be enriched with these cells, which modulate the immune response, preventing immune reactions between the mother and fetus during pregnancy. “Now we are taking advantage of those characteristics in the transplant setting.”
Another important finding was that the risk of leukemia relapse was similar among all groups, said Dr. Wagner. In view of the lower rates of GvHD, a fear was that relapse might be higher after UCB transplantation, but “it is clearly not the case,” he said.
He and his co-researchers noted a protective effect of chronic GvHD in preventing recurrent leukemia—the first time such an association has been made with umbilical cord blood as the source of hematopoietic stem cells, they said.
Relapse was higher, however, in patients who weren’t in complete remission at transplantation versus those who were.
Similar Data on Horizon
Fred Hutchinson recently submitted a study for publication with results that are similar to the Lancet Oncology study, Dr. Appelbaum said. Researchers evaluated overall survival in addition to leukemia-free survival, and as with the findings in the study by Dr. Wagner and his colleagues, found that more transplant-related deaths were associated with UCB, but that the approach also had a lower risk of leukemic relapse.
“It’s very gratifying to see similar outcomes from the registry that we’ve seen in the Fred Hutchinson Center experience,” Dr. Appelbaum said.
Current Donor Selection
The way in which Fred Hutchinson currently considers donor options is “actually quite complex,” Dr. Appelbaum explained. “But a simplified version is that we generally prioritize matched related donors, matched unrelated donors, cord blood, and then mismatched related [donors].”
Dr. Wagner said that for patients with acute leukemia, physicians generally try to determine early after diagnosis whether an 8/8 HLA-matched related donor exists within the family, and in many cases will begin an unrelated search shortly thereafter. Most cancer centers will wait several months to see if an HLA matched unrelated donor can be identified.
Based on their own center’s experience and the data published in the Lancet Oncology, Dr. Wagner and his colleagues immediately search the cord blood banks internationally even if other options are also available.
The more urgent the transplant, the more time physicians might not want to expend on finding unrelated donors, making cord blood the next reasonable option, said Dr. Stiff.
“The size of the patient should also be considered,” he added. A large patient will require more stem cells, and because cord blood contains a fixed amount of these cells, it may not be the best option.
Challenges of Umbilical Cord Blood
While use of cord blood may expand the number of people who are eligible for transplant, the procedure has many challenges.
One problem, Dr. Appelbaum, is that the rate of immune recovery is delayed, sometimes resulting in the patient being more vulnerable to the activation of latent viruses such as cytomegalovirus or the BK virus, said Dr. Appelbaum. (The BK virus was named after the initials of the renal transplant patient from whose urine it was first isolated in 1971.)
Slower recovery is due to a finite amount of blood—about three ounces—in a placenta, meaning that fewer stem cells are present, said Dr. Wagner. In contrast, physicians can usually collect as many cells as needed with bone marrow or PBPC collection.
With a lower number of cells, graft rejection is also more likely to occur, noted Dr. Appelbaum.
Another challenge is that hematopoietic stem cells in UCB are “immature and quiescent, taking longer to enter the cell cycle as compared with bone marrow or peripheral blood counterparts,” explained Dr. Wagner.
And Dr. Stiff said that the rates of complications such as bleeding and infection are higher with a delayed engraftment process and that another challenge of UBC is that if relapse were to occur in a patient, donor lymphocytes to boost immunity are not available.
Dr. Wagner said that if mortality after UCB transplant is frequently related to inadequate stem cell numbers, physicians need to figure out how to increase these counts. One promising strategy is the use of double cord blood transplants, or combining two partially HLA-matched UCB units.
Another approach is placing the cord blood in expansion culture or exposing the cells to agents that will potentially augment their homing ability so that more stem cells reach the marrow microenvironment. Others are exploring direct marrow injection as a solution to the delayed recovery time after UCB transplant, he explained.
Dr. Appelbaum said that to accelerate engraftment, physicians at Fred Hutchinson are using in vitro expansion to increase the number of available hematopoietic stem cells.
Increasing UCB hematopoietic stem cells in vitro may also speed the recovery of blood counts in patients, said Dr. Stiff, speaking of research being conducted in the StemEx trial, funded by Gamida Cell-Teva Joint Venture.
Potential Impact in the Transplant Community
Dr. Stiff said he hopes this study will encourage referring physicians to consider the use of umbilical cord blood rather than conventional chemotherapy if an unrelated donor search is taking too long and the patient is in first remission. “There’s still a sense of reluctance by referring physicians and some of my colleagues to use umbilical cord blood,” he said.
In an editorial accompanying the study by Dr. Wagner and his colleagues, Paul Szabolcs, MD, Associate Professor of Pediatrics and Assistant Professor of Immunology in the Pediatric Blood and Marrow Transplant Program at Duke University Medical Center, wrote that if patients are in imminent danger of disease progression, clinicians should move towards cord blood transplantation as long as a four-of-six HLA-matched unit is identified. The findings should also encourage “efforts to increase the inventory of public cord-blood banks, and should similarly boost accrual to living donor registries, particularly from minorities.”
And “now that outcomes are about the same,” Dr. Appelbaum said, “physicians really should think much harder about who they refer to transplantation and when they refer them.”