DURHAM, North CarolinaUmbilical cord blood transplantation may
be a viable option for adult patients with hematologic malignancies
who do not have suitably matched donors as a source of stem cells,
according to reports presented at the ASH meeting.
While allogeneic hematopoietic progenitor cell transplantation is
curative for a number of hematologic malignancies, bone marrow
failure syndromes, and inherited disorders, the application is
hampered by the lack of HLA-matched donors. Stem cells from related
and unrelated umbilical cord blood have been shown to successfully
rescue patients after myeloablative therapy, but this procedure is
generally limited to pediatric patients due to concerns that numbers
of stem cells will be insufficient for engraftment in adult patients.
Gwynn Long, MD, of Duke University Medical Center, reported on a
study there involving 38 adults treated with myeloablative therapy
followed by infusion of hematopoietic stem cells from unrelated
umbilical cord blood. The patients median age was 30 (ranging
from 18 to 58). Two patients had genetic disorders and the rest had
hematologic malignancies. This was a high-risk group, as all patients
with leukemia were beyond first remission or first chronic phase,
except one patient with chronic myelogenous leukemia who had failed
interferon. Four patients had relapsed after autologous transplant
and two after allogeneic transplants.
Survival was related to number of cells cryopreserved and number of
cells infused. The median nucleated cell dose was 1.37 x 107/kg
and the median CD34+ cell dose was 2.17 x 105/kg.
Analyses of 171 pediatric and adult patients at Duke had shown that
cell dose is the strongest single predictor of engraftment,
nonrelapse mortality, and long-term event-free survival.
The preparative regimen for most patients was total body irradiation,
melphalan (Alkeran), and antithymocyte globulin. HLA matching was 3/6
in 3 patients, 4/6 in 27 patients, 5/6 in 6 patients, and 6/6 in 3
patients. All patients received graft-versus-host disease (GVHD)
prophylaxis and G-CSF post-transplant until neutrophil recovery.
Dr. Long said that patients were selected for the protocol if they
did not have a 6/6 unrelated donor match or there was no time
to look for one, noting that their policy is to go directly to
cord blood if there is no 6/6 unrelated donor match.
Neutrophil engraftment occurred in a median of 24 days, and median
number of days to platelet transfusion independence was 58. The
median survival was 175 days (range 19 to 1,409). Acute GVHD occurred
in 13 patients out of 28 who engrafted, at a median onset of 30 days.
Three patients died of acute GVHD and five patients now have chronic
GVHD. The most common cause of death was bacterial infection, which
occurred in eight patients. Overall survival at 1 year was about 40%
and is 28% at 4 years.
The findings suggest that unrelated umbilical cord blood can be
successfully engrafted in adult patients. This approach can result in
a lower than expected incidence of acute GVHD compared to similarly
HLA-matched unrelated donor marrow transplants but is associated with
significant risk of bacterial infection. Relapse rate is no higher
than expected for patients with advanced hematologic malignancies.
The use of these transplants should be explored in patients
with earlier stage disease in whom matched related or unrelated
donors are not available or identified in a timely fashion, Dr.
Immune System Role
The report was highlighted in a poster session moderated by John E.
Wagner, MD, of the University of Minnesota, who suggested that the
positive outcomes from cord blood transplantation may be somehow
related to cord bloods immune profile. With this approach, HLA
matching becomes less crucial, he pointed out.
We already know that there is a difference in the immune
profile of cord blood lymphocytes. They dont secrete IL-4, 5,
and 10 to any significant amount. They do produce IL-2 but the
numbers of T cells are small, which may partly account for the
decreased alloreactive response. There may also be other factors less
well described, for example, a suppressor cell activity. This could
be playing a major role in reducing the risk of graft-versus-host
disease, he added.
A comparison of sibling donor cord blood to HLA-matched sibling donor
bone marrow has found the risk of GVHD to be lower, indeed, in cord
blood transplantation. This suggests there may be something
biologically different about the neonatal immune system versus older
donors, he said.
Ex Vivo Cell Expansion
Since cell dose is important to outcome, technology that will
increase cell numbers should facilitate transplant efforts,
especially in adults. In a separate report, Duke investigators from
the Pediatric Bone Marrow Program described their automated, ex vivo
expansion method, a continuous profusion culture device, known as the
Joanne Kurtzberg, MD, reiterated that cell dose greater than 2 x 107
nucleated cells or 1 x 105 CD34 cells/kg body weight is
associated with superior outcome. Patients over 60 kg often receive
insufficient numbers for engraftment.
The question of this phase I trial of 28 high-risk patients with
malignant and nonmalignant diseases was whether umbilical cord blood
cells could be expanded in the clinical transplant setting and safely
infused. The patients were cytoreduced with one of three regimens.
GVHD prophylaxis was given, plus G-CSF and additional supportive
care. Patients were given 1.5-2 x 107 nucleated cells/kg
as a conventional unmanipulated graft, and 12 days later were given
the expanded cells.
Expansion occurred in all cases, but the magnitude varied. The median
fold increase in total nucleated cells was 2.4 and median CFU-GM
increase was 70 fold. CD34 lineage negative cells did not expand, Dr.
The method was well tolerated. Compared to historical controls
receiving similar doses of unmanipulated cells, recipients had
superior 100-day survival, but time to myeloid, erythroid, or
platelet engraftment was not altered. Randomized studies are underway
to determine whether the improvement in survival was due to the
augmentation of cell dose by infusion of the expanded cells or to
Ideally, cell expansion should occur prior to transplantation to
allow for administration of expanded and unmanipulated cells on the
same day. Optimization of expansion conditions should allow for
this in the future, Dr. Kurtzberg said.