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Prepublished online as a Blood First Edition Paper on May 8, 2003; DOI 10.1182/blood-2002-11-3337.
 Previous Article | Table of Contents | Next Article 
Blood, 1 September 2003, Vol. 102, No. 5, pp. 1915-1919
TRANSPLANTATION
Rapid and complete donor chimerism in adult recipients of unrelated donor umbilical cord blood transplantation after reduced-intensity conditioning
Juliet N. Barker,
Daniel J. Weisdorf,
Todd E. DeFor,
Bruce R. Blazar,
Jeffrey S. Miller, and
John E. Wagner
From the Divisions of Medical and Pediatric Hematology, Oncology and
Transplantation, University of Minnesota Blood and Marrow Transplant Program,
Minneapolis, MN.
 |
Abstract
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Reduced-intensity conditioning may reduce transplantation-related mortality
in high-risk adults undergoing hematopoietic transplantation. We investigated
unrelated donor umbilical cord blood (UCB) transplantation after such
conditioning in 43 patients (median age, 49.5 years; range, 22-65 years) with
a primary end point of donor engraftment. The first 21 patients received
busulfan 8 mg/kg, fludarabine 200 mg/m2, and 200 cGy of total body
irradiation (Bu/Flu/TBI). Subsequent patients (n = 22) received
cyclophosphamide 50 mg/kg, fludarabine 200 mg/m2, and 200 cGy TBI
(Cy/Flu/TBI). UCB grafts (93%) were 1-2 HLA antigen–mismatched with the
recipient and contained a median cryopreserved cell dose of 3.7 x
107 (range, 1.6 x 107-6.0 x 107)
nucleated cells per kilogram of recipient body weight (NC/kg). Graft versus
host disease (GVHD) prophylaxis was cyclosporin A to day 180 plus
mycophenolate mofetil to day 30. The cumulative incidence of sustained donor
engraftment was 76% (95% confidence interval [CI], 56%-96%) for Bu/Flu/TBI
recipients and 94% (95% CI, 84%-100%) for Cy/Flu/TBI recipients. The median
day of neutrophil recovery (at least 0.5 x 109/L) for
engrafting Bu/Flu/TBI recipients was 26 days (range, 12-30 days) and for
Cy/Flu/TBI recipients was 9.5 days (range, 5-28 days). Incidence of grades
III-IV acute GVHD was 9% (95% CI, 1%-17%), and survival at 1 year was 39% (95%
CI, 23%-56%). These data demonstrate that 0-2 antigen mismatched UCB is
sufficient to engraft most adults after reduced-intensity conditioning and is
associated with a low incidence of severe acute GVHD.
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Introduction
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Bone marrow transplantation (BMT) may be curative in a variety of malignant
and nonmalignant hematopoietic
disorders.1 However,
many adults receiving conventional high-dose myeloablative conditioning
regimens, particularly recipients of unrelated donor (URD) BMT for diseases
other than chronic myelogenous leukemia (CML), experience high
transplantation-related mortality (TRM) with this
approach.2,3
Therefore, "reduced-intensity" or "nonmyeloablative"
regimens are being investigated for older patients or those with poor
performance status, organ dysfunction, or extensive prior therapy using either
related or unrelated volunteer
donors.4-12
Immunosuppression without myeloablation can be sufficient to achieve complete
donor chimerism, and a graft versus malignancy (GVM) effect can be
demonstrated in both hematologic and nonhematologic
malignancies.4-13
However, most patients do not have an available HLA-matched sibling donor.
Because 0-2 donor-recipient HLA antigen disparity appears to be more tolerable
in URD umbilical cord blood transplantation (UCBT) than in URD BMT, UCB offers
the opportunity to extend the donor pool with a low risk of severe acute graft
versus host disease
(GVHD).14-17
Also, UCB grafts can be available substantially more quickly than URD
BM.18 However,
reduced UCB alloreactivity could compromise the ability of UCB to engraft
after reduced-intensity conditioning. Therefore, we investigated a pilot study
of URD UCBT after reduced-intensity conditioning in adults not eligible for
conventional conditioning with the hypothesis that alloreactive T cells in UCB
are sufficient to effect donor engraftment after reduced-intensity
conditioning.
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Patients, materials, and methods
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URD UCBT was considered if HLA-compatible related (5 or 6 out of 6 HLA-A,
B, DRB1 matches) or unrelated BM donors (6 out of 6 HLA-A, B, DRB1 matches)
were not available or the transplantation was deemed to be urgent (required
within 3 months of referral). Criteria for a reduced-intensity preparative
regimen (rather than conventional high-dose conditioning) were (1) age at
least 45 years; (2) extensive prior therapy (high-dose conditioning and
autologous transplantation, or more than 12 months of alkylator chemotherapy,
or more than 6 months of alkylator chemotherapy with extensive radiation);
and/or (3) poor performance
status,19 including
serious concurrent medical condition, serious organ dysfunction, and/or
invasive mold infection within 60 days.
Treatment plan
A dose-intensity de-escalation approach was used. The first 21 patients
received conditioning with busulfan 2 mg/kg orally every 12 hours for 4 doses
(days –8 to –7), fludarabine 40 mg/m2 daily for 5 days
(days –6 to –2), and a single dose of 200 cGy of total body
irradiation (day –1) (Bu/Flu/TBI). Diphenylhydantoin was given to
Bu/Flu/TBI recipients on days –9 to 0. Subsequent patients (n = 22)
received an identical regimen except for a substitution of busulfan with a
single dose of cyclophosphamide 50 mg/kg on day –6 (Cy/Flu/TBI). One
Cy/Flu/TBI patient with myelodysplasia (MDS) without prior chemotherapy also
received antithymocyte globulin (ATG) 15 mg/kg every 12 hours for 6 doses on
days –3 to –1.
All patients received cyclosporin A (CSA) from day –3 for a minimum
of 6 months (aiming for a trough blood level of more than 200 µg/L). In
addition, all patients received mycophenolate mofetil 15 mg/kg twice daily
either orally or intravenously from days –3 to +30. Granulocyte
colony-stimulating factor (G-CSF) (Filgrastim; Amgen, Thousand Oaks, CA) was
administered to all patients at 5 µg/kg/d after transplantation when the
total white cell count (WCC) fell below 2.5 x 109/L until the
absolute neutrophil count (ANC) was more than 2.5 x 109/L for
2 days. The treatment protocol was approved by the Institutional Review Board
of the University of Minnesota. Written informed consent was obtained from all
patients prior to transplantation.
Patient characteristics
Patient characteristics are summarized in
Table 1. Bu/Flu/TBI patients (n
= 21) underwent transplantation between July 2000 and September 2001, and
Cy/Flu/TBI recipients (n = 22) underwent transplantation between October 2001
and September 2002. All patients had high-risk or advanced-stage hematologic
malignancy. Consistent with their high-risk or advanced disease, 19 patients
(44%) had received extensive prior therapy and 24 (55%) had poor performance
status. Thirty-two patients (74%) were aged at least 45 years with 26 (60%) of
43 patients having at least 2 of the 3 criteria warranting a reduced-intensity
transplantation approach.
UCB grafts
UCB units were obtained from the National Cord Blood Program in New York;
the St Louis Cord Blood Bank; the National Heart, Lung, and Blood Institute
(NHLBI) Cord Blood Transplantation Study (COBLT); and Netcord. UCB grafts had
at least 4 of 6 HLA-A, B, DRB1 antigens that were matched to the recipient and
had a cryopreserved cell dose of at least 1.5 x 107 nucleated
cells per kilogram of recipient body weight (NC/kg). Patients underwent
transplantation with a single UCB if the unit had a cell dose of at least 3.5
x 107 NC/kg. Patients with a single unit with a cell dose
less than 3.5 x 107 NC/kg were eligible for transplantation
with two 4 to 6 of 6 HLA-A, B, DRB1 matched UCB units if available.
HLA typing was performed using the standard 2-stage complement-dependent
microcytotoxicity assay, and antigens were assigned as defined by the World
Health Organization HLA nomenclature committee. HLA-DRB1 type was determined
by hybridization of polymerase chain reaction (PCR)–amplified DNA with
sequence-specific oligonucleotide probes with sequencing if needed.
High-resolution class II typing results for HLA-DRB1 was used to determine the
selection of all UCB units. UCB grafts were thawed using the method of
Rubinstein et
al.20
Graft characteristics are summarized in
Table 2. Nine Bu/Flu/TBI
patients (43%) and 15 Cy/Flu/TBI patients (68%) received grafts consisting of
2 UCB units. Overall, the median total cryopreserved nucleated cell dose was
3.7 x 107 NC/kg (range, 1.6 x 107-6.0
x 107 NC/kg). Bu/Flu/TBI recipients received grafts with a
significantly smaller median infused cell dose of 2.6 x 107
NC/kg (range, 1.6 x 107-3.8 x 107 NC/kg)
compared with 3.2 x 107 NC/kg (range, 1.1 x
107-5.1 x 107 NC/kg) in Cy/Flu/TBI recipients
(P = .04). However, there was no significant difference in the
CD34+ cell dose in the 2 patient cohorts (P = .39). UCB
grafts were 1-2 HLA-A, B, DRB1 antigen mismatched to the patient in 40 (93%)
of 43, with 3 patients receiving grafts that were 6 of 6 matched to the
recipient.
Donor chimerism analysis
Donor chimerism was determined serially on marrow and/or blood samples on
days +21 to +28, +50 to +60, +100, +180, +360, and annually after
transplantation and as clinically indicated. Chimerism analysis was done using
quantitative PCR of informative polymorphic variable number tandem repeat
(VNTR) or short tandem repeat (STR) regions in the recipient and
donor.21,22
Peripheral blood specimens were separated into neutrophil and mononuclear
lymphoid fractions provided the total white cell count was more than 1.0
x 109/L. Posttransplantation DNA from the recipient was
amplified with fluorescent PCR primers for markers found to distinguish
donor(s) from recipient alleles. The fluorescent PCR products were separated
either by gel electrophoresis on an Applied Biosystems 373 Sequencer or by
capillary electrophoresis on an Applied Biosystems 3100 Genetic Analyzer
(Applied Biosystems, Foster City, CA). The GeneScan software package (Applied
Biosystems) was used to correlate allele peak areas to the percentage of donor
or recipient DNA. Chimerism values had an accuracy of ± 5%.
Statistical analysis
The primary end point was donor engraftment. Other end points included
neutrophil and platelet recovery, acute GVHD (grades II-IV and III-IV),
chronic GVHD, relapse, TRM, disease-free survival (DFS), and overall survival.
Other outcomes evaluated included causes of death. Event time for neutrophil
recovery was the date of transplantation to the first of 3 consecutive days
with neutrophil recovery to at least 0.5 x 109/L. Primary
donor engraftment was defined as neutrophil recovery associated with donor
engraftment within the first month after transplantation. Sustained donor
engraftment was defined as sustained neutrophil recovery and donor
hematopoiesis beyond day +42 after transplantation. Complete donor chimerism
was considered to be marrow reconstitution of donor origin of at least 90%.
Patients were censored from the engraftment analysis if they died or had
persistent leukemia/early relapse within the first 28 days after
transplantation. The cumulative incidence of engraftment was calculated by
treating deaths from other causes as competing
risks.23
Diagnosis of acute and chronic GVHD was based on standard clinical criteria
with histopathologic confirmation where
possible.24 The
maximal grade of GVHD was determined by independent reviewers who evaluated
the cases retrospectively. The cumulative incidence of acute and chronic GVHD
was calculated by treating deaths from other causes as competing
risks.23 The
statistical end points of survival and DFS were estimated by the Kaplan-Meier
method.25 Event
times were measured from date of transplantation to date of death or date of
last contact. Event times were analyzed as of November 2002. The median
follow-up for the Bu/Flu/TBI recipients is 1.9 years (range, 1.2-2.3 years)
and for the Cy/Flu/TBI recipients is 0.6 years (range, 0.2-1.0 years).
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Results
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Hematopoietic recovery and donor chimerism
Three of the 21 Bu/Flu/TBI patients were not evaluable for donor
engraftment due to early death from relapse (n = 2) or infection (n = 1). Of
the 18 evaluable Bu/Flu/TBI recipients, the cumulative incidence of primary
donor engraftment was 88% (95% confidence interval [CI], 72%-100%) at a median
of 26 days after transplantation (range, 12-30 days). Fourteen patients
displayed sustained donor engraftment for a cumulative incidence of 76% (95%
CI, 56%-96%) (Figure 1).
Bu/Flu/TBI patients with sustained donor engraftment demonstrated rapid and
complete myeloid and lymphoid donor chimerism. The median myeloid donor
chimerism of 100% (range, 84%-100%) in day +21 BM biopsy
(Figure 2), and all patients
had 100% lymphoid chimerism in day +28 to +35 blood samples. All engrafting
patients without BM relapse were complete donor chimeras beyond 1 month after
transplantation.
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Figure 1.. Cumulative incidence of sustained donor engraftment with 0-2 antigen
mismatched UCB after Bu/Flu/TBI or Cy/Flu/TBI conditioning (P <
.01).
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Figure 2.. Comparison of myeloid donor chimerism in patients with sustained donor
engraftment after reduced-intensity UCBT using either Bu/Flu/TBI or Cy/Flu/TBI
conditioning. Achievement of complete donor chimerism was rapid for
Bu/Flu/TBI recipients (A), being a median of 100% at day 21 in BM. In
contrast, because the Cy/Flu/TBI regimen (B) was less myelosuppressive,
myeloid donor chimerism was initially mixed, taking until day 60 to reach a
median of 100%.
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Twenty-one of the 22 Cy/Flu/TBI patients were evaluable for engraftment.
The single unevaluable patient died on day +21 from pneumonitis with evidence
of donor engraftment. The cumulative incidence of primary donor engraftment
for the Cy/Flu/TBI regimen was 94% (95% CI, 84%-100%) with neutrophil recovery
occurring at a median of 9.5 days (range, 5-28 days). A single patient with
advanced myelofibrosis without prior combination chemotherapy had primary
graft failure with autologous recovery. No Cy/Flu/TBI patient had secondary
graft failure. Therefore, the cumulative incidence of sustained donor
chimerism with Cy/Flu/TBI was 94% (95% CI, 84%-100%)
(Figure 1). This was
significantly higher than seen with the Bu/Flu/TBI regimen (P = <
.01).
Due to temporary persistence of autologous hematopoiesis early after
transplantation, engrafting Cy/Flu/TBI recipients demonstrated more gradual
attainment of myeloid donor chimerism than seen with the Bu/Flu/TBI regimen,
with a median of 78% (range, 8%-100%) in day +21 BM
(Figure 2). The median myeloid
chimerism in blood at days 50 to 60 after transplantation for Cy/Flu/TBI
recipients was 100% (range, 26%-100%), with all patients except 1 having
complete donor chimerism by day +100. In contrast, attainment of complete
lymphoid donor chimerism was rapid in engrafting Cy/Flu/TBI patients, with the
median being 100% by day +28 to +35 (range, 10%-100%).
Of the 4 Bu/Flu/TBI patients with failure of donor engraftment, 2 had
primary graft failure with autologous recovery and 2 had early secondary graft
failure at days +22 and +35. These patients had diagnoses of advanced MDS or
secondary acute myelogenous leukemia (AML) without prior combination
chemotherapy (n = 2), or AML in relapse (n = 1) and relapsed non-Hodgkin
lymphoma (NHL) (n = 1), both without chemotherapy within the 4 months prior to
transplantation. The single Cy/Flu/TBI patient with primary graft failure had
advanced myelofibrosis without prior combination chemotherapy. Overall, all
patients who received either combination chemotherapy in the 4 months
preceding transplantation or a prior autologous transplantation (n = 31) had
sustained donor engraftment. This compared with failure of sustained donor
engraftment in 2 of 4 patients whose prior combination chemotherapy was more
than 4 months preceding transplantation and in 3 of 3 patients who had never
received prior combination chemotherapy. One patient with myelodysplasia and
no prior combination chemotherapy had ATG added to Cy/Flu/TBI conditioning and
had full donor engraftment.
The cumulative incidence of platelet engraftment to 2 x
109/L by day +180 was 24% (95% CI, 6%-42%) for Bu/Flu/TBI
recipients and 80% (95% CI, 57%-100%) for Cy/Flu/TBI recipients (P
< .01).
GVHD
The cumulative incidence of grades II-IV and grades III-IV acute GVHD was
44% (95% CI, 28%-62%) and 9% (95% CI, 1%-17%) for the entire group
(Figure 3), respectively, with
no differences between Bu/Flu/TBI and Cy/Flu/TBI regimens (data not shown).
The 4 patients with grades III-IV acute GVHD had involvement of skin, gut, and
liver. Two responded to corticosteroids and cyclosporine, 1 responded to ATG,
and the other had refractory disease that was fatal.
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Figure 3.. Cumulative incidence of grades II-IV and III-IV acute GVHD after 0-2
antigen mismatched UCBT using reduced-intensity conditioning.
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Thus far, 8 patients have developed chronic GVHD for a cumulative incidence
of 21% (95% CI, 8%-34%) at 1 year. Onset was de novo in 2 patients, quiescent
in 5, and progressive in 1. Organs involved were eyes (n = 2), mouth (n = 7),
skin (n = 7), gut (n = 5), and liver (n = 1), with 1 patient having autoimmune
hemolysis. All patients, except for 1 patient with progressive onset, have
responded to corticosteroids.
TRM, relapse, and survival
Treatment-related mortality at day 100 after transplantation was 48% (95%
CI, 26%-70%) for Bu/Flu/TBI recipients and 28% (95% CI, 10%-46%) for
Cy/Flu/TBI patients. For the entire group, the overall survival and DFS at 1
year were 39% (95% CI, 23%-56%) and 31% (95% CI, 15%-47%), respectively.
Bu/Flu/TBI recipients had probabilities of disease-free survival of 38% (95%
CI, 17%-59%) at day 100 and 24% (95% CI, 6%-42%) at 1 year. Cy/Flu/TBI
recipients have probabilities of disease-free survival of 68% (95% CI,
48%-88%) at day 100 and 41% (95% CI, 15%-76%) at 1 year
(Figure 4).
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Figure 4.. Kaplan-Meier estimates of disease-free survival for recipients of UCBT
with Bu/Flu/TBI and Cy/Flu/TBI conditioning. Overall, 5 Bu/Flu/TBI and 11
Cy/Flu/TBI recipients were alive and disease-free at 1 year after
transplantation, giving a probability of disease-free survival of 24% (95% CI,
6%-42%) and 41% (95% CI, 15%-76%) at 1 year, respectively. The differences
between the 2 regimens were not significant (P = .15).
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Overall, the predominant cause of death has been infection and organ
failure (n = 13), with all TRM occurring prior to day +100. Graft failure and
severe acute GVHD have accounted for 1 death each. Nine patients have died
from relapse or progressive disease. Total nucleated cell dose and
CD34+ cell dose were not associated with differences in survival
(data not shown).
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Discussion
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Reduced-intensity preparative regimens are being investigated as a method
to reduce regimen-related toxicity so the opportunity for a GVM effect may be
extended to patients not fit for conventional
conditioning.4-13
Because many patients do not have an available related or unrelated marrow
donor, we have investigated reduced-intensity conditioning with UCBT. The
Bu/Flu/TBI regimen was associated with rapid and complete donor chimerism in
most patients. However, while the intensity of Bu/Flu/TBI is less than
conventional high-dose conditioning, it resulted in prolonged neutropenia.
Furthermore, 4 cases of failure of donor engraftment were seen. Therefore, in
an attempt to achieve equivalent or greater immunosuppression with less
myelosuppression, busulfan was substituted with a single dose of
cyclophosphamide. In most patients, the Cy/Flu/TBI regimen was associated with
rapid neutrophil recovery. Therefore, this approach can ameliorate the problem
of delayed neutrophil recovery seen with myeloablative UCBT. Further,
Cy/Flu/TBI has been associated with complete donor engraftment in most
recipients, including rapid attainment of complete lymphoid chimerism.
This study did not involve randomization of patients between the 2
conditioning regimens. Therefore, it is not possible to draw firm conclusions
concerning the impact of each preparative regimen on the incidence of
sustained donor engraftment, which may have been also affected by the
confounding factors of patient and graft variables. However, it is clear that
the busulfan-based regimen is associated with prolonged neutropenia whereas
Cy/Flu/TBI can permit early neutrophil recovery in many patients. This
advantage, combined with a high incidence of donor engraftment, is reason to
continue investigation of the Cy/Flu/TBI regimen. The engraftment results with
the Cy/Flu/TBI regimen are consistent with findings of murine studies
suggesting that the immunoablation associated with the combination of
cyclophosphamide and fludarabine is conducive to donor engraftment in the
setting of HLA
mismatch.26,27
These data demonstrate that despite the low total nucleated
CD34+ and T-cell dose and reduced alloreactivity associated with
UCB, UCBT using reduced-intensity conditioning is associated with sustained
donor engraftment in most adult patients. Interestingly, graft failure was
restricted to patients without recent pretransplantation combination
chemotherapy or prior autologous transplantation. While it is difficult to
distinguish the impact of the underlying diagnosis (eg, myelodysplasia or
myelofibrosis) from that of prior therapy on engraftment, these data may
suggest that the immunosuppression resulting from pretransplantation therapy
aids engraftment. A similar finding in sibling donor transplantation after
nonmyeloablative conditioning has been reported by McSweeney et
al.10
The donor engraftment after Cy/Flu/TBI is comparable to that reported after
UCBT using traditional myeloablative
regimens.16 In
comparison to the engraftment using reduced-intensity conditioning and other
hematopoietic stem cell sources, Giralt et
al9 reported only 2
of 76 patients having graft failure after either related donor or URD BMT. In
a smaller series, Nagler et
al11 reported
complete donor engraftment in 15 of 16 recipients of URD BMT, with partial
donor chimerism in the remaining patient. More recently, Chakraverty et
al12 reported
initial full donor chimerism in 85% of recipients of URD BMT, with a number of
patients subsequently developing mixed chimerism. Overall, prospective studies
with similar conditioning regimens with control for such factors as diagnosis
and prior therapy will be required to substantiate any differences in the
engrafting potential of different hematopoietic stem cell (HSC) sources after
reduced-intensity conditioning.
Notable in this group of adult patients is the low incidence of severe
(grades III-IV) acute GVHD despite the HLA disparity of the UCB graft. These
results are lower than those reported after UCBT using traditional
myeloablative
regimens.16 This
low incidence of acute GVHD may represent an important advantage of UCB over
URD BM. In the report by Giralt et
al,9 the incidence
of severe acute GVHD was 39%, accounting for 11 of 40 deaths. This compares
with an incidence of less than 10%, accounting for only 1 death, in our UCB
series. Nonetheless, the TRM in our study is high despite the
reduced-intensity conditioning and low incidence of severe GVHD. While this is
not unexpected given the high-risk patient population enrolled in this pilot
study, and is in keeping with other reports of similar patient
populations,9
further efforts to reduce the hazards in the early posttransplantation period
are warranted. Transplantation in patients with high-risk malignancies using
reduced-intensity regimens may be more effective if initiated prior to
chemorefractory disease, extensive prior therapy, and its associated
complications. Furthermore, for patients with refractory disease or very poor
performance status, nontransplantation options may be more appropriate.
Ultimately, the success of a reduced-intensity regimen is dependent on the
ability of the transplanted cells to engraft and exert GVM effects. It is
premature to assess the potency of UCB GVM in this study that was designed to
evaluate the engraftment potential of UCB using reduced-intensity conditioning
in adults. However, given that pediatric UCBT series have not observed
increased relapse risk as compared with
BMT,17,28,29
continued investigation of this HSC source is warranted. One potential
disadvantage of UCBT is that there is no access to donor lymphocyte infusions
(DLIs). However, while reports of successful therapy of persistent or relapsed
malignancies other than CML exist, overall the efficacy of DLIs in treating
patients with diagnoses other than CML has been limited. The advantages of URD
UCB—namely, tolerance of 0-2 antigen HLA disparity, speed of
availability, and low incidence of severe acute GVHD—may outweigh the
disadvantage of lack of DLIs.
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Footnotes
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Submitted November 6, 2003;
accepted April 28, 2003.
Prepublished online as Blood First Edition Paper, May 8, 2003; DOI
10.1182/blood-2002-11-3337.
Supported in part by grants from the National Cancer Institute PO1-CA65493
(J.E.W.), R01 HL 63452 (B.R.B.), and the Children's Cancer Research Fund
(J.E.W., J.N.B.).
The publication costs of this article were defrayed in part by page charge
payment. Therefore, and solely to indicate this fact, this article is hereby
marked "advertisement" in accordance with 18 U.S.C. section
1734.
Reprints: Juliet Barker, Department of Medicine, Box 480, 420 Delaware
St, SE, Minneapolis, MN; e-mail:
barke014{at}tc.umn.edu.
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References
|
|---|
- Thomas ED, Blume K, Forman S, eds. Hematopoietic Cell
Transplantation. 2nd ed. Malden, MA: Blackwell Science;
1999.
- Sierra J, Storer B, Hansen JA, et al. Unrelated donor marrow
transplantation for acute myeloid leukemia: an update of the Seattle
experience. Bone Marrow Transplant.
2000;26:
397-404.[CrossRef][Medline]
[Order article via Infotrieve]
- Barker JN, Davies SM, DeFor TE, et al. Determinants of survival
after human leucocyte antigen matched unrelated donor bone marrow
transplantation in adults. Br J Haematol.
2002;118:
1-7.[CrossRef][Medline]
[Order article via Infotrieve]
- Giralt S, Estey E, Albitar M, et al. Engraftment of allogeneic
hematopoietic progenitor cells with purine analog-containing chemotherapy:
harnessing graft-versus-leukemia without myeloablative therapy.
Blood. 1997;89:
4531-4536.[Abstract/Free Full Text]
- Slavin S, Nagler A, Naparstek E, et al. Nonmyeloablative stem cell
transplantation and cell therapy as an alternative to conventional bone marrow
transplantation with lethal cytoreduction for the treatment of malignant and
nonmalignant hematologic diseases. Blood.
1998;91:
756-763.[Abstract/Free Full Text]
- Childs R, Clave E, Contentin N, et al. Engraftment kinetics after
nonmyeloablative allogeneic peripheral blood stem cell transplantation: full
donor T-cell chimerism precedes alloimmune responses. Blood.
1999;94:
3234-3241.[Abstract/Free Full Text]
- Sykes M, Preffer F, McAfee S, et al. Mixed lymphohaemopoietic
chimerism and graft-versus-lymphoma effects after non-myeloablative therapy
and HLA-mismatched bone-marrow transplantation. Lancet.
1999;353:
1755-1759.[CrossRef][Medline]
[Order article via Infotrieve]
- Khouri I, Keating M, Korbling M, et al. Transplantlite: induction
of graft-versus-malignancy using fludarabine-based nonablative chemotherapy
and allogeneic blood progenitor-cell transplantation as treatment for lymphoid
malignancies. J Clin Oncol.
1998;16:
2817-2824.[Abstract]
- Giralt S, Thall PF, Khouri I, et al. Melphalan and purine
analog-containing preparative regimens: reduced-intensity conditioning for
patients with hematologic malignancies undergoing allogeneic progenitor cell
transplantation. Blood.
2001;97:
631-637.[Abstract/Free Full Text]
- McSweeney PA, Niederwieser D, Shizuru JA, et al. Hematopoietic cell
transplantation in older patients with hematologic malignancies: replacing
high-dose cytotoxic therapy with graft-versus-tumor effects.
Blood. 2001;97:
3390-3400.[Abstract/Free Full Text]
- Nagler A, Aker M, Or R, et al. Low-intensity conditioning is
sufficient to ensure engraftment in matched unrelated bone marrow
transplantation. Exp Hematol.
2001;29:
362-370.[CrossRef][Medline]
[Order article via Infotrieve]
- Chakraverty R, Peggs K, Chopra R, et al. Limiting
transplantation-related mortality following unrelated donor stem cell
transplantation by using a nonmyeloablative conditioning regimen.
Blood. 2002;99:
1071-1078.[Abstract/Free Full Text]
- Childs R, Chernoff A, Contentin N, et al. Regression of metastatic
renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood
stem-cell transplantation. N Engl J Med.
2000;343:
750-758.[Abstract/Free Full Text]
- Gluckman E, Rocha V, Boyer-Chammard A, et al. Outcome of cord-blood
transplantation from related and unrelated donors. Eurocord Transplant Group
and the European Blood and Marrow Transplantation Group. N Engl J
Med. 1997;337:
373-381.[Abstract/Free Full Text]
- Rubinstein P, Stevens CE. Placental blood for bone marrow
replacement: the New York Blood Center's program and clinical results.
Baillieres Best Pract Res Clin Haematol.
2000;13:
565-584.[Medline]
[Order article via Infotrieve]
- Laughlin MJ, Barker J, Bambach B, et al. Hematopoietic engraftment
and survival in adult recipients of umbilical-cord blood from unrelated
donors. N Engl J Med.
2001;344:
1815-1822.[Abstract/Free Full Text]
- Wagner JE, Barker JN, DeFor TE, et al. Transplantation of unrelated
donor umbilical cord blood in 102 patients with malignant and nonmalignant
diseases: influence of CD34 cell dose and HLA disparity on treatment-related
mortality and survival. Blood.
2002;100:
1611-1618.[Abstract/Free Full Text]
- Barker JN, Krepski TP, DeFor TE, Davies SM, Wagner JE, Weisdorf DJ.
Searching for unrelated donor hematopoietic stem cells: availability and speed
of umbilical cord blood versus bone marrow. Biol Blood Marrow
Transplant. 2002;8:
257-260.[CrossRef][Medline]
[Order article via Infotrieve]
- Karnofsky DA. Meaningful clinical classification of therapeutic
responses to anti-cancer drugs. Clin Pharmacol Ther.
1961;2:
709-712.[Medline]
[Order article via Infotrieve]
- Rubinstein P, Dobrila L, Rosenfield RE, et al. Processing and
cryopreservation of placental/umbilical cord blood for unrelated bone marrow
reconstitution. Proc Natl Acad Sci U S A.
1995;92:
10119-10122.[Abstract/Free Full Text]
- Scharf SJ, Smith AG, Hansen JA, McFarland C, Erlich HA.
Quantitative determination of bone marrow transplant engraftment using
fluorescent polymerase chain reaction primers for human identity markers.
Blood. 1995;85:
1954-1963.[Abstract/Free Full Text]
- Schichman SA, Suess P, Vertino AM, Gray PS. Comparison of short
tandem repeat and variable number tandem repeat genetic markers for
quantitative determination of allogeneic bone marrow transplant engraftment.
Bone Marrow Transplant.
2002;29:
243-248.[CrossRef][Medline]
[Order article via Infotrieve]
- Glucksberg H, Storb R, Fefer A, et al. Clinical manifestations of
graft-versus-host disease in human recipients of marrow from HL-A-matched
sibling donors. Transplantation.
1974;18:
295-304.[Medline]
[Order article via Infotrieve]
- Lin DY. Non-parametric inference for cumulative incidence functions
in competing risks studies. Stat Med.
1997;16:
901-910.[CrossRef][Medline]
[Order article via Infotrieve]
- Kaplan EL, Meier P. Nonparametric estimation from incomplete
observations. J Am Stat Assoc.
1958;53:
457-481.[CrossRef]
- Petrus MJ, Williams JF, Eckhaus MA, Gress RE, Fowler DH. An
immunoablative regimen of fludarabine and cyclophosphamide prevents fully
MHC-mismatched murine marrow graft rejection independent of GVHD. Biol
Blood Marrow Transplant. 2000;6:
182-189.[CrossRef][Medline]
[Order article via Infotrieve]
- Luznik L, Jalla S, Engstrom LW, Iannone R, Fuchs EJ. Durable
engraftment of major histocompatibility complex-incompatible cells after
nonmyeloablative conditioning with fludarabine, low-dose total body
irradiation, and posttransplantation cyclophosphamide. Blood.
2001;98:
3456-3464.[Abstract/Free Full Text]
- Rocha, V, Wagner JE, Sobocinski KA, et al. Graft-versus-host
disease in children who have received a cord-blood or bone marrow transplant
from an HLA-identical sibling. N Engl J Med.
2000;342:
1846-1854.[Abstract/Free Full Text]
- Rocha V, Cornish J, Sievers EL, et al. Comparison of outcomes of
unrelated bone marrow and umbilical cord blood transplants in children with
acute leukemia. Blood.
2001;97:
2962-2971.[Abstract/Free Full Text]
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489 - 491.
[Abstract]
[Full Text]
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|
|
|
|
|
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January 1, 2004;
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354 - 371.
[Abstract]
[Full Text]
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|
|
|
|
|
|
|
B. A. Kaminski, S. Kadereit, R. E. Miller, P. Leahy, K. R. Stein, D. A. Topa, T. Radivoyevitch, M. L. Veigl, and M. J. Laughlin
Reduced expression of NFAT-associated genes in UCB versus adult CD4+ T lymphocytes during primary stimulation
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December 15, 2003;
102(13):
4608 - 4617.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
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Abstract
Introduction