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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Fred Hutchinson Cancer Research Center, the
University of Washington, and the Veterans Affairs Medical Center,
Seattle, WA.
A retrospective analysis of granulocyte colony-stimulating factor
(G-CSF)-mobilized peripheral blood mononuclear cell (G-PBMC) products
harvested from healthy donors indicates significant variability in both
the absolute number and relative proportion of CD34, CD3, and CD14
cells obtained. This report examined whether variations in the
cellular composition of G-PBMC products correlated with clinical
outcomes after myeloablative allogeneic transplantation. The
numbers of CD34, CD3, and CD14 cells infused into 181 human leukocyte
antigen (HLA)-identical sibling recipients were analyzed with respect
to tempo of engraftment, acute graft-versus-host-disease (GVHD),
clinical extensive chronic GVHD, overall survival, and disease relapse.
Neither acute GVHD, overall survival, nor disease relapse was
statistically significantly associated with CD34, CD3, or CD14 cell
doses or the CD14 to CD3 ratio. CD3 and CD14 cell doses and CD14 to CD3
ratios did not correlate with the tempo of neutrophil and platelet
engraftment. However, increasing CD34 cell numbers were significantly
associated with accelerated neutrophil (P = .03) and
platelet (P = .01) engraftment. Higher doses of CD34
cells (> 8.0 × 106/kg) were also associated with a
significantly increased hazard of clinical extensive chronic GVHD
(HR = 2.3, 95% confidence interval [CI] 1.4-3.7, P = .001), but neither CD3 nor CD14 doses were
statistically significantly associated with chronic GVHD. It was
concluded that CD34 cell dose in G-PBMC grafts appears to affect both
the engraftment kinetics and the development of clinical extensive
chronic GVHD in HLA-identical sibling recipients but without a
demonstrable impact on survival, relapse, and acute GVHD. Given the
morbidity associated with extensive chronic GVHD, efforts to further
accelerate engraftment in HLA-matched sibling transplants by increasing
CD34 cell number in G-PBMC products may be counterproductive.
(Blood. 2001;98:3221-3227) Successful engraftment of allogeneic hematopoietic
stem cells and clinical outcomes of transplantation are functions of
both stem and accessory cells present in the graft.1-3
Granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral
blood mononuclear cells (G-PBMCs) are now increasingly used in place of
bone marrow for allogeneic transplantation.4-8 Several
reports indicate that the clinical outcome of stem cell transplantation
in human leukocyte antigen (HLA)-identical siblings is improved by
substituting G-PBMCs for marrow cells.5,7,9,10 G-PBMCs
produce more rapid recovery of neutrophils and platelets than marrow
grafts. The improved survival among patients with advanced leukemia
appears to result from a decreased incidence of relapse but may also be
a consequence of reduced transplant-related mortality.5,7
It is not yet clear from these studies whether better survival would
also be seen in patients with less advanced leukemias, although one
preliminary report does suggest better survival in patients with less
advanced diseases due to decreased transplant-related
mortality.9 In most randomized studies comparing the use
of G-PBMCs with marrow cells for allogeneic HLA-identical
transplantation, the probability of acute graft-versus-host disease
(GVHD) was similar in recipients of G-PBMCs and recipients of marrow
grafts;6,7,11,12 however, there are conflicting data on
the risks of chronic GVHD.6-8,13
The biologic basis for the improved survival observed after G-PBMC
grafts is not clear but is likely related to differences in cellular
composition between marrow and G-PBMC grafts. The administration of
G-CSF to healthy donors and the harvesting technique of G-PBMCs with
the use of continuous-flow blood separators results in a cellular
composition of G-PBMCs that is not only quantitatively but also
qualitatively different from marrow grafts.14-17
Specifically, the number of CD3 cells can be more than 10-fold and the
number of CD14 cells up to 100-fold higher in G-PBMCs compared with
marrow. The CD14 cells express decreased levels of the T-cell
costimulation molecule B7 and secrete an increased amount of
interleukin-10, both of which serve to reduce T-cell responsiveness to
alloantigen by reducing the ability of CD4 cells to utilize the CD28
signaling pathway.18 However, this effect depends on the
CD14 to CD4 ratio.19 This ratio, as well as the number of
CD34, CD14, and CD3 cells, differs significantly among G-PBMC
products.16,20 We therefore hypothesized that variations
in the cell composition of the G-PBMC products could lead to
differences in immunologic properties, thereby affecting clinical
outcomes after HLA-identical sibling hematopoietic stem cell transplantation.
To test this hypothesis, we asked whether there was a correlation
between the cellular composition of G-PBMC grafts and clinical outcomes
in 181 HLA-identical sibling recipients treated with myeloablative
conditioning and G-PBMC transplantation for hematologic malignancies.
In this study, we retrospectively analyzed CD34, CD3, and CD14 cell
doses and the CD14 to CD3 ratio in G-PBMC grafts with respect to the
tempo of engraftment, risks of acute and clinical extensive GVHD,
disease relapse, and overall survival.
Patients
Donors
G-PBMC cell subsets enumeration Enumeration of CD34, CD14, and CD3 cells in each G-PBMC product was performed on a FACScan cytometer (Becton Dickinson, San Jose, CA) by the Cellular Therapy Laboratory, Fred Hutchinson Cancer Research Center. For each sample, 3 tubes were prepared and processed in parallel: (1) double staining with CD34 phycoerythrin (PE) (HPCA-2-PE; Becton Dickinson) and CD14 fluorescein isothiocyanate (FITC) (Leu-M3; Becton Dickinson); (2) double staining with Simultest CD3 PE and CD4 FITC (Leu 4/3A; Becton Dickinson); (3) matched isotype controls (Becton Dickinson). Viability of the specimen was determined by staining with 7-aminoactinomycin-D (7-AAD). Gates were set around forward versus side scatter and low 7-AAD staining to include only viable nucleated cells for further analysis. For CD34 determinations, additional gating to exclude CD14+ and high side scatter events was utilized. Equivalent gating on isotype controls was used for background subtraction. At least 100 000 total events were acquired on each sample.Clinical outcomes Clinical outcomes after transplantation that were considered included tempo of neutrophil and platelet engraftment; recoveries of neutrophils, monocytes, and lymphocytes within 100 days after transplantation; acute GVHD; clinical extensive chronic GVHD; overall survival; and disease relapse. Time to neutrophil engraftment was defined as the first of 3 consecutive days in which the absolute neutrophil count (ANC) exceeded 500/µL. Time to platelet engraftment was defined as the first of 7 consecutive days in which the platelet count exceeded 20 000/µL without transfusions. The absolute numbers of neutrophils, monocytes, and lymphocytes in patients after transplantation were calculated from the total number of white cells quantified by automated leukocyte counter (Sysmex E 2500, Kobe, Japan) and differential counts obtained from standard May-Grunwald-Giemsa-stained smears. One investigator graded the peak severity of acute GVHD according to previously published criteria.22 Patients were assessed for chronic GVHD after day +100 and graded by standard criteria.23Statistical analysis In order to assess the association of cell-type variables with outcome, non-cell-type variables were first examined using regression models. The non-cell-type variables examined included patient age at transplantation, patient/donor sex, patient/donor cytomegalovirus (CMV) serostatus, risk of disease (advanced vs less advanced), use of total body irradiation (TBI) for conditioning, presence of major ABO mismatch, and GVHD prophylaxis (methotrexate/cyclosporine [MTX/CSP] vs others). Non-cell-type variables that were significantly or suggestively associated with outcome were used to create a "base" model for each outcome. Once this base model was fit, each cell-type variable was added to assess the improvement to the base model. The significance of the improvement was measured by the likelihood ratio test. Each cell-type variable was modeled as a continuous variable, a log-transformed variable, and according to quartiles. Logistic regression was used for the outcome grades II-IV acute GVHD; Cox regression24 was used for the outcomes clinical extensive chronic GVHD, relapse, and survival, and linear regression was used for the engraftment outcomes among those who engrafted. The association of clinical extensive chronic GVHD with the hazard of relapse was examined by treating GVHD as a time-dependent covariate. Spearman rank correlation coefficient was used to estimate the correlation between cell types and to associate cell dose with time to engraftment. All P values are 2-sided and no adjustments were made for multiple comparisons; values between .01 and .05 should therefore be considered as suggestive of a difference rather than definitive evidence of a difference. P values from fitted regression models were derived from the Wald test. Cumulative incidence estimates were used to measure the probability of clinical extensive chronic GVHD and relapse.25 Probability of survival was estimated by the method of Kaplan and Meier.26
Cellular composition of G-PBMC grafts Table 2 shows the absolute numbers of CD34, CD3, and CD14 cells and CD14 to CD3 cell ratios in G-PBMC products. The correlation between CD34 and CD3 cells was suggestively significant, but the strength of the correlation was relatively low (R = .15, P = .04). Similarly, the correlation between CD34 and CD14 cells was statistically significant, but the strength of the association was relatively weak (R = .21, P = .005). On the other hand, the correlation between CD3 and CD14 cells was stronger (R = .58, P < .0001, Figure 1). Table 3 shows the average CD3 and CD14 cell doses as well as the average CD14 to CD3 ratio among the high and low CD34 dose groups.
Correlation between clinical outcomes and cellular composition of G-PBMC grafts Engraftment.
Twelve patients never reached a sustained neutrophil count of more than
500/µL and died at a median of 9.5 days (range, 2-46 days)
after the transplantation. Thirty-seven patients failed to reach a
sustained platelet count of more than 20 000/µL before returning to
the care of the referring physician; 35 of these 37 died at a median of
27 days (range, 2-251 days) after the transplantation. Average CD34,
CD3, and CD14 cell doses infused were similar among patients who did
and did not reach neutrophil and platelet engraftment (data not shown).
Neutrophil engraftment (> 500/µL) occurred between 10 and 33 days
(median 16 days), whereas unsupported platelet counts of more than
20 000 were achieved between 7 and 39 days (median 14 days). No
non-cell-type variables were statistically significantly associated
with time to neutrophil or platelet recoveries. Among patients who
reached a sustained neutrophil count of more than 500/µL, an
increased CD34 cell dose was suggestively associated with a shorter
time to neutrophil recovery, although the strength of the association
was relatively weak (R = .15, P = .06; Figure 2). The median (mean) day of neutrophil
recovery by quartiles of CD34 cells was 16 (17.2), 16 (15.7), 16 (15.3), and 15 (16.0), respectively. Among patients who achieved a
sustained platelet count of more than 20 000/µL, an increased CD34
cell dose was also suggestively associated with a faster time to
platelet recovery, although the association was not strong (R = .18,
P = .03; Figure 3). The
median (mean) day of platelet recovery by quartiles of CD34 cells was
14 (15.8), 14 (14.8), 13 (14.8), and 13.5 (13.2), respectively. In
contrast, neither CD3 cell dose, CD14 cell dose, nor CD14 to CD3 cell
ratio was statistically significantly associated with the tempo of
neutrophil (Table 4) or platelet
engraftment (Table 4). In addition, none of the other cell type
variables (CD3 cell dose, CD14 cell dose, CD14 to CD3 ratio)
qualitatively changed the association between CD34 cell dose and time
to neutrophil and platelet engraftment (data not shown). Table
5 summarizes the proportion of patients
who achieved sustained neutrophil and platelet engraftment according to
CD34 cell dose.
Acute GVHD. Acute GVHD grading information was missing for 8 patients at the time of analysis. Among the remaining 173, 117 (68%; 95% CI, 61%-75%) developed grades II-IV GVHD. Thirty-five patients (20%; 95% CI, 14%-26%) developed grades III-IV GVHD. Among non-cell-type variables, patient/donor CMV serostatus and patient age were suggestively associated with the probability of grades II-IV acute GVHD. After controlling for these factors, none of the cell-type variables was statistically significantly associated with the probability of acute GVHD (Table 4). Table 5 summarizes the proportion of patients who developed grades II-IV acute GVHD according to CD34 cell dose. Clinical extensive chronic GVHD.
Clinical extensive chronic GVHD developed in 81 patients at a median of
156 days (range, 76-861 days) after the transplantation. The
cumulative incidence estimate of the probability of clinical extensive
chronic GHVD among all 181 patients at 3 years was 46% (95% CI,
39%-54%). One hundred nine patients developed clinical chronic GVHD
for a cumulative incidence estimate of the probability at 3 years of
61%. Among 126 patients who survived to day 80 without relapse, the
estimate of the probability of clinical extensive GVHD at 3 years was
64% (95% CI, 56%-73%). Among non-cell-type variables, age at
transplantation, patient/donor sex, and risk of the disease were
suggestively associated with the hazard of extensive chronic GVHD when
all patients were included in the analysis. After controlling for these
factors, increased CD34 cell dose was statistically significantly
associated with an increased hazard of clinical extensive chronic GVHD
(P = .01, log-transformed CD34 dose). In comparing
"high" versus "low" CD34 doses (defined arbitrarily as above
and below the median of 8.0 × 106 cells/kg), the hazard
of clinical extensive chronic GVHD was increased among patients who
received high CD34 doses compared with those given low doses (adjusted
HR = 2.3; 95% CI, 1.4-3.7; P = .001). Figure
4 shows the probability of clinical
extensive chronic GVHD according to quartiles of CD34 cells. After
controlling for variables contained in the base model, neither CD3 nor
CD14 cell dose or CD14 to CD3 ratio showed any suggestion of an
association with the hazard of clinical extensive chronic GVHD (Table
4). In addition, none of the other cell variables qualitatively changed the association between CD34 and the hazard of clinical extensive chronic GVHD (data not shown). Table 5 summarizes the proportion of
patients who developed clinical extensive chronic GVHD according to
CD34 cell dose.
Relapse. Thirty-eight patients had a recurrence of their underlying disease. The cumulative incidence estimate of relapse at one year was 21% (95% CI, 15%-27%). Only stage of disease at the time of the transplantation (advanced vs nonadvanced) was statistically significantly associated with the hazard of relapse among the non-cell-type variables examined. After controlling for stage of disease, none of the cell-type variables showed a statistically significant association with the hazard of relapse (Table 4). This lack of association appeared to be relatively consistent according to disease type (data not shown). In addition, the presence of clinical extensive chronic GVHD showed no suggestion of being associated with a decreased hazard of relapse (adjusted HR = 1.6; 95% CI, 0.7 to 3.6; P = .25). The presence of clinical (limited or extensive) chronic GVHD also showed absolutely no suggestion of being associated with a decreased hazard of relapse (adjusted HR = 2.2; 95% CI, 0.9 to 5.4; P = .08). Table 5 summarizes the proportion of patients who relapsed according to CD34 cell dose. Survival. A total of 94 deaths had occurred by the time of final analysis. The Kaplan-Meier estimate of survival among all 181 patients at 3 years was 44% (95% CI, 36%-52%) with a median follow-up among surviving patients of 831 days (range, 84-1871 days). Among the non-cell-type variables, disease risk, patient/donor sex, and patient/donor CMV serostatus were statistically significantly associated with the hazard of mortality. After controlling for these factors, none of the cell-type variables was statistically significantly associated with the hazard of mortality (Table 4). Moreover, none of the cell-type variables was statistically significantly associated with the hazard of nonrelapse mortality (data not shown). Table 5 summarizes the proportion of patients who died according to CD34 cell dose.
In the current study, we have confirmed initial observations14,27 that the number of cells with selected cell subtypes given in G-PBMC grafts was highly variable. This was most likely caused by differences in the G-CSF-induced mobilization of CD34 and accessory cells in healthy donors or differences in the starting basal levels of those cell types in the donors and, in some cases, the disproportion between donor and recipient weights. Variations in CD34, CD3, and CD14 cell numbers in G-PBMC grafts allowed us to analyze the impact of dose of selected cell subtypes on various clinical outcomes after HLA-identical hematopoietic stem cell transplantation. The role of CD3 cells in the development of acute and chronic GVHD as well as in relapse after conventional bone marrow transplantation has been clearly established.1,28 In the current study, however, we found no statistically significant association between CD3 cell dose and the probability of acute GVHD. This is consistent with initial observations suggesting that the risk of acute GVHD is not increased after G-PBMC transplants, despite the infusion of 1 to 2 logs more T cells compared with marrow grafts.5,29 The lack of correlation between CD3 cell dose and risk of acute GVHD might be explained by the diminished alloresponsiveness of T cells in G-PBMC grafts.30-32 Alternatively, a hypothesis originally generated by Kernan et al33 would suggest that once the initial threshold of clonogenic T cells has been exceeded, a further increase in T-cell numbers does not necessarily translate into more acute GVHD for a given degree of genetic disparity between donor and recipient. Support for this hypothesis comes from the clinical studies of T-cell-depleted marrow grafts. In those studies, a threshold dose of approximately 105 residual CD3 cells/kg was identified, above which there was no correlation between the risk of acute GVHD and CD3 cell dose.33,34 We also found no statistically significant correlations between CD14 cell dose and clinical outcomes except for association of higher CD14 cell dose with higher average monocyte counts within 100 days after the transplantation. Interestingly, patients who received G-PBMC products with the highest CD14 to CD3 ratios had higher average lymphocyte counts within 100 days after the transplantation. Those findings suggest that CD14 cells may indeed play a role in the immune recovery after G-PBMC transplantations. We were specifically interested in whether the inhibitory effect of CD14 cells on T-cell functions observed in vitro31 affected the probability of acute GVHD. The apparent lack of correlation between the CD14 to CD3 cell ratio and acute GVHD may argue that this was only an in vitro epiphenomenon. However, in vitro studies showed that the inhibitory effect of monocytes on T-cell function depended on the ratio of CD14 to CD3 cells and reached its maximum when the number of monocytes was equal or higher than lymphocytes.31 In the current study, most of the patients (85%) received grafts with approximately equal or higher numbers of CD14 to CD3 cells. Therefore, there were too few patients receiving G-PBMCs with low CD14 to CD3 ratios to estimate the impact of relatively low proportions of CD14 cells. Studies using partial T-cell depletion of G-PBMCs could answer this question. A relationship between CD34 cell dose and transplantation outcome was first shown in marrow autografts in which 1 × 106 of CD34 cells/kg was identified as a safe minimum dose for engraftment.35 In the current study, increased CD34 cell dose was also suggestively associated with faster hematopoietic engraftment. However, this association might be of limited biologic significance since in the current study the difference between the median days of neutrophil engraftment for patients receiving a high (> 12 × 106/kg) and lower (4 × 106/kg-8 × 106/kg) CD34 cell dose was only 1 day, and there was no difference in days to platelet engraftment. This would be consistent with the observation made originally by Gianni et al that increasing the progenitor cell dose above a certain threshold had a limited potential to further accelerate neutrophil recovery.36 We did not observe a statistically significant association between CD34 cell dose and probability of acute GVHD. This stands in contrast to the results recently reported by Przepiorka et al.37 However, in that study, the association between CD34 cell dose and risk of acute GVHD depended on the type of postgrafting immunosuppression. The short course of methotrexate and cyclosporine, which was given to most current patients as GVHD prophylaxis, was not used in that study. Therefore, the differences in GVHD prophylaxis regimens may explain the apparent discrepancy between these 2 studies. In the current study, an increased CD34, but not CD3, cell dose was statistically significantly associated with an increased hazard of developing clinical extensive chronic GVHD. Comparable results were previously reported in abstract form by Przepiorka et al.38 Cell dose is a continuous variable, and as such it is difficult to identify a precise CD34 cell dose above which the risk of extensive chronic GVHD is markedly increased. However, both studies suggest that patients receiving CD34 cell dose in excess of 8 × 106/kg have a higher risk of developing extensive chronic GVHD. This is an important finding since chronic GVHD limits the quality of life in long-term transplantation survivors. Additionally, our study suggests that the variations in CD34 cell doses given to G-PBMC recipients may explain some of the conflicting data reported so far on the risk of chronic GVHD after G-PBMC transplantations.6-8,13 In the current study, there was no suggestion that CD34 cell dose or extensive chronic GVHD was statistically significantly associated with a decreased risk of relapse. These results differ from previously published studies that reported an inverse association between chronic GVHD and risk of relapse39,40 suggesting that the graft-versus-leukemia effect carried by G-PBMC grafts is not further improved when clinical symptoms of extensive chronic GVHD develop. Recently reported results from the International Bone Marrow Transplant Registry also suggest that increased severity of chronic GVHD did not correlate with a reduced risk of relapse among HLA-identical siblings receiving conventional hematopoietic cell transplants.41 Variations in CD34, CD3, and CD14 cells in G-PBMC grafts did not statistically significantly affect overall survival. This finding suggests that improved survival observed after G-PBMC compared with marrow grafts is unlikely to be further improved by "mega-doses" of G-PBMCs. Potential benefits of slightly faster engraftment related to an increased CD34 cell dose would appear to be offset by the increasing risk of extensive chronic GVHD, which has been reported to be more severe and more difficult to treat in G-PBMC than bone marrow recipients.42 Our results suggest that the risk of clinical extensive chronic GVHD can be lowered among patients who receive unmodified G-PBMC grafts by controlling the number of CD34 cells. CD34 cell doses of more than 4 × 106/kg and less than 8 × 106/kg may lead to a decreased hazard of developing clinical extensive chronic GVHD, compared with doses in excess of 8 × 106/kg, without compromising time to hematopoietic recovery or affecting relapse rate or survival. In fact, if time to death or chronic GVHD is analyzed as a composite end point, the conclusions for the chronic GVHD end point drawn with respect to CD34 remain qualitatively the same. Studies of the various differentiation pathways for CD34 cells in vitro and in vivo might yield insights to elucidate the pathophysiology of this association with chronic GVHD.
We thank Nancy Anderson, Beth Macleod, David Yadock, and the dedicated staff of the Fred Hutchinson Cancer Research Center Cellular Therapy Laboratory for performing all flow cytometry staining and analyses. The authors thank Chris Davis for outstanding help in data retrieval. We are very grateful to Helen Crawford, Bonnie Larson, and Karen Carbonneau for their secretarial support. We also appreciate the work of the staff of the Fred Hutchinson Cancer Research Center who provided the care to the patients.
Submitted March 26, 2001; accepted July 19, 2001.
Supported in part by grants DK51417, CA18029, CA18221, DK56465, HL54881, HL36444, and CA15704 from the National Institutes of Health, Department of Health and Human Services (DHHS), Bethesda, MD. J.M.Z is a postdoctoral fellow from the Department of Hematology, University Medical School, Gdañsk, Poland, and is also a recipient of the International Fellowship for Young PhDs, awarded by the Foundation for Polish Science, Warsaw, Poland.
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: Beverly Torok-Storb, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave North, D1-100, PO Box 19024, Seattle, WA, 98109-1024; e-mail: btorokst{at}fhcrc.org.
1. Martin PJ. The role of donor lymphoid cells in allogeneic marrow engraftment. Bone Marrow Transplant. 1990;6:283-289[Medline] [Order article via Infotrieve].
2.
Siena S, Schiavo R, Pedrazzoli P, Carlo-Stella C.
Therapeutic relevance of CD34+ cell dose in blood cell transplantation for cancer therapy.
J Clin Oncol.
2000;18:1360-1377 3. Mielcarek M, Purton LE, Torok-Storb B. Accessory cell function may be retained in CD34-selected G-CSF mobilized peripheral blood mononuclear cells. Br J Haematol. 1996;93:495-497[Medline] [Order article via Infotrieve]. 4. Gyger M, Stuart RK, Perreault C. Immunobiology of allogeneic peripheral blood mononuclear cells mobilized with granulocyte-colony stimulating factor. Bone Marrow Transplant. 2000;26:1-16[CrossRef][Medline] [Order article via Infotrieve].
5.
Champlin RE, Schmitz N, Horowitz MM, et al.
Blood stem cells compared with bone marrrow as a source of hematopoietic cells for allogeneic transplantation.
Blood.
2000;95:3702-3709
6.
Blaise D, Kuentz M, Fortanier C, et al.
Randomized trial of bone marrow versus lenograstim-primed blood cell allogeneic transplantation in patients with early-stage leukemia: a report from the Société Française de Greffe de Moelle.
J Clin Oncol.
2000;18:537-571
7.
Bensinger WI, Martin PJ, Storer B, et al.
Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers.
N Engl J Med.
2001;344:175-181 8. Schmitz N, Beksac M, Hasenclever D, et al. A randomised study from the European Group for Blood and Marrow Transplantation comparing allogeneic transplantation of filgrastim-mobilised peripheral blood progenitor cells with bone marrow transplantation in 350 patients (pts) with leukemia [abstract]. Blood. 2000;96:481aAbstract 2068. 9. Simpson DR, Couban S, Bredeson C, et al. A Canadian randomized study comparing peripheral blood (PB) and bone marrow (BM) in patients undergoing matched sibling transplants for myeloid malignancies [abstract]. Blood. 2000;96:481aAbstract 2067.
10.
Elmaagacli AH, Beelen DW, Opalka B, Seeber S, Schaefer UW.
The risk of residual molecular and cytogenetic disease in patients with Philadelphia-chromosome positive first chronic phase chronic myelogenous leukemia is reduced after transplantation of allogeneic peripheral blood stem cells compared with bone marrow.
Blood.
1999;94:384-389 11. Vigorito AC, Azevedo WM, Marques JF, et al. A randomised, prospective comparison of allogeneic bone marrow and peripheral blood progenitor cell transplantation in the treatment of haematological malignancies. Bone Marrow Transplant. 1998;22:1145-1151[CrossRef][Medline] [Order article via Infotrieve]. 12. Powles R, Mehta J, Kulkarni S, et al. Allogeneic blood and bone-marrow stem-cell transplantation in haematological malignant diseases: a randomised trial. Lancet. 2000;355:1231-1237[CrossRef][Medline] [Order article via Infotrieve]. 13. Powles R, Mehta J, Treleaven J, et al. Blood or BM for allogeneic transplantation from HLA-identical siblings? Extended follow-up of a randomized study confirms significantly higher relapse with BM [abstract]. Blood. 2000;96:196aAbstract 841. 14. Dreger P, Haferlach T, Eckstein V, et al. G-CSF-mobilized peripheral blood progenitor cells for allogeneic transplantation: safety, kinetics of mobilization, and composition of the graft. Br J Haematol. 1994;87:609-613[Medline] [Order article via Infotrieve]. 15. Theilgaard-Monch K, Raaschou-Jensen K, Andersen H, et al. Single leukapheresis products collected from healthy donors after the administration of granulocyte colony-stimulating factor contain ten-fold higher numbers of long-term reconstituting hematopoietic progenitor cells than conventional bone marrow allografts. Bone Marrow Transplant. 1999;23:243-249[CrossRef][Medline] [Order article via Infotrieve].
16.
Storek J, Dawson MA, Storer B, et al.
Immune reconstitution after allogeneic marrow versus blood stem cell transplantation.
Blood.
2001;97:3380-3389 17. Carlo-Stella C, Cesana C, Regazzi E, et al. Peripheral blood progenitor cell mobilization in healthy donors receiving recombinant human granulocyte colony-stimulating factor. Exp Hematol. 2000;28:216-224[CrossRef][Medline] [Order article via Infotrieve].
18.
Tanaka J, Mielcarek M, Torok-Storb B.
Impaired induction of the CD28-responsive complex in granulocyte colony-stimulating factor mobilized CD4 T cells.
Blood.
1998;91:347-352
19.
Mielcarek M, Graf L, Johnson G, Torok-Storb B.
Production of interleukin-10 by granulocyte colony-stimulating factor-mobilized blood products: a mechanism for monocyte-mediated suppression of T cell proliferation.
Blood.
1998;92:215-222
20.
Chatta GS, Price TH, Allen RC, Dale DC.
Effects of in vivo recombinant methionyl human granulocyte colony-stimulating factor on the neutrophil response and peripheral blood colony-forming cells in healthy young and elderly adult volunteers.
Blood.
1994;84:2923-2929 21. Deeg HJ. Prophylaxis and treatment of acute graft-versus-host disease: current state, implications of new immunopharmacologic compounds and future strategies to prevent and treat acute GVHD in high-risk patients. Bone Marrow Transplant. 1994;14:S56-S60. 22. Przepiorka D, Weisdorf D, Martin P, et al. Consensus conference on acute GVHD grading. Bone Marrow Transplant. 1995;15:825-828[Medline] [Order article via Infotrieve]. 23. Loughran TP Jr, Sullivan KM. Early detection and monitoring of chronic graft-vs-host disease. In: Burakoff SJ,Deeg HJ,Ferrara J,Atkinson K, eds. Graft-vs-Host Disease: Immunology, Pathophysiology, and Treatment. New York, NY: Marcel Dekker; 1990:631-636. 24. Cox DR. Regression models and life-tables (with discussions), Series B. J R Stat Soc. 1972;34:187-220. 25. Gooley TA, Leisenring W, Crowley J, Storer BE. Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med. 1999;18:695-706[CrossRef][Medline] [Order article via Infotrieve]. 26. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457-481[CrossRef]. 27. Zaucha JM, Bieniaszewska M, Knopiñska-Posluszny W, Halaburda K, Hellmann A. The results of collection and mobilization of progenitor cells into peripheral blood with G-CSF in healthy donors for allogeneic peripheral blood stem cell transplantaion. Acta Haematol Pol. 1998;29:61-68.
28.
Storb R, Doney KC, Thomas ED, et al.
Marrow transplantation with or without donor buffy coat cells for 65 transfused aplastic anemia patients.
Blood.
1982;59:236-246
29.
Bensinger WI, Clift R, Martin P, et al.
Allogeneic peripheral blood stem cell transplantation in patients with advanced hematologic malignancies: a retrospective comparison with marrow transplantation.
Blood.
1996;88:2794-2800 30. Leung W, Ramírez M, Mukherjee G, Perlman EJ, Civin CI. Comparisons of alloreactive potential of clinical hematopoietic grafts. Transplantation. 1999;68:628-635[CrossRef][Medline] [Order article via Infotrieve].
31.
Mielcarek M, Martin P, Torok-Storb B.
Suppression of alloantigen-induced T-cell proliferation by CD14+ cells derived from granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood mononuclear cells.
Blood.
1997;89:1629-1634 32. Reyes E, García-Castro I, Esquivel F, et al. Granulocyte colony-stimulating factor (G-CSF) transiently suppresses mitogen-stimulated T-cell proliferative response. Br J Cancer. 1999;80:229-235[CrossRef][Medline] [Order article via Infotrieve].
33.
Kernan NA, Collins NM, Juliano L, Cartagenia T, Dupont B, O'Reilly RJ.
Clonable T lymphocytes in T cell-depleted bone marrow transplants correlate with development of graft-v-host disease.
Blood.
1986;68:770-773 34. Atkinson K, Farrelly H, Cooley M, O'Flaherty E, Downs K, Biggs J. Human marrow T cell dose correlates with severity of subsequent acute graft-versus-host disease. Bone Marrow Transplant. 1987;2:51-57[Medline] [Order article via Infotrieve]. 35. Bensinger WI, Longin K, Appelbaum F, et al. Peripheral blood stem cells (PBSCs) collected after recombinant granulocyte colony stimulating factor (rhG-CSF): an analysis of factors correlating with the tempo of engraftment after transplantation. Br J Haematol. 1994;87:825-831[Medline] [Order article via Infotrieve]. 36. Gianni AM, Bregni M, Siena S, et al. Rapid and complete hemopoietic reconstitution following combined transplantation of autologous blood and bone marrow cells: a changing role for high dose chemo-radiotherapy. Hematol Oncol. 1989;7:139-148[Medline] [Order article via Infotrieve].
37.
Przepiorka D, Smith TL, Folloder J, et al.
Risk factors for acute graft-versus-host disese after allogeneic blood stem cell transplantation.
Blood.
1999;94:1465-1470 38. Przepiorka D, Anderlini P, Cleary K, et al. The risk of chronic GVHD after allogeneic blood stem cell transplantation is altered by GVHD prophylaxis and CD34+ cell dose [abstract]. Blood. 1998;92(suppl 1):457aAbstract 1886.
39.
Horowitz MM, Gale RP, Sondel PM, et al.
Graft-versus-leukemia reactions after bone marrow transplantation.
Blood.
1990;75:555-562 40. Weiden PL, Sullivan KM, Flournoy N, Storb R, Thomas ED, and the Seattle Marrow Transplant Team. Antileukemic effect of chronic graft-versus-host disease: contribution to improved survival after allogeneic marrow transplantation. N Engl J Med. 1981;304:1529-1533[Medline] [Order article via Infotrieve]. 41. Lee SJ, Klein JP, Barrett AJ, et al. Chronic graft-vs-host disease (cGVHD) severity score: effects on leukemia-free survival [abstract]. Blood. 2000;96:556aAbstract 2388. 42. Flowers MED, Matos AVB, Storer B, et al. Clinical manifestation of chronic graft-versus-host disease (cGVHD) after transplantation of peripheral blood stem cell (PBSC) compared to bone marrow (BM) [abstract]. Blood. 2000;96:203aAbstract 869.
© 2001 by The American Society of Hematology.
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 |
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  A. A. Jakubowski, T. N. Small, J. W. Young, N. A. Kernan, H. Castro-Malaspina, K. C. Hsu, M.-A. Perales, N. Collins, C. Cisek, M. Chiu, et al. T cell depleted stem-cell transplantation for adults with hematologic malignancies: sustained engraftment of HLA-matched related donor grafts without the use of antithymocyte globulin Blood, December 15, 2007; 110(13): 4552 - 4559. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Talarn, A. Urbano-Ispizua, R. Martino, J. A. Perez-Simon, M. Batlle, C. Herrera, M. Granell, A. Gaya, M. Torrebadell, F. Fernandez-Aviles, et al. Kinetics of recovery of dendritic cell subsets after reduced-intensity conditioning allogeneic stem cell transplantation and clinical outcome Haematologica, December 1, 2007; 92(12): 1655 - 1663. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Pabst, H. Schirutschke, G. Ehninger, M. Bornhauser, and U. Platzbecker The Graft Content of Donor T Cells Expressing {gamma}{delta}TCR+ and CD4+foxp3+ Predicts the Risk of Acute Graft versus Host Disease after Transplantation of Allogeneic Peripheral Blood Stem Cells from Unrelated Donors Clin. Cancer Res., May 15, 2007; 13(10): 2916 - 2922. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Rezvani, S. Mielke, M. Ahmadzadeh, Y. Kilical, B. N. Savani, J. Zeilah, K. Keyvanfar, A. Montero, N. Hensel, R. Kurlander, et al. High donor FOXP3-positive regulatory T-cell (Treg) content is associated with a low risk of GVHD following HLA-matched allogeneic SCT Blood, August 15, 2006; 108(4): 1291 - 1297. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Abbasian, D. Mahmud, N. Mahmud, S. Chunduri, H. Araki, P. Reddy, R. Hoffman, M. Arpinati, J. L. M. Ferrara, and D. Rondelli Allogeneic T cells induce rapid CD34+ cell differentiation into CD11c+CD86+ cells with direct and indirect antigen-presenting function Blood, July 1, 2006; 108(1): 203 - 208. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Z. Pavletic, S. L. Carter, N. A. Kernan, J. Henslee-Downey, A. M. Mendizabal, E. Papadopoulos, R. Gingrich, J. Casper, S. Yanovich, D. Weisdorf, et al. Influence of T-cell depletion on chronic graft-versus-host disease: results of a multicenter randomized trial in unrelated marrow donor transplantation Blood, November 1, 2005; 106(9): 3308 - 3313. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Banovic, K. P. A. MacDonald, E. S. Morris, V. Rowe, R. Kuns, A. Don, J. Kelly, S. Ledbetter, A. D. Clouston, and G. R. Hill TGF-{beta} in allogeneic stem cell transplantation: friend or foe? Blood, September 15, 2005; 106(6): 2206 - 2214. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Lee New approaches for preventing and treating chronic graft-versus-host disease Blood, June 1, 2005; 105(11): 4200 - 4206. [Abstract] [Full Text] [PDF]
|
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|
|
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|
 F. Baron, M. B. Maris, B. M. Sandmaier, B. E. Storer, M. Sorror, R. Diaconescu, A. E. Woolfrey, T. R. Chauncey, M. E.D. Flowers, M. Mielcarek, et al. Graft-Versus-Tumor Effects After Allogeneic Hematopoietic Cell Transplantation With Nonmyeloablative Conditioning J. Clin. Oncol., March 20, 2005; 23(9): 1993 - 2003. [Abstract] [Full Text] [PDF]
|
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|
|
 |
|
 S. Singhal, L. Gordon, R. Meagher, A. Evens, M. Tallman, S. Williams, J. Winter, D. Grinblatt, L. Kaminer, and J. Mehta The CD34+ Cell Dose, Even in an "Acceptable" Range, Affects Outcome of Allogeneic Blood Stem Cell Transplantation. Blood (ASH Annual Meeting Abstracts), November 16, 2004; 104(11): 1153 - 1153. [Abstract] [Full Text]
|
|
|
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|
|
E. Chklovskaia, P. Nowbakht, C. Nissen, A. Gratwohl, M. Bargetzi, and A. Wodnar-Filipowicz Reconstitution of dendritic and natural killer-cell subsets after allogeneic stem cell transplantation: effects of endogenous flt3 ligand Blood, May 15, 2004; 103(10): 3860 - 3868. [Abstract] [Full Text] [PDF]
|
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M. Stanzani, S. L. R. Martins, R. M. Saliba, L. S. St. John, S. Bryan, D. Couriel, J. McMannis, R. E. Champlin, J. J. Molldrem, and K. V. Komanduri CD25 expression on donor CD4+ or CD8+ T cells is associated with an increased risk for graft-versus-host disease after HLA-identical stem cell transplantation in humans Blood, February 1, 2004; 103(3): 1140 - 1146. [Abstract] [Full Text] [PDF]
|
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|
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|
K. J. Thomson, S. Ings, M. Watts, S. Mackinnon, and K. S. Peggs CD34+ cell dose and the occurrence of GVHD in the presence of in vivo T-cell depletion Blood, January 15, 2004; 103(2): 743 - 743. [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Stone, M. R. O'Donnell, and M. A. Sekeres Acute Myeloid Leukemia Hematology, January 1, 2004; 2004(1): 98 - 117. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Perez-Simon, M. Diez-Campelo, R. Martino, A. Sureda, D. Caballero, C. Canizo, S. Brunet, A. Altes, L. Vazquez, J. Sierra, et al. Impact of CD34+ cell dose on the outcome of patients undergoing reduced-intensity-conditioning allogeneic peripheral blood stem cell transplantation Blood, August 1, 2003; 102(3): 1108 - 1113. [Abstract] [Full Text] [PDF]
|
|
|
|
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M. Mohty, M. Kuentz, M. Michallet, J.-H. Bourhis, N. Milpied, L. Sutton, J.-P. Jouet, M. Attal, P. Bordigoni, J.-Y. Cahn, et al. Chronic graft-versus-host disease after allogeneic blood stem cell transplantation: long-term results of a randomized study Blood, October 16, 2002; 100(9): 3128 - 3134. [Abstract] [Full Text] [PDF]
|
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|
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M. E. D. Flowers, P. M. Parker, L. J. Johnston, A. V. B. Matos, B. Storer, W. I. Bensinger, R. Storb, F. R. Appelbaum, S. J. Forman, K. G. Blume, et al. Comparison of chronic graft-versus-host disease after transplantation of peripheral blood stem cells versus bone marrow in allogeneic recipients: long-term follow-up of a randomized trial Blood, June 28, 2002; 100(2): 415 - 419. [Abstract] [Full Text] [PDF]
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R. Handgretinger, P. Lang, T. Klingebiel, D. Niethammer ;, R. Storb, P. J. Martin, J. M. Zaucha, W. I. Bensinger, M. E. D. Flowers, G. Georges, et al. CD34 stem cell dose and development of extensive chronic graft-versus-host disease Blood, May 15, 2002; 99(10): 3875 - 3877. [Full Text] [PDF]
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Abstract
Introduction
