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Prepublished online as a Blood First Edition Paper on May 17, 2002; DOI 10.1182/blood-2002-01-0048.
PLENARY PAPER
From the Department of Medicine, Dalhousie University
and Queen Elizabeth II Health Sciences Centre, Halifax, NS, Canada;
North Shore Hospital, Takapuna, Auckland, New Zealand; Vancouver
Hospital and Health Sciences Centre and British Columbia Cancer Agency,
Vancouver, BC, Canada; Statistical Center of the International Bone
Marrow Transplant Registry, Health Policy Institute, Medical College of
Wisconsin, Milwaukee; Department of Medicine, Ottawa Hospital and
University of Ottawa, ON, Canada; Departments of Medicine and Oncology,
London Health Sciences Centre and London Regional Cancer Centre,
University of Western Ontario, London, ON, Canada; Weill Medical
College of Cornell University, New York Presbyterian Hospital, New
York; Department of Medicine, McMaster University, Hamilton, ON,
Canada; Division of Molecular Medicine, Faculty of Medical and Health
Sciences, University of Auckland, New Zealand; and Departments of
Medical Oncology and Biostatistics, Princess Margaret Hospital and
University of Toronto, ON, Canada.
Cytokine-mobilized peripheral blood is increasingly used instead of
bone marrow as the source of cells for allogeneic transplantation. Although cells lead to faster hematologic recovery, their effects on
graft-versus-host disease, relapse, and survival are less certain. Between January 1996 and February 2000, 228 patients with chronic myeloid leukemia, acute myeloid leukemia, or myelodysplasia were randomized to receive either bone marrow or peripheral blood allografts from HLA-matched siblings. All patients received busulfan and cyclophosphamide as conditioning chemotherapy and cyclosporine and
methotrexate as graft-versus-host disease prophylaxis. We compared the
times to neutrophil and platelet recovery, acute and chronic
graft-versus-host disease, relapse, and overall survival between the
groups. The median times to neutrophil recovery were 19 days and 23 days and the times to platelet recovery were 16 days and 22 days in the
peripheral blood and bone marrow groups, respectively
(P < .0001 for both comparisons). The cumulative incidence of grades II to IV acute graft-versus-host disease 100 days
after transplantation was 44% in both groups (hazard ratio, 0.99; 95%
confidence interval, 0.66-1.49; P > .9), and the
incidence of extensive chronic graft-versus-host disease at 30 months
after transplantation was 40% with peripheral blood and 30%
with bone marrow (hazard ratio, 1.23; 95% confidence interval,
0.78-1.96; P = .37). There was no statistically
significant difference in the probability of relapse of the underlying
disease between the groups. The probabilities of survival at 30 months
after transplantation were 68% and 60% in the peripheral
blood and bone marrow groups, respectively (hazard ratio, 0.62; 95%
confidence interval, 0.39-0.97; P = .04). In patients
with chronic myeloid leukemia, acute myeloid leukemia, and
myelodysplasia undergoing allogeneic transplantation from matched
siblings, the use of peripheral blood instead of bone marrow leads to
faster hematologic recovery, similar risk of graft-versus-host disease,
and improved survival.
(Blood. 2002;100:1525-1531) Traditionally, cells for allografting have been
harvested directly from the pelvis of donors under general anesthesia.
Hematopoietic progenitor cells also circulate in the peripheral blood,
and their numbers are increased by administration of cytokines such as
granulocyte colony-stimulating factor (G-CSF), allowing collection by
leukapheresis. In autologous transplantation, such mobilized blood
cells have largely replaced bone marrow as the source of cells for
transplantation because their use leads to more rapid neutrophil and
platelet recovery1,2 and faster immune
reconstitution.3 However, enthusiasm for the adoption of
mobilized blood cells for allogeneic transplantation has been tempered
by 3 main considerations.4 First, there was concern that
the use of cytokines such as G-CSF may cause complications in
healthy donors. Second, the peripheral blood harvest contains
10-fold more T cells than bone marrow,5-7 which may be
harmful because T cells are the predominant effector cells of
graft-versus-host disease (GVHD). Finally, the peripheral blood harvest
may contain predominantly committed progenitors and lack the
pluripotent stem cells required for long-term hematopoietic engraftment.
These concerns were allayed by initial reports of transplantations
using allogeneic peripheral blood cells that indicated that donors
tolerated G-CSF well and that patients had sustained neutrophil and
platelet recovery with no increase in acute GVHD.8-10 These reports have been supported by subsequent studies. Generally, G-CSF has been well tolerated by healthy donors, and long-term complications have not been reported.11,12 However, there
have been recent reports of nonfatal splenic rupture in 2 healthy donors receiving G-CSF.13,14 In the first
119 allogeneic peripheral blood transplantations reported, 46 patients
(39%) developed grades II to IV acute GVHD.15-19 This
incidence is similar to that expected after marrow transplantation. In
a large randomized study,20 the incidence of grades II to
IV acute GVHD was also similar in the peripheral blood and bone marrow
arms (64% versus 57%; P = .36).
Chronic GVHD has been reported to be higher in some but not all studies
of allogeneic peripheral blood transplantation.15,18,20-25 However, randomized trials20,24-27 have not been
powered to detect a difference. A retrospective analysis of 288 peripheral blood and 536 bone marrow human leukocyte antigen
(HLA)-identical sibling transplantations reported by the International
Bone Marrow Transplant Registry and the European Group for Blood and
Marrow Transplantation28 described significantly
more chronic GVHD among peripheral blood recipients at 1 year (65%
versus 53%, P = .02).
We report the results of a randomized, multicenter study comparing bone
marrow and peripheral blood in recipients of matched sibling allogeneic
transplants for myeloid malignancies. The study was designed so that
the only difference between the arms was the infusion of bone marrow or
peripheral blood cells on day 0. All patients received the same
conditioning chemotherapy and GVHD prophylaxis regimen. The primary
objective of the study was to compare the time to neutrophil recovery
in the 2 groups.
Study design
Conditioning regimen and GVHD prophylaxis
All patients received cyclosporine and methotrexate as GVHD
prophylaxis. Cyclosporine (12.5 mg/kg orally or 5 mg/kg intravenously each day in 2 divided doses) was begun on day Bone marrow and peripheral blood harvest Donors randomized to bone marrow harvest underwent this procedure on day 0. Under general or regional anesthesia, bone marrow was aspirated from the posterior iliac crests until more than 2 × 108 nucleated cells per kilogram patient weight but less than 22 mL/kg donor weight of bone marrow was obtained. The bone marrow harvest was depleted of red cells by apheresis when there was a major ABO incompatibility between donor and patient and infused on day 0.Donors randomized to peripheral blood harvest received G-CSF
(filgrastim) subcutaneously for 4 consecutive days (days Supportive care While in the hospital, patients were cared for in single rooms equipped with high-efficiency particulate air filtration from day 0 until neutrophil recovery. Patients received transfusions of irradiated red blood cells and platelets to maintain their hemoglobin above 80 g/L and platelets above 10 × 109/L, respectively. Patients seronegative for cytomegalovirus (CMV) antibody whose donors were CMV-seronegative received CMV-negative red blood cell and platelet transfusions. Patients received low-dose standard heparin (100 U · kg 1 · d1 either as a
continuous intravenous infusion or in 2 divided subcutaneous doses
every 12 hours) starting prior to the first dose of conditioning chemotherapy and continuing until day +28 or first hospital discharge as hepatic veno-occlusive disease prophylaxis.30
Broad-spectrum antibiotics were initiated at the first episode of neutropenic fever. Prophylactic ciprofloxacin (500 mg orally twice daily) during neutropenia was used at some centers according to local institutional policy. Patients at risk of herpes simplex virus infection received prophylactic low-dose acyclovir (400 mg orally or 80 mg intravenously twice daily from day 0 until day +28). Posttransplantation antifungal prophylaxis and growth factors to promote hematologic recovery were not routinely used. All patients received trimethoprim-sulfamethoxazole as Pneumocystis carinii pneumonia (PCP) prophylaxis from neutrophil recovery until at least 6 months after transplantation. Patients unable to tolerate trimethoprim-sulfamethoxazole received alternate PCP prophylaxis according to local institutional policy. Patients at risk for CMV disease underwent either preemptive therapy (surveillance bronchoscopy at days +35 and/or +49, followed by treatment with ganciclovir for patients whose bronchoalveolar lavage was positive for CMV by shell vial culture) or prophylactic therapy (ganciclovir from neutrophil recovery until day +100 for all patients at risk of CMV disease). At one center, some patients received conditioning chemotherapy, transplantation, and initial posttransplantation care on an outpatient basis. Laboratory analysis The nucleated cells, CD34+ cells, and T cells (CD3+) of each bone marrow and peripheral blood collection were measured and expressed per kilogram patient weight. The nucleated cells were enumerated by automated cell counter or manually using a counting chamber, CD34+ cells were enumerated according to the International Society of Hematotherapy and Graft Engineering methodology,31 and T cells were enumerated by flow cytometry.Study end points The primary end point was the time to neutrophil recovery. Neutrophil recovery was defined as the second of 2 consecutive days with an absolute neutrophil count greater than 0.5 × 109/L. The null hypothesis assumed no difference in time to neutrophil recovery between the treatment groups. We sought to reject this hypothesis in favor of the alternative hypothesis of a 7-day difference in neutrophil recovery for patients assigned to peripheral blood compared with those assigned to bone marrow. It was assumed that the median time to neutrophil recovery for patients assigned to bone marrow was 20 days. Furthermore, using a 2-sided alpha of 0.05 with 0.80 power, and assuming an accrual period of 1 year and a follow-up period of 100 days, 178 patients allocated in a 1:1 ratio were required to detect this difference.32 No interim analysis was planned. After the study began, the sample size was increased to have sufficient power to detect a 20% absolute difference in the incidence of chronic GVHD. Following publication of the preliminary results of the randomized study by Bensinger et al,33 an interim analysis was undertaken using a Pocock stopping boundary,34 and accrual to the study was stopped in February 2000. This report includes data on all 228 patients enrolled to February 2000 with follow-up data to February 2001.Secondary end points of the study included time to platelet recovery, outcomes related to hematologic recovery, acute GVHD, chronic GVHD, relapse, and survival. Platelet recovery was defined as the third of 3 consecutive days with a platelet count greater than 20 × 109/L and independence of platelet transfusion for 7 days. Outcomes related to hematologic recovery were number of red blood cell and platelet transfusions during the first 60 days after transplantation, number of febrile days during the first 30 days after transplantation, number of days on nonprophylactic antibiotics from day 0 until first discharge, number of days in the hospital from day 0 until first discharge, and number of days in the hospital during the first 100 days after transplantation. Acute GVHD was evaluated according to standard criteria.35 Patients who survived until at least day +14 were evaluable for acute GVHD. Chronic GVHD was evaluated according to standard criteria.36 Deaths were classified as due to either relapse of the underlying disease or nonrelapse causes. Statistical analysis The cumulative incidences of neutrophil and platelet recovery, grades II to IV and grades III to IV acute GVHD, overall and extensive chronic GVHD, relapse of disease, and nonrelapse mortality were computed according to the method described by Kalbfleisch and Prentice.37 Estimates of overall survival were calculated using the method of Kaplan and Meier.38 The 2 treatment groups were assessed for statistically significant differences of these end points using the likelihood ratio 2 statistic
derived from stratified (by disease type and center) Cox proportional
hazards models.39 Hazard ratios from these models and
their 95% confidence intervals were used to describe the relative
effectiveness of the 2 treatment groups. Differences in day +30 and day
+100 mortality between the treatment groups were assessed for
statistical significance using a z statistic with correction
for continuity.40 The statistical significance of the
difference in CD34+cells/kg collected during the first and
second apheresis was evaluated using the Wilcoxon signed rank-sum
test.40 Differences in outcomes between the treatment
groups related to hematologic recovery were assessed using the Wilcoxon
rank sum test. Where appropriate, all statistical comparisons used the
intention-to-treat principle. All reported P values are
2-sided.
Two hundred twenty-eight patient-donor pairs were randomized between January 1996 and February 2000 at 7 BMT centers in Canada and 1 in New Zealand. One pair was ineligible and excluded from analysis because the donor was the father of the patient. The remaining 227 pairs are the subject of this report. One patient who did not undergo transplantation was lost to follow-up within 1 week of randomization. The minimum follow-up of all remaining surviving patients was 12 months from randomization, with a median follow-up of 32.8 months (range, 12-61 months). Of the 227 eligible patients, 109 (48%) were randomized to peripheral
blood and 118 (52%) were randomized to bone marrow. The treatment
groups were well balanced with respect to baseline characteristics of
patients and donors (Table 1).
Peripheral blood and bone marrow harvests The characteristics of the peripheral blood and bone marrow harvests are shown in Table 2. Most patients randomized to peripheral blood (95 of 109; 87%) received peripheral blood alone. One patient randomized to peripheral blood received bone marrow alone and 2 did not undergo transplantation. Eleven patients randomized to peripheral blood received peripheral blood and bone marrow, 10 because fewer than 2.5 × 106 CD34+ cells/kg were collected with 2 aphereses, as specified in the protocol. One patient received peripheral blood and bone marrow even though more than 2.5 × 106 CD34+ cells/kg were collected with 2 aphereses; this was a protocol violation.
Among the 10 donors from whom fewer than 2.5 × 106 CD34+ cells/kg were collected by apheresis, the median number of cells collected was 1.9 × 106 CD34+ cells/kg (range, 0.7-2.4 × 106). The median CD34+ cells/kg collected with the first apheresis was 2.5 × 106 CD34+ cells/kg (range, 0.1-16.1 × 106), compared with 3.7 × 106 CD34+ cells/kg (range, 0.1-18.7 × 106) with the second apheresis (P < .0001). In 48 of 93 (52%) peripheral blood donors, more than 2.5 × 106 CD34+ cells/kg were collected during the first apheresis. Three donors required placement of a central venous catheter to facilitate the peripheral blood collections. All donors tolerated the apheresis procedures well, with mild to moderate bone pain and flulike symptoms. None experienced a serious adverse event or required hospitalization. Most patients randomized to bone marrow (115 of 118; 97%) received bone marrow alone. Two patients randomized to bone marrow received peripheral blood alone, and one did not undergo transplantation. Hematologic recovery The median times to neutrophil recovery were 19 days (range, 12-35 days) and 23 days (range, 13-68 days) in the peripheral blood and bone marrow groups, respectively (hazard ratio, 0.45; 95% confidence interval, 0.33-0.62; P < .0001) (Figure 1A). Eight patients died prior to neutrophil recovery, 3 in the peripheral blood group and 5 in the bone marrow group. The median times to platelet recovery were 16 days (range, 0-100 days) and 22 days (range, 0-100 days) in the peripheral blood and bone marrow groups, respectively (hazard ratio, 0.46; 95% confidence interval, 0.34-0.62; P < .0001) (Figure 1B). Seventeen patients died prior to platelet recovery, 4 in the peripheral blood group and 13 in the bone marrow group. There were statistically significant differences in the number of platelet transfusions, days on nonprophylactic antibiotics during the first hospitalization, and duration of the first hospitalization favoring the peripheral blood group (Table 3).
There was no difference in the cumulative incidence or severity of
acute GVHD. The cumulative incidences of grades II to IV acute GVHD at
day +100 after transplantation were 51 of 117 (44%) and 47 of 107 (44%) in the peripheral blood and bone marrow groups, respectively
(hazard ratio, 0.99; 95% confidence interval, 0.66-1.49; P > .9) (Figure 2), and the
cumulative incidences of grades III to IV acute GVHD at day +100 after
transplantation were 28 of 107 (26%) and 21 of 117 (18%) in the
peripheral blood and bone marrow groups, respectively (hazard ratio,
1.48; 95% confidence interval, 0.83-2.62; P = .18). The
cumulative incidences of chronic GVHD at 30 months after
transplantation were 85% and 69% in the peripheral blood and bone
marrow arms, respectively, and the corresponding cumulative incidences
of extensive chronic GVHD at 30 months after transplantation were 40%
and 30% in the peripheral blood and bone marrow arms, respectively
(Figure 3). Although there was a trend to
more overall and extensive chronic GVHD among patients randomized to
peripheral blood, this was not statistically significant (hazard ratio
for overall chronic GVHD, 1.09; 95% confidence interval, 0.79-1.49;
P = .62; hazard ratio for extensive chronic GVHD, 1.23; 95% confidence interval, 0.78-1.96; P = .37).
Nonrelapse mortality, relapse, and survival Overall survival was improved in recipients of peripheral blood transplants. This benefit was seen early; the actuarial probability of death at day +30 was 2.8% for patients randomized to peripheral blood and 7.6% for those randomized to bone marrow (P = .18). At day +100, the actuarial probabilities of death were 7.4% and 16.1%, respectively (P = .07). The benefit in overall survival was due to a reduction in nonrelapse deaths (Figure 4) in the peripheral blood arm, with no difference between the groups in early or late relapses (Figure 5) or deaths in relapse (Table 4).
With a median follow-up of 32.8 months (range, 12-61 months), the
overall survival of patients randomized to peripheral blood was
statistically significantly better than for those randomized to bone
marrow (Figure 6). The estimated
probability of survival at 30 months after transplantation was 68% in
the peripheral blood group and 60% in the bone marrow group (hazard
ratio, 0.62; 95% confidence interval, 0.39-0.97;
P = .04). Although the study was not powered for subgroup
analysis, among the 3 disease groups for which there had been
prospective stratification, there was a benefit in overall survival
favoring peripheral blood for patients with CML (Figure
7A) and a trend favoring peripheral blood
for patients with MDS (Figure 7C), but not for those with AML (Figure 7B). The interaction between disease type and treatment was not statistically significant (P = .18). In a post hoc
analysis, patients were grouped retrospectively into those with early
disease (first chronic phase CML, first remission AML, refractory
anemia, and refractory anemia with ringed sideroblasts) and those with
advanced disease. The overall survival of patients with early disease
was not different between the groups (Figure 7D); however, there was an
overall survival benefit in patients with advanced disease favoring the
peripheral blood group (Figure 7E). The interaction between disease
stage and treatment was not statistically significant (P = .11). There was no disease subgroup for which
peripheral blood transplantation was associated with poorer overall
survival.
In this trial of allografting for myeloid malignancies, patients randomized to receive peripheral blood had significantly better overall survival compared with those randomized to receive bone marrow. This benefit was due to lower nonrelapse mortality. Similar to results in autologous transplantation1,2 and other randomized allogeneic studies,20,24-27 the use of peripheral blood cells led to faster neutrophil and platelet recovery. Some statistically significant differences in secondary outcomes related to hematologic recovery were seen, but more important, the faster hematologic recovery probably accounts for the lower early (before day 30) nonrelapse mortality in the peripheral blood group. Interestingly, we noted a trend toward lower nonrelapse mortality in the 30- to 100-day period as well as beyond 100 days among patients randomized to receive peripheral blood. Given that the cumulative incidence of acute GVHD was similar in the 2 groups, the reduction in nonrelapse deaths is most likely due to the effects of earlier hematologic recovery and/or earlier immune reconstitution. Faster hematologic recovery may lead to an earlier return to health and allow patients to withstand subsequent complications, thereby reducing late mortality. Compared with bone marrow, peripheral blood harvests contain
approximately 10-fold more T cells, which are important effectors of
GVHD. Our study confirms the observation made by Bensinger et
al20 that this does not lead to more acute GVHD. The
observation that acute GVHD is not increased despite the 10-fold higher
number of T cells in peripheral blood may be related to the use of
G-CSF. G-CSF directs activated T cells to a Th2 type (secreting
interleukin 4 [IL-4] and IL-10) and away from a Th1 response
(secreting IL-2 and We did not observe a difference in relapse in the 2 treatment groups, despite a trend toward an increased incidence of chronic GVHD among peripheral blood recipients. In the hypothesis-generating subgroup analysis, there was a survival benefit of peripheral blood transplantation for patients with CML and those with advanced disease. Among the myeloid malignancies, CML is most likely to benefit from a graft-versus-leukemia effect, and therefore the survival benefit gained by the use of peripheral blood cells in this subgroup might have been expected to result from fewer relapse deaths. However, this was not the case, and the benefit resulted from fewer nonrelapse deaths. The difference in survival between the treatment arms was most striking for patients with advanced disease. Bensinger et al43 have also reported an overall survival benefit of peripheral blood transplantation in patients with advanced disease. Patients with advanced disease have greater difficulty tolerating the early complications of allografting and appear to benefit from the faster hematologic recovery associated with the use of blood cells. However, it is not clear why patients with CML had lower mortality with peripheral blood transplantation but patients with AML did not. Our study differs from other reported randomized trials in 2 important respects. First, all patients received the same conditioning chemotherapy and GVHD prophylaxis. Second, donors received only 4 days of low-dose G-CSF prior to leukapheresis. The median dose of G-CSF in this study was 6.2 µg/kg/d for 4 days, compared with 10 to 16 µg/kg/d for 5 days used in other randomized studies. All donors in this study were required to undergo 2 apheresis procedures, and on the first day of apheresis, donors had received only 3 doses of G-CSF. This probably explains why the median CD34+ cell counts in this study are less than those reported by others. Although only a randomized study can compare the effects of different mobilization strategies on donors and patients, the approach used in this study was well tolerated by donors and permitted the collection of an adequate harvest in most cases. Although the failure to collect more than 2.5 × 106 CD34+ cells/kg with 2 aphereses in 10% of donors may be considered high, this threshold would have been achieved in most donors with a third apheresis. Alternatively, a lower CD34+ threshold could have been accepted. In conclusion, our study demonstrates that the use of allogeneic peripheral blood cells rather than bone marrow leads to better overall survival in recipients of matched sibling allografts for myeloid malignancies. Patients assigned to receive peripheral blood had faster hematologic recovery, and there was no subgroup of patients for whom peripheral blood transplantation was associated with increased mortality compared with bone marrow. However, statistically significant improvement in survival was restricted to patients with CML and those with advanced disease. A potential disadvantage of the use of peripheral blood allografts may be an increased likelihood of chronic GVHD, and, in this regard, long-term follow-up is required. Further work is needed to determine which particular groups of patients benefit from this approach to allografting.
This study was undertaken under the auspices of the Canadian Bone Marrow Transplant Group (CBMTG). We gratefully acknowledge the patients, donors, and staff of the BMT Programs who participated in this study. We thank Ms Anthea Lau for excellent coordination of data management and Ms Isabel Cameron for her secretarial assistance.
Submitted January 8, 2002; accepted April 15, 2002.
Prepublished online as Blood First Edition Paper, May 17, 2002; DOI 10.1182/blood-2002-01-0048.
S.C. and D.R.S. contributed equally to this study.
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: Stephen Couban, Rm 417, Bethune Bldg, Queen Elizabeth II Health Sciences Centre, 1278 Tower Rd, Halifax, Nova Scotia, Canada B3H 2Y9; e-mail: scouban{at}is.dal.ca.
1. Schmitz N, Linch DC, Dreger P, et al. Randomised trial of filgrastim-mobilised peripheral blood progenitor cell transplantation versus autologous bone-marrow transplantation in lymphoma patients. Lancet. 1996;347:353-357[CrossRef][Medline] [Order article via Infotrieve]. 2. To LB, Roberts MM, Haylock DN, et al. Comparison of haematological recovery times and supportive care requirements of autologous recovery phase peripheral blood stem cell transplants, autologous bone marrow transplants and allogeneic bone marrow transplants. Bone Marrow Transplant. 1992;9:277-284[Medline] [Order article via Infotrieve]. 3. Roberts MM, To LB, Gillis D, et al. Immune reconstitution following peripheral blood stem cell transplantation, autologous bone marrow transplantation and allogeneic bone marrow transplantation. Bone Marrow Transplant. 1993;12:469-475[Medline] [Order article via Infotrieve].
4.
Appelbaum FR.
Choosing the source of stem cells for allogeneic transplantation: no longer a peripheral issue.
Blood.
1999;94:381-383 5. Dreger P, Marquardt P, Haferlach T, et al. Effective mobilisation of peripheral blood progenitor cells with 'Dexa-BEAM' and G-CSF: timing of harvesting and composition of the leukapheresis product. Br J Cancer. 1993;68:950-957[Medline] [Order article via Infotrieve]. 6. Weaver CH, Clift RA, Deeg HJ, et al. Effect of graft-versus-host disease prophylaxis on relapse in patients transplanted for acute myeloid leukemia. Bone Marrow Transplant. 1994;14:885-893[Medline] [Order article via Infotrieve]. 7. 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].
8.
Korbling M, Przepiorka D, Huh YO, et al.
Allogeneic blood stem cell transplantation for refractory leukemia and lymphoma: potential advantage of blood over marrow allografts.
Blood.
1995;85:1659-1665
9.
Schmitz N, Dreger P, Suttorp M, et al.
Primary transplantation of allogeneic peripheral blood progenitor cells mobilized by filgrastim (granulocyte colony-stimulating factor).
Blood.
1995;85:1666-1672
10.
Bensinger WI, Weaver CH, Appelbaum FR, et al.
Transplantation of allogeneic peripheral blood stem cells mobilized by recombinant human granulocyte colony-stimulating factor.
Blood.
1995;85:1655-1658 11. Cavallaro AM, Lilleby K, Majolino I, et al. Three to six year follow-up of normal donors who received recombinant human granulocyte colony-stimulating factor. Bone Marrow Transplant. 2000;25:85-89[CrossRef][Medline] [Order article via Infotrieve].
12.
Rowley SD, Donaldson G, Lilleby K, Bensinger WI, Appelbaum FR.
Experiences of donors enrolled in a randomized study of allogeneic bone marrow or peripheral blood stem cell transplantation.
Blood.
2001;97:2541-2548 13. Brown SL, Dale DC. Spontaneous splenic rupture following administration of granulocyte colony-stimulating factor (G-CSF): occurrence in an allogeneic donor of peripheral blood stem cells. Biol Blood Marrow Transplant. 1997;3:341-343[Medline] [Order article via Infotrieve]. 14. Falzetti F, Aversa F, Minelli O, Tabilio A. Spontaneous rupture of spleen during peripheral blood stem-cell mobilisation in a healthy donor [letter]. Lancet. 1999;353:555[Medline] [Order article via Infotrieve]. 15. Majolino I, Saglio G, Scime R, et al. High incidence of chronic GVHD after primary allogeneic peripheral blood stem cell transplantation in patients with hematologic malignancies. Bone Marrow Transplant. 1996;17:555-560[Medline] [Order article via Infotrieve].
16.
Brown RA, Adkins D, Khoury H, et al.
Long-term follow-up of high-risk allogeneic peripheral-blood stem-cell transplant recipients: graft-versus-host disease and transplant-related mortality.
J Clin Oncol.
1999;17:806-812 17. Pavletic ZS, Bishop MR, Tarantolo SR, et al. Hematopoietic recovery after allogeneic blood stem-cell transplantation compared with bone marrow transplantation in patients with hematologic malignancies. J Clin Oncol. 1997;15:1608-1616[Abstract]. 18. Urbano-Ispizua A, Solano C, Brunet S, et al. Allogeneic peripheral blood progenitor cell transplantation: analysis of short-term engraftment and acute GVHD incidence in 33 cases. Allo-PBPCT Spanish Group. Bone Marrow Transplant. 1996;18:35-40[Medline] [Order article via Infotrieve].
19.
Przepiorka D, Smith TL, Folloder J, et al.
Risk factors for acute graft-versus-host disease after allogeneic blood stem cell transplantation.
Blood.
1999;94:1465-1470
20.
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
21.
Storek J, Gooley T, Siadak M, et al.
Allogeneic peripheral blood stem cell transplantation may be associated with a high risk of chronic graft-versus-host disease.
Blood.
1997;90:4705-4709 22. Levine JE, Wiley J, Kletzel M, et al. Cytokine-mobilized allogeneic peripheral blood stem cell transplants in children result in rapid engraftment and a high incidence of chronic GVHD. Bone Marrow Transplant. 2000;25:13-18[CrossRef][Medline] [Order article via Infotrieve].
23.
Przepiorka D, Anderlini P, Saliba R, et al.
Chronic graft-versus-host disease after allogeneic blood stem cell transplantation.
Blood.
2001;98:1695-1700 24. 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].
25.
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 Societe Francaise de Greffe de Moelle.
J Clin Oncol.
2000;18:537-546 26. 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]. 27. Schmitz N, Bacigalupo A, Hasenclever D, et al. Allogeneic bone marrow transplantation vs filgrastim-mobilised peripheral blood progenitor cell transplantation in patients with early leukaemia: first results of a randomised multicentre trial of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant. 1998;21:995-1003[CrossRef][Medline] [Order article via Infotrieve].
28.
Champlin RE, Schmitz N, Horowitz MM, et al.
Blood stem cells compared with bone marrow as a source of hematopoietic cells for allogeneic transplantation. IBMTR Histocompatibility and Stem Cell Sources Working Committee and the European Group for Blood and Marrow Transplantation (EBMT).
Blood.
2000;95:3702-3709
29.
Bearman SI, Appelbaum FR, Buckner CD, et al.
Regimen-related toxicity in patients undergoing bone marrow transplantation.
J Clin Oncol.
1988;6:1562-1568
30.
Attal M, Huguet F, Rubie H, et al.
Prevention of hepatic veno-occlusive disease after bone marrow transplantation by continuous infusion of low-dose heparin: a prospective, randomized trial.
Blood.
1992;79:2834-2840 31. Sutherland DR, Anderson L, Keeney M, Nayar R, Chin-Yee I. The ISHAGE guidelines for CD34+ cell determination by flow cytometry. International Society of Hematotherapy and Graft Engineering. J Hematother. 1996;5:213-226[Medline] [Order article via Infotrieve]. 32. Lachin JM, Foulkes MA. Evaluation of sample size and power for analyses of survival with allowance for nonuniform patient entry, losses to follow-up, noncompliance, and stratification. Biometrics. 1986;42:507-519[CrossRef][Medline] [Order article via Infotrieve]. 33. Bensinger W, Martin P, Clift R, et al. A prospective, randomized trial of peripheral blood stem cells (PBSC) or marrow (BM) for patients undergoing allogeneic transplantation for hematologic malignancies. Blood. 1999;94:368a.
34.
Pocock SJ.
Group sequential methods in the design and analysis of clinical trials.
Biometrika.
1977;64:191-199 35. Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995;15:825-828[Medline] [Order article via Infotrieve]. 36. Sullivan KM, Agura E, Anasetti C, et al. Chronic graft-versus-host disease and other late complications of bone marrow transplantation. Semin Hematol. 1991;28:250-259[Medline] [Order article via Infotrieve]. 37. Kalbfleisch JD, Prentice RL. The Statistical Analysis of Failure Time Data. New York, NY: John Wiley; 1980. 38. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457-481[CrossRef]. 39. Cox DR. Regression models and lifetables. J Royal Stat Soc Series B. 1972;34:187-202. 40. Altman DG. Practical Statistics for Medical Research. London: Chapman and Hall; 1991.
41.
Pan L, Delmonte J Jr, Jalonen CK, Ferrara JL.
Pretreatment of donor mice with granulocyte colony-stimulating factor polarizes donor T lymphocytes toward type-2 cytokine production and reduces severity of experimental graft-versus-host disease.
Blood.
1995;86:4422-4429
42.
Zeng D, Dejbakhsh-Jones S, Strober S.
Granulocyte colony-stimulating factor reduces the capacity of blood mononuclear cells to induce graft-versus-host disease: impact on blood progenitor cell transplantation.
Blood.
1997;90:453-463
43.
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
© 2002 by The American Society of Hematology.
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  D. Gallardo, R. de la Camara, J. B. Nieto, I. Espigado, A. Iriondo, A. Jimenez-Velasco, C. Vallejo, C. Martin, D. Caballero, S. Brunet, et al. Is mobilized peripheral blood comparable with bone marrow as a source of hematopoietic stem cells for allogeneic transplantation from HLA-identical sibling donors? A case-control study Haematologica, September 1, 2009; 94(9): 1282 - 1288. [Abstract] [Full Text] [PDF]
|
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|
 J. L. Irani, C. S. Cutler, E. E. Whang, T. E. Clancy, S. Russell, R. S. Swanson, S. W. Ashley, M. J. Zinner, and C. P. Raut Severe Acute Gastrointestinal Graft-vs-Host Disease: An Emerging Surgical Dilemma in Contemporary Cancer Care Arch Surg, November 1, 2008; 143(11): 1041 - 1045. [Abstract] [Full Text] [PDF]
|
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|
G. Gahrton, S. Iacobelli, G. Bandini, B. Bjorkstrand, P. Corradini, C. Crawley, U. Hegenbart, G. Morgan, N. Kroger, A. Schattenberg, et al. Peripheral blood or bone marrow cells in reduced-intensity or myeloablative conditioning allogeneic HLA identical sibling donor transplantation for multiple myeloma Haematologica, November 1, 2007; 92(11): 1513 - 1518. [Abstract] [Full Text] [PDF]
|
|
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 |
|
 N. Schmitz, M. Eapen, M. M. Horowitz, M.-J. Zhang, J. P. Klein, J. D. Rizzo, F. R. Loberiza, A. Gratwohl, and R. E. Champlin Long-term outcome of patients given transplants of mobilized blood or bone marrow: a report from the International Bone Marrow Transplant Registry and the European Group for Blood and Marrow Transplantation Blood, December 15, 2006; 108(13): 4288 - 4290. [Abstract] [Full Text] [PDF]
|
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|
K. M. Pastos, W. B. Slayton, L. M. Rimsza, L. Young, and M. C. Sola-Visner Differential effects of recombinant thrombopoietin and bone marrow stromal-conditioned media on neonatal versus adult megakaryocytes Blood, November 15, 2006; 108(10): 3360 - 3362. [Abstract] [Full Text] [PDF]
|
|
|
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|
|
C. Crawley, R. Szydlo, M. Lalancette, A. Bacigalupo, A. Lange, M. Brune, G. Juliusson, A. Nagler, A. Gratwohl, J. Passweg, et al. Outcomes of reduced-intensity transplantation for chronic myeloid leukemia: an analysis of prognostic factors from the Chronic Leukemia Working Party of the EBMT Blood, November 1, 2005; 106(9): 2969 - 2976. [Abstract] [Full Text] [PDF]
|
|
|
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 |
|
 S. Z. Pavletic, I. F. Khouri, M. Haagenson, R. J. King, P. J. Bierman, M. R. Bishop, M. Carston, S. Giralt, A. Molina, E. A. Copelan, et al. Unrelated Donor Marrow Transplantation for B-Cell Chronic Lymphocytic Leukemia After Using Myeloablative Conditioning: Results From the Center for International Blood and Marrow Transplant Research J. Clin. Oncol., August 20, 2005; 23(24): 5788 - 5794. [Abstract] [Full Text] [PDF]
|
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|
Stem Cell Trialists' Collaborative Group Allogeneic Peripheral Blood Stem-Cell Compared With Bone Marrow Transplantation in the Management of Hematologic Malignancies: An Individual Patient Data Meta-Analysis of Nine Randomized Trials J. Clin. Oncol., August 1, 2005; 23(22): 5074 - 5087. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. C. Lipkin, P. Lenssen, and B. J. Dickson Nutrition Issues in Hematopoietic Stem Cell Transplantation: State of the Art Nutr Clin Pract, August 1, 2005; 20(4): 423 - 439. [Abstract] [Full Text] [PDF]
|
|
|
|
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H. Wallen, T. A. Gooley, H. J. Deeg, J. M. Pagel, O. W. Press, F. R. Appelbaum, R. Storb, and A. K. Gopal Ablative Allogeneic Hematopoietic Cell Transplantation in Adults 60 Years of Age and Older J. Clin. Oncol., May 20, 2005; 23(15): 3439 - 3446. [Abstract] [Full Text] [PDF]
|
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|
T. M. Cao, J. A. Shizuru, R. M. Wong, K. Sheehan, G. G. Laport, K. E. Stockerl-Goldstein, L. J. Johnston, M. J. Stuart, F. C. Grumet, R. S. Negrin, et al. Engraftment and survival following reduced-intensity allogeneic peripheral blood hematopoietic cell transplantation is affected by CD8+ T-cell dose Blood, March 15, 2005; 105(6): 2300 - 2306. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Wall Allogeneic Peripheral Blood Versus Bone Marrow Transplantation: Children Are Small Adults and More J. Clin. Oncol., December 15, 2004; 22(24): 4865 - 4866. [Full Text] [PDF]
|
|
|
|
|
|
M. Eapen, M. M. Horowitz, J. P. Klein, R. E. Champlin, F. R. Loberiza Jr, O. Ringden, and J. E. Wagner Higher Mortality After Allogeneic Peripheral-Blood Transplantation Compared With Bone Marrow in Children and Adolescents: The Histocompatibility and Alternate Stem Cell Source Working Committee of the International Bone Marrow Transplant Registry J. Clin. Oncol., December 15, 2004; 22(24): 4872 - 4880. [Abstract] [Full Text] [PDF]
|
|
|
|
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|
R. Diaconescu, C. R. Flowers, B. Storer, M. L. Sorror, M. B. Maris, D. G. Maloney, B. M. Sandmaier, and R. Storb Morbidity and mortality with nonmyeloablative compared with myeloablative conditioning before hematopoietic cell transplantation from HLA-matched related donors Blood, September 1, 2004; 104(5): 1550 - 1558. [Abstract] [Full Text] [PDF]
|
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|
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 C. S. Leger and T. J. Nevill Hematopoietic stem cell transplantation: a primer for the primary care physician Can. Med. Assoc. J., May 11, 2004; 170(10): 1569 - 1577. [Abstract] [Full Text] [PDF]
|
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D.C. Taussig, A.J. Davies, J.D. Cavenagh, H. Oakervee, D. Syndercombe-Court, S. Kelsey, J.A.L. Amess, A.Z.S. Rohatiner, T.A. Lister, and M.J. Barnett Durable Remissions of Myelodysplastic Syndrome and Acute Myeloid Leukemia After Reduced-Intensity Allografting J. Clin. Oncol., August 15, 2003; 21(16): 3060 - 3065. [Abstract] [Full Text] [PDF]
|
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 M. H. Cottler-Fox, T. Lapidot, I. Petit, O. Kollet, J. F. DiPersio, D. Link, and S. Devine Stem Cell Mobilization Hematology, January 1, 2003; 2003(1): 419 - 437. [Abstract] [Full Text] [PDF]
|
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D. G. Maloney, B. M. Sandmaier, S. Mackinnon, and J. A. Shizuru Non-Myeloablative Transplantation Hematology, January 1, 2002; 2002(1): 392 - 421. [Abstract] [Full Text]
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Top
Abstract
Introduction
7 to day
-interferon) that promotes acute
GVHD.