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Effect of Total Nucleated and CD34

þ

Cell Dose on Outcome

after Allogeneic Hematopoietic Stem Cell Transplantation

Mats Remberger

1

,

2

,

*

, Johan Törlén

2

, Olle Ringdén

2

, Mats Engström

1

,

2

, Emma Watz

1

,

3

,

Michael Uhlin

1

,

2

, Jonas Mattsson

1

,

2

1Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden

2Center for Allogeneic Stem Cell Transplantation, Karolinska University Hospital Huddinge, Stockholm, Sweden

3Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden

Article history: Received 4 November 2014 Accepted 26 January 2015 Key Words: Cell dose CD34

Hematopoietic stem cell transplantation Graft-versus-host disease Bone marrow

Peripheral blood stem cells

a b s t r a c t

During more recent years only few studies have analyzed the effect of total nucleated cell (TNC) and CD34þ cell dose in allogeneic hematopoietic stem cell transplantation (HSCT). A single-center analysis included 544 patients, 227 with a sibling donor and 317 with an unrelated donor. Most patients (n¼292) were treated with myeloablative conditioning, whereas the remaining patients (n¼ 252) received reduced-intensity conditioning. Bone marrow (BM) (n¼121) and peripheral blood stem cell (PBSC) grafts (n¼423) were analyzed separately. Median TNC and CD34þcell dose was 3.2108/kg versus 11.6108/kg in BM and 3.9 106/kg versus 8.1106/kg in PBSC. In the BM group we found a higher TNC and CD34þ cell dose was associated with a faster neutrophil engraftment (P<.001 andP¼.02). In the PBSC group we found patients given a very high (11106/kg) CD34þcell dose had decreased rates of survival (P¼.001) and increased relapse (P¼.02). A high CD34þcell dose correlated with faster platelet engraftment (P<.01). In HSCT using PBSCs, the CD34þcell doses should be kept below 11106/kg but over 2.5106/kg.

Ó2015 American Society for Blood and Marrow Transplantation.

INTRODUCTION

Hematopoietic stem cell transplantation (HSCT) is a

potentially curative treatment for several hematological

malignancies, bone marrow (BM) failure syndromes, and

some inherited metabolic disorders

[1]

. An adequate number

of nucleated or CD34

þ

cells in the graft are of utmost

importance to achieve sustained engraftment and good

survival

[2]

. Historically, the approach of more is better has

been applied at many centers. This is 1 contributory rationale

for the increasing use of peripheral blood stem cells (PBSCs)

in HSCT, becasue a PBSC graft contains approximately 5 to 10

times more CD34

þ

and T cells compared with a BM graft

[3]

.

Higher cell numbers in the graft decrease the risk of rejection

and shorten the phase of aplasia

[4-10]

. However, many

studies have shown the risk for chronic graft-versus-host

disease (GVHD) is increased in patients receiving PBSC

compared with BM, probably because of the higher cell

content

[11-13]

. More recently, only a few studies have

evaluated the effect of cell dose on outcome after HSCT

[4,14-16]

. Hence, it is important to establish which cell dose

is optimal for outcome when using BM or PBSC in the

modern era of HSCT.

METHODS Patients

The effect of the graft cell dose was studied in 544 consecutive HSCT pa-tients transplanted between January 2000 and December 2011 at Karolinska University Hospital, Sweden. Only patients with a malignant disease receiving either BM or PBSCs from a HLA-identical sibling or a HLA-A, -B, and -DR matched unrelated donor were included. Patients transplanted because of solid

tumors (n¼62) were excluded because this was an experimental treatment.

Patient characteristics are displayed inTable 1. Patients receiving a BM

or PBSC graft were analyzed separately because the cell dose differs considerably between these 2 types of grafts and BM is preferentially given to children. The study was approved by the Research Ethics Committee of Karolinska Institutet. The procedures were in accordance with the Helsinki Declaration.

HLA Typing

All patients and donors were typed using PCResequence-specific primer

high-resolution typing for both HLA class I and II alleles[17].

Conditioning Regimen and GVHD Prophylaxis

Reduced-intensity conditioning was given to 252 patients and consisted offludarabine 30 mg/m2

/d for 3 to 6 days in combination with (1)

cyclo-phosphamide 60 mg/kg/d for 2 days (n¼26), (2) 23 Gy total body

irra-diation (TBI) and cyclophosphamide 60 mg/kg/d for 2 days (n¼44), (3) 2 Gy

Financial disclosure:See Acknowledgments on page 892.

*Correspondence and reprint requests: Mats Remberger, Professor,

CAST-unit, Karolinska University Hospital, SE-14186 Stockholm, Sweden.

E-mail address:mats.remberger@ki.se(M. Remberger).

http://dx.doi.org/10.1016/j.bbmt.2015.01.025

1083-8791/Ó2015 American Society for Blood and Marrow Transplantation.

Biology of Blood and

Marrow Transplantation

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TBI (n ¼ 19), (4) treosulfan 14 g/m2 for 3 days (n ¼ 24), or (5)

4 mg/kg/d busulfan orally for 2 days (n¼139)[18-20]. Myeloablative

con-ditioning consisted of cyclophosphamide 60 mg/kg/d for 2 days in

combi-nation with (1) 7.5 to 10 Gy single fraction TBI (n¼2), (2) 43 Gy

fractionated TBI (n¼115), or (3) 4 mg/kg/d busulfan for 4 days (n¼175)

[21]. Antithymocyte globulin was given to all patients with an unrelated

donor as part of the conditioning regimen with the last dose on the day

before transplantation[22]. Three hundred twenty-one patients received

Thymoglobulin (Genzyme, Cambridge, MA) at a total dose of 4 to 10 mg/kg, whereas 5 patients received ATG-Fresenius (Fresenius, Bad Homburg, Germany) (25 to 30 mg/kg) and 32 patients received alemtuzumab (30 to 90 mg).

Prophylaxis against GVHD consisted of cyclosporine A (CsA) in

combi-nation with methotrexate (n¼462), prednisolone (n¼1), or

mycopheno-late mofetil (n¼11). Sirolimus and tacrolimus were given to 63 patients, and

2 received tacrolimus and mycophenolate mofetil [23]. Five patients

received CsAþmethotrexate and cyclophosphamide on days 3 and 4 after

HSCT[24]. During thefirst month, blood CsA levels were kept at 100 ng/mL

or 200 to 300 ng/mL when a sibling donor or unrelated donor was used, respectively. In the absence of GVHD, for patients with malignant diseases, CsA was discontinued at 3 to 4 months in HLA-identical transplants and at 6 months in unrelated transplants, whereas it was discontinued after 12 to 24 months in patients with nonmalignant disorders.

Stem Cell Source

BM was the graft source in 121 patients and PBSCs in 423. Before aphaeresis to obtain PBSCs, stem cells were mobilized with subcutaneous

granulocyte colony-stimulating factor (G-CSF) daily for 4 to 6 days[25].

Supportive Care

Supportive care was previously described in detail[26,27].

Statistics

Overall survival (OS) was calculated using the Kaplan-Meier method and compared with the log-rank test. Survival time was calculated from the day of transplantation until death or last follow-up. The incidence of transplant-related mortality (TRM), relapse, and GVHD were obtained using an esti-mator of cumulative incidence curves. Patients were censored at the time of death or last follow-up.

Univariate and multivariate predictive analyses for relapse, TRM, and GVHD were performed with the proportional subdistribution hazard

regression model of Fine and Gray[28], whereas analysis of OS, graft

failure (GF), and engraftment were performed using the Cox proportional

hazards model. Factors with P <.10 in the univariate analysis were

included in the backward elimination multivariate analysis. The main aim

was to evaluate the effect of total nucleated cell (TNC) and CD34þcell dose

on the outcome after HSCT with PBSCs or BM. Analyses were performed using the cmprsk package (developed by Gray, June 2001), Splus 6.2 (Insightful, Seattle, WA), and Statistica software (StatSoft, Tulsa, OK).

RESULTS

Cell Doses

The median TNC dose was approximately 4-fold higher

for patients receiving PBSCs compared with BM, whereas the

CD34

þ

dose was

z

2-fold higher (

Table 1

). Because of these

differences, further analyses were performed separately

depending on the graft stem cell source, BM or PBSCs.

Bone Marrow

In univariate analysis we found no effect of the TNC and

the CD34

þ

cell dose on OS (

P

¼

.57 and

P

¼

.86), nonrelapse

mortality (

P

¼

.94 and

P

¼

.74), relapse (

P

¼

.32 and

P

¼

.84),

GF (

P

¼

.32 and

P

¼

.56), acute GVHD (

P

¼

.70 and

P

¼

.23), and

chronic GVHD (

P

¼

.86 and

P

¼

.36). However, a higher TNC

dose was correlated with faster neutrophil engraftment (

P

<

.001). A higher CD34

þ

cell dose tended to correlate to a faster

neutrophil engraftment (

P

¼

.08). The results from the

uni-variate analysis are displayed in

Supplemental Table 1

.

In the BM cohort the multivariate analysis showed a

correlation between a higher TNC and CD34

þ

cell dose and a

faster neutrophil engraftment (hazard ratio [HR], 1.07; 95%

con

dence interval [CI], 1.04 to 1.11;

P

<

.001 and HR, 1.05;

95% CI, 1.01 to 1.09;

P

¼

.02, respectively). The complete

re-sults from the multivariate analysis in BM grafts are

dis-played in

Table 2

.

Peripheral Blood Stem Cells

In univariate analysis we found no correlation between

the TNC dose and OS (

P

¼

.77), nonrelapse mortality (

P

¼

.21),

relapse (

P

¼

.91), GF (

P

¼

.32), acute GVHD (

P

¼

.60), chronic

GVHD (

P

¼

.60), or neutrophil and platelet engraftment

(

P

¼

.85 and

P

¼

.37). Furthermore, we found no correlation

between the CD34

þ

cell dose and GF (

P

¼

.56), nonrelapse

mortality (

P

¼

.22), acute GVHD (

P

¼

.85), chronic GVHD

(

P

¼

.97), or neutrophil engraftment (

P

¼

.37). A higher CD34

þ

cell dose correlated with a lower OS (

P

¼

.003), higher relapse

(

P

¼

.001), and a trend for faster platelet engraftment

(

P

¼

.10). The results from the univariate analysis are

dis-played in

Supplemental Table 1

.

In the PBSC cohort, the multivariate analysis found a

correlation between a higher CD34

þ

cell dose and a lower

OS (HR, 1.04; 95% CI, 1.01 to 1.07;

P

¼

.002), higher relapse

incidence (HR, 1.04; 95% CI, 1.01 to 1.09;

P

¼

.03), and a

faster platelet engraftment (HR, 1.02; 95% CI, 1.01 to 1.04;

P

<

.01). The effect of the CD34

þ

cell dose was studied

more carefully. We found that a very high (

11

10

6

/kg)

and a very low (

2.5

10

6

/kg) CD34

þ

cell dose was

associated with worse OS (

P

¼

.001) (

Figure 1

). A very high

(

11

10

6

/kg) CD34

þ

cell dose was associated with an

increased incidence of relapse (

P

¼

.02) (

Figure 2

). The

complete results from the multivariate analysis in PBSC

grafts are displayed in

Table 2

.

BM versus PBSC

Overall, PBSC showed a nonsigni

cantly better OS rate

compared with BM, 62% versus 53% (

P

¼

.22). A

rich BM

graft

containing more than median TNC dose (

>

3.2

10

8

/kg)

Table 1

Patient Characteristics Receiving Either BM or PBSCs

BM (n¼121) PBSCs (n¼423)

Median age, yr (range) 14 (<1-64) 48 (<1-69)

Sex (male/female) 76/45 243/180 Diagnose Acute leukemia 66 (55%) 216 (51%) Chronic leukemia 19 (16%) 66 (16%) Lymphoma 12 (10%) 37 (9%) MDS 21 (17%) 72 (17%) Other 3 32 (8%) Late stage (>CR1/CP1) 76 (63%) 224 (53%) Donor Sibling 51 (42%) 176 (42%) MUD 70 (58%) 247 (58%)

Median donor age, yr (range) 29 (.5-63) 38 (16-71)

Female to male 26 (21%) 56 (13%) Median TNC dose,108/kg (range) 3.2 (.8-47) 11.6 (2.0-63.8) Median CD34 dose,106/kg (range) 3.9 (.3-26.6) 8.1 (1.6-56.4) Conditioning MAC/RIC 95/26 (79%/21%) 197/226 (47%/53%) TBI-based 51 (42%) 129 (30%) Chemotherapy-based 70 (58%) 294 (70%) ATG 73 (60%) 285 (67%) GVHD prophylaxis CsAþMTX 106 (88%) 356 (84%) Tacrolimusþsirolimus 11 (9%) 52 (12%) Other 4 (3%) 15 (4%)

MDS indicates myelodysplastic syndrome; CR1/CP1,first complete

remis-sion/first chronic phase; MUD, HLA-A, -B, and -DR matched unrelated donor; MAC, myeloablative conditioning; RIC, reduced-intensity condi-tioning; ATG, antithymocyte globulin; MTX, methotrexate.

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was not associated with a better OS rate compared with

PBSC, 47% versus 62% (

P

¼

.07). A similar result was seen

when categorized by CD34 cell dose. However, a PBSC graft

containing less than 11

10

6

/kg CD34

þ

cells had a signi

-cantly better OS rate compared with BM, regardless of cell

dose (66% versus 53%,

P

¼

.03). TRM was 19% using BM and

PBSC. Relapse tended to be lower (26% versus 39%,

P

¼

.06)

and chronic GVHD higher (40% versus 21%,

P

<

.001) using

PBSC compared with BM.

DISCUSSION

Only a few studies have evaluated the effect of cell dose

on clinical outcome after HSCT

[4,14-16]

. Many centers still

rely on the study from Seattle in the late 1970s even though it

only included a small number of patients with severe aplastic

Table 2

Results from Multivariate Analysis of Factors Affecting Various Outcome Variables after HSCT with PBSCs and BM

PBSC BM

Characteristic HR, 95% CI, andPValue Characteristic HR, 95% CI, andPValue

Mortality

Age (decades) 1.25, 1.11-1.40,P<.001 Donor age (decades) 1.40, 1.15-1.70,P<.001

CD34þdose (1106) 1.04, 1.01-1.07,P¼.002 Year of HSCT .91, .87-.96,P<.001 Sibling donor .63, .45-.89,P<.01 Late disease 1.59, 1.15-2.19,P<.01 DRI 1.52, 1.19-1.93,P<.001 GF

Sibling donor .12, .02-.61,P¼.01 Major AB0 mismatch 6.38, 1.08-37.6,P¼.04

RIC 5.94, 1.27-27.9,P¼.02

Female to male 10.0, 2.95-24.2,P<.001

TRM

Acute leukemia .47, .30-.73,P<.001 Sibling donor .14, .03-.58,P<.01

Year of HSCT .80, .67-.96,P¼.02 Major AB0 mismatch 3.86, 1.65-9.04,P<.01

DRI 1.59, 1.14-2.21,P<.01 MDS 3.62, 1.49-8.80,P<.01

Relapse

Late disease 1.60, 1.11-2.32,P¼.02 MDS .21, .05-.88,P¼.03

CD34þdose (1106) 1.04, 1.01-1.09,P¼.03

Acute GVHD grades II-IV

ATG .68, .49-.93,P¼.02 Age (decades) .80, .68-.96,P¼.01

RIC .55, .40-.76,P<.001 ATG .54, .30-.97,P¼.04

Late disease 2.13, 1.08-4.18,P¼.03

Acute leukemia .46, .25-.84,P¼.01

Chronic GVHD

Chronic leukemia 1.66, 1.13-2.43,P¼.01 Age (decades) 1.28, 1.05-1.56,P¼.02

Sibling donor 2.07, 1.50-2.85,P<.001 Year of HSCT .95, .90-.98,P¼.02 Neutrophil engraftment MDS .70, .53-.91,P<.01 CD34 cell dose (1106) 1.05, 1.01-1.09,P¼.02 RIC .71, .58-.87,P<.001 TNC dose (1108) 1.07, 1.04-1.11,P<.001 G-CSF 1.93, 1.43-2.63,P<.001 G-CSF 2.59, 1.60-4.14,P<.001 Platelet engraftment CD34þdose (1106) 1.02, 1.01-1.04,P<.01 G-CSF .61, .41-.91,P¼.02 Sibling donor 1.66, 1.36-2.05,P<.001 CsAþMTX .59, .45-.77,P<.001 G-CSF .88, .44-.73,P<.001

DRI indicates disease risk index; Female to male, female donor to male recipient; GF, graft failure; TRM, transplant related mortality.

Figure 1.The effect of the CD34þcell dose (106/kg) on OS in recipients of PBSCs. The various thresholds were determined by quartiles, whereas the very

low dose group (2.5106/kg) was randomly selected.

Figure 2.The effect of the CD34þcell dose (106/kg) on relapse incidence in recipients of PBSCs. The various thresholds were determined by quartiles.

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anemia (SAA)

[2]

. To create a contemporary point of reference,

we evaluated the effect of TNC and CD34

þ

cell dose on

outcome after HSCT at our center during the last 12 years. We

found that a high TNC dose and a high CD34

þ

cell dose

correlated with faster engraftment of neutrophils in patients

receiving a BM graft. A higher CD34

þ

cell dose correlated with

faster platelet engraftment in patients receiving a PBSC graft.

Although many studies have shown a correlation

between the CD34

þ

dose and time to neutrophil engraftment

[4-10]

, some studies analyzing BM and PBSC grafts have

failed to show such a correlation

[10,29-31]

, possibly because

threshold levels differ between the studies probably as a

consequence of diverse patient populations, treatments,

aspiration techniques, and methods of quanti

cation of

CD34

þ

cells. Another explanation may be that the use of

G-CSF may also contribute to the lack of correlation between

cells infused and neutrophil recovery in other studies. In our

analysis we corrected for the use of G-CSF.

The use of a PBSC graft is associated with faster

engraft-ment compared with BM, and this is often primarily

attrib-uted to the higher cell dose

[3,31-35]

. In patients receiving a

PBSC graft, there was no correlation between cell dose and

time to neutrophil engraftment, in line with many other

studies

[10,29-31]

. This may be because the cell doses in

PBSC grafts are suf

ciently high already and that a further

increase does not reduce time to engraftment. However, a

higher CD34

þ

dose resulted in faster platelet engraftment,

also in conformity with other studies

[5,8]

. The cell dose

threshold for platelet engraftment may be higher than for

neutrophil engraftment.

In line with previous studies, we were unable to

nd a

correlation between the BM TNC and CD34

þ

cell dose and

acute GVHD

[33,36]

. It has been reported that a high CD34

cell dose is associated with an increased risk of severe acute

GVHD

[37,38]

.

Although a high CD34

þ

dose was associated with faster

platelet engraftment, it correlated with reduced OS in the

PBSC group. This is contradictory to most previously

pub-lished results showing that a higher CD34

þ

cell dose

increased survival

[9,10,29,39-41]

. However, 2 studies

showed increased mortality among patients receiving higher

doses of CD34

þ

PBSCs

[7,15]

, mainly because of a signi

cantly

higher cGVHD-associated mortality. An optimal CD34

þ

cell

dose ranging between 4 and 8

10

6

/kg was proposed in

some studies

[6,7,15]

. However, Kamel et al.

[4]

suggested a

higher but very narrow optimum CD34

þ

dose range of 9 to

10

10

6

cells/kg.

In our study we propose a wider range of CD34

þ

cell dose

between 2.5 and 11

10

6

/kg. This difference may be due to

patient population, size of study, and methods of quanti

-cation of CD34

þ

cells. We found that a high CD34

þ

cell dose

was associated with relapse. In autologous SCT similar results

with a higher relapse incidence among patients receiving the

highest CD34

þ

cell dose was reported

[42,43]

, probably

because of contaminating malignant cells.

It is unclear why the relapse incidence increased with

increasing CD34

þ

doses (

>

11

10

6

cells/kg in our analysis)

after allogeneic HSCT. One explanation may be that grafts with

very high numbers of CD34

þ

cells also are very rich in

regula-tory T cells with the capacity to down-regulate the

antileu-kemic effect. This theory is supported by the fact that the

CD34

þ

cell dose did not correlated to chronic GVHD in our

study.

In our study, unmanipulated grafts were used and all

donors were HLA-A, -B, and -DR matched. Compared with

many other studies, our cell doses were relatively high, with

at least 10% of patients receiving a very high cell dose. Some

patients received a CD34

þ

cell dose of up to 50

10

6

/kg.

A study from the European Group for Blood and Marrow

Transplantation showed that a

rich BM

gave better

outcome than PBSCs or less rich BM, linked to a diminution of

the relapse incidence

[44]

. We could not verify these results.

Overall, PBSCs showed a nonsigni

cantly better OS rate

compared with BM, 62% versus 53% (

P

¼

.22). Furthermore, a

PBSC graft containing

<

11.0

10

6

/kg CD34

þ

cells gave better

results than a rich BM.

One drawback may be the heterogeneity of the patients,

including many different diagnoses, both sibling donor and

matched unrelated donor HSCT, and both reduced-intensity

and myeloablative conditioning. However, this is our

clin-ical reality, and we believe our results may help clinicians to

make the right considerations. We propose that when a graft

with a very high cell dose is used, a part may be removed and

frozen for later use as boost, back-up, or donor lymphocyte

infusion. This treatment strategy will improve the clinical

outcome of the HSCT per se and may also save time and

money if a donor lymphocyte infusion or boost is needed.

To conclude, a higher BM TNC and CD34

þ

dose was

associated with faster neutrophil engraftment. A higher PBSC

CD34

þ

cell dose was correlated with faster platelet

engraft-ment but increased mortality and relapse.

ACKNOWLEDGMENTS

Financial disclosure:

This study was supported by grants

from the Swedish Children Cancer Foundation (J014/09).

Con

ict of interest statement:

There are no con

icts of

interest to report.

SUPPLEMENTARY DATA

Supplementary data related to this article can be found at

http://dx.doi.org/10.1016/j.bbmt.2015.01.025

.

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41.Singhal S, Powles R, Treleaven J, et al. A low CD34þcell dose results in higher mortality and poorer survival after blood or marrow stem cell transplantation from HLA-identical siblings: should 210(6) CD34þ cells/kg be considered the minimum threshold?Bone Marrow Trans-plant. 2000;26:489-496.

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44.Gorin NC, Labopin M, Rocha V, et al. Marrow versus peripheral blood for geno-identical allogeneic stem cell transplantation in acute myelocytic leukemia: influence of dose and stem cell source shows better outcome with rich marrow.Blood. 2003;102:3043-3051.

893 w w w . b b m t . o r g Ljungman P, Bregni M, Brune M, et al. Allogeneic and autologoustransplantation for haematological diseases, solid tumours and Storb R, Prentice RL, Thomas ED. Marrow transplantation for treatmentof aplastic anemia. An analysis of factors associated with graft rejection. Remberger M, Ringdén O, Blau I, et al. No difference in graft-versus-host disease, relapse and survival comparing peripheral stem cells Kamel AM, El-Sharkawy N, Mahmoud HK, et al. Impact of CD34 subsetson engraftment kinetics in allogeneic peripheral blood stem cell Niederwieser D, Pepe M, Storb R, et al. Improvement in rejection,engraftment rate and survival without increase in graft-versus-host Zaucha JM, Gooley T, Bensinger WI, et al. CD34 cell dose in granulocytecolony-stimulating factor-mobilized peripheral blood mononuclear cell Mohty M, Bilger K, Jourdan E, et al. Higher doses of CD34þ Sierra J, Storer B, Hansen JA, et al. Transplantation of marrow cells fromunrelated donors for treatment of high-risk acute leukemia: the effect Bittencourt H, Rocha V, Chevret S, et al. Association of CD34 cell dosewith hematopoietic recovery, infections, and other outcomes after Mavroudis D, Read E, Cottler-Fox M, et al. CD34þ Ringden O, Labopin M, Bacigalupo A, et al. Transplantation of periph-eral blood stem cells as compared with bone marrow from Eapen M, Horowitz MM, Klein JP, et al. Higher mortality after alloge-neic peripheral-blood transplantation compared with bone marrow in Singhal S, Powles R, Kulkarni S, et al. Comparison of marrow and bloodcell yields from the same donors in a double-blind, randomized study Pulsipher MA, Chitphakdithai P, Logan BR, et al. Donor, recipient, andtransplant characteristics as risk factors after unrelated donor PBSC Singh AK, Savani BN, Albert PS, Barrett AJ. Effi Tsirigotis P, Shapira MY, Or R, et al. The number of infused CD34þ 225-235 2003;101:1620-1629 756-763 Uzunel M, Remberger M, Sairafi 2723-2730 Remberger M, Svahn B-M, Hentschke P, et al. Effect on cytokine releaseand graft-versus-host disease of different anti-T cell antibodies during Cutler C, Kim HT, Hochberg E, et al. Sirolimus and tacrolimus withoutmethotrexate as graft-versus-host disease prophylaxis after matched Luznik L, O’ Ringden O, Remberger M, Runde V, et al. Peripheral blood stem celltransplantation from unrelated donors: a comparison with marrow Forslow U, Mattsson J, Ringden O, et al. Decreasing mortality rate inearly pneumonia following hematopoietic stem cell transplantation. Svahn BM, Remberger M, Myrback KE, et al. Home care during thepancytopenic phase after allogeneic hematopoietic stem cell Fine J, Gray R. Proportional hazard model for the sub-distribution ofcompeting risks. Morariu-Zamfi Pavletic ZS, Bishop MR, Tarantolo SR, et al. Hematopoietic recoveryafter allogeneic blood stem-cell transplantation compared with bone Lickliter JD, McGlave PB, DeFor TE, et al. Matched-pair analysis of pe-ripheral blood stem cells compared to marrow for allogeneic Bensinger WI, Clift R, Martin P, et al. Allogeneic peripheral blood stemcell transplantation in patients with advanced hematologic Blaise D, Kuentz M, Fortanier C, et al. Randomized trial of bone marrowversus lenograstim-primed blood cell allogeneic transplantation in Ringden O, Hagglund H, Runde V, et al. Faster engraftment of periph-eral blood progenitor cells compared to bone marrow from unrelated 1487-1496 Champlin RE, Schmitz N, Horowitz MM, et al. Blood stem cellscompared with bone marrow as a source of hematopoietic cells for Gaziev J, Isgro A, Marziali M, et al. Higher CD3( Przepiorka D, Smith TL, Folloder J, et al. Risk factors for acute graft-versus-host disease after allogeneic blood stem cell transplantation. 2006;24:3959-3966 Ringden O, Barrett AJ, Zhang MJ, et al. Decreased treatment failure inrecipients of HLA-identical bone marrow or peripheral blood stem cell Singhal S, Powles R, Treleaven J, et al. A low CD34 Gorin NC, Labopin M, Reiffers J, et al. Higher incidence of relapse inpatients with acute myelocytic leukemia infused with higher doses of Feller N, Schuurhuis GJ, van der Pol MA, et al. High percentage of CD34-positive cells in autologous AML peripheral blood stem cell products Gorin NC, Labopin M, Rocha V, et al. Marrow versus peripheral bloodfor geno-identical allogeneic stem cell transplantation in acute

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