Infections after Transplantation of Bone Marrow or

Infections after Transplantation of Bone Marrowor Peripheral Blood Stem Cells from UnrelatedDonorsJo-Anne H. Young, University of MinnesotaBrent R. Logan, Medical College of WisconsinJuan Wu, The EMMES CorporationJohn R. Wingard, University of FloridaDaniel J. Weisdorf, University of MinnesotaCathryn Mudrick, The EMMES CorporationKristin Knust, The EMMES CorporationMary M. Horowitz, Medical College of WisconsinDennis L. Confer, National Marrow Donor ProgramErik R. Dubberke, Washington University

Only first 10 authors above; see publication for full author list.

Journal Title: Biology of Blood and Marrow TransplantationVolume: Volume 22, Number 2Publisher: Elsevier | 2016-02-01, Pages 359-370Type of Work: Article | Post-print: After Peer ReviewPublisher DOI: 10.1016/j.bbmt.2015.09.013Permanent URL: https://pid.emory.edu/ark:/25593/rwq6j

Final published version: http://dx.doi.org/10.1016/j.bbmt.2015.09.013

Copyright information:© 2016 American Society for Blood and Marrow Transplantation.This is an Open Access work distributed under the terms of the CreativeCommons Attribution-NonCommercial-NoDerivatives 4.0 International License(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Accessed March 13, 2022 11:37 AM EDT

https://pid.emory.edu/ark:/25593/rwq6j

http://dx.doi.org/10.1016/j.bbmt.2015.09.013

http://creativecommons.org/licenses/by-nc-nd/4.0/

Infections following Transplantation of Bone Marrow or Peripheral-Blood Stem Cells from Unrelated Donors

Jo-Anne H. Young1,*, Brent R. Logan2, Juan Wu3, John R. Wingard4, Daniel J. Weisdorf1, Cathryn Mudrick3, Kristin Knust3, Mary M. Horowitz2, Dennis L. Confer5, Erik R. Dubberke6, Steven A. Pergam7, Francisco M. Marty8, Lynne M. Strasfeld9, Janice (Wes) M. Brown10, Amelia A. Langston11, Mindy G. Schuster12, Daniel R. Kaul13, Stanley I. Martin14, and Claudio Anasetti15 for the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Trial 02011Department of Medicine, University of Minnesota, Minneapolis, MN

2Medical College of Wisconsin, Milwaukee, WI

3The EMMES Corporation, Rockville, MD

4Shands Cancer Center, University of Florida, Gainesville, FL

5National Marrow Donor Program, Minneapolis, MN

6Washington University School of Medicine, St. Louis, MO

7Fred Hutchinson Cancer Research Center, Seattle, WA

8Dana-Farber Cancer Institute, Boston, MA

9Oregon Health & Science University, Portland, OR

10Stanford University, Palo Alto, CA

11Emory University, Atlanta, GA

12University of Pennsylvania, Philadelphia, PA

13Univeristy of Michigan, Ann Arbor, MI

14Ohio State University, Columbus, OH

Corresponding author: Jo-Anne H. Young, MD. Address: MMC 250, 420 Delaware St SE, Minneapolis, MN 55455. [email protected]. Phone: (612) 625-8462. Fax: (612) 625-4410.

Authorship ContributionJ.H.Y. and D.J.W. designed the infectious disease analysis for this study protocol and wrote the paper; C.A., J.R.W., M.M.H. and D.J.W. were senior advisors in the design, conduct, and analysis of the study; K.K. and C.M. organized and maintained the database, J.H.Y., J.R.W, E.R.D., S.A.P., F.M.M. L.M.S., J.M.B., A.A.L., M.G.S., D.R.K., and S.I.M. audited many infection summaries; J.W. and J.H.Y. analyzed data; B.R.L., and J.W. provided statistical analysis; all authors reviewed and provided insightful comments to better the manuscript; and J.W. and J.H.Y. drew the figures.

Disclosure of potential conflicts of interestThe authors declare no competing financial interests.

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

HHS Public AccessAuthor manuscriptBiol Blood Marrow Transplant. Author manuscript; available in PMC 2017 February 01.

Published in final edited form as:Biol Blood Marrow Transplant. 2016 February ; 22(2): 359–370. doi:10.1016/j.bbmt.2015.09.013.

Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

15H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL

Abstract

Infection is a major complication of hematopoietic cell transplantation. Prolonged neutropenia and

graft versus host disease are the two major complications with an associated risk for infection, and

these complications differ according to the graft source. A phase 3, multicenter, randomized trial

(BMT CTN 0201) of transplantation of bone marrow (BM) versus peripheral-blood stem cells

(PBSC) from unrelated donors (URD) showed no significant differences in two-year survival

between these graft sources. In an effort to provide data regarding whether bone marrow or

peripheral-blood stem cells could be used as a preferential graft source for transplantation, we

report a detailed analysis of the infectious complications for 2 years following transplantation

from the BMT CTN 0201 trial. A total of 499 patients in this study had full audits of infection

data. A total of 1347 infection episodes of moderate or greater severity were documented in 384

(77%) patients; 201/249 (81%) of the evaluable patients had received a BM graft and 183/250

(73%) had received a PBSC graft. Of 1347 infection episodes, 373 were severe and 123 were life-

threatening and/or fatal; 710 (53%) of these episodes occurred on the BM arm and 637 (47%) on

the PBSC arm, resulting in a two-year cumulative incidence 84.7% (95% confidence interval [CI]:

79.6–89.8) for BM vs. 79.7% (95%CI, 73.9–85.5) for PBSC, P = .013. The majority of these

episodes, 810 (60%), were due to bacteria, with a two-year cumulative incidence of 72.1% and

62.9% in BM versus PBSC recipients, respectively (P = .003). The cumulative incidence of

bloodstream bacterial infections during the first 100 days was 44.8% (95%CI, 38.5–51.1) for BM

vs. 35.0% (95%CI, 28.9–41.1) for PBSC (P = .027). The total infection density (# infection

events / 100 patient days at risk) was .67 for BM and .60 for PBSC. The overall infection density

for bacterial infections was .4 in both arms; for viral infections was .2 in both arms; and for

fungal/parasitic infections was .04 and .05 for BM and PBSC, respectively. The cumulative

incidence of infection prior to engraftment was 47.9% (95%CI, 41.5–53.9) for BM vs. 32.8%

(95%CI, 27.1–38.7) for PBSC (P = .002), possibly related to quicker neutrophil engraftment using

PBSC. Infections remain frequent following URD HCT, particularly following BM grafts.

Keywords

Infection; unrelated donor transplantation; bacteremia; cytomegalovirus; aspergillosis; pre-engraftment

INTRODUCTION

Blood and Marrow Transplant Clinical Trials Network (BMT CTN) protocol 0201 was a

phase 3, multicenter, randomized trial of transplantation of bone marrow (BM) versus

granulocyte-colony stimulating factor mobilized peripheral-blood stem cells (PBSC) from

HLA compatible unrelated donors in patients with hematologic malignancies. There were no

significant differences in 2-year survival probabilities [1]. Only 5% of patients who died had

infection listed as the primary cause of death. Analysis of pre-specified secondary endpoints

showed that the median time to neutrophil engraftment was 5 days shorter for those

randomly assigned to receive PBSC. The total incidence of graft failure was 3% in the

PBSC group, compared to 9% in the BM group. These significant findings, as well as data

Young et al. Page 2

Biol Blood Marrow Transplant. Author manuscript; available in PMC 2017 February 01.

Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

from other clinical trials, have led some to choose PBSC as a preferential graft source [2–6].

However, the 53% incidence of chronic graft-versus host disease at 2 years in the PBSC

group was significantly higher when compared to 41% for the BM group, a finding

confirmed by other studies [2–4,7–10]. These secondary analyses suggest that it may be

important for patients who are immunosuppressed from prior chemotherapy, and have a

lower risk of graft rejection, receive BM grafts, while patients with malignant diseases who

have never undergone cytotoxic chemotherapy, who may be at increased risk of rejection of

a BM graft, undergo transplant with a PBSC graft. In an effort to provide additional data

regarding whether BM or PBSC could be used as a preferential graft source for

transplantation, we report a detailed analysis of the infectious complications for 2 years

following transplantation from the BMT CTN 0201 trial.

METHODS

Protocol Synopsis

BMT CTN Protocol 0201 opened for accrual in March 2004 and closed in September 2009

meeting the target accrual objective of 550 donor-recipient pairs. Randomization was

performed 1:1 to either PBSC or BM and stratified by transplant center and disease risk.

Details of the treatment schemes have been reported [1]. Key baseline characteristics were

similar in the 2 treatment arms. The primary objective was to compare two-year survival

probabilities in the two study arms using an intent-to-treat analysis. Secondary objectives

included incidences of neutrophil and platelet engraftment, graft failure, acute graft-versus-

host disease (GVHD), chronic GVHD, time off all immunosuppressive therapy, relapse,

adverse events, immune reconstitution, and quality of life. Moderate or more severe

infections were reported on an event-driven Case Report Form, excluding those that

occurred pre-transplant, and were tabulated for two years following transplantation.

Infection Prophylaxis

Among the 40 participating transplant centers, infection prophylaxis followed local

protocols that were based on national guidelines [11]. Patients underwent their transplant

procedure in rooms ventilated with high efficiency particulate air filtration systems to

prevent acquisition of exogenous mold infections [12]. During periods of neutropenia,

broad-spectrum antibacterial agents were administered that included anti-pseudomonal

antibacterial agents for febrile neutropenia [13]. During periods of fever, assessment for

infection and augmentation of antimicrobial agents included empirical treatment for yeasts

and molds for persistent fever [14]. Medication to prevent Pneumocystis infections generally

started within one month after transplantation, following engraftment [15]. Acyclovir was

used to prevent herpes simplex and varicella infections. Monitoring guidelines were

followed to detect and preemptively treat cytomegalovirus (CMV) infection.[16] Diagnostic

strategies for individual pathogens, particularly viral and fungal infections, varied between

centers based on local laboratory practices.

Data Collection and Audit

Transplant centers prospectively reported infections for study subjects. Infection onset date,

organism, body site, clinical severity, and treatment were captured. Classification of

Young et al. Page 3


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

infection severity, including a fatal category, were modified from the definitions used in

previous studies [17,18]: A) Life-threatening infections were those complicated by

hypotension or any another event considered life-threatening; B) Severe infections often

required treatment with intravenous antibiotics or involved other clinical circumstances that

were considered severe.

Based on previous studies that had shown the importance of infection data auditing [17–22],

the 0201 Infection Team contacted each transplant center to audit the infection data reported

for local study patients. In 2012, a pilot audit of infectious disease data for 78 subjects at 15

centers involved with this study indicated value for a full data audit for all transplanted

subjects. The BMT CTN Infection reporting form and Instructions for the BMT CTN 0201

Infection Data Review are included as supplementary files to this manuscript. To perform

both the pilot audit and entire study audit, the Data and Coordinating Center (The EMMES

Corporation, Rockville, MD) prepared an infection summary for each study patient listing

the date, organism, body site, severity, and comments regarding each infection as

prospectively reported. The auditor confirmed database information by reviewing

electronically generated medical records of microbiology, virology, imaging, and surgical

pathology reports. Study subjects who were not audited for infection data (n=27, 5%) were

excluded from these analyses.

Staphylococcus epidermidis bloodstream infections were counted as an episode of infection

if they were treated (even when just one positive blood culture led to treatment) because the

treatment course then could have affected whether a second blood culture turned positive,

altered the flora of the subject, and created the potential for drug toxicity. CMV, human

herpes virus-6, and polyomavirus infections were differentiated as viremia or disease using

the BMT CTN Infection reporting form which specifies a body site code; a comment box to

add detail about an infection was later reviewed by the audit committee (and JHY) during

data cleaning; and the specified definitions of infection severity based on body site affected.

All Epstein Barr Virus (EBV) “infections” had the comments specifically reviewed to

categorize infections as EBV lymphoproliferative disorder, viremia, or report of a serologic

antibody status.

The BMT CTN Definitions of Infection Severity clarify that fever of undetermined origin,

upper respiratory infections presumed viral, and potential infections where antibiotics were

given without infectious etiology identified were not to be reported. If reported, they were

removed from the dataset during final data review.

Statistical Analysis

Infectious complications were analyzed by comparison of the two treatment arms (PBSC

versus BM) and adjusted by other relevant clinical risk factors. All data on time to infections

or other events were calculated from the date of transplantation. Patients were censored at

last follow-up, relapse, second transplant, or 2 years after transplant, whichever came first.

When a single organism was recovered multiple times, we followed the algorithm for

infection recurrence intervals that were specific to each microorganism, as reported

previously [17].

Young et al. Page 4


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

Analysis of infection incidence (by frequency and cumulative incidence) [17] and infection

density (number of infections over time for patients with repeated infections) [20] was

performed for overall infections, bacterial infections, viral infections and fungal/parasitic

infections, over different time periods (Day 0 to Day 100, Day 100 to 6 months, 6 months to

1 year, 1 year to 2 years, and overall within 2 years of transplantation), by treatment arm.

Death was considered a competing risk in cumulative incidence analysis. Infection density

was computed by infection frequencies over 100 patient days at risk. The number of patients

with infections reported was summarized for each infection type and by treatment arm;

specific infectious organisms of interest were explored in descriptive and cumulative

incidence analyses.

Multivariate regression analyses were performed to test the contribution of the randomized

stem cell source (PBSC versus BM) and other relevant covariates to the incidence of

infections. Proportional rates/means models were used to model the infection density over

time, with a robust variance estimator to account for within subject correlation [23]. All

variables were checked for proportionality using time dependent covariates. The effect of

acute and chronic GVHD on infection density was obtained using time-dependent

covariates. Multivariate analyses were performed to test the impact of various types of

infections on overall survival following transplantation. Cox regression models were used to

model survival. The treatment arm variable was forced into all models and baseline

covariates were selected using forward stepwise algorithm. Various types of infections were

treated as time-dependent covariates in the model. SAS version 9.3 (SAS Institute) was used

for data manipulation, infection frequency analysis, and multivariate modeling. R version

2.15.1 was used for cumulative incidence analysis.

RESULTS

Study Population and Total Infections

Among 551 patients enrolled at 48 centers between 01/2004 and 10/2009, 526 patients

received a transplant. Response rate was 95% for the infection data audit (249 of the BM

arm and 250 on the PBSC arm), resulting in a study population for this analysis of 499

audited patients. Table 1 lists the baseline characteristics of the patients by treatment arm.

Baseline characteristics were balanced between the arms and no significant differences were

noted.

Overall, 384 patients developed infections of moderate or greater severity: 201 on the BM

arm and 183 on the PBSC arm. Of 1347 infection episodes (373 severe and 123 life-

threatening and/or fatal), 710 (53%) occurred on the BM arm and 637 (47%) on the PBSC

arm (Figure 1). The majority of infection episodes on each treatment arm were of moderate

severity (Figure 1a). However, when patients were categorized by infection of worst

severity, 84 patients on the BM arm had a severe infection as their most clinically serious

infection, compared to 68 patients on the PBSC arm (Figure 1b, p = 0.6).

Young et al. Page 5


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

Cumulative Incidence

Cumulative incidence described the proportion of patients developing at least one infection,

with an estimated 2-year incidence of 84.7% (95% confidence interval [CI], 79.6–89.8) for

the BM arm, vs. 79.7% (95%CI, 73.9–85.5) for the PBSC arm, Gray’s test P = .013 (Figure

2). In a subset analysis of the 465 patients who engrafted (excluding 34 patients with

primary or secondary graft failure), the 2-year cumulative incidence rate was 85.3% (95%

CI: 79.2–89.7) for the BM arm, vs. 79.8% (95%CI, 73.2–85.0) for the PBSC arm (P = .014).

Among 810 bacterial infection episodes, 431 occurred in patients on the BM arm and 379 in

patients on the PBSC arm, with a 2-year cumulative incidence of 72.1% and 62.9%,

respectively (Figure 3a, P = .003). Among Gram-positive organisms, coagulase negative

Staphylococcus accounted for 224 infection episodes in 149 patients, Staphylococcus aureus

for 40 infections in 29 patients, and Enterococcus (all species) for 103 infections in 82

patients (Table 2). Among Gram-negative infections, Escherichia coli accounted for 39

infection episodes in 34 patients, Klebsiella species for 36 infections in 29 patients,

Pseudomonas species for 32 infections in 25 patients, Enterobacter for 14 infections in 12

patients, and Stenotrophomonas for 13 infections in 12 patients. There were 123 Clostridium

difficile, 5 Nocardia, and 2 non-tuberculous mycobacterial infections. No cases of

tuberculosis were reported. Of the bacterial infections, 413 were recovered from the

bloodstream. The cumulative incidence of bloodstream bacterial infections during the first

100 days following transplantation was 44.8% (95%CI, 38.5–51.1) for the BM arm vs.

35.0% (95%CI, 28.9–41.1) for the PBSC arm (Figure 3b, P = .092), possibly related to

quicker neutrophil engraftment using PBSC.

Among 438 viral infection episodes (136 severe and 48 life-threatening and/or fatal), 234

were on the BM arm and 204 on the PBSC arm (Figure 3c). Herpesvirus infections

accounted for the majority of infections. CMV accounted for 159 infection episodes in 118

patients, herpes simplex for 38 infections in 31 patients, Epstein-Barr virus for 36 infections

in 27 patients (none of these 27 patients had anti-thymocyte globulin use reported in the

graft versus host disease treatment form), and varicella for 22 infections in 20 patients.

Respiratory viruses accounted for 93 infection episodes including 35 for influenza, 23

respiratory syncytial virus, 17 parainfluenza virus, 14 adenovirus, and 4 rhinovirus.

Additional clinically significant viral infections included a total of 54 infection episodes

among 49 patients due to polyomavirus (BK virus); 10 due to human herpes virus-6; 2 due

to enterovirus; and 2 due to rotavirus. The 2-year cumulative incidence of CMV infection

was 25.9% (95%CI, 20.2–31.6) for the BM arm, vs. 24.4% (95%CI, 18.8–30.0) for the

PBSC arm (Figure 3d, P = .62). Among 248 CMV-seropositive recipients, the cumulative

incidence of CMV infection was 40.6% (95%CI, 31.8–49.2) in the BM arm compared with

36.9% (95%CI, 27.9–46.0) in the PBSC arm (P = .47). CMV infection episodes occurred in

the bloodstream only in 78.6% of CMV-infected patients, versus progression to non-

bloodstream sites in 21.4%. Among the CMV-infected patients, a later episode of infection

occurred beyond two months from the first infection in 20.3%, although further detail

regarding whether these were recurrent, refractory, or resistant infections is not within the

scope of data collected by this trial. CMV seropositivity did not impact survival in the

models.

Young et al. Page 6


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

Among 89 fungal infections (Figure 3e), there were 37 due to yeast (including 1 case of

Saccharomyces cerevisiae in the bloodstream), 31 due to mold (20 cases of aspergillosis, 7

of mucormycosis, 2 cases of penicilliosis, 1 case of cavitary pulmonary Microascus, and 1

of fusariosis), and 1 case of coccidioidomycosis. Twenty infection episodes classified as

fungal were cases of infection that were assessed to be responsive to antifungal therapy.

Thirty-one of the fungal infection episodes were severe and 25 were life-threatening and/or

fatal, distributed among 34 patients (13 severe and 9 life-threatening and/or fatal) on the BM

arm and 37 (13 and 9) on the PBSC arm. There were 3 Pneumocystis infections and 1 case

of toxoplasmosis. The Aspergillus species included 11 A. fumigatus, 2 A. niger, and 1 A.

flavus. Six cases of aspergillosis were not speciated. The 2-year cumulative incidence of

invasive aspergillosis was 3.9% (95%CI, 1.2–6.6) for the BM arm, vs. 3.6% (95%CI, 1.0–

6.2) for the PBSC arm (Figure 3f, P = .81).

Infection Density

The overall infection density for the study was 0.63 events per 100 patient days at risk; 0.67

for BM and 0.60 for PBSC (Figure 4a). The infection density of bacterial infections was 0.4

for both arms (Figure 4b). The infection density for viral infections was 0.2 in both arms

(Figure 4c). The infection density for fungal/parasitic infections was 0.04 and 0.05 for the

BM and the PBSC arm, respectively (Figure 4d). Infection density for each assessment

period was computed by looking into the infections reported during this period over the risk

days during this period. For example, bacterial bloodstream and non-bloodstream infections

had their highest density during the Day 0 to Day 100 interval (Figure 4e and 4f), and

decreased over time (Table 3). The infection density for infections of moderate, severe, and

life-threatening and/or fatal severity followed a similar trend with regard to infection density

over time (Figures 4g, 4h, and 4i).

Relationship of Infection to GVHD: Multivariate Analyses

The baseline covariates in Table 1 were considered in the multivariate analyses. In

multivariate analyses of infection density, there were no significant differences between

PBSC and BM for density of bacterial or fungal infections (Table 4). For viral infections, a

significant interaction was detected between graft type and disease risk (P < 0.001), so that

for early disease the risk of viral infections was lower with PBSC compared to BM, while

for advanced / late disease, risks of viral infection were higher with PBSC. However, there

was no overall significant effect of graft type on viral infections if this interaction was

ignored.

Both acute and chronic GVHD were associated with increased rates of bacterial and fungal

infections in both the BM and PBSC arms (Table 5). Only acute (but not chronic) GVHD

was associated with increased rates of viral infections.

After adjustment for significant covariates including age, conditioning regimen, HLA

matching, and disease risk, bacterial and fungal, but not viral or even specifically CMV,

infections were associated with worse survival in both BM and PBSC recipient groups

(Table 6).

Young et al. Page 7


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

Infections within 30 days prior to Death

Infection was reported as a primary cause of death for 11 of 133 deceased patients on the

BM arm and for 9 of 139 on the PBSC arm. Patients where infection was a de novo cause of

death included 2 viral infections (2/11 = 18% of BM, and 22% of PBSC, or ~ 20%) and 1

fungal infection (9% of BM, and 11% of PBSC, or ~ 10%) on each arm, with the remainder

being bacterial infections generally associated with multiorgan failure (73% of BM, and

67% of PBSC, or ~ 70%). We reviewed infections within 30 days of death to examine the

proximate relationship of any infections to death. On the BM arm, 111 infections were

reported on 50 patients within 30 days prior to death; on the PBSC arm, 96 infections were

reported on 39 patients. Of these 207 infections reported within 30 days of death, bacteria

accounted for 138, viruses for 38, and fungi/parasites for 30. Patients with acute or chronic

GVHD reported as the cause of death, and an infection noted as being the most severe

within 30 days of death, had a high percentage of fungal infections (20/52 or ~ 38%), with

fewer viral (~ 14%), bacterial (~44%), or protozoal infections (~ 4%).

Relationship of Infection to Engraftment

The cumulative incidence of infections that occurred among engrafted patients, 1 year

following engraftment, was 71.1% (95%CI, 64.4–76.9) for the BM arm vs. 67.2% (95%CI,

60.1–73.2) for the PBSC arm (P = .23) (Figure 5a). The cumulative incidence of pre-

engraftment infections (occurring before Day 30) was 47.9% (95%CI, 41.5–53.9) for the

BM arm vs. 32.8% (95%CI, 27.1–38.7) for the PBSC arm (P = .002) (Figure 5b).

DISCUSSION

We analyzed all infection events during two years of follow-up for two randomly assigned

graft source treatment arms for unrelated donor myeloablative hematopoietic cell

transplantation patients who participated in BMT CTN 0201 (a minority were not

myeloablative). When the trial was designed, we hypothesized that infection may play a

major role in augmenting morbidity and mortality in this randomized trial, so infection

events were collected prospectively as a prespecified secondary outcome. This multicenter,

randomized phase 3 trial demonstrated that infections remain common and occurred for 85%

of BM recipients and 80% of PBSC recipients. Strengths of this prospective study are the

large sample size, as well as the detailed and audited data capture on all infections during

extended follow-up. No previous comparison of these 2 graft sources for use in

transplantation has such a rich and detailed infection database with which to examine

infectious complications for this important question of PBSC or BM as the graft source for

allogeneic hematopoietic cell transplantation.

In this large randomized study of allogeneic hematopoietic cell transplantation, we observed

a cumulative incidence of bacterial infections that is higher among patients who received

BM rather than PBSC grafts for transplantation. The cumulative incidence of infections was

driven by bacterial infections occurring before Day 100. Since the median time to neutrophil

engraftment was 5 days longer for BM recipients than for those randomly assigned to

receive PBSC, it is not surprising to see many bacterial infections early after transplant.

These bacterial infections were more common prior to engraftment and over the two years

Young et al. Page 8


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

following transplantation, but speed of engraftment or graft failure alone did not wholly

account for this finding. Bacterial bloodstream infections accounted for 30% of all

infections, a finding similar to an earlier prospective study of T cell depletion to limit

GVHD after unrelated donor hematopoietic cell transplantation [17].

There are no data regarding pre- or peri-transplant prophylaxis agents used, especially

relevant for quinolones with the 123 cases of Clostridium difficile infection during this time

prior to use of toxin-based PCR assays. As a result, antibacterial prophylaxis is a baseline

characteristic that probably modulates the events seen but cannot otherwise be assessed.

During the analysis of transplant-related endpoints for this study, recipients of PBSC grafts

had a higher rate of chronic GVHD, so infections that occurred after Day 100 were of

particular interest, especially viral and fungal infections. CMV infections were not more

frequent using BM or PBSC, even in the setting of GVHD. This study is the first

comparative, long-term follow-up trial with infection data and does not support late CMV

disease as a common event. Our database was not structured to capture self-limited (i.e.,

untreated) CMV viremia. Our database did not capture recurrent, refractory, or resistant

CMV.

The probability of developing a clinically important CMV infection was less than 30% in

each arm, a rate consistent with other studies published in the last 10 years, and lower than

studies published earlier [17,24–26]. In our study, there were 61 CMV infection episodes on

the BM arm and 57 infections for patients transplanted using PBSC. The infection density

for CMV infections was 0.25 for BM and 0.24 for PBSC during the Day 0 to Day 100

interval, declining to 0.06 for BM and to 0.10 for PBSC during the Day 100 to Day 180

interval, and to 0.03 for BM and to 0.05 for PBSC during the Day 181 to Day 365 interval.

Survival among patients who developed a CMV infection was 41% for the BM arm and

49% for the PBSC arm. Regardless of study arm, this overall improved rate of any CMV

infection, in comparison to studies published over the last 20 years, likely reflects changes in

CMV monitoring/preemptive schemas, anti-CMV prophylaxis, the stem cell product itself,

and in conditioning regimens over time. The rapid turnaround time in the newest generation

of CMV diagnostic testing, and the availability of oral antiviral agents (e.g., valganciclovir),

may have contributed to the low and comparable rates of CMV between the study arms.

By 2 years after transplant, the cumulative incidence of Aspergillus infection was 4% in

each study arm, much lower than previously reported rates of 10–15% [17,27]. The 4% rate

(20 cases) represents some form of culture and/or histopathologic documentation, so these

are cases of proven or probable infection but not possible infection. This is the lowest

estimate of invasive aspergillosis in any allogeneic hematopoietic stem cell transplant series.

The low rates of invasive aspergillosis may be related to ascertainment bias. Centers

participating in this Clinical Trials Network perform bronchoscopies with various levels of

aggressiveness, and when a bronchoscopy is performed, may have variable testing for

Aspergillus galactomannan using lavage fluid. Thus, there is an undercount of probable and

proven invasive aspergillosis since many of these pneumonias end up being “possible”

invasive fungal infections or merely are treated empirically as fungal infection; in fact, there

Young et al. Page 9


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

were 20 infection episodes classified as fungal that were cases of infection that were

assessed to be responsive to antifungal therapy.

Diagnostic testing for fungal infections was in a state of evolution during the years that this

study was conducted. While the improvement in cumulative incidence is likely related to

advances in antifungal agents that can be successfully employed with less toxicity and with

prophylactic intent over the last 15 years, there was still a nontrivial rate of invasive fungal

infections for the patients on this study. The 2-year cumulative incidence of invasive fungal

infections was 16% for BM patients and 18% for PBSC patients. This includes 7 cases of

mucormycosis, a fungal organism that is not within the spectrum of activity of either

voriconazole or echinocandins, as well as 25 cases of “other fungus”, some of which were

clinical cases of pulmonary nodules responsive to antifungal therapy.

This detailed review of prospectively reported infectious disease events speaks to the

challenges to infection data completeness and accuracy, even in this prospective and

carefully monitored randomized trial. Despite prospective reporting, the initial audit of 15%

of the patients (583 infections for 78 patients) identified frequent minor errors among one or

more of the different data points associated with each infection (date, organism, body site,

clinical severity). While these disagreements were not entirely correct as originally entered,

most of these disagreements were minor did not affect the final results.

Accuracy of infection reporting goes down markedly after Day 100, when most patients

leave the transplant center. When the accumulated list of all the infections was compared to

the primary source documents, 65 previously unreported infections were identified. More

than half of these infections occurred after Day 100. Twenty-two infections occurred after

engraftment but before Day 100, of which two thirds were bacterial often coagulase negative

Staphylococcus and one third were viral often CMV. The follow-up site self-audit used for

this study indicates the importance of data accuracy, and argues for this type of approach in

future studies evaluating complex, multiple endpoint infectious disease data, even if

prospectively collected.

The data coordinating center has submitted all study data from this clinical trial, including

these infection data, to the National Heart, Lung, and Blood Institute (NHLBI) data

repository, so that future users should be able to access the data from a public end.

There are several limitations to interpreting a complex infection database when collected

from hospitals across the study. There are differences in diagnostic testing at the various

sites, and incidence rates may be altered based on current testing strategies (particularly for

respiratory viruses and fungal infections). Additionally, with the detailed and complete

retrospective audit of the protocol prescribed monitoring of infections, it is unlikely that

many major infections were unrecognized.

This study noted a tremendous burden of infection among transplanted patients. Fortunately,

infection was an uncommon cause of death. The incidence and severity of infection is lower

than historical cohorts. The greatest differences were seen in the pre-engraftment time

period. We need ways to continue to drive down the burden of infection for all patients.

Morbidity and mortality from infection following transplantation was frequent using either

Young et al. Page 10


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

graft source, with no observed differences in fungal or viral infection rates. Among those

who died, few had infection reported as the primary cause of death although many infections

occurred in the final month of life. The higher observed risks of bacterial infections using

BM grafts may suggest either augmented prophylaxis or heightened surveillance after these

transplants.

Supplementary Material

Refer to Web version on PubMed Central for supplementary material.

Acknowledgments

Supported by a grant from the National Heart, Lung, and Blood Institute and the National Cancer Institute (U10HL069294), by the Office of Naval Research, and by the National Marrow Donor Program. Disclosure forms were provided by the authors. We thank the transplantation-center teams in the United States and Canada for enrolling patients in this trial; the donor-center teams in the United States, Canada, and Germany for recruiting the donors for the trial; and the National Marrow Donor Program coordinating center for facilitating the transplantations.

We thank the infectious disease auditors at each center: Nathalie Lachapelle and Jean Roy (Hôpital Maisonneuve-Rosemont), Susan Durham (Cohen Children’s Medical Center), Karen Parrott (University of Iowa Hospitals and Clinics), Andrea Ortega (Hackensack University Medical Center), Mindy Shuster (University of Pennsylvania Cancer Center), Jessica Piggee (Vanderbilt University Medical Center), Margaret Shea and Francisco Marty (Dana-Farber Cancer Institute and Brigham and Women’s Hospital), Erik Dubberke (Washington University: Barnes-Jewish), Juliana Ongley (University of California, San Diego), Lisa Malick (University of Maryland Cancer Center), Stanley Martin (Ohio State: Arthur G. James Cancer Hospital), Valerie Dorcas (Queen Elizabeth II Health Sciences Centre), JoDell McCracken (Texas Transplant Institute), Lisa Dutton (Mayo Clinic, Rochester), Lynne Strasfeld (Oregon Health & Science University), Daniel Kaul (University of Michigan Health System), Ginger Butterworth (Baylor University Medical Center), Lisa Williams (University of Alabama at Birmingham), Michael Pulsipher (Primary Children’s Hospital/Utah BMT), David Hurd (Wake Forest University), Tia Thomas (Washington University: St. Louis Children’s Hospital), Melissa Moynihan (Vancouver General Hospital), Amy O’Sullivan, Brittni Prosdocimo, and Mounzer Agha (University of Pittsburgh Cancer Institute), Janice (Wes) Brown (Stanford Hospital and Clinics), Greg McFadden (University of Nebraska Medical Center), Lynn Savoie (Tom Baker Cancer Centre), Patti Cunningham (Oklahoma University Medical Center), Adina Londrc (City of Hope National Medical Center), John Wingard (University of Florida: College of Medicine), Rebecca Gerkin (Emory University Hospital), Tammy DeGelder (McMaster University Medical Centre: Hamilton Health Sciences), Shaun DeJarnette and Abhyankar (University of Kansas Medical Center), Carol Cutrone (Loyola University Medical Center), Sofia Qureshi (MD Anderson Cancer Center), Jueleah Expose’-Spencer (University of California, San Francisco), Isabel Belen (University of Toronto: Princess Margaret), Jessica Greene (Roswell Park Cancer Institute), Mitch Horwitz (Duke University Medical Center), and Steven Pergam (Fred Hutchinson Cancer Research Center).

References

1. Anasetti C, Logan BR, Lee SJ, et al. Peripheral-blood stem cells versus bone marrow from unrelated donors. N Engl J Med. 2012; 367:1487–1496. [PubMed: 23075175]

2. Holtick U, Albrecht M, Chemnitz JM, et al. Comparison of bone marrow versus peripheral blood allogeneic hematopoietic stem cell transplantation for hematological malignancies in adults-a systematic review and meta-analysis. Crit Rev Oncol Hematol. 2014

3. Holtick U, Albrecht M, Chemnitz JM, et al. Bone marrow versus peripheral blood allogeneic haematopoietic stem cell transplantation for haematological malignancies in adults. Cochrane Database Syst Rev. 2014; 4:CD010189. [PubMed: 24748537]

4. Stamatovic D, Balint B, Tukic L, et al. Impact of stem cell source on allogeneic stem cell transplantation outcome in hematological malignancies. Vojnosanit Pregl. 2011; 68:1026–1032. [PubMed: 22352263]

5. Korbling M. Peripheral Blood Stem Cells: A Novel Source for Allogeneic Transplantation. Oncologist. 1997; 2:104–113. [PubMed: 10388037]



Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

6. Appelbaum FR. Choosing the source of stem cells for allogeneic transplantation: no longer a peripheral issue. Blood. 1999; 94:381–383. [PubMed: 10397703]

7. Campregher PV, Hamerschlak N, Colturato VA, et al. Survival and graft-versus-host disease in patients receiving peripheral stem cell compared to bone marrow transplantation from HLA-matched related donor: retrospective analysis of 334 consecutive patients. Eur J Haematol. 2015

8. Serody JS, Sparks SD, Lin Y, et al. Comparison of granulocyte colony-stimulating factor (G-CSF)--mobilized peripheral blood progenitor cells and G-CSF--stimulated bone marrow as a source of stem cells in HLA-matched sibling transplantation. Biol Blood Marrow Transplant. 2000; 6:434–440. [PubMed: 10975512]

9. 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. [PubMed: 10845900]

10. Barge RM, Brouwer RE, Beersma MF, et al. Comparison of allogeneic T cell-depleted peripheral blood stem cell and bone marrow transplantation: effect of stem cell source on short- and long-term outcome. Bone Marrow Transplant. 2001; 27:1053–1058. [PubMed: 11438820]

11. Tomblyn M, Chiller T, Einsele H, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant. 2009; 15:1143–1238. [PubMed: 19747629]

12. Sherertz RJ, Belani A, Kramer BS, et al. Impact of air filtration on nosocomial Aspergillus infections. Unique risk of bone marrow transplant recipients. American Journal of Medicine. 1987; 83:709–718. [PubMed: 3314494]

13. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis. 2011; 52:e56–93. [PubMed: 21258094]

14. Pollack M, Heugel J, Xie H, et al. An international comparison of current strategies to prevent herpesvirus and fungal infections in hematopoietic cell transplant recipients. Biol Blood Marrow Transplant. 2011; 17:664–673. [PubMed: 20699126]

15. Tuan IZ, Dennison D, Weisdorf DJ. Pneumocystis carinii pneumonitis following bone marrow transplantation. Bone Marrow Transplant. 1992; 10:267–272. [PubMed: 1422481]

16. Boeckh M, Boivin G. Quantitation of cytomegalovirus: methodologic aspects and clinical applications. Clin Microbiol Rev. 1998; 11:533–554. [PubMed: 9665982]

17. van Burik J-AH, Carter SL, Freifeld AG, et al. Higher-risk of cytomegalovirus and aspergillus infections in recipients of T cell depleted unrelated bone marrow: Analysis of infectious complications in patients treated with T cell depletion versus immune suppressive therapy to prevent graft-versus-host disease. Biology of Blood and Marrow Transplant. 2007; 13:1487–1498.

18. Copelan E, Casper JT, Carter SL, et al. A scheme for defining cause of death and its application in the T cell depletion trial. Biol Blood Marrow Transplant. 2007; 13:1469–1476. [PubMed: 18022577]

19. Kurtzberg J, Prasad VK, Carter SL, et al. Results of the Cord Blood Transplantation Study (COBLT): clinical outcomes of unrelated donor umbilical cord blood transplantation in pediatric patients with hematologic malignancies. Blood. 2008; 112:4318–4327. [PubMed: 18723429]

20. Tomblyn M, Young JA, Haagenson MD, et al. Decreased infections in recipients of unrelated donor hematopoietic cell transplantation from donors with an activating KIR genotype. Biol Blood Marrow Transplant. 2010; 16:1155–1161. [PubMed: 20197104]

21. Barker JN, Hough RE, van Burik JA, et al. Serious infections after unrelated donor transplantation in 136 children: impact of stem cell source. Biol Blood Marrow Transplant. 2005; 11:362–370. [PubMed: 15846290]

22. Bachanova V, Brunstein CG, Burns LJ, et al. Fewer infections and lower infection-related mortality following non-myeloablative versus myeloablative conditioning for allotransplantation of patients with lymphoma. Bone Marrow Transplant. 2009; 43:237–244. [PubMed: 18806838]

23. Lin D, Wei L, Yang I, Ying Z. Semiparametric Regression for the Mean and Rate Functions of Recurrent Events. Journal of the Royal Statistical Society. 2000; 62:711–730.



Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

24. Boeckh M, Gooley TA, Myerson D, Cunningham T, Schoch G, Bowden RA. Cytomegalovirus pp65 antigenemia-guided early treatment with ganciclovir versus ganciclovir at engraftment after allogeneic marrow transplantation: a randomized double-blind study. Blood. 1996; 88:4063–4071. [PubMed: 8916975]

25. Qayed M, Khurana M, Hilinski J, et al. Risk for CMV reactivation in children undergoing allogeneic hematopoietic stem cell transplantation. Pediatr Blood Cancer. 2014

26. Walker CM, van Burik JA, De For TE, Weisdorf DJ. Cytomegalovirus infection after allogeneic transplantation: comparison of cord blood with peripheral blood and marrow graft sources. Biol Blood Marrow Transplant. 2007; 13:1106–1115. [PubMed: 17697973]

27. Wald A, Leisenring W, van Burik JA, Bowden RA. Epidemiology of Aspergillus infections in a large cohort of patients undergoing bone marrow transplantation. J Infect Dis. 1997; 175:1459–1466. [PubMed: 9180187]



Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

Highlights

• Infections following unrelated donor transplantation remain frequent using

either graft source, with no difference in fungal or viral rates

• Bone marrow graft recipients had higher rates of bacterial and pre-engraftment

infections



Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

Figure 1. Descriptive Analysis of Infection SeverityInfection Severity by Treatment Arm. (A) All infection events. (B) Maximum severity of

infections (p = 0.6).



Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

Figure 2. Cumulative Incidence of All Infections



Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript



Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript



Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript



Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript



Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

Figure 3. Cumulative Incidence of Specific Infections. (A) Bacteria from all sites. (B) Bloodstream

bacteria. (C) All viruses. (D) Cytomegalovirus. (E) All Fungal/Parasitic Infections. (F)

Aspergillus infections.



Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

Figure 4. Infection Density for each time period. (A) Total infection density. (B) Bacterial infection.

(C) Viral infection. (D) Fungal infection. (E) Bloodstream bacterial infection. (F) Non-

bloodstream bacterial infection. (G) Moderate infection. (H) Severe infection. (I) Life-

threatening infection.



Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

Figure 5.



Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

Relationship of Infection to Engraftment. (A) Cumulative incidence of infections that

occurred among engrafted patients. (B) Cumulative incidence of pre-engraftment infections.



Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript


Table 1

Baseline Characteristics

Characteristics Treatment Arm*

Bone MarrowN (%)

Peripheral Blood Stem CellsN (%)

Total (N=499) 249 (100.0) 250 (100.0)

Age (years)

Median 44.1 43.8

<40 105 (42.2) 103 (41.2)

>=40 144 (57.8) 147 (58.8)

Recipient Gender

Male 147 (59.0) 135 (54.0)

Race

White 226 (90.8) 227 (90.8)

Others 23 (9.2) 23 (9.2)

Ethnicity

Hispanic or Latino 9 (3.6) 12 (4.8)

Others 240 (96.4) 238 (95.2)

Karnofsky Performance Score

90–100 165 (66.3) 150 (60.0)

<90 64 (25.7) 71 (28.4)

Unknown 20 (8.0) 29 (11.6)

Primary Disease at Enrollment

Acute Myelogenous Leukemia 116 (46.6) 122 (48.8)

Acute Lymphoblastic Leukemia 54 (21.7) 52 (20.8)

Chronic Myelogenous Leukemia 27 (10.8) 32 (12.8)

Myelodysplastic Syndrome 46 (18.5) 37 (14.8)

Chronic Myelomonocytic Leukemia 4 (1.6) 3 (1.2)

Disease risk

Early 182 (73.1) 181 (72.4)

Advanced 67 (26.9) 69 (27.6)

Donor/Recipient Gender

Female/Female 33 (13.3) 50 (20.0)

Male/Male 115 (46.2) 102 (40.8)

Female/Male 32 (12.8) 33 (13.2)

Male/Female 69 (27.7) 65 (26.0)

Donor/Recipient CMV Status

Positive/Positive 42 (16.9) 52 (20.8)

Negative/Negative 87 (34.9) 102 (40.8)

Positive/Negative 30 (12.0) 30 (12.0)

Negative/Positive 89 (35.7) 65 (26.0)

Unknown/Negative 1 (0.4) 1 (0.4)

Number of allele level HLA mismatches at HLA-A,-B,-C,-DRB1


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript


Characteristics Treatment Arm*

Bone MarrowN (%)

Peripheral Blood Stem CellsN (%)

0 189 (76.2) 202 (80.8)

1 52 (21.0) 46 (18.4)

>=2 7 (2.8) 2 (0.8)

Unknown 1 (0.4) 0 (0.0)

Conditioning regimen

Cyclophosphamide and Total Body Irradiation (Cy-TBI) 115 (46.2) 121 (48.4)

Busulfan and Cyclophosphamide (Bu-Cy) 80 (32.1) 65 (26.0)

Fludarabine and Melphalan (Flu-Mel) 16 (6.4) 24 (9.6)

Fludarabine, Busulfan, and ATG (Flu-Bu-ATG) 38 (15.3) 40 (16.0)

Graft versus host disease Prophylaxis

Cyclosporine and Methotrexate 59 (23.7) 47 (18.8)

Tacrolimus and Methotrexate 163 (65.5) 187 (74.8)

Other 27 (10.8) 16 (6.4)

Note:

*no significant p-values for baseline characteristics between the two treatment arms


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript


Table 2

Pathogen Frequency by Treatment Arm (only the top 5 organisms for each infection type are listed)

OrganismBone Marrow

N (%)Peripheral Blood Stem Cells

N (%)

Bacterial infections

Staphylococcus (coagulase negative) 123 (82) 101 (67)

Enterococcus (all species) 54 (42) 49 (40)

Clostridium difficile 69 (52) 54 (41)

Staphylococcus (coagulase positive) 10 (9) 30 (20)

Escherichia (also E. coli) 16 (15) 23 (19)

Viral infections

Cytomegalovirus (CMV) 78 (61) 81 (57)

Polyomavirus 27 (25) 27 (24)

Herpes Simplex (HSV1, HSV2) 16 (14) 22 (17)

Epstein-Barr Virus (EBV) 15 (12) 21 (15)

Influenza 22 (19) 13 (13)

Fungal/Parasitic infections

Other (suspected) Fungus 12 (11) 13 (12)

Yeast other than Candida albicans 5 (4) 12 (10)

Candida albicans 6 (6) 10 (8)

Aspergillus fumigatus 5 (5) 6 (5)

Mucormycosis (Zygomycetes, Rhizopus) 5 (4) 2 (2)

Pneumocystis 1 (1) 2 (2)

Toxoplasma 1 (1) 1 (1)


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript


Tab

le 3

Ove

rall

Sum

mar

y of

infe

ctio

n fr

eque

ncie

s

Ove

rall

Infe

ctio

ns *

Bon

e M

arro

wP

erip

hera

l Blo

od S

tem

Cel

ls

Day

0-E

NG

R§

EN

GR

-100

§10

1–18

018

1–36

536

6–73

0O

vera

llD

ay0-

EN

GR

§E

NG

R-1

00§

101–

180

181–

365

366–

730

Ove

rall

Tot

al I

nfec

tion

Eve

nts

179

283

102

7868

710

121

266

8281

8763

7

B

y se

veri

ty

Mod

erat

e12

417

658

4433

435

7417

950

5855

416

Seve

re43

8832

2924

216

3960

2215

2115

7

Lif

e th

reat

enin

g/fa

tal

1219

125

1159

827

108

1164

B

y ty

pe

Bac

teri

al in

fect

ion

130

164

5844

3543

198

147

4643

4537

9

Vir

al in

fect

ion

3711

035

2527

234

1310

429

2731

204

Fung

al in

fect

ion

127

88

540

815

610

1049

Para

sitic

infe

ctio

n0

10

01

20

00

11

2

Oth

er ty

pes

01

11

03

20

10

03

B

acte

rial

sub

grou

ps *

Blo

odst

ream

infe

ctio

n85

8728

136

219

5783

2315

1619

4

Non

bloo

dstr

eam

infe

ctio

n45

7730

3129

212

4164

2328

2918

5

Clo

stri

dium

dif

fici

le in

fect

ion

2329

87

269

2214

510

354

V

iral

sub

grou

ps *

CM

V in

fect

ions

1245

99

378

549

1412

181

Res

pira

tory

infe

ctio

ns12

1010

1115

582

55

613

31

Non

-CM

V n

on-r

espi

rato

ry15

5617

610

104

651

1010

1895

EB

V in

fect

ions

18

41

115

014

31

321

Var

icel

la0

55

15

160

01

23

6

F

unga

l sub

grou

ps *

Yea

st in

fect

ions

71

41

013

311

24

323

Mol

d in

fect

ions

24

35

115

11

44

313

Asp

ergi

llus

21

24

110

10

34

210


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript


Ove

rall

Infe

ctio

ns *

Bon

e M

arro

wP

erip

hera

l Blo

od S

tem

Cel

ls

Day

0-E

NG

R§

EN

GR

-100

§10

1–18

018

1–36

536

6–73

0O

vera

llD

ay0-

EN

GR

§E

NG

R-1

00§

101–

180

181–

365

366–

730

Ove

rall

Oth

er (

susp

ecte

d) f

ungu

s3

21

24

124

30

24

13

Not

e:

* Cat

egor

ies

are

not m

utua

lly e

xclu

sive

. e.g

. A C

MV

infe

ctio

n or

an

EB

V in

fect

ion

may

als

o fa

ll in

to th

e ca

tego

ry o

f re

spir

ator

y in

fect

ion,

and

vic

e ve

rsa.

Cat

egor

ies

are

liste

d ba

sed

on th

e st

udy

inte

rest

.

§ The

day

of

engr

aftm

ent (

EN

GR

) w

as c

onsi

dere

d fo

r ea

ch in

divi

dual

, for

cla

ssif

icat

ion

into

pre

- ve

rsus

pos

t-en

graf

tmen

t. M

edia

n en

graf

tmen

t was

20

days

for

Bon

e M

arro

w a

nd 1

5 da

ys f

or P

erip

hera

l B

lood

.


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript


Tab

le 4

Mul

tivar

iate

Ana

lysi

s M

odel

of

Infe

ctio

n D

ensi

ty

Var

iabl

eB

acte

rial

infe

ctio

nsV

iral

infe

ctio

nsF

unga

l inf

ecti

ons

Rel

ativ

e de

nsit

y (9

5%C

I)P

-val

ueR

elat

ive

inte

nsit

y (9

5%C

I)P

-val

ueR

elat

ive

inte

nsit

y (9

5%C

I)P

-val

ue

Gra

ft t

ype

Inte

ract

ed w

ith d

isea

se r

isk

<0.

001

B

one

Mar

row

1.00

1.00

Pe

riph

eral

Blo

od0.

88 (

0.71

–1.1

0)0.

262

1.38

(0.

84–2

.28)

0.20

7

Dis

ease

ris

k

Ear

ly1.

00

B

M1.

00

PB

SC0.

68 (

0.49

–0.9

3)0.

016

Adv

ance

d1.

39 (

1.10

–1.7

5)0.

006

B

M1.

00

PB

SC1.

68 (

1.1–

2.57

)0.

017

Rec

ipie

nt C

MV

sta

tus

N

egat

ive

1.00

1.00

1.00

Po

sitiv

e1.

24 (

1.00

–1.5

3)0.

046

1.49

(1.

15–1

.94)

0.00

31.

66 (

1.03

–2.6

8)0.

038

HL

A M

atch

Sta

tus

0.01

0<

0.00

1

8/

81.

001.

001.

00<

0.00

1

7/

81.

41 (

1.07

–1.8

6)0.

015

1.70

(1.

28–2

.26)

<0.

001

1.40

(0.

76–2

.59)

0.28

3

<

=6/

81.

90 (

1.00

–3.6

3)0.

050

0.76

(0.

47–1

.23)

0.26

57.

05 (

3.28

–15.

15)

<0.

001

Gen

der

M

ale

1.00

Fe

mal

e1.

30 (

1.05

–1.6

1)0.

014

Kar

nofs

ky P

erfo

rman

ce S

core

>

=90

1.00

<

902.

23 (

1.33

–3.7

4)0.

002

U

nkno

wn

1.50

(0.

61–3

.66)

0.37

7

Con

diti

onin

g re

gim

en

Cyc

loph

osph

amid

e an

d T

otal

Bod

y Ir

radi

atio

n (C

-TB

I)1.

00

Bus

ulfa

n an

d C

yclo

phos

pham

ide

(Bu-

Cy)

1.30

(0.

95–1

.77)

0.09

5


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript


Var

iabl

eB

acte

rial

infe

ctio

nsV

iral

infe

ctio

nsF

unga

l inf

ecti

ons

Rel

ativ

e de

nsit

y (9

5%C

I)P

-val

ueR

elat

ive

inte

nsit

y (9

5%C

I)P

-val

ueR

elat

ive

inte

nsit

y (9

5%C

I)P

-val

ue

Flud

arab

ine

and

Mel

phal

an (

Flu-

Mel

)1.

76 (

1.16

–2.6

8)0.

008

Flud

arab

ine,

Bus

ulfa

n, a

nd A

TG

(Fl

u-B

u-A

TG

)1.

77 (

1.31

–2.3

9)<

0.00

1


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript


Tab

le 5

Mul

tivar

iate

Mod

el o

f In

fect

ion

Den

sity

: Im

pact

of

Gra

ft V

ersu

s H

ost D

isea

se

Var

iabl

eB

acte

rial

infe

ctio

nV

iral

infe

ctio

nF

unga

l inf

ecti

on

Rel

ativ

e in

tens

ity

(95%

CI)

P-v

alue

Rel

ativ

e in

tens

ity

(95%

CI)

P-v

alue

Rel

ativ

e in

tens

ity

(95%

CI)

P-v

alue

Non

e1.

001.

001.

00

Acu

te G

VH

D o

nly

2.24

(1.

71–2

.92)

<0.

001

1.68

(1.

30–2

.17)

<0.

001

3.30

(1.

56–7

.01)

<0.

001

Chr

onic

GV

HD

onl

y2.

39 (

1.47

–3.8

8)<

0.00

11.

16 (

0.69

–1.9

6)0.

571

7.47

(2.

81–1

9.91

)<

0.00

1

Bot

h4.

16 (

2.60

–6.6

4)<

0.00

11.

40 (

0.85

–2.3

2)0.

183

5.52

(1.

90–1

6.07

)<

0.00

1

Not

e: o

ther

cov

aria

tes

in th

e m

odel

incl

uded

thos

e lis

ted

in T

able

4.


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript


Table 6

Multivariate Analysis of Overall Survival with Infection as time-dependent covariate

Variable Level Hazard Ratio (95%CI) P-value

Graft type

Bone Marrow 1.00

Peripheral Blood Stem Cells 1.09 (0.85–1.40) 0.487

Age <0.001

0–20 1.00

21–30 2.06 (1.12–3.79) 0.021

31–40 1.82 (0.97–3.40) 0.060

41–50 2.22 (1.22–4.05) 0.009

51–60 3.30 (1.85–5.90) <0.001

>=60 (combine with 51–60?) 3.92 (2.04–7.52) <0.001

Disease risk

Low 1.00

High 1.45 (1.12–1.89) 0.005

HLA Match Status <0.001

8/8 1.00

7/8 1.72 (1.29–2.30) <0.001

<=6/8 3.77 (1.68–8.44) 0.001

Conditioning regimen 0.081

Cyclophosphamide and Total Body Irradiation (Cy-TBI) 1.00

Busulfan and Cyclophosphamide (Bu-Cy) 0.67 (0.49–0.92) 0.012

Fludarabine and Melphalan (Flu-Mel) 0.74 (0.45–1.21) 0.230

Fludarabine, Busulfan, and ATG (Flu-Bu-ATG) 0.88 (0.59–1.29) 0.503

Any bacterial infection after transplant (time-dependent covariate)

No 1.00

Yes 1.49 (1.14–1.96) 0.004

Any viral infection after transplant (time-dependent covariate)

No 1.00

Yes 1.15 (0.88–1.50) 0.317

Any fungal infection after transplant (time-dependent covariate)

No 1.00

Yes 2.40 (1.71–3.35) <0.001


Documents

Infections after Transplantation of Bone Marrow or