- Email: [email protected]
The Concentration of Total Nucleated Cells in Harvested Bone Marrow for Transplantation Has Decreased over Time
Accepted Manuscript
The concentration of total nucleated cells in harvested bone marrow for transplantation has decreased over time. Nicole L. Prokopishyn PhD , Brent R. Logan PhD , Deidre M. Kiefer MPH , Jennifer A. Sees MPH , Pintip Chitphakdithai PhD , Ibrahim A. Ahmed MD , Paolo N. Anderlini MD , Amer M. Beitinjaneh MD, MPH , Christopher Bredeson MD, MSc , Jan Cerny MD, PhD , Saurabh Chhabra MD, MS , Andrew Daly MDCM , Miguel Angel Diaz MD, PhD , Nosha Farhadfar MD , Haydar A. Frangoul MD , Siddhartha Ganguly MD , Dennis A. Gastineau MD , Usama Gergis MBA , Gregory A. Hale MD , Peiman Hematti MD , Rammurti T. Kamble MD , Kimberly A. Kasow DO , Hillard M. Lazarus MD , Jane L. Liesveld MD , Hemant S. Murthy MD , Maxim Norkin MD, PhD , Richard F. Olsson MD, PhD , Mona Papari MD , Bipin N. Savani MD , Jeffrey Szer MBBS , Edmund K. Waller MD, PhD , Baldeep Wirk MD , Jean A. Yared MD , Michael A. Pulsipher MD , Nirali N. Shah MD , Galen E. Switzer PhD , Paul V. O’Donnell MD, PhD , Dennis L. Confer MD , Bronwen E. Shaw MBChB, PhD PII: DOI: Reference:
S1083-8791(19)30092-8 https://doi.org/10.1016/j.bbmt.2019.01.034 YBBMT 55478
To appear in:
Biology of Blood and Marrow Transplantation
Received date: Accepted date:
5 November 2018 29 January 2019
Please cite this article as: Nicole L. Prokopishyn PhD , Brent R. Logan PhD , Deidre M. Kiefer MPH , Jennifer A. Sees MPH , Pintip Chitphakdithai PhD , Ibrahim A. Ahmed MD , Paolo N. Anderlini MD , Amer M. Beitinjaneh MD, MPH , Christopher Bredeson MD, MSc , Jan Cerny MD, PhD , Saurabh Chhabra MD, MS , Andrew Daly MDCM , Miguel Angel Diaz MD, PhD , Nosha Farhadfar MD , Haydar A. Frangoul MD , Siddhartha Ganguly MD , Dennis A. Gastineau MD , Usama Gergis MBA , Gregory A. Hale MD , Peiman Hematti MD , Rammurti T. Kamble MD , Kimberly A. Kasow DO , Hillard M. Lazarus MD , Jane L. Liesveld MD , Hemant S. Murthy MD , Maxim Norkin MD, PhD , Richard F. Olsson MD, PhD , Mona Papari MD , Bipin N. Savani MD , Jeffrey Szer MBBS , Edmund K. Waller MD, PhD , Baldeep Wirk MD , Jean A. Yared MD , Michael A. Pulsipher MD , Nirali N. Shah MD , Galen E. Switzer PhD , Paul V. O’Donnell MD, PhD , Dennis L. Confer MD , Bronwen E. Shaw MBChB, PhD , The concentration of total nucleated cells in harvested bone marrow for transplantation has decreased over time., Biology of Blood and Marrow Transplantation (2019), doi: https://doi.org/10.1016/j.bbmt.2019.01.034
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The concentration of total nucleated cells in harvested bone marrow for transplantation has decreased over time.
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Nicole L. Prokopishyn, PhD1, Brent R. Logan, PhD2,3, Deidre M. Kiefer, MPH4, Jennifer A. Sees, MPH4, Pintip Chitphakdithai, PhD4, Ibrahim A. Ahmed, MD5, Paolo N. Anderlini, MD6, Amer M. Beitinjaneh, MD, MPH7, Christopher Bredeson, MD, MSc8, Jan Cerny, MD, PhD9, Saurabh Chhabra, MD, MS10, Andrew Daly, MDCM11, Miguel Angel Diaz, MD, PhD12, Nosha Farhadfar, MD13, Haydar A. Frangoul, MD14, Siddhartha Ganguly, MD15, Dennis A. Gastineau, MD16, Usama Gergis, MBA17, Gregory A. Hale, MD18, Peiman Hematti, MD19, Rammurti T. Kamble, MD20, Kimberly A. Kasow, DO21, Hillard M. Lazarus, MD22, Jane L. Liesveld, MD23, Hemant S. Murthy, MD13, Maxim Norkin, MD, PhD13, Richard F. Olsson, MD, PhD24,25, Mona Papari, MD26, Bipin N. Savani, MD27, Jeffrey Szer, MBBS28, Edmund K. Waller, MD, PhD29, Baldeep Wirk, MD30, Jean A. Yared, MD31, Michael A. Pulsipher, MD32, Nirali N. Shah, MD33, Galen E. Switzer, PhD34, Paul V. O'Donnell, MD, PhD35, Dennis L. Confer, MD4,36, Bronwen E. Shaw, MBChB, PhD2 University of Calgary, Calgary, Alberta, Canada; 2CIBMTR® (Center for International Blood and Marrow Transplant Research), Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA; 3Division of Biostatistics, Institute for Health and Society, Medical College of Wisconsin, Milwaukee, WI, USA; 4CIBMTR® (Center for International Blood and Marrow Transplant Research), National Marrow Donor Program/Be The Match, Minneapolis, MN, USA; 5 Department of Hematology Oncology and Bone Marrow Transplantation, The Children's Mercy Hospitals and Clinics, Kansas City, MO, USA; 6Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA; 7 University of Miami, Miami, FL, USA; 8The Ottawa Hospital Blood and Marrow Transplant Program and the Ottawa Hospital Research Institute, Ottawa, ON, Canada; 9Division of Hematology/Oncology, Department of Medicine, University of Massachusetts Medical Center, Worcester, MA, USA; 10Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA; 11Tom Baker Cancer Center, Calgary, Alberta, Canada; 12Department of Hematology/Oncology, Hospital Infantil Universitario Nino Jesus, Madrid, Spain; 13Division of Hematology/Oncology, University Florida College of Medicine, Gainesville, FL, USA; 14The Children's Hospital at TriStar Centennial and Sarah Cannon Research Institute, Nashville, TN, USA; 15Division of Hematological Malignancy and Cellular Therapeutics, University of Kansas Health System, Kansas City, KS, USA; 16Mayo Clinic Rochester, Rochester, MN, USA; 17Hematolgic Malignancies & Bone Marrow Transplant, Department of Medical Oncology, New York Presbyterian Hospital/Weill Cornell Medical College, New York, NY, USA; 18Department of Hematology/Oncology, Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA; 19Division of Hematology/Oncology/Bone Marrow Transplantation, Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, WI, USA; 20Division of Hematology and Oncology, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA; 21University of North Carolina, Chapel Hill, NC, USA; 22Seidman Cancer Center-University Hospitals Cleveland Medical Center, Cleveland, OH, USA; 23Strong Memorial Hospital - University of Rochester Medical Center, Rochester, NY, USA; 24Division of Therapeutic Immunology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; 25Centre for Clinical Research Sormland, Uppsala University, Uppsala, Sweden; 26ITxM Clinical Services Cord Blood Lab, Rosemont, IL, USA; 27Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; 28Clinical Haematology at Peter MacCalluma Cancer Centre and The Royal Melbourne Hospital, Victoria, Australia; 29Emory University Hospital, Atlanta, GA, USA; 30 Division of Bone Marrow Transplant, Seattle Cancer Care Alliance, Seattle, WA, USA; 31Blood & Marrow Transplantation Program, Division of Hematology/Oncology, Department of Medicine,
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Corresponding author: Bronwen E. Shaw, MBChB, PhD 9200 West Wisconsin Avenue Suite C5500 Milwaukee, WI 53226 Phone: (414) 805-8293 Email: [email protected]
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Keywords: Unrelated donors, bone marrow, TNC
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Greenebaum Cancer Center, University of Maryland, Baltimore, MD, USA; 32Division of Hematology, Oncology, and Blood and Marrow Transplantation, Children's Hospital Los Angeles, USC Keck School of Medicine, Los Angeles, CA, USA; 33Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; 34University of Pittsburgh, Pittsburgh, PA, USA; 35Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; 36National Marrow Donor Program/Be The Match, Minneapolis, MN, USA
Running title: Decreased Bone Marrow Quality over Time
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Abstract: 273 Manuscript: 2,523 References: 28 Figures: 4 Tables: 3
ABSTRACT
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Bone Marrow (BM) is an essential hematopoietic stem cell (HSC) source for many allogeneic
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hematopoietic cell transplant (HCT) recipients, including adult patients (for specific diseases and transplant strategies) and the majority of pediatric transplants. However, since the advent of
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Granulocyte-colony stimulating factor (G-CSF) mobilized peripheral blood stem cells (PBSC), there has been a significant decrease in utilization of BM in transplant patients, predominantly
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thought to be due to the increased logistical challenges around BM harvesting compared to PBSC, and generally no significant survival advantage of BM or PBSC. The decreased frequency of collection has the potential to impact the quality of BM harvests. In this study, we examined >15,000 BM donations collected at National Marrow Donor Program (NMDP) centers between 1994 and 2016, and revealed a significant decline in the quality of BM products (defined by concentration of total nucleated cells (TNC) – TNC/mL). TNC concentration dropped
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from 21.8 x 106/mL in the earliest era (1994-1996) to 18.7 TNC x106/mL in the most recent era (2012-2016) (Means Ratio 0.83, p<0.001). This decline in BM quality was seen despite selection of more donors perceived to be optimal (e.g. younger age and male). Multivariate regression analysis showed that higher volume centers, performing more than 30 collections per
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era, had better quality harvests with higher concentrations of TNC collected. In conclusion, we show a significant decrease in the quality of BM collections over time and lower volume
collection centers had poorer quality harvests. In this analysis we could not elucidate the direct cause for this finding, suggesting that further studies investigating the key factors responsible,
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as well as exploring the impact on the transplant recipient, are required.
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INTRODUCTION Bone marrow (BM) is the original, and an essential, hematopoietic stem cell (HSC) source for many allogeneic hematopoietic cell transplant (HCT) recipients. However, with the advent of Granulocyte-colony stimulating factor (G-CSF) mobilized peripheral blood stem cells (PBSC)
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and the logistic benefits of PBSC collection over BM collection, a significant decrease in the utilization of BM has occurred at many transplant centers. Since the introduction of PBSC, use of BM as the HSC source in the unrelated donor setting has declined from 100% in the early 1990s, to 19% in 2017.1 Regardless, BM is the preferred cell source for specific disease
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indications in adults (e.g. Aplastic Anemia), for the majority of pediatric transplants, and when the benefits of a decreased risk of chronic graft versus host disease (cGVHD) outweigh other considerations.2−5 Indeed, several studies have demonstrated that recipients of BM experience less cGVHD than recipients receiving PBSC.3,6,7 In addition, studies have demonstrated that
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pediatric patients receiving BM as a transplant product have a survival advantage over patients receiving PBSC.4,8,9 Recent utilization of mismatch and haploidentical transplants at some
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centers and current clinical trials has also led to increased use of BM as a source in these
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settings, due to a presumed increased risk of GVHD overall.10,11
Decreased utilization of BM in allogeneic HCT has a number of potential consequences,
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including negatively affecting the overall quality of BM due to lack of experience with the procedure at both a center and operator level. Although standard operating procedures (SOPs)
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are in place, and centers perform initial training, ongoing competency assessment is often difficult with only minimal procedures performed per year in many centers. The Foundation for Accreditation of Cellular Therapies (FACT) standard requires the BM harvest team of an accredited facility to perform a minimum of 1 BM harvest per year average in the accreditation cycle (that is, a minimum of 3 BM harvests in the accreditation cycle of 3 years), perform quality assessment of collection procedures, and implement standardized protocols.12 However, FACT
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standards do not address individual collector experience, minimum collections per individual collector per year, specific staff training, and collection techniques. Additionally, proper assessment of BM harvest metrics, including total nucleated cell (TNC) dose collected as compared to target dose, quality of BM collected, and adverse reactions in donors following
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collection, is difficult to report in an individual collection center when limited procedures are performed and comparable evaluations from other centers are not easily obtained.
In a single center study, quality measurements found that TNC in BM products collected
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externally and received for individual patients decreased over time (personal communication, N. Prokopishyn). We sought to confirm and explore potential reasons for this observation in a validation cohort. The aim of this study was, therefore, to examine the trends in BM harvest quality in a large cohort of National Marrow Donor Program (NMDP) donors over several
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decades to establish if this single-center observation could be generalized. To this end, the BM quality (defined as concentration of TNC per BM volume collected) in harvests performed by
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NMDP centers from 1994-2016, was assessed. In addition to the number of harvests per center per era, other donor and procedure factors were examined to determine their impact on BM
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METHODS
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quality.
Study Population
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The population includes domestic unrelated first-time BM donors, with products collected by NMDP centers from 1994-2016. Data on donor and donation characteristics were collected using standard data forms by the NMDP. All donors included in this study provided written informed consent for participation in Center for International Blood and Marrow Transplant Research (CIBMTR) studies that were approved by the NMDP Institutional Review Board.
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Marrow Donation Marrow was collected in an operating room from the posterior iliac crests under general or regional anesthesia following NMDP standards. NMDP standards require that no more than 20 mL/kg (donor weight) of marrow be aspirated, the duration of anesthesia should not exceed .13
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150 minutes, and the duration of the collection should be less than 120 minutes
Data Collection
All data utilized were reported by collection centers to the NMDP/CIBMTR at the time of
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collection/transplant. The number of collections per center per era was calculated using the number of collections reported to NMDP in this population.
Endpoints
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The primary outcome of this study is the examination of TNC collected per milliliter (TNC/mL) of BM, as an estimate of HSC product quality. TNC/mL for each harvest was calculated based on
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TNC in the product and the volume (mL) of final product including additives. TNC/mL was calculated prior to any processing at the transplant center. The number of collections performed
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per harvest center and era was assessed.
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Statistical Methods
The population was analyzed over 5 eras: 1994 – 1996, 1997 – 2001, 2002 – 2006, 2007 –
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2011, and 2012-2016. Eras were selected to represent 5 years per period, excluding the initial era that only covers 3 years. The initial era was limited to 1994-1996 as prior to 1994 sufficient data was unavailable for analysis. A variety of donor characteristics, including sex, age, and Body Mass Index (BMI), as well as collection volume with and without additives per donor weight, were compared between eras using chi-square tests. Donor weight, duration of anesthesia, duration of collection procedure, product volume with additive, and TNC
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concentration in the BM product were compared using the Kruskal-Wallis test. Collection centers were subdivided based on collection center volume per harvest center per era. High volume centers were defined as centers collecting 30 or more BM products per center per era
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and low volume centers collecting under 30 BM products per center per era
For multivariate analysis, log transformation was applied to TNC concentrations to induce
normality. Multiple linear regression was used to model log TNC concentrations as a function of the primary variable of interest (era of donation) as well as donor characteristics including donor
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sex, race, age, and weight, and number of donations per harvest center per era. Donations per collection center were divided into low volume centers and high volume centers. Stepwise variable selection was used to select variables in addition to the primary variable of interest. Interactions between the primary variable of interest and the other covariates were assessed.
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Effects are summarized as ratios of means of the TNC concentrations, due to the use of the log transformation for modeling. We also investigated accounting for potential harvest center
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effects through the use of linear mixed models including a random effect for harvest center. However there was not a significant center effect and the results were not meaningfully
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RESULTS
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impacted by adjusting for random center effects, so those results are omitted.
Over 15,000 BM donations collected between 1994 and 2016 were examined in the study.
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Donor, collection, and product demographics are shown in Table 1. We found a significant decline in the concentration of TNC in the product over time, from 21.8 TNC x 106/mL in the earliest era (1994-1996) to 18.7 TNC x106/mL in the most recent time era (2012-2016) (Means Ratio 0.83, p<0.001) (Table 2 and Figure 1).
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In recent years, donors are significantly more likely to be young (p<0.001) and male (p<0.001) (Table 1). In the 2012-2016 era, 54% of the donors were under the age of 30 as compared to the 1994-1996 and 1997–2001 eras where only 25% of the donors were under the age of 30. Similarly, 65% of the donors were male in the 2012-2016 era, compared to 53% in the 1994-
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1996 era. As well, there was a significant difference in donor weight over time with donors in the 2012-2016 having a greater weight (kg) than donors’ in earlier eras (Figure 2). Univariate
analysis on recipient weight indicated that recipient weight was significantly different over time
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(Figure 3).
The number of centers performing collections varied from a high of 106 centers in the 19972001 era to a low of 73 centers in the most present era examined (2012-2016) (Table 1). The 1997-2001 era had the highest number of total BM collections. The mean number of collections
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per center was highest in the 2012-2016 era. The average number of collections per era increased over the last 3 eras (Table 1) even though the number of collection centers
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performing BM harvests declined.
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Multivariate analysis confirmed the impact of era on a reduction in BM quality over time with a ratio of means TNC concentration of 0.83 in era 2012-2016 as compared to 1994-1996 (CI 0.81-
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0.84, p<0.001). Donor race was also found to be associated with a reduction of BM quality over time, with Hispanic, African/African American, Asian Pacific Islander all having significantly
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lower TNC/ml when compared to Caucasians (Mean Ratio 0.98, CI 0.96-0.99; Mean Ratio 0.85, CI 0.84-0.87; Mean Ratio 0.90, CI 0.88-0.92; respectively). Older donors had a lower BM quality as compared to the youngest donors aged 18 to 29. Donor factors associated with an increase in BM quality included female donors compared to male donors (Mean Ratio 1.04, CI 1.031.06), and heavier donors compared to lighter donors. The heaviest donor group, weighing more than 83 kg, had a mean ratio of 1.14 compared to the lightest donors weighting 69 kg or
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less (CI 1.12-1.16). The number of BM collections at a center per era was also associated with BM quality, with centers performing 30 or more collections per era having a significantly positive association with BM quality compared to centers performing less than 30 collections in an era
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(Mean Ratio 1.02, CI 1.01-1.04).
DISCUSSION
In this large study of unrelated BM donor harvests, we show a significant decrease in the quality of BM products over time as demonstrated by a drop in the TNC/mL collected in recent years.
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Interestingly, these results are evident despite the increased use of what are considered optimal donors in more recent eras (e.g. younger males).14−17 The utilization of younger male donors has been demonstrated to result in higher TNC in BM products;15,17 however, this finding was not consistent in our study, where lower BM quality was associated with male sex. Older age,
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and all other races except White and Native American were associated with lower TNC/mL collected. Although there was a change in racial diversity of the donor population over time,
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with a reduction from 81% White in the earliest era to 61% White in the most recent era, racial diversity is unlikely responsible for the lower TNC/mL over time since race is adjusted for in the
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multivariate model and the effect is still significant. Donor weight over 69 kg, was associated with higher BM quality. Interestingly, we observed in this study an increase in donor weight in
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the recent era. However, this increase in donor weight and its purported positive effects on BM quality did not prevent the significant decline in BM quality in the current era. As such, shifts in
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donor types utilized in BM collection in present times do not explain the decline in TNC concentration in products observed. Unfortunately, about 34% of donors did not have an associated recipient weight reported. As such, no conclusions could be made regarding impact of time on the dose of TNC collected per kg recipient weight. A reduction in recipient weight in the later era was observed which may be a result of an increased proportion of the BM products utilized for pediatric recipients.
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Multivariate analysis showed that volume of collection center BM harvests may play a crucial role in BM quality, as we found that higher volume collection centers collected higher quality BM products. Specifically, collection centers that collect 30 or more BM per era collect higher quality
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products than those centers collecting fewer than 30 BM products per era. Therefore, factors such as collector experience, collection center policies and procedures, collection team
training/continuing competency, and collection technique may play a significant role. Indeed, Fagioli et al. spoke to the importance of collector training and standardized procedures in the
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quality of BM harvested.18 In small volume centers, the number of harvests performed per
collector may be insufficient to maintain the appropriate level of expertise in BM procedures.
In addition, specific technical aspects of the BM collection which may differ from center to
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center, may have profound influences on the concentration of TNC collected. For example, the speed of the collection and harvest draws can impact the concentration of cells (TNC/mL)
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collected, with faster collections yielding lower TNC concentrations.15,19 The speed of collection can be influenced both by harvester technique and the type of needle utilized in the
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collection.19,20 Additionally, previous literature suggests that large volume collections and longer collection times can result in a decreased chance of obtaining desired TNC dose.21,22
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Furthermore, larger aspirate volumes have been shown to produce decreased TNC and CD34+ cell counts as compared to smaller aspirate volumes.21,23,24 Indeed, Helgestad et al. reported
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that small volume marrow aspirates give more representative marrow results with less blood contamination.25 Interestingly, our data showed that the volume of BM collected increased while the duration (in minutes) of the harvest decreased in the later era. Previous studies have indicated that larger product volumes are being collected in short time-periods most likely to obtain the requested cell dose for recipients.26 Although reduced collection times are beneficial and reduce donor adverse reactions,27 the faster collection times may be negatively affecting
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the product quality28 suggesting that a compromise between these extremes may be optimal. It is unknown if the decreased TNC concentrations observed in our study were the result of larger aspirates during the harvest as aspirate volume and speed of draw were not reported. Moreover, the type of needle utilized for the BM collection was not reported; and therefore, it is
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impossible to determine the implications harvesting equipment and supplies played in our observations..
Furthermore, details regarding collector experience, technique, training, and staff turnover were
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not available. Further studies examining the collection process including training, techniques, equipment, and donor characteristics will help to better understand the entire process and aid in improving the quality of the products collected. For example, examination of the role of educational tools, such as the NMDP BM collection video, and impact on technique
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standardization, would be beneficial to determine if specific variables can help improve BM quality. As well, consolidation of BMT harvests into centralized ‘super-centers’ may affect a
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large number of these variables and address several concerns, although ‘super-centers’ may not be feasible in many settings. Interestingly, the number of centers performing BM harvests
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has decreased more than 30% since a peak of 106 centers in 1997-2001 (Table 1). However, it is unknown how many of the collections were performed by these centers that no longer
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perform collections.
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In conclusion, we found that the quality of BM harvests has decreased over time and that collection centers collecting smaller numbers of BM per year collected lower quality BM products. This decline in BM quality persisted even though centers select more optimal donors in recent eras. Further studies will be required to elucidate the exact factors that are responsible for this significant decrease in BM quality and, critically, to determine the impact this decline in
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BM quality has on transplant outcomes in the patients. It is essential to determine these factors so that we can ensure that BM remains a quality source of HSC for transplant.
ACKNOWLEDGEMENTS
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The CIBMTR is supported primarily by Public Health Service Grant/Cooperative Agreement 5U24CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); a Grant/Cooperative Agreement 1U24HL138660 from NHLBI and NCI; a contract
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HHSH250201700006C with Health Resources and Services Administration (HRSA/DHHS); three Grants N00014-17-1-2388, N00014-17-1-2850 and N00014-18-1-2045 from the Office of Naval Research; and grants from Adaptive Biotechnologies; *Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Astellas Pharma US; Atara Biotherapeutics, Inc.; Be the
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Match Foundation; *bluebird bio, Inc.; *Bristol Myers Squibb Oncology; *Celgene Corporation; *Chimerix, Inc.; *CytoSen Therapeutics, Inc.; Fred Hutchinson Cancer Research Center;
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Gamida Cell Ltd.; Gilead Sciences, Inc.; HistoGenetics, Inc.; Immucor; *Incyte Corporation; Janssen Scientific Affairs, LLC; *Jazz Pharmaceuticals, Inc.; Karius, Inc.; Karyopharm
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Therapeutics, Inc.; *Kite Pharma, Inc.; Medac, GmbH; *Mediware; The Medical College of Wisconsin; *Merck & Co, Inc.; *Mesoblast; MesoScale Diagnostics, Inc.; Millennium, the Takeda
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Oncology Co.; *Miltenyi Biotec, Inc.; Mundipharma EDO; National Marrow Donor Program; Novartis Pharmaceuticals Corporation; PCORI; *Pfizer, Inc; *Pharmacyclics, LLC; PIRCHE AG;
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*Sanofi Genzyme; *Seattle Genetics; Shire; Spectrum Pharmaceuticals, Inc.; St. Baldrick’s Foundation; Swedish Orphan Biovitrum, Inc.; *Takeda Oncology; and University of Minnesota. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration (HRSA) or any other agency of the U.S. Government.
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*Corporate Members
AUTHORSHIP CONTRIBUTIONS Nicole L. Prokopishyn: Study conception and design, literature search, data interpretation,
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manuscript writing and review. Corresponding author.
Brent R. Logan, Diedre M. Keifer, Jennifer A. Sees: Study design, data collection, data
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analysis, figure and table generation, manuscript writing and review.
Pintip Chitphakdithai: Study design, data interpretation, manuscript review.
Ibrahim Ahmed, Paolo Anderlini, Amer Beitinjaneh, Chris Bredeson, Jan Cerny, Saurabh
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Chhabra, Dennis L. Confer, Andrew Daly, Miguel Angel Diaz, Nosha Farhadfar, Haydar Frangoul, Siddhartha Ganguly, Dennis Gastineau, Usama Gergis, Gregory Hale, Peiman
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Hematti, Rammurti Kamble, Kimberly Kasow, Hillard Lazarus, Jane Liesveld, Hemant Murthy, Maxim Norkin, Paul V. O’Donnel, Richard Olsson, Mona Papari, Michael A. Pulsipher, Bipin
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Savani, Nirali N. Shah, Galen E. Switzer, Jeff Szer, Edmund Waller, Baldeep Wirk, Jean Yared:
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Study design, literature review, manuscript writing and review.
Bronwen E. Shaw : Study design, literature search, data interpretation, manuscript writing and
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review.
DISCLOSURE OF CONFLICT OF INTEREST The authors have no relevant conflicts to declare.
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and an HLA-matched sibling donor. Pediatr Blood Cancer 2013 Sep;60(9):1513-1519. Anasetti C, Logan BR, Lee SJ, et al. Peripheral-Blood Stem Cells versus Bone Marrow from Unrelated Donors. N Engl J Med 2012 Oct 18;367(16):1487-1496. 11.
Bashey A., Zhang MJ, McCurdy SR, et al. Mobilized Peripheral Blood Stem Cells Versus
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Unstimulated Bone Marrow As a Graft Source for T-Cell-Replete Haploidentical Donor Transplantation Using Post-Transpant Cyclophosphamide. J Clin Oncol 2017 Sep 10;35(26):3002-3009. 12.
Factweb.org. (2018). FACT. Available at:
ns [Accessed 2018].
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24th Edition National Marrow Donor Program Standards, 2018.
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Fettah A, Ozbek N, Ozguner M, et al. Factors associated with bone marrow stem cell
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yield for pediatric allogeneic stem cell transplantation: The impact of donor characteristics. Pediatr Transplant 2017 Feb;21(1):1-6. Anthias C, Billen A, Arkwright R, Szydlo RM, Madrigal JA, Shaw BE. Harvests from bone
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marrow donors who weigh less than their recipients are associated with a significantly
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increased probability of a supoptimal harvest yield. Transfusion 2016 May;56(5):10521057.
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Lannert H, Able T, Becker S, et al. Optimizing BM harvesting from normal adult donors. Bone Marrow Transplant 2008 Oct;42(7):443-447.
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Shaw BE, Logan BR, Kiefer DM, et al. Analysis of the Effect of Race, Socioeconomic Status, and Center Size on Unrelated National Marrow Donor Program Donor
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Fagioli F, Quarello P, Pollichieni S, et al. Quality of harvest and role of cell dose in unrelated bone marrow transplantation: An Italian Bone Marrow Registry -- Gruppo
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Italiano Trapianto di Midollo Osseo Study. Hematology 2014 Jan;19(1):1-9. Kao RH, Li CC, Shaw CK, et al. Correlation between characteristics of unrelated bone marrow donor and cell density of total nucleated cell in bone marrow harvest. Int J Hematol 2009 Jan 8;89(2):227-230.
Wang RF, Chu SC, Chen SH, et al. The Effect of Different Harvest Strategies on the
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Nucleated Cell Yields of Bone Marrow Collection. Biol Blood Marrow Transplant 2011 Mar;17(3):351-355. 21.
Witt V, Pichler H, Fritsch G, Peters C. Multiple small versus few large amount aspirations
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for bone marrow harvesting in autologous and allogeneic bone marrow transplantation. Transfusion and Apheresis Science 2016;55:221-224. Shyr DC, Hsieh FF, Reems JA. Single center experience with total nucleated cell, CD34
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Helgestad J, Rosthoj S, Johansen P, Varming K, Ostergaard E. Bone marrow aspiration technique may have an impact on therapy stratification in children with acute lymphoblastic leukaemia. Pediatr Blood Cancer 25 Feb 2011;57(2):224-226
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Fabrizio V, Armeson K, Warnek S, Jaroscak JJ, Hudspeth, M. Trends in cell dose requests for a NMDP Bone Marrow Collection center. Biol Blood Marrow Transplant 2017;23:S336.
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Jaddini E, Hjortholm N, Snarski E. Effective pain reduction during bone marrow biopsy
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and aspiration - technique over experience. Acta Haematol Pol 2016:226-231. Pruszczyk K, Skwierawska K, Krol M, et al. Bone marrow harvest from unrelated donors
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-- up-to-date methodology. Eur J Haematol 2017;99:357-365.
TABLES Table 1: Donor, Collection, and Product demographics by era
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2007 to 2011 N (%) 2999 80
806 (47) 914 (53)
2026 (46) 2413 (54)
1263 (40) 1872 (60)
1164 (39) 1835 (61)
1267 (35) 2316 (65)
1400 (81) 109 ( 6) 94 ( 5) 63 ( 4) 19 ( 1) 19 ( 1) 16 ( 1)
3235 (73) 472 (11) 294 ( 7) 240 ( 5) 74 ( 2) 94 ( 2) 30 ( 1)
2318 (74) 291 ( 9) 200 ( 6) 134 ( 4) 48 ( 2) 121 ( 4) 23 ( 1)
1999 (67) 357 (12) 194 ( 6) 181 ( 6) 36 ( 1) 210 ( 7) 22 ( 1)
2174 (61) 516 (14) 270 ( 8) 215 ( 6) 28 ( 1) 352 (10) 28 ( 1)
1089 (25) 1600 (36) 1357 (31) 393 ( 9) 37 (19-61)
927 (30) 1060 (34) 867 (28) 281 ( 9) 36 (19-61)
1175 (39) 917 (31) 690 (23) 217 ( 7) 33 (19-61)
1946 (54) 939 (26) 519 (14) 179 ( 5) 29 (19-60)
<0.001
1720 76 (26-175)
4439 79 (9-200)
3135 82 (14-193)
2999 82 (40-164)
3583 81 (41-150)
<0.001
0 (.-.)
0 (.-.)
1546 90 (26-248)
2987 92 (25-355)
1682 88 (34-301)
0.042
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1997 to 2001 N (%) 4439 106
424 (25) 640 (37) 514 (30) 142 ( 8) 37 (19-58)
2002 to 2006 N (%) 3135 91
2012 to 2016 a N (%) 3583 73
1994 to 1996 N (%) 1720 90
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Variable Number of donors Number of centers Sex Female Male Race Caucasian Hispanic African / African American Asian / Pacific Islander Native American Multiple races / other Unknown / declined Age at donation 18 to 29 30 to 39 40 to 49 50+ Median (range) Weight, kg N Eval Median (range) Collection-Related Variables Duration of anesthesia in minutes N Eval Median (range)
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p-value b
<0.001
<0.001
<0.001
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0 0 0 4439 (N/A) (.-.)
1718 1200 (91-2782)
1559 55 (7-194)
689 (44) 695 (44) 181 (12) 1570 (N/A) 1064 (68-2360)
2989 51 (2-208)
1302 (44) 1304 (44) 370 (12) 23 (N/A) 1067 (119-2323)
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0 0 0 0 1720 (N/A) (.-.)
0 (.-.)
0 0 0 0 4439 (N/A) (.-.)
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0 0 0 1720 (N/A) (.-.)
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Collection volume with additive per donor weight <10 mL/kg 10 to <15 mL/kg 15 to <20 mL/kg ≥ 20 mL/kg Unknown Median (range) Product volume, with additive (mL) N Eval Median (range)
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Duration of collection procedure in minutes N Eval Median (Range) Product-Related Variables Collection volume, without additives <1 L 1-1.5 L ≥ 1.5 L Unknown Median (Range), in L
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4424 1257 (180-3110)
1686 48 (0-221)
1490 (42) 1424 (40) 606 (17) 63 (N/A) 1090 (125-2214)
<0.001 <0.001
<0.001 <0.001
482 (31) 490 (31) 519 (33) 74 ( 5) 1570 (N/A) 13.1 (0.7-23.6)
898 (30) 984 (33) 904 (30) 190 ( 6) 23 (N/A) 13.1 (1.2-29.0)
1029 (29) 1033 (29) 1087 (31) 371 (11) 63 (N/A) 13.6 (1.3-40.2)
3127 1266 (128-2767)
2993 1246 (139-2557)
3550 1290 (108-2720)
<0.001
<0.001
2002 to 2006 N (%) 3135 91
3121 19.8 (0.3-1320.0)
2007 to 2011 N (%) 2999 80
2012 to 2016 N (%) 3583 73
2989 19.5 (3.1-16236.7)
3547 18.7 (1.2-349.8)
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Table 2. Concentration of TNC with additive over time 1994 to 1996 1997 to 2001 Variable N (%) N (%) Number of donors 1720 4439 Number of centers 90 106 Concentration of TNC with additive, x106/mL N Eval 1718 4420 Median (range) 21.8 20.3 (4.3-3450.0) (4.3-2400.0)
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p-value a
<0.001
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Table 3. Multivariate model using linear regression on log TNC concentration
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0.90 0.87 0.86 0.81
0.96 0.84 0.88 0.99 0.95 0.87
CI Upper
pvalue
0.93 0.90 0.89 0.84
<0.001 <0.001 <0.001 <0.001 <0.001
0.99 0.87 0.92 1.09 0.99 0.97
<0.001 0.003 <0.001 <0.001 0.083 0.014 0.003
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1.00 0.98 0.85 0.90 1.04 0.97 0.92
CI Lower
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1.00 0.92 0.89 0.87 0.83
1.00 1.04
1.03
1.06
<0.001 <0.001
1.00 1.02
1.01
1.04
<0.001 <0.001
1.00 0.98 0.92 0.89
0.97 0.91 0.87
0.99 0.93 0.91
<0.001 <0.001 <0.001 <0.001
1.07 1.09 1.16
<0.001 0.004 <0.001 <0.001
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Variable Collection year 1994 to 1996 1997 to 2001 2002 to 2006 2007 to 2011 2012 to 2016 Donor race Caucasian Hispanic African / African American Asian Pacific Islander Native American Multiple race/ other Unknown/ declined Donor sex Male Female Number of collections per center < 30 30 ≤ Donor age at collection 18 to 29 30 to 39 40 to 49 50+ Donor weight, kg ≤ 69 69 to 71 71 to 83 83 <
Relative effect (relative change in TNC concentration)
1.00 1.04 1.07 1.14
1.01 1.05 1.12
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FIGURES
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Figure 1: Median concentration of TNC with additive, x106/ mL over era of collection-bycollection center size.
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Figure 2: Donor weight (kg) increases significantly over time (p<0.001). Represented is the Donor Weight (1st Pctl, Lower quartile, Median, Upper quartile, 99th Pctl) subdivided into the examined time periods...
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Figure 3: Reduction in weight of BM recipient over time. Represented above is recipient weight (kg) Median (.), with (1st Pctl, Lower quartile and Upper quartile, 99th Pctl. An N=10,437 were examined as for only 66% of donors was the associated recipient weight data available.
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Figure 4: Number of collections per year is represent for each of the eras with the Mean (x) and Median (♦) indicated. The maximum number of collections performed per year in the era is represented numerically, with the box representing the 25th and 75th percentiles. The arrows indicate the maximum number of collections per era, which are beyond 60 (230 for 1994-1996, 477 for 1997-2001, 479 for 2007-2011, and 920 for 2012-2016), and are not represented to more accurately depict the difference in quartile values across eras.
The concentration of total nucleated cells in harvested bone marrow for transplantation has decreased over time. Nicole L. Prokopishyn PhD , Brent R. Logan PhD , Deidre M. Kiefer MPH , Jennifer A. Sees MPH , Pintip Chitphakdithai PhD , Ibrahim A. Ahmed MD , Paolo N. Anderlini MD , Amer M. Beitinjaneh MD, MPH , Christopher Bredeson MD, MSc , Jan Cerny MD, PhD , Saurabh Chhabra MD, MS , Andrew Daly MDCM , Miguel Angel Diaz MD, PhD , Nosha Farhadfar MD , Haydar A. Frangoul MD , Siddhartha Ganguly MD , Dennis A. Gastineau MD , Usama Gergis MBA , Gregory A. Hale MD , Peiman Hematti MD , Rammurti T. Kamble MD , Kimberly A. Kasow DO , Hillard M. Lazarus MD , Jane L. Liesveld MD , Hemant S. Murthy MD , Maxim Norkin MD, PhD , Richard F. Olsson MD, PhD , Mona Papari MD , Bipin N. Savani MD , Jeffrey Szer MBBS , Edmund K. Waller MD, PhD , Baldeep Wirk MD , Jean A. Yared MD , Michael A. Pulsipher MD , Nirali N. Shah MD , Galen E. Switzer PhD , Paul V. O’Donnell MD, PhD , Dennis L. Confer MD , Bronwen E. Shaw MBChB, PhD PII: DOI: Reference:
S1083-8791(19)30092-8 https://doi.org/10.1016/j.bbmt.2019.01.034 YBBMT 55478
To appear in:
Biology of Blood and Marrow Transplantation
Received date: Accepted date:
5 November 2018 29 January 2019
Please cite this article as: Nicole L. Prokopishyn PhD , Brent R. Logan PhD , Deidre M. Kiefer MPH , Jennifer A. Sees MPH , Pintip Chitphakdithai PhD , Ibrahim A. Ahmed MD , Paolo N. Anderlini MD , Amer M. Beitinjaneh MD, MPH , Christopher Bredeson MD, MSc , Jan Cerny MD, PhD , Saurabh Chhabra MD, MS , Andrew Daly MDCM , Miguel Angel Diaz MD, PhD , Nosha Farhadfar MD , Haydar A. Frangoul MD , Siddhartha Ganguly MD , Dennis A. Gastineau MD , Usama Gergis MBA , Gregory A. Hale MD , Peiman Hematti MD , Rammurti T. Kamble MD , Kimberly A. Kasow DO , Hillard M. Lazarus MD , Jane L. Liesveld MD , Hemant S. Murthy MD , Maxim Norkin MD, PhD , Richard F. Olsson MD, PhD , Mona Papari MD , Bipin N. Savani MD , Jeffrey Szer MBBS , Edmund K. Waller MD, PhD , Baldeep Wirk MD , Jean A. Yared MD , Michael A. Pulsipher MD , Nirali N. Shah MD , Galen E. Switzer PhD , Paul V. O’Donnell MD, PhD , Dennis L. Confer MD , Bronwen E. Shaw MBChB, PhD , The concentration of total nucleated cells in harvested bone marrow for transplantation has decreased over time., Biology of Blood and Marrow Transplantation (2019), doi: https://doi.org/10.1016/j.bbmt.2019.01.034
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The concentration of total nucleated cells in harvested bone marrow for transplantation has decreased over time.
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Nicole L. Prokopishyn, PhD1, Brent R. Logan, PhD2,3, Deidre M. Kiefer, MPH4, Jennifer A. Sees, MPH4, Pintip Chitphakdithai, PhD4, Ibrahim A. Ahmed, MD5, Paolo N. Anderlini, MD6, Amer M. Beitinjaneh, MD, MPH7, Christopher Bredeson, MD, MSc8, Jan Cerny, MD, PhD9, Saurabh Chhabra, MD, MS10, Andrew Daly, MDCM11, Miguel Angel Diaz, MD, PhD12, Nosha Farhadfar, MD13, Haydar A. Frangoul, MD14, Siddhartha Ganguly, MD15, Dennis A. Gastineau, MD16, Usama Gergis, MBA17, Gregory A. Hale, MD18, Peiman Hematti, MD19, Rammurti T. Kamble, MD20, Kimberly A. Kasow, DO21, Hillard M. Lazarus, MD22, Jane L. Liesveld, MD23, Hemant S. Murthy, MD13, Maxim Norkin, MD, PhD13, Richard F. Olsson, MD, PhD24,25, Mona Papari, MD26, Bipin N. Savani, MD27, Jeffrey Szer, MBBS28, Edmund K. Waller, MD, PhD29, Baldeep Wirk, MD30, Jean A. Yared, MD31, Michael A. Pulsipher, MD32, Nirali N. Shah, MD33, Galen E. Switzer, PhD34, Paul V. O'Donnell, MD, PhD35, Dennis L. Confer, MD4,36, Bronwen E. Shaw, MBChB, PhD2 University of Calgary, Calgary, Alberta, Canada; 2CIBMTR® (Center for International Blood and Marrow Transplant Research), Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA; 3Division of Biostatistics, Institute for Health and Society, Medical College of Wisconsin, Milwaukee, WI, USA; 4CIBMTR® (Center for International Blood and Marrow Transplant Research), National Marrow Donor Program/Be The Match, Minneapolis, MN, USA; 5 Department of Hematology Oncology and Bone Marrow Transplantation, The Children's Mercy Hospitals and Clinics, Kansas City, MO, USA; 6Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA; 7 University of Miami, Miami, FL, USA; 8The Ottawa Hospital Blood and Marrow Transplant Program and the Ottawa Hospital Research Institute, Ottawa, ON, Canada; 9Division of Hematology/Oncology, Department of Medicine, University of Massachusetts Medical Center, Worcester, MA, USA; 10Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA; 11Tom Baker Cancer Center, Calgary, Alberta, Canada; 12Department of Hematology/Oncology, Hospital Infantil Universitario Nino Jesus, Madrid, Spain; 13Division of Hematology/Oncology, University Florida College of Medicine, Gainesville, FL, USA; 14The Children's Hospital at TriStar Centennial and Sarah Cannon Research Institute, Nashville, TN, USA; 15Division of Hematological Malignancy and Cellular Therapeutics, University of Kansas Health System, Kansas City, KS, USA; 16Mayo Clinic Rochester, Rochester, MN, USA; 17Hematolgic Malignancies & Bone Marrow Transplant, Department of Medical Oncology, New York Presbyterian Hospital/Weill Cornell Medical College, New York, NY, USA; 18Department of Hematology/Oncology, Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA; 19Division of Hematology/Oncology/Bone Marrow Transplantation, Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, WI, USA; 20Division of Hematology and Oncology, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA; 21University of North Carolina, Chapel Hill, NC, USA; 22Seidman Cancer Center-University Hospitals Cleveland Medical Center, Cleveland, OH, USA; 23Strong Memorial Hospital - University of Rochester Medical Center, Rochester, NY, USA; 24Division of Therapeutic Immunology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; 25Centre for Clinical Research Sormland, Uppsala University, Uppsala, Sweden; 26ITxM Clinical Services Cord Blood Lab, Rosemont, IL, USA; 27Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; 28Clinical Haematology at Peter MacCalluma Cancer Centre and The Royal Melbourne Hospital, Victoria, Australia; 29Emory University Hospital, Atlanta, GA, USA; 30 Division of Bone Marrow Transplant, Seattle Cancer Care Alliance, Seattle, WA, USA; 31Blood & Marrow Transplantation Program, Division of Hematology/Oncology, Department of Medicine,
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Corresponding author: Bronwen E. Shaw, MBChB, PhD 9200 West Wisconsin Avenue Suite C5500 Milwaukee, WI 53226 Phone: (414) 805-8293 Email: [email protected]
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Keywords: Unrelated donors, bone marrow, TNC
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Greenebaum Cancer Center, University of Maryland, Baltimore, MD, USA; 32Division of Hematology, Oncology, and Blood and Marrow Transplantation, Children's Hospital Los Angeles, USC Keck School of Medicine, Los Angeles, CA, USA; 33Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; 34University of Pittsburgh, Pittsburgh, PA, USA; 35Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; 36National Marrow Donor Program/Be The Match, Minneapolis, MN, USA
Running title: Decreased Bone Marrow Quality over Time
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Abstract: 273 Manuscript: 2,523 References: 28 Figures: 4 Tables: 3
ABSTRACT
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Bone Marrow (BM) is an essential hematopoietic stem cell (HSC) source for many allogeneic
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hematopoietic cell transplant (HCT) recipients, including adult patients (for specific diseases and transplant strategies) and the majority of pediatric transplants. However, since the advent of
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Granulocyte-colony stimulating factor (G-CSF) mobilized peripheral blood stem cells (PBSC), there has been a significant decrease in utilization of BM in transplant patients, predominantly
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thought to be due to the increased logistical challenges around BM harvesting compared to PBSC, and generally no significant survival advantage of BM or PBSC. The decreased frequency of collection has the potential to impact the quality of BM harvests. In this study, we examined >15,000 BM donations collected at National Marrow Donor Program (NMDP) centers between 1994 and 2016, and revealed a significant decline in the quality of BM products (defined by concentration of total nucleated cells (TNC) – TNC/mL). TNC concentration dropped
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from 21.8 x 106/mL in the earliest era (1994-1996) to 18.7 TNC x106/mL in the most recent era (2012-2016) (Means Ratio 0.83, p<0.001). This decline in BM quality was seen despite selection of more donors perceived to be optimal (e.g. younger age and male). Multivariate regression analysis showed that higher volume centers, performing more than 30 collections per
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era, had better quality harvests with higher concentrations of TNC collected. In conclusion, we show a significant decrease in the quality of BM collections over time and lower volume
collection centers had poorer quality harvests. In this analysis we could not elucidate the direct cause for this finding, suggesting that further studies investigating the key factors responsible,
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as well as exploring the impact on the transplant recipient, are required.
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INTRODUCTION Bone marrow (BM) is the original, and an essential, hematopoietic stem cell (HSC) source for many allogeneic hematopoietic cell transplant (HCT) recipients. However, with the advent of Granulocyte-colony stimulating factor (G-CSF) mobilized peripheral blood stem cells (PBSC)
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and the logistic benefits of PBSC collection over BM collection, a significant decrease in the utilization of BM has occurred at many transplant centers. Since the introduction of PBSC, use of BM as the HSC source in the unrelated donor setting has declined from 100% in the early 1990s, to 19% in 2017.1 Regardless, BM is the preferred cell source for specific disease
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indications in adults (e.g. Aplastic Anemia), for the majority of pediatric transplants, and when the benefits of a decreased risk of chronic graft versus host disease (cGVHD) outweigh other considerations.2−5 Indeed, several studies have demonstrated that recipients of BM experience less cGVHD than recipients receiving PBSC.3,6,7 In addition, studies have demonstrated that
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pediatric patients receiving BM as a transplant product have a survival advantage over patients receiving PBSC.4,8,9 Recent utilization of mismatch and haploidentical transplants at some
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centers and current clinical trials has also led to increased use of BM as a source in these
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settings, due to a presumed increased risk of GVHD overall.10,11
Decreased utilization of BM in allogeneic HCT has a number of potential consequences,
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including negatively affecting the overall quality of BM due to lack of experience with the procedure at both a center and operator level. Although standard operating procedures (SOPs)
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are in place, and centers perform initial training, ongoing competency assessment is often difficult with only minimal procedures performed per year in many centers. The Foundation for Accreditation of Cellular Therapies (FACT) standard requires the BM harvest team of an accredited facility to perform a minimum of 1 BM harvest per year average in the accreditation cycle (that is, a minimum of 3 BM harvests in the accreditation cycle of 3 years), perform quality assessment of collection procedures, and implement standardized protocols.12 However, FACT
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standards do not address individual collector experience, minimum collections per individual collector per year, specific staff training, and collection techniques. Additionally, proper assessment of BM harvest metrics, including total nucleated cell (TNC) dose collected as compared to target dose, quality of BM collected, and adverse reactions in donors following
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collection, is difficult to report in an individual collection center when limited procedures are performed and comparable evaluations from other centers are not easily obtained.
In a single center study, quality measurements found that TNC in BM products collected
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externally and received for individual patients decreased over time (personal communication, N. Prokopishyn). We sought to confirm and explore potential reasons for this observation in a validation cohort. The aim of this study was, therefore, to examine the trends in BM harvest quality in a large cohort of National Marrow Donor Program (NMDP) donors over several
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decades to establish if this single-center observation could be generalized. To this end, the BM quality (defined as concentration of TNC per BM volume collected) in harvests performed by
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NMDP centers from 1994-2016, was assessed. In addition to the number of harvests per center per era, other donor and procedure factors were examined to determine their impact on BM
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METHODS
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quality.
Study Population
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The population includes domestic unrelated first-time BM donors, with products collected by NMDP centers from 1994-2016. Data on donor and donation characteristics were collected using standard data forms by the NMDP. All donors included in this study provided written informed consent for participation in Center for International Blood and Marrow Transplant Research (CIBMTR) studies that were approved by the NMDP Institutional Review Board.
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Marrow Donation Marrow was collected in an operating room from the posterior iliac crests under general or regional anesthesia following NMDP standards. NMDP standards require that no more than 20 mL/kg (donor weight) of marrow be aspirated, the duration of anesthesia should not exceed .13
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150 minutes, and the duration of the collection should be less than 120 minutes
Data Collection
All data utilized were reported by collection centers to the NMDP/CIBMTR at the time of
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collection/transplant. The number of collections per center per era was calculated using the number of collections reported to NMDP in this population.
Endpoints
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The primary outcome of this study is the examination of TNC collected per milliliter (TNC/mL) of BM, as an estimate of HSC product quality. TNC/mL for each harvest was calculated based on
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TNC in the product and the volume (mL) of final product including additives. TNC/mL was calculated prior to any processing at the transplant center. The number of collections performed
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per harvest center and era was assessed.
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Statistical Methods
The population was analyzed over 5 eras: 1994 – 1996, 1997 – 2001, 2002 – 2006, 2007 –
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2011, and 2012-2016. Eras were selected to represent 5 years per period, excluding the initial era that only covers 3 years. The initial era was limited to 1994-1996 as prior to 1994 sufficient data was unavailable for analysis. A variety of donor characteristics, including sex, age, and Body Mass Index (BMI), as well as collection volume with and without additives per donor weight, were compared between eras using chi-square tests. Donor weight, duration of anesthesia, duration of collection procedure, product volume with additive, and TNC
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concentration in the BM product were compared using the Kruskal-Wallis test. Collection centers were subdivided based on collection center volume per harvest center per era. High volume centers were defined as centers collecting 30 or more BM products per center per era
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and low volume centers collecting under 30 BM products per center per era
For multivariate analysis, log transformation was applied to TNC concentrations to induce
normality. Multiple linear regression was used to model log TNC concentrations as a function of the primary variable of interest (era of donation) as well as donor characteristics including donor
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sex, race, age, and weight, and number of donations per harvest center per era. Donations per collection center were divided into low volume centers and high volume centers. Stepwise variable selection was used to select variables in addition to the primary variable of interest. Interactions between the primary variable of interest and the other covariates were assessed.
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Effects are summarized as ratios of means of the TNC concentrations, due to the use of the log transformation for modeling. We also investigated accounting for potential harvest center
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effects through the use of linear mixed models including a random effect for harvest center. However there was not a significant center effect and the results were not meaningfully
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RESULTS
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impacted by adjusting for random center effects, so those results are omitted.
Over 15,000 BM donations collected between 1994 and 2016 were examined in the study.
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Donor, collection, and product demographics are shown in Table 1. We found a significant decline in the concentration of TNC in the product over time, from 21.8 TNC x 106/mL in the earliest era (1994-1996) to 18.7 TNC x106/mL in the most recent time era (2012-2016) (Means Ratio 0.83, p<0.001) (Table 2 and Figure 1).
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In recent years, donors are significantly more likely to be young (p<0.001) and male (p<0.001) (Table 1). In the 2012-2016 era, 54% of the donors were under the age of 30 as compared to the 1994-1996 and 1997–2001 eras where only 25% of the donors were under the age of 30. Similarly, 65% of the donors were male in the 2012-2016 era, compared to 53% in the 1994-
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1996 era. As well, there was a significant difference in donor weight over time with donors in the 2012-2016 having a greater weight (kg) than donors’ in earlier eras (Figure 2). Univariate
analysis on recipient weight indicated that recipient weight was significantly different over time
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(Figure 3).
The number of centers performing collections varied from a high of 106 centers in the 19972001 era to a low of 73 centers in the most present era examined (2012-2016) (Table 1). The 1997-2001 era had the highest number of total BM collections. The mean number of collections
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per center was highest in the 2012-2016 era. The average number of collections per era increased over the last 3 eras (Table 1) even though the number of collection centers
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performing BM harvests declined.
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Multivariate analysis confirmed the impact of era on a reduction in BM quality over time with a ratio of means TNC concentration of 0.83 in era 2012-2016 as compared to 1994-1996 (CI 0.81-
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0.84, p<0.001). Donor race was also found to be associated with a reduction of BM quality over time, with Hispanic, African/African American, Asian Pacific Islander all having significantly
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lower TNC/ml when compared to Caucasians (Mean Ratio 0.98, CI 0.96-0.99; Mean Ratio 0.85, CI 0.84-0.87; Mean Ratio 0.90, CI 0.88-0.92; respectively). Older donors had a lower BM quality as compared to the youngest donors aged 18 to 29. Donor factors associated with an increase in BM quality included female donors compared to male donors (Mean Ratio 1.04, CI 1.031.06), and heavier donors compared to lighter donors. The heaviest donor group, weighing more than 83 kg, had a mean ratio of 1.14 compared to the lightest donors weighting 69 kg or
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less (CI 1.12-1.16). The number of BM collections at a center per era was also associated with BM quality, with centers performing 30 or more collections per era having a significantly positive association with BM quality compared to centers performing less than 30 collections in an era
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(Mean Ratio 1.02, CI 1.01-1.04).
DISCUSSION
In this large study of unrelated BM donor harvests, we show a significant decrease in the quality of BM products over time as demonstrated by a drop in the TNC/mL collected in recent years.
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Interestingly, these results are evident despite the increased use of what are considered optimal donors in more recent eras (e.g. younger males).14−17 The utilization of younger male donors has been demonstrated to result in higher TNC in BM products;15,17 however, this finding was not consistent in our study, where lower BM quality was associated with male sex. Older age,
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and all other races except White and Native American were associated with lower TNC/mL collected. Although there was a change in racial diversity of the donor population over time,
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with a reduction from 81% White in the earliest era to 61% White in the most recent era, racial diversity is unlikely responsible for the lower TNC/mL over time since race is adjusted for in the
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multivariate model and the effect is still significant. Donor weight over 69 kg, was associated with higher BM quality. Interestingly, we observed in this study an increase in donor weight in
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the recent era. However, this increase in donor weight and its purported positive effects on BM quality did not prevent the significant decline in BM quality in the current era. As such, shifts in
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donor types utilized in BM collection in present times do not explain the decline in TNC concentration in products observed. Unfortunately, about 34% of donors did not have an associated recipient weight reported. As such, no conclusions could be made regarding impact of time on the dose of TNC collected per kg recipient weight. A reduction in recipient weight in the later era was observed which may be a result of an increased proportion of the BM products utilized for pediatric recipients.
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Multivariate analysis showed that volume of collection center BM harvests may play a crucial role in BM quality, as we found that higher volume collection centers collected higher quality BM products. Specifically, collection centers that collect 30 or more BM per era collect higher quality
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products than those centers collecting fewer than 30 BM products per era. Therefore, factors such as collector experience, collection center policies and procedures, collection team
training/continuing competency, and collection technique may play a significant role. Indeed, Fagioli et al. spoke to the importance of collector training and standardized procedures in the
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quality of BM harvested.18 In small volume centers, the number of harvests performed per
collector may be insufficient to maintain the appropriate level of expertise in BM procedures.
In addition, specific technical aspects of the BM collection which may differ from center to
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center, may have profound influences on the concentration of TNC collected. For example, the speed of the collection and harvest draws can impact the concentration of cells (TNC/mL)
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collected, with faster collections yielding lower TNC concentrations.15,19 The speed of collection can be influenced both by harvester technique and the type of needle utilized in the
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collection.19,20 Additionally, previous literature suggests that large volume collections and longer collection times can result in a decreased chance of obtaining desired TNC dose.21,22
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Furthermore, larger aspirate volumes have been shown to produce decreased TNC and CD34+ cell counts as compared to smaller aspirate volumes.21,23,24 Indeed, Helgestad et al. reported
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that small volume marrow aspirates give more representative marrow results with less blood contamination.25 Interestingly, our data showed that the volume of BM collected increased while the duration (in minutes) of the harvest decreased in the later era. Previous studies have indicated that larger product volumes are being collected in short time-periods most likely to obtain the requested cell dose for recipients.26 Although reduced collection times are beneficial and reduce donor adverse reactions,27 the faster collection times may be negatively affecting
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the product quality28 suggesting that a compromise between these extremes may be optimal. It is unknown if the decreased TNC concentrations observed in our study were the result of larger aspirates during the harvest as aspirate volume and speed of draw were not reported. Moreover, the type of needle utilized for the BM collection was not reported; and therefore, it is
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impossible to determine the implications harvesting equipment and supplies played in our observations..
Furthermore, details regarding collector experience, technique, training, and staff turnover were
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not available. Further studies examining the collection process including training, techniques, equipment, and donor characteristics will help to better understand the entire process and aid in improving the quality of the products collected. For example, examination of the role of educational tools, such as the NMDP BM collection video, and impact on technique
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standardization, would be beneficial to determine if specific variables can help improve BM quality. As well, consolidation of BMT harvests into centralized ‘super-centers’ may affect a
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large number of these variables and address several concerns, although ‘super-centers’ may not be feasible in many settings. Interestingly, the number of centers performing BM harvests
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has decreased more than 30% since a peak of 106 centers in 1997-2001 (Table 1). However, it is unknown how many of the collections were performed by these centers that no longer
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perform collections.
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In conclusion, we found that the quality of BM harvests has decreased over time and that collection centers collecting smaller numbers of BM per year collected lower quality BM products. This decline in BM quality persisted even though centers select more optimal donors in recent eras. Further studies will be required to elucidate the exact factors that are responsible for this significant decrease in BM quality and, critically, to determine the impact this decline in
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BM quality has on transplant outcomes in the patients. It is essential to determine these factors so that we can ensure that BM remains a quality source of HSC for transplant.
ACKNOWLEDGEMENTS
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The CIBMTR is supported primarily by Public Health Service Grant/Cooperative Agreement 5U24CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); a Grant/Cooperative Agreement 1U24HL138660 from NHLBI and NCI; a contract
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HHSH250201700006C with Health Resources and Services Administration (HRSA/DHHS); three Grants N00014-17-1-2388, N00014-17-1-2850 and N00014-18-1-2045 from the Office of Naval Research; and grants from Adaptive Biotechnologies; *Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Astellas Pharma US; Atara Biotherapeutics, Inc.; Be the
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Match Foundation; *bluebird bio, Inc.; *Bristol Myers Squibb Oncology; *Celgene Corporation; *Chimerix, Inc.; *CytoSen Therapeutics, Inc.; Fred Hutchinson Cancer Research Center;
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Gamida Cell Ltd.; Gilead Sciences, Inc.; HistoGenetics, Inc.; Immucor; *Incyte Corporation; Janssen Scientific Affairs, LLC; *Jazz Pharmaceuticals, Inc.; Karius, Inc.; Karyopharm
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Therapeutics, Inc.; *Kite Pharma, Inc.; Medac, GmbH; *Mediware; The Medical College of Wisconsin; *Merck & Co, Inc.; *Mesoblast; MesoScale Diagnostics, Inc.; Millennium, the Takeda
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Oncology Co.; *Miltenyi Biotec, Inc.; Mundipharma EDO; National Marrow Donor Program; Novartis Pharmaceuticals Corporation; PCORI; *Pfizer, Inc; *Pharmacyclics, LLC; PIRCHE AG;
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*Sanofi Genzyme; *Seattle Genetics; Shire; Spectrum Pharmaceuticals, Inc.; St. Baldrick’s Foundation; Swedish Orphan Biovitrum, Inc.; *Takeda Oncology; and University of Minnesota. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration (HRSA) or any other agency of the U.S. Government.
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*Corporate Members
AUTHORSHIP CONTRIBUTIONS Nicole L. Prokopishyn: Study conception and design, literature search, data interpretation,
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manuscript writing and review. Corresponding author.
Brent R. Logan, Diedre M. Keifer, Jennifer A. Sees: Study design, data collection, data
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analysis, figure and table generation, manuscript writing and review.
Pintip Chitphakdithai: Study design, data interpretation, manuscript review.
Ibrahim Ahmed, Paolo Anderlini, Amer Beitinjaneh, Chris Bredeson, Jan Cerny, Saurabh
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Chhabra, Dennis L. Confer, Andrew Daly, Miguel Angel Diaz, Nosha Farhadfar, Haydar Frangoul, Siddhartha Ganguly, Dennis Gastineau, Usama Gergis, Gregory Hale, Peiman
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Hematti, Rammurti Kamble, Kimberly Kasow, Hillard Lazarus, Jane Liesveld, Hemant Murthy, Maxim Norkin, Paul V. O’Donnel, Richard Olsson, Mona Papari, Michael A. Pulsipher, Bipin
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Savani, Nirali N. Shah, Galen E. Switzer, Jeff Szer, Edmund Waller, Baldeep Wirk, Jean Yared:
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Study design, literature review, manuscript writing and review.
Bronwen E. Shaw : Study design, literature search, data interpretation, manuscript writing and
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review.
DISCLOSURE OF CONFLICT OF INTEREST The authors have no relevant conflicts to declare.
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Remberger M, Beelen DW, Fauser A, et al. Increased risk of extensive chronic graftversus-host disease after allogeneic peripheral blood stem cell transplantation using unrelated donors. Blood 2005;105:548-551.
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Eapen, M. Unrelated donor transplantation: peripheral blood or bone marrow -- does it matter? Best Pract Res Clin Haematol 2014;27:78-82.
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TABLES Table 1: Donor, Collection, and Product demographics by era
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2007 to 2011 N (%) 2999 80
806 (47) 914 (53)
2026 (46) 2413 (54)
1263 (40) 1872 (60)
1164 (39) 1835 (61)
1267 (35) 2316 (65)
1400 (81) 109 ( 6) 94 ( 5) 63 ( 4) 19 ( 1) 19 ( 1) 16 ( 1)
3235 (73) 472 (11) 294 ( 7) 240 ( 5) 74 ( 2) 94 ( 2) 30 ( 1)
2318 (74) 291 ( 9) 200 ( 6) 134 ( 4) 48 ( 2) 121 ( 4) 23 ( 1)
1999 (67) 357 (12) 194 ( 6) 181 ( 6) 36 ( 1) 210 ( 7) 22 ( 1)
2174 (61) 516 (14) 270 ( 8) 215 ( 6) 28 ( 1) 352 (10) 28 ( 1)
1089 (25) 1600 (36) 1357 (31) 393 ( 9) 37 (19-61)
927 (30) 1060 (34) 867 (28) 281 ( 9) 36 (19-61)
1175 (39) 917 (31) 690 (23) 217 ( 7) 33 (19-61)
1946 (54) 939 (26) 519 (14) 179 ( 5) 29 (19-60)
<0.001
1720 76 (26-175)
4439 79 (9-200)
3135 82 (14-193)
2999 82 (40-164)
3583 81 (41-150)
<0.001
0 (.-.)
0 (.-.)
1546 90 (26-248)
2987 92 (25-355)
1682 88 (34-301)
0.042
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1997 to 2001 N (%) 4439 106
424 (25) 640 (37) 514 (30) 142 ( 8) 37 (19-58)
2002 to 2006 N (%) 3135 91
2012 to 2016 a N (%) 3583 73
1994 to 1996 N (%) 1720 90
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Variable Number of donors Number of centers Sex Female Male Race Caucasian Hispanic African / African American Asian / Pacific Islander Native American Multiple races / other Unknown / declined Age at donation 18 to 29 30 to 39 40 to 49 50+ Median (range) Weight, kg N Eval Median (range) Collection-Related Variables Duration of anesthesia in minutes N Eval Median (range)
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p-value b
<0.001
<0.001
<0.001
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0 0 0 4439 (N/A) (.-.)
1718 1200 (91-2782)
1559 55 (7-194)
689 (44) 695 (44) 181 (12) 1570 (N/A) 1064 (68-2360)
2989 51 (2-208)
1302 (44) 1304 (44) 370 (12) 23 (N/A) 1067 (119-2323)
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0 0 0 0 1720 (N/A) (.-.)
0 (.-.)
0 0 0 0 4439 (N/A) (.-.)
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0 0 0 1720 (N/A) (.-.)
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Collection volume with additive per donor weight <10 mL/kg 10 to <15 mL/kg 15 to <20 mL/kg ≥ 20 mL/kg Unknown Median (range) Product volume, with additive (mL) N Eval Median (range)
0 (.-.)
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Duration of collection procedure in minutes N Eval Median (Range) Product-Related Variables Collection volume, without additives <1 L 1-1.5 L ≥ 1.5 L Unknown Median (Range), in L
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4424 1257 (180-3110)
1686 48 (0-221)
1490 (42) 1424 (40) 606 (17) 63 (N/A) 1090 (125-2214)
<0.001 <0.001
<0.001 <0.001
482 (31) 490 (31) 519 (33) 74 ( 5) 1570 (N/A) 13.1 (0.7-23.6)
898 (30) 984 (33) 904 (30) 190 ( 6) 23 (N/A) 13.1 (1.2-29.0)
1029 (29) 1033 (29) 1087 (31) 371 (11) 63 (N/A) 13.6 (1.3-40.2)
3127 1266 (128-2767)
2993 1246 (139-2557)
3550 1290 (108-2720)
<0.001
<0.001
2002 to 2006 N (%) 3135 91
3121 19.8 (0.3-1320.0)
2007 to 2011 N (%) 2999 80
2012 to 2016 N (%) 3583 73
2989 19.5 (3.1-16236.7)
3547 18.7 (1.2-349.8)
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Table 2. Concentration of TNC with additive over time 1994 to 1996 1997 to 2001 Variable N (%) N (%) Number of donors 1720 4439 Number of centers 90 106 Concentration of TNC with additive, x106/mL N Eval 1718 4420 Median (range) 21.8 20.3 (4.3-3450.0) (4.3-2400.0)
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p-value a
<0.001
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Table 3. Multivariate model using linear regression on log TNC concentration
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0.90 0.87 0.86 0.81
0.96 0.84 0.88 0.99 0.95 0.87
CI Upper
pvalue
0.93 0.90 0.89 0.84
<0.001 <0.001 <0.001 <0.001 <0.001
0.99 0.87 0.92 1.09 0.99 0.97
<0.001 0.003 <0.001 <0.001 0.083 0.014 0.003
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1.00 0.98 0.85 0.90 1.04 0.97 0.92
CI Lower
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1.00 0.92 0.89 0.87 0.83
1.00 1.04
1.03
1.06
<0.001 <0.001
1.00 1.02
1.01
1.04
<0.001 <0.001
1.00 0.98 0.92 0.89
0.97 0.91 0.87
0.99 0.93 0.91
<0.001 <0.001 <0.001 <0.001
1.07 1.09 1.16
<0.001 0.004 <0.001 <0.001
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Variable Collection year 1994 to 1996 1997 to 2001 2002 to 2006 2007 to 2011 2012 to 2016 Donor race Caucasian Hispanic African / African American Asian Pacific Islander Native American Multiple race/ other Unknown/ declined Donor sex Male Female Number of collections per center < 30 30 ≤ Donor age at collection 18 to 29 30 to 39 40 to 49 50+ Donor weight, kg ≤ 69 69 to 71 71 to 83 83 <
Relative effect (relative change in TNC concentration)
1.00 1.04 1.07 1.14
1.01 1.05 1.12
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FIGURES
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Figure 1: Median concentration of TNC with additive, x106/ mL over era of collection-bycollection center size.
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Figure 2: Donor weight (kg) increases significantly over time (p<0.001). Represented is the Donor Weight (1st Pctl, Lower quartile, Median, Upper quartile, 99th Pctl) subdivided into the examined time periods...
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Figure 3: Reduction in weight of BM recipient over time. Represented above is recipient weight (kg) Median (.), with (1st Pctl, Lower quartile and Upper quartile, 99th Pctl. An N=10,437 were examined as for only 66% of donors was the associated recipient weight data available.
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Figure 4: Number of collections per year is represent for each of the eras with the Mean (x) and Median (♦) indicated. The maximum number of collections performed per year in the era is represented numerically, with the box representing the 25th and 75th percentiles. The arrows indicate the maximum number of collections per era, which are beyond 60 (230 for 1994-1996, 477 for 1997-2001, 479 for 2007-2011, and 920 for 2012-2016), and are not represented to more accurately depict the difference in quartile values across eras.