Donor Safety

Predictors of general discomfort, limitations in activities of daily living and intention of a second donation in unrelated hematopoietic stem cell donation

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Abstract

We performed a retrospective study of 1868 consecutive unrelated donors to predict the risk factors related to general discomfort, limitations in activities of daily living (ADLs) and intention of a second donation in hematopoietic stem cell (HSC) donation. General discomfort and limitations in ADLs were assessed by numerical measurement (scores of 0–10) and donor’s intention of a second donation by yes or no reply. The post-donation questionnaires were completed within 48 h after HSC collection and at 1 week, 4 weeks, and 4 months thereafter. Predictors of general discomfort included female sex (P<0.0001), bone marrow (BM) collection (P<0.0001) or PBSC collection through a central line (CL; P=0.0349), 2-day collection (P=0.0150) and negative or undetermined intention of a second donation on day 1 (P<0.0001). Predictors of limitations in ADLs included age group of 30–39 years (P=0.0046), female sex (P<0.0001), BM collection (P<0.0001) or PBSC collection through a CL (P<0.0001) and negative or undetermined intention of a second donation on day 1 (P<0.0001). The only predictor of positive intention of a second donation was male sex (P=0.0007). Age, sex and collection method and period should be considered risk factors when unrelated HSC donation is performed.

Introduction

Hematopoietic stem cell (HSC) harvest centers as well as HSC transplantation centers are responsible for understanding the safety of donors, for pursuing efforts to minimize the risks in HSC collection and for ensuring that donors are fully informed. Our review of data from large-scale trials revealed that many donors reported bone pain, headache, paresthesia, myalgia and fatigue following HSC donation via either bone marrow (BM) collection or cytokine-mobilized PBSC collection.1, 2, 3, 4 Moreover, there were rare cases of serious adverse events (SAEs) but no fatalities. However, Horowitz and Confer5 described nine deaths, six in marrow donors and three in peripheral blood donors, among marrow and peripheral blood HSC donors in the literature. In addition, fatal AEs have been observed in five related donors and in one unrelated donor.6, 7 The purposes of the current study were to answer the following questions. What was the incidence of AEs after HSC donations among the unrelated donors registered in the Korea Marrow Donor Program (KMDP)? What donor factors influenced general discomfort and limitations in the activities of daily living (ADLs) at the time of donation? What prohibited altruistic volunteers from a second donation?

Subjects and methods

Subjects

This was a retrospective analysis of data collected in the KMDP registry. As of January 2016, there were 46 HSC transplantation centers in South Korea for allogeneic HSC transplantation from unrelated donors. The subjects of this study were 1868 consecutive unrelated volunteer donors who donated HSCs through the KMDP between November 2007 and April 2014. Donor informed consent was obtained from all unrelated donors for the collection of HSCs by a physician at each harvest center. All donors were evaluated to assess medical suitability for HSC collection and donation. This study was approved by the institutional review board of Konkuk University Medical Center.

HSC donation

BM collections were performed, without administration of G-CSF, in an operating room under general, spinal or epidural anesthesia. The donor’s marrow was collected from the posterior iliac crests. The KMDP guidelines recommended a maximum of 20 mL marrow per kg donor body weight to be collected. During the harvest procedures, the amount of BM collected was about 10–15 mL/kg of donor body weight.

PBSC collections were performed after mobilization with G-CSF administered SC for 4 or 5 consecutive days at a daily dose of around 10 mcg/kg of body weight. The target number of CD34-positive cells collected with a cell separator (COBE Spectra, TerumoBCT, Inc., Lakewood, CO, USA) was 5.0 × 106/kg of recipient body weight. If the CD34-positive cell number was <5.0 × 106/kg after the 1-day collection, the donor was possibly requested to undergo a second collection on the next day. In general, 15 000 mL of whole blood was processed during the first collection, followed by 10 000 mL of whole blood during the second collection if needed.

Donor assessment

General discomfort was assessed using a visual analog scale (numerical measurement, 0–10, with 10 being the worst discomfort), and other symptoms were assessed with replies of either yes or no to each item. Limitations in ADLs were assessed by using a modified scale (numerical measurement, 0–10, 10 representing the greatest limitation for ADL). There were five items in the modified scale: dressing, bathing, transferring, toileting, and walking. Scoring of each item was as follows: 0 point for independence, 1 point for limited assistance, and 2 points for extensive assistance. The donor’s intention of a second donation was assessed by 'yes' or 'no' responses. Intention of a second donation was intended to examine whether or not the donors would agree to a hypothetical future donation on request. The post-donation questionnaires, including procedure-related symptoms, general discomfort, limitations in ADLs and intention of a second donation, were completed within 48 h after HSC collection and at 1 week, 4 weeks and 4 months thereafter.

Statistical analysis

Descriptive statistics were used to summarize the data, including frequencies and percentages for categorical variables and means and SDs for continuous variables. Demographic and clinical characteristics were analyzed using chi-square or Fisher’s exact test for categorical variables and analysis of variance for continuous variables. Predonation and post-donation predictors of general discomfort and limitations in ADLs were identified using univariate and multivariate linear regression considering donor demographic and clinical characteristics (age, sex, stem cell source, G-CSF administration, collection method, collection period) and the intention of a second donation at day 1. Predonation and post-donation predictors of the intention of a second donation were identified using univariate and multivariate logistic regression considering donor demographic and clinical characteristics (age, sex, collection method, collection period). A conventional alpha of 0.05 and two-tailed level of significance was used. All analyses were conducted using SAS version 9.3 (SAS Institute Inc., Cary, NC, USA).

Results

Donor characteristics

Demographic and clinical characteristics of the 1868 unrelated donors are summarized in Table 1. Men represented 76.77% of donors. The median age at donation was 28 years, and about 93.00% of donors were aged <40 years. Among HSC collection, 61.88% were completed in a day. PBSC and BM collections accounted for 94.49% and 5.51% of HSC collections, respectively. According to routine practice for HSC collection, the majority of donors were hospitalized for 2–4 days.

Table 1 Demographic and clinical characteristics of unrelated donors at stem cell donation (N=1868)

AEs associated with BM collection

AEs associated with BM collection, reported by 103 donors within 48 h after the collection, listed in descending order of frequency, were as follows: pain at the BM harvest site, pain around the collection site, sore throat, dizziness, dysuria, nausea or vomiting, headache, anorexia, pain at IV line site, fever, and fatigue (refer to Supplementary Figure S1a).

The procedure-related symptoms ameliorated over time and had disappeared by 1 week after BM collection, with the exception of pain at the BM harvest site, fatigue, dizziness and headache. About one-quarter of donors complained of pain at the BM collection sites up to 4 weeks after the collection. As compared with within 48 h after the collection, fatigue developed even more frequently at 1 week after the collection (refer to Supplementary Figure S1a).

AEs associated with PBSC collection

AEs associated with G-CSF administration for 1765 donors, in descending order of frequency, were as follows: bone and joint pain, headache, fatigue, fever, insomnia, nausea, dyspnea, edema, and rash. The majority of donors complained of bone and joint pain following G-CSF administration.

AEs associated with PBSC collection through a peripheral line, reported by 1671 donors within 48 h after the collection, were as follows: pain at the peripheral line site, numbness in hands and feet, dizziness, headache, perioral numbness, chills, fatigue, nausea or vomiting, and abdominal pain (refer to Supplementary Figure S1b).

AEs associated with PBSC collection through a central line (CL), reported by 94 donors within 48 h after the collection, were as follows: pain at the CL site, numbness in hands and feet, perioral numbness, dizziness, chills, headache, nausea or vomiting, fatigue, and abdominal pain (refer to Supplementary Figure S1c).

The peripheral line- and CL-related symptoms ameliorated over time and had disappeared by 1 week after PBSC collection, with the exception of pain at the peripheral or CL site, fatigue, headache and dizziness. Fatigue developed more frequently at 1 week after PBSC collection, as mentioned in the results for BM collection (refer to Supplementary Figures S1b and c).

General discomfort within 48 h after HSC collection

Table 2 shows the measurements of general discomfort at the time of HSC collection for 1867 donors. These differed significantly with the variables of sex, stem cell source, collection method, collection period and intention of a second donation on day 1. Table 3 summarizes the predictors of general discomfort. The only significant predonation predictor of general discomfort was female sex. Significant post-donation predictors included BM collection or PBSC collection through a CL compared with PBSC collection through a peripheral line, 2 day-collection and negative or undetermined intention of a second donation on day 1 compared with positive intention of a second donation.

Table 2 General discomfort (N=1867) and limitations in ADLs (N=1865) within 48 h after stem cell collection, numerical measurement (scores of 0–10)
Table 3 Univariate and multivariate linear regression analyses of general discomfort within 48 h after stem cell collection

The mean values with SD of general discomfort for each time point of the follow-up period were as follows: within 48 h after HSC collection, 3.78 (2.486); at 1 week, 0.56 (1.349); at 4 weeks, 0.12 (0.590); and at 4 months, 0.01 (0.150).

Limitations in ADLs within 48 h after HSC collection

Table 2 shows the measurements of limitations in ADLs at the time of HSC collection for 1865 donors. These differed significantly with the variables of age at donation, sex, stem cell source, collection method and intention of a second donation on day 1. Table 4 summarizes the predictors of limitations in ADLs. Significant predonation predictors of limitations in ADLs included donor age group of 30–39 years as compared with the age group of 19–29 years and female sex. Significant post-donation predictors included BM collection or PBSC collection through a CL and negative or undetermined intention of a second donation on day 1.

Table 4 Univariate and multivariate linear regression analyses of limitations in ADLs within 48 h after stem cell collection

The mean values with SD of limitations in ADLs for each time point of the follow-up period were as follows: within 48 h after HSC collection, 2.15 (2.313); at 1 week, 0.03 (0.317); at 4 weeks, 0.00 (0.000); and at 4 months, 0.00 (0.000).

Intention of a second donation within 48 h after HSC collection

Table 5 shows the replies regarding intention of a second donation at the time of HSC collection for 1428 donors. These differed significantly with the variables of sex, stem cell source and collection method. Table 6 summarizes the predictors of intention of a second donation. The only significant predictor of positive intention of a second donation was male sex.

Table 5 Intention of a second donation within 48 h after HSC collection, yes or no reply (N=1428)
Table 6 Univariate and multivariate logistic regression analyses of intention of a second donation within 48 h after stem cell collection

Discussion

In this retrospective study, we focused on general discomfort and limitations in ADLs in unrelated donors to assess the risks of donation and to improve the level of donor safety. Our results showed that general discomfort was significantly predicted by sex, collection method, collection period and intention of a second donation. Limitations in ADLs were significantly predicted by age, sex, collection method and intention of a second donation.

Similar to the results of previous studies,2, 3 this study showed that, during G-CSF administration for PBSC mobilization, the majority of donors experienced bone pain (91.6%) and about half of the donors reported headache (57.1%) and fatigue (42.9%). Furthermore, smaller portions of donors reported fever/chills (23.8%), insomnia (15.8%), nausea (7.5%), dyspnea (4.0%), edema (2.2%) and skin rash (1.1%). During apheresis for PBSC collection, the most frequent symptom, other than pain at the site of venipuncture, was the mild form of tetany associated with hypocalcemia, manifested by symptoms such as numbness in the hands and feet and perioral numbness. Compared with those of the previous studies,2, 3 the donors of the current study experienced more frequently symptoms of dizziness, headache and fatigue. In particular, they reported fatigue more frequently at 1 week after PBSC collection (refer to Supplementary Figures S1b and c).

In this study, overall AEs seemed to develop more frequently in donors in whom a CL was used for PBSC collection compared with those in whom a peripheral line was used. AEs associated with HSC collection appeared rarely by 4 months after the donations, and pain at the collection sites, fatigue and dizziness remained in only a small portion of donors by 1 month after the donations.

In contrast to the findings of previous studies,8, 9 the present study showed that the frequency of fatigue increased more at 1 week after BM and PBSC collection than within 48 h after collection. In the National Marrow Donor Program (NMDP) survey, fatigue was reported in 59% and 70% of BM and PBSC donors, respectively.8 Fatigue was the most frequently reported symptom by BM and PBSC donors other than pain, which persisted up to 1 year post-donation in a small portion of donors. The cause or pathogenesis of fatigue in HSC donors has not yet been clarified. However, it is assumed that psychological stress as well as physical stress contributes to this symptom.

In the current study, BM or PBSC collection through a CL was a significant predictor of general discomfort and limitations in ADLs (for BM, P<0.0001 and P<0.0001, respectively; for CL, P=0.0349 and P<0.0001, respectively). BM donation was associated with more physical morbidity and negative effects on quality of life up to 1 month after donation than PBSC donation.10 In a comparison study including 2726 BM donors and 6758 PBSC donors between 2004 and 2009 through the NMDP, BM donors had an increased risk of SAEs (2.38% vs 0.56%, P<0.001).11 A prospective trial from the NMDP reported that BM donors were more likely to have persistent pain at 1 week and 1 month after donation (P<0.001) and less likely to experience complete recovery after BM collection as compared with PBSC donors (P<0.001).4 In contrast, the European Group for Blood and Marrow Transplantation analyzed 27 770 BM donors and 23 254 PBSC donors and reported 5 fatal events, among which only 1 was in a BM donor, and 37 SAEs, which occurred in 12 BM donors and 24 PBSC donors (P<0.05).6 There is still a need for additional clinical studies and more accurate and longer follow-up donor-reporting system to identify the safer type of donation. Particular attention should be paid to donor evaluation with the intent of protecting the donor from the risk of SAEs and offering the recipients the best quality of treatment.

In this study, female sex was a significant predictor of general discomfort and limitations in ADLs (P<0.0001 and P<0.0001, respectively). Gordon et al.12 reported that headache, muscle pain and fatigue were significantly associated with female sex (P<0.03) and bone pain was strongly associated with female sex (P=0.07) when 512 PBSC donors receiving G-CSF were analyzed for adverse reactions. In the NMDP study including 3686 female donors and 5808 male donors, female donors were twice as likely to experience SAEs compared with male donors (P=0.005).11 Another prospective study showed that female donors were more likely to experience pain, toxicities and fatigue compared with male donors (P<0.01) and less likely to experience complete recovery (P<0.001).4

In the current study, the donor age group of 30–39 years, as compared with the age group of 19–29 years, was a significant predictor of limitations in ADLs (P=0.0046). The median age at donation was 28 years, with a range of 19–51 years. This means that the relatively older donors were at risk of limitations in ADLs. Pulsipher et al.4 reported that older donors were at a decreased risk of pain during the peri-collection period (P<0.01) but more likely to experience persistent pain, fatigue and other toxicities at 1 week after HSC collection (P<0.01).

In this study, there was no baseline predonation questionnaire to compare between predonation and post-donation symptoms. This could be of a particular consideration in interpretation of the findings that older donors and female donors were more likely to experience limitations in ADLs after HSC collection. Billen et al.9 found that predonation health-related quality of life markers contributed significantly to recovery and toxicity profile after BM or PBSC donation when health-related quality of life was measured using the SF-36 questionnaire before donation and at 4 weeks and 3 months after donation for 275 PBSC and 37 BM donors. Poorer predonation physical health was associated with longer recovery (P=0.017) and experiencing fatigue (P=0.002) and pain (P<0.005) in PBSC donors. Poorer predonation mental health was associated with longer recovery in BM donors (P=0.026) and with episodes of pain (P=0.003) and dizziness (P=0.003) in PBSC donors.

Because female sex, collection method and collection period were observed to be dependent on each other as per our data analysis, it was important to clarify whether we had drawn statistical erroneous conclusions. There were statistically significant correlations between sex and collection method and between sex and collection period (P<0.0001 and P=0.0004, respectively). For this reason, the interaction between sex and collection method and that between sex and collection period were added to the factors (variables) of multivariate analyses for general discomfort and limitations in ADLs. As shown in Supplementary Tables S1 and S2, however, the interaction between sex and collection method and that between sex and collection period were not statistically significant factors in multivariate analyses for general discomfort and limitations in ADLs (P>0.05). Because of the lack of statistical significance found when examining these factors during the multivariate analysis, we believe that the interactions between sex and both collection method and collection period need not be considered in the analysis of our data.

Based on the analysis of our data just as it was, we described that a negative or undetermined intention of a second donation on day 1 was a post-donation predictor of general discomfort and limitation in ADLs within 48 h after HSC collection. However, it would be more reasonable to describe that general discomfort and limitation in ADLs were a predictor of a negative or undetermined intention of a second donation on day 1.

In conclusion, donor age and sex and collection method and period should be considered as risk factors when HSC donation from unrelated donors is performed. As a collection method, PBSC collection through a peripheral line is recommended to alleviate physical stress and to improve ADLs. Female donors are more sensitive to HSC collection than male donors, and male sex of the donor is predictive of positive intention of a second donation.

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Acknowledgements

We thank the unrelated volunteer donors for their altruistic and generous spirit. We also thank the physicians, coordinators and nurses of all collection centers for their generosity to the unrelated donors.

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Correspondence to M H Lee.

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The authors declare no conflict of interest.

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Supplementary Information accompanies this paper on Bone Marrow Transplantation website

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Lee, M., Jang, J., Min, H. et al. Predictors of general discomfort, limitations in activities of daily living and intention of a second donation in unrelated hematopoietic stem cell donation. Bone Marrow Transplant 52, 258–263 (2017) doi:10.1038/bmt.2016.260

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