Stem Cell Procurement

PBSC collection from family donors in Japan: a prospective survey

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Severe adverse events (SAE) and late hematological malignancies have been reported after PBSC donation. No prospective data on incidence and risk factors have been available for family donors so far. The Japan Society for Hematopoietic Cell Transplantation (JSHCT) introduced therefore in 2000 a mandatory registration system. It defined standards for donor eligibility and asked harvest centers to report any SAE immediately. All donors were examined at day 30 and were to be contacted once each year for a period of 5 years. Acute SAEs within day 30 were reported from 47/3264 donations (1.44%) with 14 events considered as unexpected and severe (0.58%). No donor died within 30 days. Late SAEs were reported from 39/1708 donors (2.3%). The incidence of acute SAEs was significantly higher among donors not matching the JSHCT standards (P=0.0023). Late hematological malignancies in PBSC donors were not different compared with a retrospective cohort of BM donors (N:1/1708 vs N:2/5921; P=0.53). In conclusion, acute and late SAEs do occur in PBSC donors at relatively low frequency but risk factors can be defined.


Allogeneic PBSC harvest has gained wide acceptance for hematopoietic SCT (HSCT). The stem cell harvest procedure is more convenient for both donors and medical teams,1, 2, 3 the speed of post-transplant, hematological recovery is faster in recipients,4, 5, 6, 7 and outcomes are similar compared to that of BMT.8, 9, 10 However, there have been occasional reports of mortalities11, 12, 13, 14, 15 and severe complications such as splenic rupture.16, 17 Most of these severe adverse events (SAE) occurred with family donors, appeared as anecdotal or were based on retrospective analyses. No standardized or centralized reporting database was available 13 years ago.18 Therefore, a prospective reporting study was initiated for family donors in Japan in the year 2000 to monitor the types and frequencies of adverse events potentially associated with PBSC donation, and to define factors associated with such events. We present here a comprehensive report summarizing the early adverse events (defined as within 30 days post donation) and late adverse events within 5 years post donation among 3264 consecutively pre-registered PBSC family donors from April 2000 to March 2005. The follow-up was completed in March 2010 and the data were analyzed as of September 2010. Furthermore, these PBSC donor data have been compared with the BM family donor data obtained via retrospective questionnaires shared with EBMT.19

Materials and methods

Study design

This was a prospective controlled study on all PBSC donations in Japan for a period of 5 years of recruitment and 5 years of additional follow-up. The prospective study was accompanied by a retrospective survey of an earlier cohort of patients transplanted with BM as stem cell source.

JSHCT pre-registration mailings to institutes in 2000

JSHCT provided information to all hematology teams that were performing allogeneic PBSC transplants in 2000 or were interested in doing so. The package included: standards for donor eligibility; guidelines for G-CSF mobilization, harvest and storage of PBSC; informed consent form; donor pre-registration instructions including donor name, birth date, gender, relationship to recipient, agreement to annual health check, compliance with JSHCT standards, past/present illness, batch of G-CSF and preliminary information on recipient; donor follow-up procedure and acute SAEs report form. The registration period extended from 1 April 2000 to 31 March 2005 (5 years) and the annual long-term follow-up for 5 years was scheduled for each individual donor from April 2001 to March 2010. A day 30 short-term report had to be submitted in the fourth week after the harvest with the following information: (1) donor profiles, (2) laboratory data pre- and post donation, (3) dose of G-CSF and batch details, (4) harvested PBSC count and (5) any adverse events other than those urgently reported. A long-term report was sent by JSHCT to all donors who did consent to follow-up. It contained the following information: (1) current laboratory data and (2) any adverse events before the day of each health check. The participating transplant/harvest teams were obliged to report any adverse events to the JSHCT registration center via an emergency reporting system. Acute and late SAEs were defined as follows: (1) death, (2) events dangerous to life, (3) prolongation of hospitalization, (4) morbidity, (5) potential morbidity, (6) other events with levels equivalent to (1)–(5), (7) disease or abnormality inherited to offspring and (8) any malignancy ((7) and (8) were designated only for late events).

JSHCT eligibility criteria for PBSC family donors

The JSHCT did define formal standards for the eligibility of PBSC family donors. They were in part derived from blood donation standards, in part out of safety concerns: donor candidates should not have (1) allergy to G-CSF, (2) pregnancy, (3) cardiovascular risk factors defined as history of hypertension, coronary disease, cerebrovascular disease, diabetes mellitus or hyperlipidemia (4) splenomegaly determined by sonography, (5) hematological abnormality, (6) history of of interstitial pneumonitis, (7) history of of any malignancy, (8) ongoing heart, lung or renal disease requiring treatment, (9) ongoing autoimmune disease, (10) ongoing liver disease or (11) history of neurological disorders. Recommended donor age was between 10 and 65 years. Finally, each harvest team was required to have a third-party team to confirm the eligibility of each donor. The harvest team was free to choose a non-JHSCT-standard donor upon request of the family or the patient if no other donor was available; in any case they had to report the donor follow-up as well. No information was obtained on the number of donors rejected during the donor check-up evaluation or on the factors associated with such a decision.

Comparison with adverse events in BM family donors in Japan

To compare the frequency and the SAEs among PBSC donors to those of BM donors, a retrospective survey was conducted in collaboration between JSHCT members and EBMT for all BM donations between 1990 and 2004. The questionnaire items covered (1) any death within 30 days after donation of BM cells, (2) any SAE within 30 days after donation of BM cells and (3) any hematological malignancies (lymphoid/myeloid) at any time post donation of BM in recipients. These items were identical as reported earlier by the European Group for Blood and Marrow Transplantation EBMT.19

Statistical analysis

Correlation between groups was examined using the χ2 test. Incidence of low-frequency events was compared using a Poisson regression analysis. Data were analyzed with STATA statistical software (Stata Cooperation, College Station, TX, USA). Predictive factors on PBSC donation outcomes within 30 days were examined by a logistic regression model. Factors included in the model were (1) donor profiles age (<19, 20–59 and >60 years), gender, body weight (<39, 40–69 and >70 kg), past and current health conditions and previous PBSC donation, (2) pre-and post-donation laboratory data, (3) total dose of G-CSF administered (<2499, 2500–2999, 3000–3499, >3500 μg, converted into dose of Filgrastim), (4) the occurrence of any adverse events such as thrombocytopenia, prolongation of hospitalized period, any clinical symptoms (bone pain, fatigue, headache, insomnia, anorexia, nausea and vomiting), splenomegaly and (5) numbers of mobilized CD34+cells.

All statistical analyses were performed using the Statistical Analysis System (SAS 9.1, Cary, NC, USA).


Participation in the Japanese family donor PBSC pre-registration system

From 1 January 2000 to 31 March 2005, data on 3264 PBSC donations from 3188 donors (3114 with one, 72 with two and 2 with three donations) were reported to the registration system by 233 harvest teams (see Supplementary Information). This corresponds to the participation of 231 out of the 311 transplant teams that performed allogeneic HSCT during this time period (74.3%). The participating teams performed a total of 11 405 allogeneic HSCT during the same time period; hence, the proportion of PB donation concerned 28% of all allogeneic HSCT. Over the same period, the JSHCT patient registry independently reported 3262 PBSC transplants from family donors (data not shown). This confirms a close correspondence between the donors included in this survey and the actual total PBSC donations performed in Japan during this period. From the 3264 donations, 2873 (88.0%) day 30 check reports were submitted and analyzed. At the close of the projects in March 2010, 6233 reports of annual health checks had been submitted from 1708 donors. Of these 1708, 833 received all five consecutive annual health checks. The numbers of pre-registration, day 30 reports and the annual health-check forms are summarized in Figure 1.

Figure 1

The cumulative numbers of pre-registered donors and Day 30 reports for 5 years, and the status of 5-year follow-up of each donor (April 2000—March 2010) are shown. The numbers of pre-registered donors, the numbers of donors whose day 30 reports were submitted and the numbers of donors who received annual health check at least once for their 5-year follow-up period are 3264, 2873 and 1708, respectively.

Early SAEs

Out of 3264 PBSC donations, 47 donors (1.44%) were reported by the harvest teams to have experienced one or more SAEs either during the harvest or within the 30-day period as summarized in Table 1. The 47 events were classified by the JSHCT into three sub-groups: (1) unexpected and severe (19; 0.58%), (2) transient, probably G-CSF-associated (9; 0.27%) and (3) transient, probably apheresis-associated (19; 0.58%). Some SAEs were potentially life-threatening (subarachnoid hematoma, interstitial pneumonitis), still all donors recovered. All SAEs were reported immediately as requested by the system. A comparison of the urgently reported SAEs with the standard day 30 reports revealed no inconsistencies or additional events.

Table 1 Forty-seven acute severea adverse events reported as emergencies to the JSHCT donor registration center between April 2000 and March 2005

Factors associated with early outcomes

The factors associated with early outcomes are summarized in Table 2. Risk factors for thrombocytopenia were higher total dose of G-CSF and older age. Risk factors for prolonged hospitalization were older age, low body weight, higher total dose of G-CSF, any past and present illness and previous stem cell donations. Risk factor for bone pain was any present illness. Female gender was the only risk factor for fatigue, headache, insomnia, anorexia or nausea. Younger age was a risk factor for vomiting. Risk factors for splenomegaly (>150% enlargement from baseline by abdominal sonography) were older age and higher total dose of G-CSF. Risk factors for lower CD34+ cell mobilization/donor body weight (<2 × 106 CD34+ cells/kg) were age above 60 years (HR 2.55, P<0.01), female gender (HR 1.52, P<0.01) and previous stem cell donation (HR 3.10, P<0.001). Age below 20 years (HR 2.81, P<0.001) was the only parameter associated with higher CD34+ cell mobilization/donor body weight (>9 × 106 CD34+ cells/kg).

Table 2 Factors associated with adverse events after PBSC donation

Late events

A total of 6233 annual reports from 1708 donors were received by 31 March 2010. Hence, 52.3% of all donors had received the annual health check at least once during this 5-year period; 833 (25.5%) completed all five annual health checks. In total, 1223 donors (71.6%) reported no complaint while 485 donors (28.4%) reported one or more complaints. Of these, 108 (6.4%) donors had their complaints already before donation; 133 donors (7.8%) reported new but transient events (such as a traffic accident, common cold, hypertension, diabetes mellitus, surgical operation or pregnancy). Health problems that arose after donation and could have been related to the donation were reported by 243 (14.2%) donors. They were classified by JSHCT in 204 cases (11.9%) as non-malignant and non-significant diseases, in 26 (1.5%) as non-malignant but significant diseases, in 12 (0.7%) as non-hematological malignancies and in 1 (0.06%) as hematological malignancy.20 Hence, 39 of 1708 donors (2.3%) were considered to have had severe complications that could have been related to the donation as judged by either the harvest teams or the JSHCT registration center. Classified as non-malignant but significant events were seven donors with thyroid dysfunction (10–34 mo), three with uterine fibroid (14–36 mo), two with rheumatoid arthritis (20, 23 mo), two with cerebral infarction (7, 33 mo) and one each with subarachnoidal hemorrhage, (9 mo), cataract (7 mo), ocular bleeding (33 mo), atopic dermatitis (12 mo), uveitis (20 mo), bronchial asthma (20 mo), ITP (27 mo), endometriosis (20 mo), mole (9 mo), cerebral aneurysm (24 mo), pancreatic cyst (53 mo) and IgA nephritis (44 mo). The 12 cases of non-hematological malignant diseases reported were 6 donors with breast cancer (443 mo) and one each with gastric cancer (23 mo), uterus cancer (10 mo), brain tumor (6 mo), pharyngeal cancer (13 mo), lung cancer (54 mo) and prostatic cancer (55 mo). There was one case of hematological malignancy (0.06%) and one donor developed AML. It should be noted that one donor with a chronic myeloproliferative disorder at the time of donation (defined later), who developed acute myelogeneous leukemia 4 years after donation, was not included among the 39 cases.

Donor eligibility and frequency of severe acute and late events

Out of 3264 donors, 133 (4.07%) did not meet the eligibility criteria, 90 because of age (53 older and 37 younger than required by the standards) and 43 because of concurrent health problems. Follow-up with the annual health check was the same, for donors meeting or not meeting the standards at donation (4.3%, 74 donors). As indicated in Table 3, acute and late events tended to increase with age, although neither association was statistically significant. In contrast, early SAEs but not late events were clearly and significantly associated with concurrent health problems at the time of donation.

Table 3 Impact of age and JHSCT standards on acute and late events

Comparison of adverse events between PBSC donation (prospective study) and BM donation (retrospective study) of family donors in Japan

To estimate the incidence of acute and late adverse events among BM family donors in Japan, questionnaires corresponding to those used by EBMT19 were sent to 286 transplant teams belonging to JSHCT. A total of 191 teams (67%) responded with information from 5921 BM harvests from family donors performed between 1991 and 2003. Based on the HSCT Recipient Registry information, 89.7% of all related BMTs performed in Japan during the reporting period were represented. One of the 5921 donors, who died 1 year after BM donation following anoxia and brain damage during harvest, was counted as a death within 30 days following donation.21 SAE within 30 days of donation occurred in 25 out of the 5921 (0.42%) donors (for details see Table 4). As for hematological malignancies, 2 donors developed AML after BM donation. The frequencies of adverse events among BM family donors was not significantly different from those following PBSC in terms of either 30-day mortality, frequency of SAE (unexpected SAE being adopted for PBSC donations) within 30 days or frequency of hematological malignancies.

Table 4 Comparison of adverse events between PBSC harvest (prospective study) and BM harvest (retrospective study) in Japan


PBSC donation is considered by many to be less stressful for a donor than BM donation.22, 23 Nevertheless, it involves other potential stress factors. These include G-CSF administration to healthy individuals, the short- and long-term effects of which remain insufficiently characterized.24, 25, 26, 27 Recent publications have reported that the administration of G-CSF can influence the blood coagulation system of healthy donors.28, 29, 30 Some studies indicated genetic and epigenetic alterations in lymphocytes of healthy donors after G-CSF stimulation31 while others could not identify such changes.32, 33 The leukapheresis procedure itself may be a stress factor; more blood is processed and a longer time for harvest is needed34 compared with a platelet collection, an apheresis procedure for which donor safety is relatively well established.

To evaluate the safety and risks of PBSC donation, JSHCT initiated a nation-wide pre-registration system followed by an annual health check for family donors. This included consecutive pre-registration for 5 years, emergency reports at any time (for both acute and late events), a formal day 30 report of the laboratory data post donation and an annual health check report for 5 years. Nearly 100% of the collected pre-registration forms and emergency reports were received on time and >80% of day 30 check reports were obtained. The collection rate of the annual health check reports was 50%. The JSHCT eligibility criteria, specifically lack of donors to fulfill these criteria appeared to be predictive for the occurrence of severe acute adverse events. Still, the 19 donors with unexpected severe events ranged in their age between 10 and 65 years and had no health problems at the time of donation. Of interest, these 19 events were of cardiovascular (angina, thrombosis and so on), hemorrhagic (subarachnoid/retroperitoneal hematoma and so on.) or inflammatory nature (interstitial pneumonitis and so on). Other information and techniques, such as high-sensitivity CRP assay that might predict the presence of active cardiovascular disorders, should be tested to see whether these measures can identify patients at increased risk of severe acute adverse events.35

There were no mortality cases within 30 days in our cohort. Our numbers could still be too low. Mortality has been reported in about one death per 10 000–15 000 donations.19 Still, we consider this absence of mortality to be in part a consequence of pre-registration and setting the eligibility standards for family donors. We cannot identify a single critical factor but pre-registration and nation-wide standards might raise awareness for potential risks in a harvest team. As evidence defines specific factors that define donors at increased risk for SAEs, the harvest team might then refuse harvest of unsuitable family donors despite their request.36

To compare the risk of PBSC donation to that of BM donation, the questionnaires shared with EBMT were sent to JSHCT member institutes. The results confirm that the incidence of deaths, unexpected SAEs within 30 days of donation or subsequent hematological malignancies were not different between PBSC and BM donors. There is a note of caution: events were characterized differently in the two cohorts, one was a prospective study (PBSC donation), one a retrospective study (BM harvest) and both were performed in different time periods (PBSC: 2000–2005; BM harvest: 1990–2004). A prospective follow-up system should also be applied for family BM donors.

The donor’s safety is an essential part and prerequisite in allogeneic stem cell donation. For BM harvesting, an anesthesiologist usually assesses the suitability of the candidate donor and acts as a life-saving third-party expert for the hematology team. Furthermore, the harvest procedure is performed in a fully equipped operation room. In contrast, PBSC harvest can be performed by a hematology team by its own in an apheresis room; an objective risk assessment and risk management might be compromised. Allogeneic PBSC donation and transplantation are excellent medical procedures; donor safety remains an essential part in order to ascertain the future use of these techniques.18, 37 Our study has shown that the life-threatening SAEs can occur during or immediately after the donation process. These events are not erratic and risk factors can be identified. Tools are required to reduce the complication rate. Strict standards for donor eligibility and an independent third-party evaluation of donor’s suitability might eliminate the conflict of interests of transplant physicians and increase donor safety. Both have been a sine qua non for unrelated donors in advanced blood and marrow donor bank systems such as NMDP38or DKMS,39 and only a few unexpected SAEs have been reported. The same pre-donation approach and donor follow-up should become the standard-of-care for all HSCTs, from family or unrelated donors as well. It will serve to provide more accurate information about early and late effects of PBSC donation, which is needed now more than ever.40, 41


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We thank R Kodera, K Kawai, T Shimizu and Y Yamada (EPS Co.) for their generous assistance in the course of the survey. The study was partially supported by Health and Labor Sciences Research Grants, Research on Tissue Engineering, Ministry of Health, Labor and Welfare, Japan. JH and AG were in part supported by the Swiss National Foundation grant NRP 63.

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Correspondence to Y Kodera.

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The authors declare no conflict of interest.

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Author Contributions

YK, KY and MH designed the study and wrote the paper. YM, HD, SA, MI, KK, SK and MT collected and organized the data. YK, RT, SS, SWK, KN, MH, KM and RS supervised the process of data collection. NH, MF and AK performed the statistical analysis. JH, NS, DN and AG consulted with the study concept and reviewed the results.

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Kodera, Y., Yamamoto, K., Harada, M. et al. PBSC collection from family donors in Japan: a prospective survey. Bone Marrow Transplant 49, 195–200 (2014) doi:10.1038/bmt.2013.147

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  • PBSC harvest (PBSCH)
  • family donors
  • prospective study
  • acute adverse events
  • late health problems
  • predictive factors

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