Bone Marrow Transplantation (2014) 49, 729–736 & 2014 Macmillan Publishers Limited All rights reserved 0268-3369/14 www.nature.com/bmt
REVIEW
A review of the haematopoietic stem cell donation experience: is there room for improvement? A Billen1,2, JA Madrigal1,2 and BE Shaw1,2,3 Donation of haematopoietic stem cells, either through BM or PBSC collection, is a generally safe procedure for healthy donors although adverse reactions are a definite risk. The invaluable source of donation and its central role in transplantation implies that every effort should be made to alleviate possible difficulties the donor encounters. The physical and psychological reactions to donation have been established for some time, but less is known about the factors that are associated with a poorer donation experience. In this article, we provide an overview of the physical and psychological donation experience and focus attention on demographic, physical and psychological factors that may influence this donation experience. Understanding that toxicity profiles vary with certain donor characteristics is crucial as this knowledge could influence practice in numerous ways including the modification of joining and recruitment policies and the improvement of supportive measures and donor follow-up procedures. Although this review deals with both unrelated and related donors (RDs), there is a relative paucity of regulation of RD care and we call for more attention to this area. Owing to the relative rarity of donation in each country, a global effort to collect donor outcome data is needed. Bone Marrow Transplantation (2014) 49, 729–736; doi:10.1038/bmt.2013.227; published online 27 January 2014 Keywords: PBSC donation; BM donation; donation experience; influencing factors; recovery
INTRODUCTION Haematopoietic SCT is a curative procedure for life-threatening haematological diseases. The number of allogeneic SCTs has steadily increased by up to 10% annually on a global scale1,2 with currently up to 30 000 allogeneic SCTs being performed every year in over 1000 transplant centres worldwide. During the last decade, PBSCs have replaced BM as the main source of haematopoietic stem cells. Furthermore, new conditioning regimens have led to an increased use of donor lymphocyte infusions. Surveys from Europe and the United States show that there are now more unrelated than related haematopoietic stem cell donations in these areas.1,3 Although the donation process is generally considered safe, adverse reactions (ARs) are a known and definable risk. Optimizing the donation experience is important for several reasons. The act of donating BM or PBSC for haematopoietic cell transplantation is to submit to a procedure for which the individual will not derive any direct physical benefit. Thus, any harm that might result will not be offset by a benefit to the donor, except for the potential sense of satisfaction derived from an altruistic act.4 Therefore, care must be taken to minimize the potential of harm and donor registries should have donor safety as their first priority. In addition, stem cell donation requires us to balance the inherent tension between ensuring sufficient donors are registered while protecting the safety of donors. An excellent reputation of the donation process is needed if we want adequate numbers of donors on our registers. It will similarly allow transplant centre physicians to recognize that donors will be available and be well looked after. The overall experience of the donor includes both physical and psychological aspects, from the time of their first contact with the
registry until full recovery. In this review, we discuss the most common short-term physical and psychological reactions to the donation process and concentrate specifically on the factors that may influence these. We mention mechanisms that are already in place to ensure donor safety and consider possible strategies for the future. SHORT-TERM PHYSICAL ARS PBSC donation involves four or five daily s.c. injections with G-CSF followed by leukapheresis. Although this is preferentially performed using peripheral venous access, a central venous catheter insertion might be needed if donors have inadequate veins. Common side effects of PBSC donation are summarized in Table 1.5–14 Other complications can be related to the insertion of a catheter and the process of leukapheresis. The latter might cause symptomatic hypovolemia, and hypocalcaemia is common as a result of the use of citrate anticoagulation in the circuit. The discomfort following PBSC donation starts within 24–48 h of administration of G-CSF but resolves fairly quickly after collection is complete, with just over 10% of donors reporting discomfort at 1-week after collection.7 The discussion concerning the long-term safety of G-CSF has been published elsewhere15,16 and falls outside the scope of this paper. BM donation involves general or spinal anaesthesia followed by repeated insertion of large bore needles into the donor’s posterior iliac crests to remove up to 2 L of marrow. In many centres, autologous red cell units are collected before the harvest.17–19 Others see no need to collect autologous units arguing that red cell donation renders donors anaemic on the day of surgery, making transfusion—autologous or even allogeneic—more
1 UCL Cancer Institute, London, UK; 2Anthony Nolan, London, UK and 3Royal Marsden Hospital, London, UK. Correspondence: Dr A Billen, Anthony Nolan, 2 Heathgate Place, 75-87 Agincourt Road, London NW3 2NU, UK. E-mail: [email protected] Received 27 September 2013; revised 29 November 2013; accepted 2 December 2013; published online 27 January 2014
A review of the haematopoietic stem cell donation experience A Billen et al
730 likely.20 In addition, red cell donations often expire because of postponement of the donation. The most common post-donation complications are summarized in Table 1.5,7,11,17,19,21,22 The average hospital stay is 8–72 h.17,19,21 At 1-month after donation, pain had resolved for 80% of donors11 and complete recovery was reported in 67% of donors.7 Although the peak symptom burden of PBSC donors does not differ from those reported by BM donors, the temporal patterns differ with some studies showing that discomfort peaks on day þ 5 of G-CSF for PBSC donors compared with 48-h after collection for BM donors.7,23 The latter are likely to have a delayed recovery compared with PBSC donors.7,21,24–26 Despite considerable pain and physical limitations, general health scores remain high following BM donation.19 Prospective studies have reported an incidence of serious ARs (SARs) ranging from 1.34 to 2.38% in BM donors and from 0.6 to 1.1% in PBSC donors.6,8,11,12,27 SARs have not been well defined in all studies, which render incidences difficult to compare. A large retrospective analysis of data collected by the European Group for Blood and Marrow Transplantation (EBMT), reported 7.25 SARs per 10 000 and significantly less in BM than PBSC donors.28 This is, however, a retrospective study, questionnaire based and has very low overall rates of SARs so might represent underreporting. Most SARs have been reported as case reports or by retrospective studies, hence causality can usually not be determined.29 Some of these SARs, such as thrombotic and cardiovascular events or splenic rupture, may be explained by the biological effects of G-CSF15,28–32 or are associated with the collection procedure used (harvest site pain with subsequent disability, anaesthesia or central venous catheter related).21,27–29,33 Halter et al.28 reported that the incidence of donor fatalities was 0.98 per 10 000 donors, all in related donors (RDs), one after a BM donation and four after peripheral blood donation. The cases reported included cardiac arrest and pulmonary embolus. In most of these donors, preexisting medical conditions were identified post-mortem, highlighting the need for strict medical eligibility criteria and assessment of donors. Death in unrelated donors (URDs) is exceedingly rare with only one death reported to the World Marrow Donor Association (WMDA) between 2003 and 2012, caused by an extensive haemothorax secondary to traumatic jugular vein catheter insertion. Second donations of stem cells are not associated with an increased risk of donor complications, however, the need for adequate informed consent is clear.34 Literature on the topic of RD safety has been scarce5,6,13,14,21,23–25,33,35–37 and ARs are not as well characterized in terms of frequency and severity compared with URDs. Current research suggests that the risks associated with donation seem to be higher for RDs compared with URDs.28 This increased risk has several explanations. The same transplant centre and occasionally the same physician caring for the recipient may evaluate the RD.38 This could represent potential conflict of interest in favour of the
Table 1.
recipient. Transplant centres may use less stringent criteria to determine donor eligibility in RDs.36 To the benefit of the donor, an independent physician for donor clearance, follow-up and counselling ought to be provided.38–40 Children who are being evaluated as potential donors require special attention to their clinical, psychological and social needs. Often parents are expected to consent for their children, which may create additional conflict of interest situations.38,41 In Europe, any potential donation of BM or PBSC from adults who lack the capacity to consent and children who lack the competence to consent, must be assessed by an Accredited Assessor.42 In addition, as data show better survival after URD transplantation when a young donor is used, this has led to clinicians choosing the youngest available URD. This is in contrast with RDs who often match the age of their recipients. These donor groups have specific issues (size issues in paediatric donors and increased endorgan dysfunction and cancer in older donors). As opposed to URDs, RDs are not self-selected, have personal motivations and are likely to be willing to take more risks and underreport conditions that could impact ARs. Studies comparing RD and URD outcomes are limited.43 Chang et al.43 reported that related marrow donors experience more acute physical pain, possibly resulting from higher stress levels being manifested by an increased vulnerability to pain. A study comparing RD and concurrently enrolled NMDP URD outcomes is planned.44
MECHANISMS TO ENSURE DONOR SAFETY URD safety is prioritized through published WMDA standards covering donor recruitment, consent, medical assessment, donor follow-up and a global collaborative effort in adverse event reporting.45,46 No equivalent regulations currently exist for RD care. Several mechanisms that aim to maintain donor safety are summarized in Table 2. The pre-donation history, which addresses risks both to the donor and the recipient, should focus on matters relevant to the anticipated donation, including psychological issues. In general, donors with moderate or severe organ impairment are deferred and this commonly includes those with coronary artery disease, renal or hepatic impairment.47 Many other medical conditions may prevent donation for the sake of donor safety.
Table 2.
Current mechanisms to optimize donor safety
Recruitment and confirmatory typing (unrelated donors)
Medical screening and exclusion of donors who have medical conditions that would increase their risk Questionnaire based
Medical consultation
Formal medical assessment and exclusion of donors who have medical conditions that would increase their risk History: addresses risks both to the donor and the recipient, including psychological issues Clinical examination ECG Often urine dip, chest X-ray Informed consent
Donation
Advanced harvest centre facilities Experienced harvest physicians
Post-donation
Reporting of serious adverse events through the WMDA (only for unrelated donors) Donor follow-up
Common side effects of PBSC and BM donation5–14,17,19,21,22
Adverse reaction
PBSC donation
BM donation
Bone pain (PBSC)/harvest site pain (BM) Fatigue Headache Joint pain Insomnia Myalgia Anorexia Nausea Throat pain Harvest site reactions
61–97%
23–87%
33–77% 27–74% 40% 1–48% 29–90% 11–22% 11–26% Not applicable Not applicable
38–88% 15–18% Rare 10–15% 22–25% 8–10% 6–26% 30–33% 11–15%
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Abbreviations: ECG ¼ electrocardiogram; WMDA ¼ World Marrow Donor Association.
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A review of the haematopoietic stem cell donation experience A Billen et al
731 PREDICTIVE FACTORS FOR DEVELOPING ARS Studies assessing factors that influence the donation experience are limited. Table 3 lists donor and treatment-related characteristics that have been found to influence the donation experience.
Potential donors ought to receive a full description of the procedure, its risks and potential alternatives at the time of their medical assessment. It is recommended that donors are counselled about the possibility of subsequent donations of stem cells or lymphocytes before their first donation.34 Special regulations exist for donors who are donating on research protocols,48 however, we do not discuss that here in detail as this is beyond the scope of this paper. The reporting of serious adverse events is mandatory for all WMDA-accredited registries, representing the vast majority of unrelated adult donations worldwide. Although most URD registers are collecting some degree of donor follow-up, there is no centralized system in place at the moment.
Table 3.
Gender Multiple studies have shown that female gender is associated with a higher risk of both apheresis and BM donation-related ARs compared with men.7–10,17,41,49–51 Women are also more likely to experience serious complications11,50 and are almost twice as likely to require extended hospitalization.7,8 The explanation for
Factors influencing donor adverse reactions (in PBSC donation, BM donation or both)
Factor
Outcome
PBSC or BM donation
Female gender
More likely to require extended hospitalization following donation.7 7,19,41,49
Greater physical difficulty with donation.
Associated with more serious complications.11,50 Higher incidence of most apheresis-related ARs.7,8,10,519,14,51 More likely to require a line.8 More fatigue following donation (likely due to higher relative blood volume depletion).17 Less likely to experience complete recovery.7
PBSC and BM PBSC and BM PBSC and BM PBSC PBSC BM BM
Higher incidence of headache in donors aged under 35.9 Older donors more likely to experience citrate-related toxicity50 No influence on ARs.10,51 Older donors reported somewhat less difficulty with donation.49
PBSC and BM PBSC and BM PBSC PBSC PBSC BM
Weight
Higher BMI (425) associated with more G-CSF side effects (fatigue, myalgia, sweats).10 Obese donors experienced more pain and toxicity.7,8
PBSC PBSC
Donors with smaller total blood volumes
Higher incidence of ARs.50
PBSC
Lower net fluid balance
Associated with pre-syncopal complications.50
PBSC
Higher G-CSF doses
Doses 49 mcg/kg associated with higher incidence of headache and fatigue9,14 Associated with more toxicity10,88
PBSC
Peripheral blood WBC count
Higher WBC count after the third dose of G-CSF associated with fatigue10 High WBC (450 109/L) following five doses of G-CSF not associated with more side effects during mobilization than those with WBC o50 109/L.10 Baseline mononuclear cell count 42.7 109/L associated with increased fatigue and pain peri-collection.7
PBSC
Blood donors
More physical difficulty with donating.49 Correlated with higher number of days off work in male donors.17
BM
Related vs unrelated
More moderate to severe pain in related donors.43
BM
Active vs sitting job
Active job associated with more number of days off work.17
BM
Age
Older donors at less risk of pain in the peri-collection period, but more likely to experience persistent pain, fatigue and other toxicities at 1-week following donation.7 Older donors at risk of more serious complications.11
19
Longer duration of harvest
Associated with physical limitations. Associated with serious complications.11
BM BM
Average blood volume depletion
Associated with higher number of days off work in female donors.17
BM
Regional vs general anaesthesia
No difference found.18,61–63 Regional anaesthesia associated with serious complications.11
BM
Abbreviations: AR ¼ adverse reaction; BMI ¼ body mass index.
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732 these findings is unclear, but is likely multifactorial. Research in other medical specialties has shown higher pain scores in various conditions in women.52 This might reflect a gender difference in the perception of pain52 and physical functioning.53 The increased incidence of fatigue in female BM donors could be explained by the lower post-donation Hb levels in women following BM donation with an average Hb drop in women from 12.8–13.6 to 10.3–11.1 g/ dL (versus 15.2–15.4 to 12.4–13.4 g/dL in men).11,17 Yuan et al.50 stated that a smaller total blood volume in women may partially explain the increased incidence of citrate toxicity, however, a multivariate analysis could not be performed in this study because of the low number of ARs. In addition, an increased incidence of ARs related to drugs in women, which may be explained by pharmacokinetic, immunological and hormonal differences, has been described.54 Other studies have found that women need a central line in 21% of cases versus 5% of men8 and are more likely to develop post-donation haematomas.50 This can be explained by the finding that female donors tend to have a smaller body size and smaller veins. They are therefore more prone to vascular injuries when access needles of the same gauge are used. Age Younger donors have not been shown to be at increased risk of experiencing complications during PBSC donation,7,10,50,51 apart from headache and grades II–IV pain.7,9 Furthermore, a positive correlation between younger donors and increased pre-syncopal and syncopal events as demonstrated in whole blood donors, has not been established in PBSC donation.50,55,56 This finding is surprising, given that the extracorporeal blood volume can exceed 20% of the donor’s blood volume during apheresis57 and most apheresis machines do not routinely provide saline infusions. Conversely, older PBSC donors were more likely to experience citrate-related toxicity and persistent toxicities at 1 week,7,50 reflecting a slower recovery period than younger donors for all aspects of the donation process. This slower recovery is also described in older BM donors.7 The actual day of donation is generally tolerated better in older BM donors.7,49 Young donors may have been less experienced with and more fearful of medical procedures in general.49 Weight There have been no studies examining the influence of weight on ARs in BM donors. Many centres already have strict body mass index restrictions for BM donors because of procedural difficulties in heavier donors. There is some evidence that donors who are overweight or obese tend to have more pain following PBSC donation.7,8,10 This may be a consequence of a relatively higher dose of G-CSF received in this population10 as extracellular fluid and haematopoietic mass do not increase in direct proportion to weight. Full blood count There is no conclusive evidence of a link between baseline haematology results and ARs7,10 and therefore no indication for monitoring white cell counts during G-CSF administration exists. In addition, the increase in spleen size secondary to G-CSF does not appear to be associated with higher peripheral blood white cell counts.58,59 BM harvest procedure A longer duration of BM harvest has been consistently associated with increased post-donation physical limitations and complications.11,19 It is unclear whether it is the procedure’s duration per se that is a predictor or the product volume harvested. The volume of marrow harvested—which has been shown to be correlated with duration of the procedure19—predicted donor recovery in one study17 but not in others.19 The duration of harvest may also reflect the total number of puncture holes. Further effort should be directed to recording the Bone Marrow Transplantation (2014) 729 – 736
number of bone punctures, developing a valid measure of ‘difficulty of harvest’ and studying whether they affect donors’ recovery.19 This matter is complicated by the knowledge that small volume marrow aspirations and multiple puncture sites optimize the yields of the BM harvest.60 There are few reports that compare general versus regional anaesthesia for BM harvesting.11,18,61–63 Local anaesthesia has reduced risk of trauma, because the patient is awake and vigilant, whereas general anaesthesia may produce a minor respiratory risk, because the donor has a secured airway.64 Most studies found no difference regarding numbers of adverse events during or after the procedure. This strongly suggests that the choice of anaesthesia depends on the donor or the anaesthetist’s preference.18 Jobs involving mild to moderate daily work activities have been associated with fewer of days off work following BM donation compared with jobs involving more heavy duties.17 Blood donors had more physical difficulty with donation; their previous experience with blood donation may have led them to underestimate the physical impact of BM donation.49 Being a blood donor is also correlated with higher number of days off work, this may be secondary to lower baseline Hb levels in those donors.17 PSYCHOLOGICAL ASPECTS OF DONATION Most studies have focussed on the physical outcomes following donation and only few have assessed the psychological impact of donation. The psychological reactions following donation are generally positive.65 Common experiences are feeling like a better person as a result of donation65 and most subjects felt deep personal satisfaction and gratitude for an opportunity to donate.66 Donors felt they were actualizing a central trait in their identity67 and most donors would donate a second time.66,68 Outcomes appear mainly reliant on the outcome in the recipient, physical ARs experienced during the donation process and the psychological state of ambivalence (Table 4). One study looking into reactions of unrelated BM donors when the recipient dies, concluded that death of the recipient produced feelings of grief and was often surprisingly intense, given the fact that the recipient was a stranger.69 Studies in RDs are complicated by the direct connection of donors with the patient. Poor outcomes can have devastating effects and ‘survivor’s guilt’ is well documented in the literature. A study in 23 BM donors found that donors whose sibling died had significantly higher scores on the Beck Depression Inventory—a validated depression scale— compared with those whose siblings remained alive.70 These are interesting findings given that most registries allow information exchange or contact between the donor and recipient after a certain period of time. Limiting information about the recipient may result in more positive psychological outcomes in these donors. However, other strategies such as psychological counselling services that relieve donor grief could be considered. Butterworth et al.65 assessed the psychosocial effects of BM donation in 493 URDs. The donors experienced the donation as quite positive in general and they were more likely to think of themselves as a better person as a result of the donation. They also showed that donors with longer collection times or lower back pain were more likely to have less positive psychosocial outcomes. A large Canadian randomized trial assessed mood states and quality of life before donation and 1 week and 4 weeks following donation in BM and PBSC donors.25 Both the mood and quality of life scores were worse after BM donation, compared with PBSC donation. The authors commented that physical morbidity can affect mood and this is in keeping with a delayed physical recovery in BM versus PBSC donors. The psychological condition of the donor should be assessed, in particular the donor’s motivations for considering donation. Switzer et al.49 reported that a psychological state of ambivalence was a better predictor of a negative donation experience than actual physical difficulty with donation. Persons & 2014 Macmillan Publishers Limited
A review of the haematopoietic stem cell donation experience A Billen et al
733 Table 4.
Factors influencing psychological outcomes
Death of the recipient/worse outcome in recipient
Unrelated donors: Grief was often surprisingly intense, given the fact that the recipient was a stranger, feelings of guilt were rare.69 Related donors: Associated with a more stressful experience.66 Recipient deterioration may significantly adversely impact donor psychosocial status.89 Significantly higher Beck depression scores 6 months following donation.70 Donors felt less as if their donation had really helped their sibling as time passed. However, bereaved donors experienced global psychological gains including enhanced self-esteem, happiness and lifesatisfaction compared with donors whose siblings were still living.90
More physical difficulty with donation
Associated with feeling less positive psychologically about the donation.49 BM donation was associated with more physical morbidity and negative effects on QOL up to 1 month after donation than was PBSC donation (BM vs PBSC).25 BM donors mood scores were worse 1 week after compared with before donation, whereas PBSC scores did not change (BM vs PBSC).25 More likely to experience donation as stressful.65,66
Longer collection times/large volumes collected
Less positive psychological outcomes.65 Less willing to donate again in future.65
Ambivalence
Greater ambivalence associated with more physical and psychological difficulties with donation.49 Factors associated with higher ambivalence: higher education, donors who were discouraged by others,49 exchange motives (weighing costs and benefits), idealized helping motives,72 extrinsic pressure,71 some ethnicities (Asian Americans)73 Factors associated with lower ambivalence: more frequent blood donors, happier individuals, those who believed the patient’s chances of survival were better,49 empathy motives,72 intrinsic commitment.71
Related vs unrelated
Depression scores significantly higher in related donors, before and after donation.43
Family dynamics and emotional support
More positive experience if better emotional support from family, friends and hospital staff.66,74 Married donors had fewer negative psychological reactions shortly following donation.49
Preparation for donation
Adequacy of preparation for donation influences experience.74
Abbreviation: QOL ¼ quality of life.
especially at risk for pre-donation ambivalence were more educated, less likely to have been blood donors, less happy in general and less optimistic about the patient’s chances of survival.49,71–73 Donors who are motivated by an intrinsic commitment to donate, rather than extrinsic pressure, are less ambivalent about donating.71 The same author reported ethnic variation in the donation experience. He found that Asian Americans were more ambivalent and more anxious than all other ethnic groups.73 RDs may have different motivations from URDs and may be subject to increased emotional and physical stress associated with donation.66 A more positive experience has been reported if there is a better emotional support from family, friends and hospital staff.74 Routine provision of psychosocial support to donors as well as recipients is therefore important. POSSIBLE FUTURE STRATEGIES Understanding that toxicity profiles vary with certain donor characteristics is important as this knowledge could influence practice in numerous ways including: modification of joining and recruitment policies, management of expectations and the improvement of supportive measures and donor follow-up procedures. Donors who are found to be at high risk of ARs are excluded from donation. For example, the knowledge that G-CSF can cause flareups of autoimmune disease15 has led to stricter eligibility criteria concerning autoimmune diseases within many stem cell registers. Selection criteria may be altered in the future based on the awareness that toxicity profiles vary with certain donor characteristics. Recently, some registers have started to concentrate & 2014 Macmillan Publishers Limited
on the recruitment of male donors. Although this is often driven by increased availability and stem cell yields among males, it may also result in fewer ARs75–78 and a reduced incidence of GVHD.79 Conversely, restricting the recruitment to male donors may influence the numbers of donors on the register and the overall HLA repertoire. Similarly, the finding that older donors are at a higher risk of experiencing SARs, could further enhance the trend towards registries recruiting younger donors. This practice is currently mainly driven by the finding that transplant outcomes are improved when using younger donors.80–82 Heavier donors have been found to experience more bone pain, although this was mainly classified as being mild. Restricting the recruitment to ‘lighter’ donors would carry an inherent conflict as several studies have shown that stem cell yields are positively correlated with donor weight.83,84 The management of donors’ expectations can similarly be important, especially in donors at increased risk of ARs. High-risk groups ought to be made aware of this at the time of their medical assessment. For instance, regular blood donors who are asked to donate BM should be specifically informed about the increased risk of anaemia following donation and the likely need for iron replacement therapy. In addition, a more stringent shortterm follow-up could be considered in donors who are at increased risk to allow early intervention. Some groups, such as obese PBSC donors, may benefit from pre-emptive analgesia.85 The physical state of ambivalence was found to be a better predictor of a negative donation experience, even more so than the actual physical difficulty with donation. Recruitment staff have a critical role, for example, in reducing ambivalence and consequently reducing donation difficulties among new recruits by clearly providing information to the donor concerning the medical risks of the donation. Strategies to enhance commitment Bone Marrow Transplantation (2014) 729 – 736
A review of the haematopoietic stem cell donation experience A Billen et al
734 at recruitment could involve a two-stage process, where the decision to join the register needs to be reaffirmed. Other options may include strategies where it is made easier for donors to opt out of the register. CONCLUSION Voluntary donation of BM or PBSC for haematopoietic cell transplantation is a well-established altruistic act, performed by thousands of healthy RDs or URDs throughout the world. Although allogeneic stem cell donation is a safe procedure with very low rates of serious ARs, the risk exists and every effort should be made to minimalize this. Several mechanisms to ensure donor safety are already in place and the increasing amount of data on factors that may increase the risk of ARs will further allow registries to tailor their donor care. Nevertheless, we have encountered some major limitations. Although stem cell registers are the richest source of URD outcome data, only a fraction of these data are currently published. Most registers collect some level of donor outcome data but few have large-scale donor follow-up programs. Further effort should be directed to standardize operational definitions on post-donation physical and psychological outcomes and ARs and to develop a prospective global data collection.86 The EBMT has recently developed a reporting system for both RD and URD outcomes, but this is not a mandatory requirement yet and only covers EBMT centres. Furthermore, a continued effort to develop clinical trials is required. Future research areas of interest may include the development of an index that measures the ‘difficulty’ of a BM harvest procedure and the detection of certain harvestrelated factors that are most strongly associated with poorer donor outcomes. Other areas are the use of validated general physical and psychological wellbeing questionnaires before donation and the impact of these scores on donor outcomes. Another major restriction the community faces is the lack of international guidelines for RD care. Although the care of family donors has been carefully considered and managed in transplant centres internationally, there is currently a lack of standardized guidelines for the management of family donors40 (although some exceptions exist87). Although key ethical considerations between RDs and URDs differ, the underlying principles of family donor care are in many ways similar to those involving URDs. Further research needs to be directed at reviewing the feasibility of a model of RD care, which separates this from the transplant team’s responsibility. An increased collaboration between those caring for RD and URD is important and the WMDA and WBMT have started to provide some guidance in this area.40 CONFLICT OF INTEREST The authors declare no conflict of interest.
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Unrelated allogeneic bone marrow donation: short- and long-term follow-up of 103 consecutive volunteer donors. Bone Marrow Transplant 2001; 28: 369–374. 18 Machaczka M, Kalaitzakis E, Eleborg L, Ljungman P, Hagglund H. Comparison of general vs regional anaesthesia for BM harvesting: a retrospective study of anaesthesia-related complications. Bone Marrow Transplant 2010; 45: 53–61. 19 Nishimori M, Yamada Y, Hoshi K, Akiyama Y, Hoshi Y, Morishima Y et al. Healthrelated quality of life of unrelated bone marrow donors in Japan. Blood 2002; 99: 1995–2001. 20 Boulton FE, James V. Guidelines for policies on alternatives to allogeneic blood transfusion. 1. Predeposit autologous blood donation and transfusion. Transfus Med 2007; 17: 354–365. 21 Favre G, Beksac M, Bacigalupo A, Ruutu T, Nagler A, Gluckman E et al. Differences between graft product and donor side effects following bone marrow or stem cell donation. Bone Marrow Transplant 2003; 32: 873–880. 22 Stroncek DF, Holland PV, Bartch G, Bixby T, Simmons RG, Antin JH et al. Experiences of the first 493 unrelated marrow donors in the National Marrow Donor Program. Blood 1993; 81: 1940–1946. 23 Rowley SD, Donaldson G, Lilleby K, Bensinger WI, Appelbaum FR. Experiences of donors enrolled in a randomized study of allogeneic bone marrow or peripheral blood stem cell transplantation. Blood 2001; 97: 2541–2548. 24 Heldal D, Brinch L, Tjonnfjord G, Solheim BG, Egeland T, Gadeholt G et al. Donation of stem cells from blood or bone marrow: results of a randomised study of safety and complaints. Bone Marrow Transplant 2002; 29: 479–486. 25 Bredeson C, Leger C, Couban S, Simpson D, Huebsch L, Walker I et al. An evaluation of the donor experience in the canadian multicenter randomized trial of bone marrow versus peripheral blood allografting. Biol Blood Marrow Transplant 2004; 10: 405–414. 26 Siddiq S, Pamphilon D, Brunskill S, Doree C, Hyde C, Stanworth S. Bone marrow harvest versus peripheral stem cell collection for haemopoietic stem cell donation in healthy donors. Cochrane Database Syst Rev 2009; 21: Cd006406. 27 Pulsipher M. Increased risk of severe adverse events after BM vs PBSC donation: Results of a prospective study of 9494 NMDP donors (2004-2009). http://
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52 Ruau D, Liu LY, Clark JD, Angst MS, Butte AJ. Sex differences in reported pain across 11 000 patients captured in electronic medical records. J Pain 2012; 13: 228–234. 53 Taenzer AH, Clark C, Curry CS. Gender affects report of pain and function after arthroscopic anterior cruciate ligament reconstruction. Anesthesiology 2000; 93: 670–675. 54 Rademaker M. Do women have more adverse drug reactions? Am J Clin Dermatol 2001; 2: 349–351. 55 Eder AF, Hillyer CD, Dy BA, Notari EPt, Benjamin RJ. Adverse reactions to allogeneic whole blood donation by 16- and 17-year-olds. JAMA 2008; 299: 2279–2286. 56 Wiltbank TB, Giordano GF, Kamel H, Tomasulo P, Custer B. Faint and prefaint reactions in whole-blood donors: an analysis of predonation measurements and their predictive value. Transfusion 2008; 48: 1799–1808. 57 Amrein K, Valentin A, Lanzer G, Drexler C. Adverse events and safety issues in blood donation-a comprehensive review. Blood Rev 2012; 26: 33–42. 58 Stroncek D, Shawker T, Follmann D, Leitman SF. G-CSF-induced spleen size changes in peripheral blood progenitor cell donors. Transfusion 2003; 43: 609–613. 59 Platzbecker U, Prange-Krex G, Bornhauser M, Koch R, Soucek S, Aikele P et al. Spleen enlargement in healthy donors during G-CSF mobilization of PBPCs. Transfusion 2001; 41: 184–189. 60 Spitzer TR, Areman EM, Cirenza E, Yu M, Dickerson S, Kotula PL et al. The impact of harvest center on quality of marrows collected from unrelated donors. J Hematother 1994; 3: 65–70. 61 Lavi A, Efrat R, Feigin E, Kadari A. Regional versus general anesthesia for bone marrow harvesting. J Clin Anesth 1993; 5: 204–206. 62 Knudsen LM, Johnsen HE, Gaarsdal E, Jensen L. Spinal versus general anaesthesia for bone marrow harvesting. Bone Marrow Transplant 1995; 15: 486–487. 63 Burmeister MA, Standl T, Brauer P, Ramsperger K, Kroger N, Zander A et al. Safety and efficacy of spinal vs general anaesthesia in bone marrow harvesting. Bone Marrow Transplant 1998; 21: 1145–1148. 64 Bosi A, Bartolozzi B. Safety of bone marrow stem cell donation: a review. Transplant Proc 2010; 42: 2192–2194. 65 Butterworth VA, Simmons RG, Bartsch G, Randall B, Schimmel M, Stroncek DF. Psychosocial effects of unrelated bone marrow donation: experiences of the National Marrow Donor Program. Blood 1993; 81: 1947–1959. 66 Christopher KA. The experience of donating bone marrow to a relative. Oncol Nurs Forum 2000; 27: 693–700. 67 Simmons RG, Schimmel M, Butterworth VA. The self-image of unrelated bone marrow donors. J Health Soc Behav 1993; 34: 285–301. 68 Switzer GE, Goycoolea JM, Dew MA, Graeff EC, Hegland J. Donating stimulated peripheral blood stem cells vs bone marrow: do donors experience the procedures differently? Bone Marrow Transplant 2001; 27: 917–923. 69 Butterworth VA, Simmons RG, Schimmel M. When altruism fails: reactions of unrelated bone marrow donors when the recipient dies. Omega 1992; 26: 161–173. 70 Chang G, McGarigle C, Koby D, Antin JH. Symptoms of pain and depression in related marrow donors: changes after transplant. Psychosomatics 2003; 44: 59–64. 71 Switzer GE, Myaskovsky L, Goycoolea JM, Dew MA, Confer DL, King R. Factors associated with ambivalence about bone marrow donation among newly recruited unrelated potential donors. Transplantation 2003; 75: 1517–1523. 72 Switzer GE, Dew MA, Butterworth VA, Simmons RG, Schimmel M. Understanding donors’ motivations: a study of unrelated bone marrow donors. Soc Sci Med 1997; 45: 137–147. 73 Switzer GE, Dew MA, Harrington DJ, Crowley-Matoka M, Myaskovsky L, Abress L et al. Ethnic differences in donation-related characteristics among potential hematopoietic stem cell donors. Transplantation 2005; 80: 890–896. 74 Pillay B, Lee SJ, Katona L, De Bono S, Warren N, Fletcher J et al. The psychosocial impact of haematopoietic SCT on sibling donors. Bone Marrow Transplant 2012; 47: 1361–1365. 75 Ings SJ, Balsa C, Leverett D, Mackinnon S, Linch DC, Watts MJ. Peripheral blood stem cell yield in 400 normal donors mobilised with granulocyte colonystimulating factor (G-CSF): impact of age, sex, donor weight and type of G-CSF used. Br J Haematol 2006; 134: 517–525. 76 Vasu S, Leitman SF, Tisdale JF, Hsieh MM, Childs RW, Barrett AJ et al. Donor demographic and laboratory predictors of allogeneic peripheral blood stem cell mobilization in an ethnically diverse population. Blood 2008; 112: 2092–2100. 77 Platzbecker U, Bornhauser M, Zimmer K, Lerche L, Rutt C, Ehninger G et al. Second donation of granulocyte-colony-stimulating factor-mobilized peripheral blood progenitor cells: risk factors associated with a low yield of CD34 þ cells. Transfusion 2005; 45: 11–15. 78 Miflin G, Charley C, Stainer C, Anderson S, Hunter A, Russell N. Stem cell mobilization in normal donors for allogeneic transplantation: analysis of safety and factors affecting efficacy. Br J Haematol 1996; 95: 345–348.
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736 79 Spierings E, Kim YH, Hendriks M, Borst E, Sergeant R, Canossi A et al. Multicenter analyses demonstrate significant clinical effects of minor histocompatibility antigens on GvHD and GvL after HLA-matched related and unrelated hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2013; 19: 1244–1253. 80 Kroger N, Zabelina T, de Wreede L, Berger J, Alchalby H, van Biezen A et al. Allogeneic stem cell transplantation for older advanced MDS patients: improved survival with young unrelated donor in comparison with HLA-identical siblings. Leukemia 2013; 27: 604–609. 81 Ayuk F, Zabelina T, Wortmann F, Alchalby H, Wolschke C, Lellek H et al. Donor choice according to age for allo-SCT for AML in complete remission. Bone Marrow Transplant 2013; 48: 1028–1032. 82 Kollman C, Howe CW, Anasetti C, Antin JH, Davies SM, Filipovich AH et al. Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age. Blood 2001; 98: 2043–2051. 83 Anderlini P, Przepiorka D, Seong C, Smith TL, Huh YO, Lauppe J et al. Factors affecting mobilization of CD34 þ cells in normal donors treated with filgrastim. Transfusion 1997; 37: 507–512. 84 Martino M, Callea I, Condemi A, Dattola A, Irrera G, Marcuccio D et al. Predictive factors that affect the mobilization of CD34( þ ) cells in healthy donors treated
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with recombinant granulocyte colony-stimulating factor (G-CSF). J Clin Apher 2006; 21: 169–175. Chern B, McCarthy N, Hutchins C, Durrant ST. Analgesic infiltration at the site of bone marrow harvest significantly reduces donor morbidity. Bone Marrow Transplant 1999; 23: 947–949. Pamphilon D, Siddiq S, Brunskill S, Doree C, Hyde C, Horowitz M et al. Stem cell donation-what advice can be given to the donor? Br J Haematol 2009; 147: 71–76. Kodera Y, Yamamoto K, Harada M, Morishima Y, Dohy H, Asano S et al. PBSC collection from family donors in Japan: a prospective survey. Bone Marrow Transplant 2014; 49: 195–200. Engelhardt M, Bertz H, Afting M, Waller CF, Finke J. High-versus standard-dose filgrastim (rhG-CSF) for mobilization of peripheral-blood progenitor cells from allogeneic donors and CD34( þ ) immunoselection. J Clin Oncol 1999; 17: 2160–2172. Wolcott DL, Wellisch DK, Fawzy FI, Landsverk J. Psychological adjustment of adult bone marrow transplant donors whose recipient survives. Transplantation 1986; 41: 484–488. Switzer GE, Dew MA, Magistro CA, Goycoolea JM, Twillman RK, Alter C et al. The effects of bereavement on adult sibling bone marrow donors’ psychological wellbeing and reactions to donation. Bone Marrow Transplant 1998; 21: 181–188.
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REVIEW
A review of the haematopoietic stem cell donation experience: is there room for improvement? A Billen1,2, JA Madrigal1,2 and BE Shaw1,2,3 Donation of haematopoietic stem cells, either through BM or PBSC collection, is a generally safe procedure for healthy donors although adverse reactions are a definite risk. The invaluable source of donation and its central role in transplantation implies that every effort should be made to alleviate possible difficulties the donor encounters. The physical and psychological reactions to donation have been established for some time, but less is known about the factors that are associated with a poorer donation experience. In this article, we provide an overview of the physical and psychological donation experience and focus attention on demographic, physical and psychological factors that may influence this donation experience. Understanding that toxicity profiles vary with certain donor characteristics is crucial as this knowledge could influence practice in numerous ways including the modification of joining and recruitment policies and the improvement of supportive measures and donor follow-up procedures. Although this review deals with both unrelated and related donors (RDs), there is a relative paucity of regulation of RD care and we call for more attention to this area. Owing to the relative rarity of donation in each country, a global effort to collect donor outcome data is needed. Bone Marrow Transplantation (2014) 49, 729–736; doi:10.1038/bmt.2013.227; published online 27 January 2014 Keywords: PBSC donation; BM donation; donation experience; influencing factors; recovery
INTRODUCTION Haematopoietic SCT is a curative procedure for life-threatening haematological diseases. The number of allogeneic SCTs has steadily increased by up to 10% annually on a global scale1,2 with currently up to 30 000 allogeneic SCTs being performed every year in over 1000 transplant centres worldwide. During the last decade, PBSCs have replaced BM as the main source of haematopoietic stem cells. Furthermore, new conditioning regimens have led to an increased use of donor lymphocyte infusions. Surveys from Europe and the United States show that there are now more unrelated than related haematopoietic stem cell donations in these areas.1,3 Although the donation process is generally considered safe, adverse reactions (ARs) are a known and definable risk. Optimizing the donation experience is important for several reasons. The act of donating BM or PBSC for haematopoietic cell transplantation is to submit to a procedure for which the individual will not derive any direct physical benefit. Thus, any harm that might result will not be offset by a benefit to the donor, except for the potential sense of satisfaction derived from an altruistic act.4 Therefore, care must be taken to minimize the potential of harm and donor registries should have donor safety as their first priority. In addition, stem cell donation requires us to balance the inherent tension between ensuring sufficient donors are registered while protecting the safety of donors. An excellent reputation of the donation process is needed if we want adequate numbers of donors on our registers. It will similarly allow transplant centre physicians to recognize that donors will be available and be well looked after. The overall experience of the donor includes both physical and psychological aspects, from the time of their first contact with the
registry until full recovery. In this review, we discuss the most common short-term physical and psychological reactions to the donation process and concentrate specifically on the factors that may influence these. We mention mechanisms that are already in place to ensure donor safety and consider possible strategies for the future. SHORT-TERM PHYSICAL ARS PBSC donation involves four or five daily s.c. injections with G-CSF followed by leukapheresis. Although this is preferentially performed using peripheral venous access, a central venous catheter insertion might be needed if donors have inadequate veins. Common side effects of PBSC donation are summarized in Table 1.5–14 Other complications can be related to the insertion of a catheter and the process of leukapheresis. The latter might cause symptomatic hypovolemia, and hypocalcaemia is common as a result of the use of citrate anticoagulation in the circuit. The discomfort following PBSC donation starts within 24–48 h of administration of G-CSF but resolves fairly quickly after collection is complete, with just over 10% of donors reporting discomfort at 1-week after collection.7 The discussion concerning the long-term safety of G-CSF has been published elsewhere15,16 and falls outside the scope of this paper. BM donation involves general or spinal anaesthesia followed by repeated insertion of large bore needles into the donor’s posterior iliac crests to remove up to 2 L of marrow. In many centres, autologous red cell units are collected before the harvest.17–19 Others see no need to collect autologous units arguing that red cell donation renders donors anaemic on the day of surgery, making transfusion—autologous or even allogeneic—more
1 UCL Cancer Institute, London, UK; 2Anthony Nolan, London, UK and 3Royal Marsden Hospital, London, UK. Correspondence: Dr A Billen, Anthony Nolan, 2 Heathgate Place, 75-87 Agincourt Road, London NW3 2NU, UK. E-mail: [email protected] Received 27 September 2013; revised 29 November 2013; accepted 2 December 2013; published online 27 January 2014
A review of the haematopoietic stem cell donation experience A Billen et al
730 likely.20 In addition, red cell donations often expire because of postponement of the donation. The most common post-donation complications are summarized in Table 1.5,7,11,17,19,21,22 The average hospital stay is 8–72 h.17,19,21 At 1-month after donation, pain had resolved for 80% of donors11 and complete recovery was reported in 67% of donors.7 Although the peak symptom burden of PBSC donors does not differ from those reported by BM donors, the temporal patterns differ with some studies showing that discomfort peaks on day þ 5 of G-CSF for PBSC donors compared with 48-h after collection for BM donors.7,23 The latter are likely to have a delayed recovery compared with PBSC donors.7,21,24–26 Despite considerable pain and physical limitations, general health scores remain high following BM donation.19 Prospective studies have reported an incidence of serious ARs (SARs) ranging from 1.34 to 2.38% in BM donors and from 0.6 to 1.1% in PBSC donors.6,8,11,12,27 SARs have not been well defined in all studies, which render incidences difficult to compare. A large retrospective analysis of data collected by the European Group for Blood and Marrow Transplantation (EBMT), reported 7.25 SARs per 10 000 and significantly less in BM than PBSC donors.28 This is, however, a retrospective study, questionnaire based and has very low overall rates of SARs so might represent underreporting. Most SARs have been reported as case reports or by retrospective studies, hence causality can usually not be determined.29 Some of these SARs, such as thrombotic and cardiovascular events or splenic rupture, may be explained by the biological effects of G-CSF15,28–32 or are associated with the collection procedure used (harvest site pain with subsequent disability, anaesthesia or central venous catheter related).21,27–29,33 Halter et al.28 reported that the incidence of donor fatalities was 0.98 per 10 000 donors, all in related donors (RDs), one after a BM donation and four after peripheral blood donation. The cases reported included cardiac arrest and pulmonary embolus. In most of these donors, preexisting medical conditions were identified post-mortem, highlighting the need for strict medical eligibility criteria and assessment of donors. Death in unrelated donors (URDs) is exceedingly rare with only one death reported to the World Marrow Donor Association (WMDA) between 2003 and 2012, caused by an extensive haemothorax secondary to traumatic jugular vein catheter insertion. Second donations of stem cells are not associated with an increased risk of donor complications, however, the need for adequate informed consent is clear.34 Literature on the topic of RD safety has been scarce5,6,13,14,21,23–25,33,35–37 and ARs are not as well characterized in terms of frequency and severity compared with URDs. Current research suggests that the risks associated with donation seem to be higher for RDs compared with URDs.28 This increased risk has several explanations. The same transplant centre and occasionally the same physician caring for the recipient may evaluate the RD.38 This could represent potential conflict of interest in favour of the
Table 1.
recipient. Transplant centres may use less stringent criteria to determine donor eligibility in RDs.36 To the benefit of the donor, an independent physician for donor clearance, follow-up and counselling ought to be provided.38–40 Children who are being evaluated as potential donors require special attention to their clinical, psychological and social needs. Often parents are expected to consent for their children, which may create additional conflict of interest situations.38,41 In Europe, any potential donation of BM or PBSC from adults who lack the capacity to consent and children who lack the competence to consent, must be assessed by an Accredited Assessor.42 In addition, as data show better survival after URD transplantation when a young donor is used, this has led to clinicians choosing the youngest available URD. This is in contrast with RDs who often match the age of their recipients. These donor groups have specific issues (size issues in paediatric donors and increased endorgan dysfunction and cancer in older donors). As opposed to URDs, RDs are not self-selected, have personal motivations and are likely to be willing to take more risks and underreport conditions that could impact ARs. Studies comparing RD and URD outcomes are limited.43 Chang et al.43 reported that related marrow donors experience more acute physical pain, possibly resulting from higher stress levels being manifested by an increased vulnerability to pain. A study comparing RD and concurrently enrolled NMDP URD outcomes is planned.44
MECHANISMS TO ENSURE DONOR SAFETY URD safety is prioritized through published WMDA standards covering donor recruitment, consent, medical assessment, donor follow-up and a global collaborative effort in adverse event reporting.45,46 No equivalent regulations currently exist for RD care. Several mechanisms that aim to maintain donor safety are summarized in Table 2. The pre-donation history, which addresses risks both to the donor and the recipient, should focus on matters relevant to the anticipated donation, including psychological issues. In general, donors with moderate or severe organ impairment are deferred and this commonly includes those with coronary artery disease, renal or hepatic impairment.47 Many other medical conditions may prevent donation for the sake of donor safety.
Table 2.
Current mechanisms to optimize donor safety
Recruitment and confirmatory typing (unrelated donors)
Medical screening and exclusion of donors who have medical conditions that would increase their risk Questionnaire based
Medical consultation
Formal medical assessment and exclusion of donors who have medical conditions that would increase their risk History: addresses risks both to the donor and the recipient, including psychological issues Clinical examination ECG Often urine dip, chest X-ray Informed consent
Donation
Advanced harvest centre facilities Experienced harvest physicians
Post-donation
Reporting of serious adverse events through the WMDA (only for unrelated donors) Donor follow-up
Common side effects of PBSC and BM donation5–14,17,19,21,22
Adverse reaction
PBSC donation
BM donation
Bone pain (PBSC)/harvest site pain (BM) Fatigue Headache Joint pain Insomnia Myalgia Anorexia Nausea Throat pain Harvest site reactions
61–97%
23–87%
33–77% 27–74% 40% 1–48% 29–90% 11–22% 11–26% Not applicable Not applicable
38–88% 15–18% Rare 10–15% 22–25% 8–10% 6–26% 30–33% 11–15%
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Abbreviations: ECG ¼ electrocardiogram; WMDA ¼ World Marrow Donor Association.
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A review of the haematopoietic stem cell donation experience A Billen et al
731 PREDICTIVE FACTORS FOR DEVELOPING ARS Studies assessing factors that influence the donation experience are limited. Table 3 lists donor and treatment-related characteristics that have been found to influence the donation experience.
Potential donors ought to receive a full description of the procedure, its risks and potential alternatives at the time of their medical assessment. It is recommended that donors are counselled about the possibility of subsequent donations of stem cells or lymphocytes before their first donation.34 Special regulations exist for donors who are donating on research protocols,48 however, we do not discuss that here in detail as this is beyond the scope of this paper. The reporting of serious adverse events is mandatory for all WMDA-accredited registries, representing the vast majority of unrelated adult donations worldwide. Although most URD registers are collecting some degree of donor follow-up, there is no centralized system in place at the moment.
Table 3.
Gender Multiple studies have shown that female gender is associated with a higher risk of both apheresis and BM donation-related ARs compared with men.7–10,17,41,49–51 Women are also more likely to experience serious complications11,50 and are almost twice as likely to require extended hospitalization.7,8 The explanation for
Factors influencing donor adverse reactions (in PBSC donation, BM donation or both)
Factor
Outcome
PBSC or BM donation
Female gender
More likely to require extended hospitalization following donation.7 7,19,41,49
Greater physical difficulty with donation.
Associated with more serious complications.11,50 Higher incidence of most apheresis-related ARs.7,8,10,519,14,51 More likely to require a line.8 More fatigue following donation (likely due to higher relative blood volume depletion).17 Less likely to experience complete recovery.7
PBSC and BM PBSC and BM PBSC and BM PBSC PBSC BM BM
Higher incidence of headache in donors aged under 35.9 Older donors more likely to experience citrate-related toxicity50 No influence on ARs.10,51 Older donors reported somewhat less difficulty with donation.49
PBSC and BM PBSC and BM PBSC PBSC PBSC BM
Weight
Higher BMI (425) associated with more G-CSF side effects (fatigue, myalgia, sweats).10 Obese donors experienced more pain and toxicity.7,8
PBSC PBSC
Donors with smaller total blood volumes
Higher incidence of ARs.50
PBSC
Lower net fluid balance
Associated with pre-syncopal complications.50
PBSC
Higher G-CSF doses
Doses 49 mcg/kg associated with higher incidence of headache and fatigue9,14 Associated with more toxicity10,88
PBSC
Peripheral blood WBC count
Higher WBC count after the third dose of G-CSF associated with fatigue10 High WBC (450 109/L) following five doses of G-CSF not associated with more side effects during mobilization than those with WBC o50 109/L.10 Baseline mononuclear cell count 42.7 109/L associated with increased fatigue and pain peri-collection.7
PBSC
Blood donors
More physical difficulty with donating.49 Correlated with higher number of days off work in male donors.17
BM
Related vs unrelated
More moderate to severe pain in related donors.43
BM
Active vs sitting job
Active job associated with more number of days off work.17
BM
Age
Older donors at less risk of pain in the peri-collection period, but more likely to experience persistent pain, fatigue and other toxicities at 1-week following donation.7 Older donors at risk of more serious complications.11
19
Longer duration of harvest
Associated with physical limitations. Associated with serious complications.11
BM BM
Average blood volume depletion
Associated with higher number of days off work in female donors.17
BM
Regional vs general anaesthesia
No difference found.18,61–63 Regional anaesthesia associated with serious complications.11
BM
Abbreviations: AR ¼ adverse reaction; BMI ¼ body mass index.
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732 these findings is unclear, but is likely multifactorial. Research in other medical specialties has shown higher pain scores in various conditions in women.52 This might reflect a gender difference in the perception of pain52 and physical functioning.53 The increased incidence of fatigue in female BM donors could be explained by the lower post-donation Hb levels in women following BM donation with an average Hb drop in women from 12.8–13.6 to 10.3–11.1 g/ dL (versus 15.2–15.4 to 12.4–13.4 g/dL in men).11,17 Yuan et al.50 stated that a smaller total blood volume in women may partially explain the increased incidence of citrate toxicity, however, a multivariate analysis could not be performed in this study because of the low number of ARs. In addition, an increased incidence of ARs related to drugs in women, which may be explained by pharmacokinetic, immunological and hormonal differences, has been described.54 Other studies have found that women need a central line in 21% of cases versus 5% of men8 and are more likely to develop post-donation haematomas.50 This can be explained by the finding that female donors tend to have a smaller body size and smaller veins. They are therefore more prone to vascular injuries when access needles of the same gauge are used. Age Younger donors have not been shown to be at increased risk of experiencing complications during PBSC donation,7,10,50,51 apart from headache and grades II–IV pain.7,9 Furthermore, a positive correlation between younger donors and increased pre-syncopal and syncopal events as demonstrated in whole blood donors, has not been established in PBSC donation.50,55,56 This finding is surprising, given that the extracorporeal blood volume can exceed 20% of the donor’s blood volume during apheresis57 and most apheresis machines do not routinely provide saline infusions. Conversely, older PBSC donors were more likely to experience citrate-related toxicity and persistent toxicities at 1 week,7,50 reflecting a slower recovery period than younger donors for all aspects of the donation process. This slower recovery is also described in older BM donors.7 The actual day of donation is generally tolerated better in older BM donors.7,49 Young donors may have been less experienced with and more fearful of medical procedures in general.49 Weight There have been no studies examining the influence of weight on ARs in BM donors. Many centres already have strict body mass index restrictions for BM donors because of procedural difficulties in heavier donors. There is some evidence that donors who are overweight or obese tend to have more pain following PBSC donation.7,8,10 This may be a consequence of a relatively higher dose of G-CSF received in this population10 as extracellular fluid and haematopoietic mass do not increase in direct proportion to weight. Full blood count There is no conclusive evidence of a link between baseline haematology results and ARs7,10 and therefore no indication for monitoring white cell counts during G-CSF administration exists. In addition, the increase in spleen size secondary to G-CSF does not appear to be associated with higher peripheral blood white cell counts.58,59 BM harvest procedure A longer duration of BM harvest has been consistently associated with increased post-donation physical limitations and complications.11,19 It is unclear whether it is the procedure’s duration per se that is a predictor or the product volume harvested. The volume of marrow harvested—which has been shown to be correlated with duration of the procedure19—predicted donor recovery in one study17 but not in others.19 The duration of harvest may also reflect the total number of puncture holes. Further effort should be directed to recording the Bone Marrow Transplantation (2014) 729 – 736
number of bone punctures, developing a valid measure of ‘difficulty of harvest’ and studying whether they affect donors’ recovery.19 This matter is complicated by the knowledge that small volume marrow aspirations and multiple puncture sites optimize the yields of the BM harvest.60 There are few reports that compare general versus regional anaesthesia for BM harvesting.11,18,61–63 Local anaesthesia has reduced risk of trauma, because the patient is awake and vigilant, whereas general anaesthesia may produce a minor respiratory risk, because the donor has a secured airway.64 Most studies found no difference regarding numbers of adverse events during or after the procedure. This strongly suggests that the choice of anaesthesia depends on the donor or the anaesthetist’s preference.18 Jobs involving mild to moderate daily work activities have been associated with fewer of days off work following BM donation compared with jobs involving more heavy duties.17 Blood donors had more physical difficulty with donation; their previous experience with blood donation may have led them to underestimate the physical impact of BM donation.49 Being a blood donor is also correlated with higher number of days off work, this may be secondary to lower baseline Hb levels in those donors.17 PSYCHOLOGICAL ASPECTS OF DONATION Most studies have focussed on the physical outcomes following donation and only few have assessed the psychological impact of donation. The psychological reactions following donation are generally positive.65 Common experiences are feeling like a better person as a result of donation65 and most subjects felt deep personal satisfaction and gratitude for an opportunity to donate.66 Donors felt they were actualizing a central trait in their identity67 and most donors would donate a second time.66,68 Outcomes appear mainly reliant on the outcome in the recipient, physical ARs experienced during the donation process and the psychological state of ambivalence (Table 4). One study looking into reactions of unrelated BM donors when the recipient dies, concluded that death of the recipient produced feelings of grief and was often surprisingly intense, given the fact that the recipient was a stranger.69 Studies in RDs are complicated by the direct connection of donors with the patient. Poor outcomes can have devastating effects and ‘survivor’s guilt’ is well documented in the literature. A study in 23 BM donors found that donors whose sibling died had significantly higher scores on the Beck Depression Inventory—a validated depression scale— compared with those whose siblings remained alive.70 These are interesting findings given that most registries allow information exchange or contact between the donor and recipient after a certain period of time. Limiting information about the recipient may result in more positive psychological outcomes in these donors. However, other strategies such as psychological counselling services that relieve donor grief could be considered. Butterworth et al.65 assessed the psychosocial effects of BM donation in 493 URDs. The donors experienced the donation as quite positive in general and they were more likely to think of themselves as a better person as a result of the donation. They also showed that donors with longer collection times or lower back pain were more likely to have less positive psychosocial outcomes. A large Canadian randomized trial assessed mood states and quality of life before donation and 1 week and 4 weeks following donation in BM and PBSC donors.25 Both the mood and quality of life scores were worse after BM donation, compared with PBSC donation. The authors commented that physical morbidity can affect mood and this is in keeping with a delayed physical recovery in BM versus PBSC donors. The psychological condition of the donor should be assessed, in particular the donor’s motivations for considering donation. Switzer et al.49 reported that a psychological state of ambivalence was a better predictor of a negative donation experience than actual physical difficulty with donation. Persons & 2014 Macmillan Publishers Limited
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733 Table 4.
Factors influencing psychological outcomes
Death of the recipient/worse outcome in recipient
Unrelated donors: Grief was often surprisingly intense, given the fact that the recipient was a stranger, feelings of guilt were rare.69 Related donors: Associated with a more stressful experience.66 Recipient deterioration may significantly adversely impact donor psychosocial status.89 Significantly higher Beck depression scores 6 months following donation.70 Donors felt less as if their donation had really helped their sibling as time passed. However, bereaved donors experienced global psychological gains including enhanced self-esteem, happiness and lifesatisfaction compared with donors whose siblings were still living.90
More physical difficulty with donation
Associated with feeling less positive psychologically about the donation.49 BM donation was associated with more physical morbidity and negative effects on QOL up to 1 month after donation than was PBSC donation (BM vs PBSC).25 BM donors mood scores were worse 1 week after compared with before donation, whereas PBSC scores did not change (BM vs PBSC).25 More likely to experience donation as stressful.65,66
Longer collection times/large volumes collected
Less positive psychological outcomes.65 Less willing to donate again in future.65
Ambivalence
Greater ambivalence associated with more physical and psychological difficulties with donation.49 Factors associated with higher ambivalence: higher education, donors who were discouraged by others,49 exchange motives (weighing costs and benefits), idealized helping motives,72 extrinsic pressure,71 some ethnicities (Asian Americans)73 Factors associated with lower ambivalence: more frequent blood donors, happier individuals, those who believed the patient’s chances of survival were better,49 empathy motives,72 intrinsic commitment.71
Related vs unrelated
Depression scores significantly higher in related donors, before and after donation.43
Family dynamics and emotional support
More positive experience if better emotional support from family, friends and hospital staff.66,74 Married donors had fewer negative psychological reactions shortly following donation.49
Preparation for donation
Adequacy of preparation for donation influences experience.74
Abbreviation: QOL ¼ quality of life.
especially at risk for pre-donation ambivalence were more educated, less likely to have been blood donors, less happy in general and less optimistic about the patient’s chances of survival.49,71–73 Donors who are motivated by an intrinsic commitment to donate, rather than extrinsic pressure, are less ambivalent about donating.71 The same author reported ethnic variation in the donation experience. He found that Asian Americans were more ambivalent and more anxious than all other ethnic groups.73 RDs may have different motivations from URDs and may be subject to increased emotional and physical stress associated with donation.66 A more positive experience has been reported if there is a better emotional support from family, friends and hospital staff.74 Routine provision of psychosocial support to donors as well as recipients is therefore important. POSSIBLE FUTURE STRATEGIES Understanding that toxicity profiles vary with certain donor characteristics is important as this knowledge could influence practice in numerous ways including: modification of joining and recruitment policies, management of expectations and the improvement of supportive measures and donor follow-up procedures. Donors who are found to be at high risk of ARs are excluded from donation. For example, the knowledge that G-CSF can cause flareups of autoimmune disease15 has led to stricter eligibility criteria concerning autoimmune diseases within many stem cell registers. Selection criteria may be altered in the future based on the awareness that toxicity profiles vary with certain donor characteristics. Recently, some registers have started to concentrate & 2014 Macmillan Publishers Limited
on the recruitment of male donors. Although this is often driven by increased availability and stem cell yields among males, it may also result in fewer ARs75–78 and a reduced incidence of GVHD.79 Conversely, restricting the recruitment to male donors may influence the numbers of donors on the register and the overall HLA repertoire. Similarly, the finding that older donors are at a higher risk of experiencing SARs, could further enhance the trend towards registries recruiting younger donors. This practice is currently mainly driven by the finding that transplant outcomes are improved when using younger donors.80–82 Heavier donors have been found to experience more bone pain, although this was mainly classified as being mild. Restricting the recruitment to ‘lighter’ donors would carry an inherent conflict as several studies have shown that stem cell yields are positively correlated with donor weight.83,84 The management of donors’ expectations can similarly be important, especially in donors at increased risk of ARs. High-risk groups ought to be made aware of this at the time of their medical assessment. For instance, regular blood donors who are asked to donate BM should be specifically informed about the increased risk of anaemia following donation and the likely need for iron replacement therapy. In addition, a more stringent shortterm follow-up could be considered in donors who are at increased risk to allow early intervention. Some groups, such as obese PBSC donors, may benefit from pre-emptive analgesia.85 The physical state of ambivalence was found to be a better predictor of a negative donation experience, even more so than the actual physical difficulty with donation. Recruitment staff have a critical role, for example, in reducing ambivalence and consequently reducing donation difficulties among new recruits by clearly providing information to the donor concerning the medical risks of the donation. Strategies to enhance commitment Bone Marrow Transplantation (2014) 729 – 736
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734 at recruitment could involve a two-stage process, where the decision to join the register needs to be reaffirmed. Other options may include strategies where it is made easier for donors to opt out of the register. CONCLUSION Voluntary donation of BM or PBSC for haematopoietic cell transplantation is a well-established altruistic act, performed by thousands of healthy RDs or URDs throughout the world. Although allogeneic stem cell donation is a safe procedure with very low rates of serious ARs, the risk exists and every effort should be made to minimalize this. Several mechanisms to ensure donor safety are already in place and the increasing amount of data on factors that may increase the risk of ARs will further allow registries to tailor their donor care. Nevertheless, we have encountered some major limitations. Although stem cell registers are the richest source of URD outcome data, only a fraction of these data are currently published. Most registers collect some level of donor outcome data but few have large-scale donor follow-up programs. Further effort should be directed to standardize operational definitions on post-donation physical and psychological outcomes and ARs and to develop a prospective global data collection.86 The EBMT has recently developed a reporting system for both RD and URD outcomes, but this is not a mandatory requirement yet and only covers EBMT centres. Furthermore, a continued effort to develop clinical trials is required. Future research areas of interest may include the development of an index that measures the ‘difficulty’ of a BM harvest procedure and the detection of certain harvestrelated factors that are most strongly associated with poorer donor outcomes. Other areas are the use of validated general physical and psychological wellbeing questionnaires before donation and the impact of these scores on donor outcomes. Another major restriction the community faces is the lack of international guidelines for RD care. Although the care of family donors has been carefully considered and managed in transplant centres internationally, there is currently a lack of standardized guidelines for the management of family donors40 (although some exceptions exist87). Although key ethical considerations between RDs and URDs differ, the underlying principles of family donor care are in many ways similar to those involving URDs. Further research needs to be directed at reviewing the feasibility of a model of RD care, which separates this from the transplant team’s responsibility. An increased collaboration between those caring for RD and URD is important and the WMDA and WBMT have started to provide some guidance in this area.40 CONFLICT OF INTEREST The authors declare no conflict of interest.
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