uniform examination of stem cell donors

Uniform examination of stem cell donorsA. Brand and the ISBT ⁄ AABB Joint Working Party on Cellular Therapy

Sanquin Blood Supply & Leiden University Medical Centre, Leiden, Netherlands

In contrast to unrelated donors who are counselled and examined according to inter-national guidelines, related donors of allogeneic bone marrow (BM) or mobilizedperipheral blood stem cells (PBSC) often are recruited, examined and followed other-wise. Currently, mostly PBSC instead of BM donation is used. The higher CD34+yield is preferred for non-myeloablated recipients, allowing transplantation of olderpatients. Consequently related sibling donors are aging and prone to suffer more co-morbidity as compared to unrelated donors. With respect to counselling it is obviousthat donor recruitment and motivation between related and unrelated donors differ.The related donor however needs protection by an independent physician safeguard-ing the health of the donor. Although financial and logistic reasons may play a role,several differences between related and unrelated donor management are eligiblefor harmonization. In addition it is important to reach agreement among donor cen-tres on uniform decisions for deferral and long-term follow-up. This requiresexchange of information, not only of serious adverse reactions but also of potentialhazardous situations, in order to develop more evidence-based recommendations.

Key words: donors, stem cell transplantation.

Introduction

For allogeneic haematopoietic stem cell transplantation

(HSCT) three sources of stem cells can be used. Although

safety of collection of cord blood is sometimes questioned,

the donor is not exposed to inconvenience and the risk of

long-term sequels is unlikely. The last decade granulocyte

colony-stimulating factor (G-CSF) mobilized peripheral

blood stem cells (PBSC) are increasingly used instead of

bone marrow (BM). For donors below 14–18 years of age,

in many countries ⁄ hospitals G-CSF mobilization is not

allowed. In particular for older patients, the higher CD34+

yield of PBSC associated with faster haematopoietic recov-

ery enables transplantation using non-myeloablative con-

ditioning. Consequently, related sibling donors are ageing

and may suffer co-morbidity. In contrast to unrelated

donors who are counselled and examined according to

international guidelines, for related donors such strict pro-

cedures are lacking. The purpose of this survey is to make

an inventory of (solvable) obstacles to harmonize proce-

dures for related and unrelated donors.

Guidelines and recommendations

The several phases of stem cell donation include donor

recruitment, information and consent, HLA typing, medical

checks intended for donor safety to undergo donation and

product safety for the recipient, release of the donor to

donate, stem cell harvesting, (serious) adverse events

reporting, stem cell product quality, short- and long-term

follow-up and consent to contact the donor in case of a sec-

ond donation request. Eventually permission for participa-

tion in a research program is needed. For unrelated donors,

guidelines and recommendations are provided by the Foun-

dation for the Accreditation of Cell Therapy & Joint Accred-

itation Committee-ISCT & EBMT (FACT-JACIE) [1], the

World Marrow Donor Association (WMDA) [2], the National

Marrow Donor Program (NMDP) [3] and the Council of Eur-

ope [4]. These intend to safeguard unrelated volunteer

donors and both WMDA, FACT-JACIE and EU formulated

requirements for the quality of the stem cell products. The

European Bone Marrow Transplantation (EBMT), the Center

for International Blood and Marrow Transplant Research

(CIBMTR) and the World Wide Group for Blood and Marrow

Transplantation (WBMT) mainly register patient outcome.

Besides, often national guidelines are available. G-CSF for

Correspondence: A. Brand, Sanquin Blood Supply, Plesmanlaan 1a, 2333BZ Leiden, the Netherlandsemail: [email protected]

ISBT Science Series (2011) 6, 160–164

STATE OF THE ART 3D-S11 ª 2011 The Author(s).ISBT Science Series ª 2011 International Society of Blood Transfusion

160

healthy donors is still an experimental treatment and sub-

ject for review by institutional review boards. The 3rd edi-

tion of the EU guide [5] prescribes that all living donors of

organs, tissues and cells must be registered and offered life-

long follow-up; this applies to related and unrelated

donors. All these organizations and registries offer their

expertise and experience or have already installed subcom-

mittees to give recommendations and advices to safeguard

related donors [6]. However, in practice for related donors

often local ⁄ hospital-based policies are in use.

Donor recruitment

For obvious reasons the recruitment of related donors differs

from that of unrelated donors. Often the patient’s physician,

exploring the possibility of related stem cell transplantation,

initiates donor recruitment. Related donors have a stronger

motivation to donate and may be willing to take certain risks

associated with the procedure, in particular when it concerns

parent to child transplantation. Moreover, for the patient

and the transplant centre (TC) the use of a related donor

means less delay and lower costs. An important ethical ques-

tion is whether and to which extend the responsible physi-

cian honours the wish of the donor and the TC. The Ethics

and Clinical working groups of the WMDA recommends that

a member of the transplant team not involved in the care of

the patient should fulfil the donor advocate role [7].

Although related stem cell donor recruitment is not a

voluntary process, the procedure to guide and protect

the donor’s interest can be better safeguarded by a

knowledgeable health care person not involved in

care of the patient.

HLA typing

Hospitals treating haemato-oncological patients tend to

refer a patient to a TC when an HLA compatible donor is

available. The WMDA advices to perform an enquiry about

donor health and willingness to donate prior to tissue typ-

ing. This can be done by telephone interview [7].

Information about donor health and willingness to

donate prior to tissue typing may circumvent conflict

of interest situations that may arise once a matched

donor has been identified.

Informed consent procedure

An unrelated donor is offered a choice between BM and

PBSC donation. In case of a related donor often only the

TC’s preferred source of stem cells is explained to the

donor without offering a choice of method of stem cell

donation. The risk for an intravascular catheter, the testing

for transmittable infectious diseases and DNA storage (and

purpose) and the possibility of a subsequent donation

request must be explicitly mentioned in the information

brochure.

The written donor information should mention the

inconveniences and risks of donation procedures

irrespective the TC preference. Testing for transmitta-

ble diseases, medical investigations, research (pur-

poses) should be undersigned by the donor.

Donor eligibility

When a donor has an acceptable HLA match with the

patient and agrees to donate stem cells, a medical evalua-

tion is performed. Detailed selection and rejection criteria

with respect to medical history and medical and laboratory

checks for unrelated donors for BM and PBSC are available.

It is unknown which proportion of related donors are

declared fit for donation, despite ineligibility for unrelated

donation.

Some differences between related and unrelated donors

could have been identified prior to tissue typing, but never-

theless are often neglected and weighted afterwards in the

decision to release a donor as fit for donation. For instance,

for unrelated donors, age between 18 and 60 years is

allowed (WMDA ⁄ NMDP).

For related donors no formal age restriction exists and

this is at the judgement of the physician in charge of the

donor. It has been repeatedly observed that older donors

tend to produce a lower CD34+ cell number requiring fre-

quently more than one leukopheresis as compared to youn-

ger donors [8–11]. Repeated leukopheresis can pose a donor

at increased risks, in particular to deeper and longer throm-

bocytopenia [12]. Another risk factor is the donor body

mass index (BMI), which for unrelated donors may not

exceed 40, whereas such restriction does not exist for

related donors. Adipositas is more often associated with co-

morbidity and the need of intravascular catheters, the latter

enhancing complications.

The use of drugs to treat chronic diseases such as

hypertension, diabetes type 1 or 2, asthmatic bronchitis

are only under strict circumstances allowed for unrelated

donors.

Related donors have a more than twofold higher risk

for haematological malignancies and when older have a

higher risk for cardio-vascular co-morbidity and for the

presence of monoclonal gammopathies of undetermined

significance and of monoclonal B-cell lymphocytosis

[13,14]. In this respect the guidelines intended for unre-

lated donors are not very helpful. For unrelated donors a

bone marrow investigation is not recommended. The

Stem cell donor counseling 161

� 2011 The Author(s).ISBT Science Series � 2011 International Society of Blood Transfusion, ISBT Science Series (2011) 6, 160–164

NMDP requires a limited protein analysis and none of the

other guidelines prescribes a sensitive M-protein detection

technique or peripheral blood flow cytometric analysis.

This aspect regards donor and patient safety. As yet the

(long-term) effect of G-CSF on the behaviour of monoclo-

nal B- and plasma cells is unknown and some centres

consider it prudent to abstain from PBSC in the interest of

the donor and to leave the decision to accept BM from

these donors to the TC. In this respect there is no agree-

ment on donor counselling. Niederwieser suggests deter-

mining M-proteins in both donor and recipient, but does

not advocate BM investigation unless there is a family

history of malignancy [15], others advocate BM aspiration

in all older related donors [16]. Considering the huge

number of allogeneic HSCT performed the last decades,

the reported number of donor derived haematological

malignancies in recipients is low, although this may

increase using more sensitive techniques to detect donor

derived cells and with increase of aged donor ⁄ recipient

pairs [17]. Obviously with older age the chance for occult

malignancy increases. It has been reported that recipients

of HSCT from donors who developed cancer after stem

cell donation are associated with a higher relapse rate in

the recipient [18].

Organizations, responsible to protect unrelated

donors, have a zero-risk policy and give strict guide-

lines for their (accredited) Donor Collection Centres.

There are no consensus recommendations to counsel

related donors to detect (occult) pathology and on

the decision to defer the donor. Although, all advices

recommend that the physician responsible for risk

assessment of related donors is not involved in the

care of the patient, this physician cannot rely on

guidelines.

Inconvenience, burden, (S)AE and reporting

A Cochrane analysis, based on six trials comprising 807

donors, compared BM and PBSC donation on the inci-

dence of short term pain and psychological morbidity

[19]. In case of PBSC donation the burden was most

prominent prior, and for BM donation after, the collec-

tion. The authors conclude that the study was of limited

value given lack of uniform QoL evaluations and long-

term follow-up. As yet, both PBSC and BM donation are

considered as safe procedures with a low incidence of

life-threatening events. However, potentially dangerous

situations may be more frequent in PBSC donation. For

instance a 10% enlargement of the spleen is observed in

all donors [20]. Increase by more than 20% was observed

in one-third of the donors, returning to base levels after

3–7 days. In contrast to animal studies the degree of

spleen enlargement in humans is not clearly related to

white blood cell count, race, gender or age, but the study

cohorts are small [20,21]. Other frequent, sub-clinical find-

ings are thrombocytopenia up to 2 weeks after leukophere-

sis and, up to at least 2 years, persistence of a lower

leucocyte count, albeit without infectious symptoms [22].

Examples of lethal or life-threatening complications of

the PBSC procedure are cardiac arrest, anaphylaxis, acute

lung injury, capillary leak syndrome, rhabdomyolysis, sple-

nic rupture, stroke, thrombotic events and fatal sickle cell

crisis, mostly reported as case reports without a denomina-

tor [23–29].

A large retrospective EBMT study comprises more than

50 000 PBSC and BM donations of which circa 70% by

related donors [30]. Four of five fatalities, all in related

donors, occurred after PBSC donation. Serious adverse

events (SAEs) were reported in 37 donors (10 cardiovascu-

lar, 8 thrombo-embolic events, 5 splenic rupture, 3 bleed-

ing, 2 pulmonary and 8 miscellaneous complications) and

the incidence was twofold higher in (mainly related) PBSC

donors as compared to BM donations. In unrelated donors

no mortality and a lower incidence of life-threatening

events have been reported and adverse events requiring

diagnostic procedures or hospitalization occur in 0Æ5–2%

[31–34].

The last years, the WMDA ⁄ NMDP introduced a report-

ing system of SAERs in unrelated donors [35].The need

for a similar registration system for related donors is

widely recognized in order to come to better risk assess-

ment of related donors. However, besides a few excep-

tions, even at the national levels such registries are not

operative.

Reporting serious events and adverse effects regis-

tries (SAERSs) to registries safeguarding unrelated

stem cell donors is in place. Whereas all organiza-

tions involved in allogeneic HSCT underscore the

need for similar reporting systems for related donors,

this is not operational. A beginning could be to coop-

erate at regional ⁄ national level with the registry for

unrelated donors.

Long-term follow-up

Long-term increased risks of PBSC donation have not been

identified [36,37], but remain of concern, in particular

development of haematological malignancy, solid tumours,

myelodysplasia, vascular and autoimmune diseases. In the

retrospective EBMT study, a follow-up questionnaire

revealed that 20 out of 51 000 donors had developed a hae-

matological malignancy between 4 months and 12 years

post-donation (15 related donors and 5 not reported) [30].

The large unrelated donor registries now collect long-term

162 A. Brand


outcome data of donors in a systematic prospective manner

[33–37].

The WMDA recently suggested a minimum of 10 years

follow-up [31].The EU demands that the (related or unre-

lated) donor is offered life-long follow-up. Besides organi-

zational obstacles, the long-term follow-up of related

donors also implies cost aspects for the TCs. In countries

where the patient’s health care provider pays for donor

costs, a long-term follow-up is not included in this fee.

Long-term follow-up of G-CSF administration to

healthy donors is essential. It may be an option to

explore whether prospective long-term data of

related donors can be collected by national registries

for unrelated donors.

Conclusion

In a thoughtful article Pamphilon and colleagues made up

the state of information to advice a donor on HSC donation

[38]. They conclude there are still lacking data, in particular

for the very young and elder donors. Harmonization of sur-

veillance of related and unrelated donors is the more urgent

because of new developments, e.g. new stem cell mobiliz-

ers, increasing second (and subsequent) donation requests

and the use of paediatric PBSC donors. These advances in

the field of HSCT are posing already new medical and ethi-

cal questions [39,40].

Disclosures

The author declares that there are no potential conflicts of

interest.

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164 A. Brand


uniform examination of stem cell donors

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