Bone Marrow Transplantation

https://doi.org/10.1038/s41409-019-0499-z

REVIEW ARTICLE

The European Society for Blood and Marrow Transplantation (EBMT)

consensus recommendations for donor selection in haploidentical
hematopoietic cell transplantation
Stefan O. Ciurea1 et al.

Received: 3 December 2018 / Revised: 25 January 2019 / Accepted: 20 February 2019

© Springer Nature Limited 2019

Abstract
The number of HLA-haploidentical hematopoietic cell transplants continues to increase worldwide due to recent
improvements in outcomes, allowing more patients with hematological malignancies and non-malignant disorders to
benefit from this procedure and have a chance to cure their disease. Despite these encouraging results, questions remain as
multiple donors are usually available for transplantation, and choosing the best HLA-haploidentical donor for
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transplantation remains a challenge. Several approaches to haploidentical transplantation have been developed over time
and, based on the graft received, can be grouped as follows: T-cell depleted haploidentical transplants, either complete or
partial, or with T-cell replete grafts, performed with post-transplant cyclophosphamide-based graft-versus-host disease
(GVHD) prophylaxis, or G-CSF-primed bone marrow graft and enhanced GVHD prophylaxis. Carefully selecting the
donor can help optimize transplant outcomes for recipients of haploidentical donor transplants. Variables usually
considered in the donor selection include presence of donor-specific antibodies in the recipient, donor age, donor/recipient
gender and ABO combinations, and immunogenic variables, such as natural killer cell alloreactivity or KIR haplotype.
Here we provide a comprehensive review of available evidence for selecting haploidentical donors for transplantation, and
summarize the recommendations from the European Society for Blood and Marrow Transplantation (EBMT) on donor
selection for different transplant platforms.

Introduction complications, such as primary graft failure, delayed

immunologic recovery or graft-versus-host disease (GVHD).
HLA-haploidentical donors are now largely employed for Several platforms have been developed over time using
allogeneic hematopoietic cell transplantation (AHCT) for either a T-cell depleted (TCD) graft (complete or partial
those patients who lack of an HLA-matched donor or need elimination of donor T lymphocytes) [3–6], or T-cell
an urgent allograft. The field of haploidentical hemato- replete (TCR) graft and effective GVHD prevention [using
poietic cell transplantation (HHCT) has grown significantly post-transplantation cyclophosphamide (PTCy) or G-CSF-
over the past decade [1, 2]. According to the 2015 Eur- primed bone marrow graft and enhanced GVHD prophy-
opean Society for Blood and Marrow Transplant (EBMT) laxis] [7, 8]. Following these advances, recent results from
activity survey report, the use of haploidentical donors has multiple studies have shown that HHCT can provide long-
dramatically surged by almost 300% since the year 2005 term survival benefit equivalent to that of HLA-matched
[2]. This significant growth is primarily the result of the donor transplantation [7, 9–19]. Haploidentical donors can
successful development of several novel methods to over- be identified for nearly all patients who require a transplant
come the alloreactivity generated by major donor–recipient [20]. Based on data from the Johns Hopkins, at least 1
human leukocyte antigen (HLA)-disparity, and improve- HLA-haploidentical first-degree relative can be identified in
ments in prevention and treatment of post-transplant more than 95% of patients, and the average number of
haploidentical donors per patient is two or more. In addi-
tion, second degree related donors with a full haplotype
* Stefan O. Ciurea match with the recipient, have been successfully used for
[email protected] transplantation [20]. Consequently, with more than one
Extended author information available on the last page of the article. haploidentical donor usually available for transplantation, a
 S. O. Ciurea et al.

crucial question is which donor can lead to the best trans- activation of a suicide gene included in engineered donor
plant outcomes. lymphocytes [35].
In this review, a panel of members of the European
Society for Blood and Marrow Transplantation (EBMT) Selective alpha-beta T cells depletion
and affiliates provide a comprehensive analysis of avail-
able data regarding outcomes of haploidentical transplants The αβ T-cell receptor-positive T cells has been recog-
based on different donor characteristics and summarize nized as the T cell subset mainly responsible for the
recommendations regarding selection of best HLA- occurrence of GVHD [36], while innate-like γδ T cells
haploidentical donors for different haploidentical trans- may provide an important contribution to control oppor-
plant platforms. tunistic infections and to exert an anti-tumor effect,
without inducing GVHD. Therefore, selective depletion
of αβ T-cell receptor-positive T cells, in combination with
Haploidentical donor transplant platforms removal of CD19 + B cells from the graft for reducing the
incidence of EBV-related post-transplant lymphoproli-
To date, several methods have been developed and suc- ferative disorders (EBV-PTLD) was found to prevent
cessfully used to control bi-directional alloreactivity from GVHD. This method, primarily used in pediatric popu-
a major HLA-disparity between the donor and the reci- lation, spares γδ T-cell receptor-positive T cells and nat-
pient in HHCT, such as multiple approaches using ex vivo ural killer (NK) cells, is providing anti-tumor immunity
T-cell depletion [3–6, 21–23], either complete or partial, and may help facilitate immune reconstitution post-
with or without T cell addback, as well as TCR (unma- transplant [5, 37]. Bertaina and colleagues recently
nipulated) haploidentical transplants with post-transplant reported updated data in pediatric patients with acute
high-dose cyclophosphamide [9, 24, 25], or G-CSF/anti- leukemia and showed that αβ TCD HHCT was associated
thymocyte globulin (ATG)-based GVHD prevention with a low incidence of acute and chronic GVHD, as well
[7, 8, 15–17, 26–28]. as better survival compared with unrelated donor trans-
plants, in particular when the donor showed 1 or more
T cell depleted haploidentical transplantation HLA-disparity with the recipient [38].

T-cell depletion has been used to minimize morbidity and TCR (unmanipulated) haploidentical transplantation
mortality associated with GVHD. Unfortunately, the
complete removal of T cells from the graft has been To avoid complexity and cost associated with an ex vivo
shown to be associated with an increased risk of graft manipulation of T cells, several platforms of HHCT using
failure, delay in immunologic reconstitution post-trans- TCR graft with intensified post-transplant immunosup-
plant, and, in most studies, disease relapse [3, 23, 29–32]. pression have been developed with promising results. These
Consequently, several novel graft manipulation techni- are widely adopted as TCR HHCT platforms.
ques have been developed to compensate for these
limitations and improve immune reconstitution and graft- Post-transplantation cyclophosphamide
versus-tumor (GVT) effect, while limiting the develop-
ment of GVHD. Since the initial reports suggesting that high-dose cyclo-
phosphamide given after AHCT could induce immunologic
Ex vivo T cell depleted haploidentical transplant with T cell tolerance and suppress GVHD without causing global
addback immunosuppression or graft failure [7, 39–42], several
groups have successfully translated this approach into
To facilitate engraftment and immune reconstitution clinical practice [43, 44]. The main mechanism by which
T-cell addback has been used by several groups. Infusion PTCy can induce immune tolerance lays on the selective
of conventional T cells along with regulatory cells (Tregs) elimination of host and donor alloreactive T cells, while
[4] or of donor T cells genetically modified with a suicide sparing hematopoietic progenitor cells and regulatory
gene has been shown to partially compensate for the T cells. The use of PTCy overcomes the need for extensive
limitations associated with complete T-cell depletion host and donor T-cell depletion to achieve sustained
[21, 33, 34]. Infusion of sufficient donor T cells may engraftment and effectively control GVHD, respectively, in
contribute to antiviral and anti-tumor responses, while HLA-partially mismatched AHCT, and has become the
GVHD was prevented by either Tregs [4] or photo- most common method used for GVHD prophylaxis in TCR
depletion of alloreactive T cells [6] or regulated by HHCT [7].
The European Society for Blood and Marrow Transplantation (EBMT) consensus recommendations for donor. . .

GCSF-primed bone marrow and enhanced ATG-based GVHD [47–57]. The ability of DSAs to cause primary graft failure
prophylaxis seems to depend on both antibody levels and activation of
the complement system. The MDACC group demonstrated
The group from Peking University first established HHCT that DSAs that activate the complement system, detected
based on G-CSF-primed bone marrow and peripheral blood by the c1q assay, associate with high antibody levels and
graft and intensified, ATG-based GVHD prophylaxis with a very high likelihood of developing graft rejection,
cyclosporine, mycophenolate mofetil, methotrexate and ATG underlining the importance of antibody detection prior
[8, 15–17, 26–28]. Results obtained in both benign diseases to HHCT [48]. Considering these evidences, EBMT now
and hematologic malignancies showed that the Beijing recommends routine testing for DSAs before choosing
Protocol can provide comparable outcomes to those of haploidentical donors for transplantation. Using hemato-
HLA-identical sibling donor or unrelated donor transplanta- poietic stem cells from a donor without the corresponding
tion [15–17, 26], suggesting a strong graft-versus-leukemia HLA antigens is an ideal option for a recipient with HLA
effect, while a higher incidence of chronic GVHD has been antibodies. However, if there are no such donors available,
observed. Although primarily used in China, other centers in recipients with DSAs should undergo desensitization treat-
Asia and Europe have adopted this approach [45, 46]. ment prior to transplantation to prevent graft failure. Current
All these HHCT platforms have been shown to be approaches have been detailed recently in the recent EBMT
associated with very good outcomes and allow HHCT to be consensus guidelines for detection and treatment of patients
safely performed. However, differences in outcomes have with DSAs in HHCT [58].
been observed based on various donor types and careful
selecting donors may further improve these outcomes. In Donor age
addition, differences in the cost associated with different
platforms and resource utilization remains the area unmet Although donor age does not appear to be a limitation for
need and will need to be explored in the future. the AHCT in HLA-matched transplants, transplantation
using stem cells from a younger donor is strongly associated
Donor characteristics influencing outcomes of with a lower incidence of both acute and chronic GVHD, as
haploidentical stem cell transplantation well as with better survival [59–61]. The benefit of using a
younger donor has been confirmed both in TCD and TCR
Donor-specific anti-HLA antibodies HHCT. González-Vicent et al. showed an improved
immune recovery, less acute GVHD, lower non-relapse
Several studies have clearly confirmed the association of mortality (NRM) and better disease-free survival (DFS)
preformed donor-specific anti-HLA antibodies (DSAs) and when using younger donors for pediatric patients with high-
the occurrence of primary graft failure in patients receiving risk leukemia receiving CD3/CD19 and TCRαb+/CD19
AHCT, in particular in HLA-mismatched transplantation TCD HHCT [62]. In TCR HHCT, donor age has also been
[47–50]. In HHCT, this issue can be more challenging shown to influence outcomes of transplantation. Using the
especially in the child donor to mother recipient setting, Beijing protocol, Wang et al. [27] found that donors
since the recipient might be allosensitized and form anti- younger than 30 years were significantly associated with
bodies against the non-shared donor’s HLA antigens during lower NRM and better survival compared with older
pregnancy [48]. The incidence of DSAs in HHCT ranges donors. The impact of donor age seems to be more relevant
between ~10–21%, being higher in females compared with in older than in younger HHCT recipients. The most recent
male recipients [47–50]. A study from MD Anderson report on acute leukemia patients receiving TCR HHCT
Cancer Center (MDACC) reported outcomes of 122 conducted by the Acute Leukemia Working Party (ALWP)
patients treated with both TCD and TCR HHCT, and of the EBMT demonstrated an increased NRM, inferior
showed a high incidence of DSAs (18%) and a strong leukemia-free survival (LFS), overall survival (OS) and
association with primary graft failure. Moreover, the time to GVHD-free, relapse-free survival (GRFS) when patients
engraftment was significantly delayed in patients with over the age of 40 were transplanted using stem cells from
DSAs [48]. Likewise, Yoshihara and colleagues revealed an older donor, whereas donor age did not predict transplant
that a high level of DSAs (>5000 MFI) was the only sig- outcomes in recipients younger than 40 years [63]. Like-
nificant risk factor for graft failure in recipients of unma- wise, Ciurea et al. found that younger donor age (</=40
nipulated HHCT [49]. Beside primary graft failure and years) was an independent predictor for better OS in older
delayed engraftment, the development of DSAs was also patients (>/=55 years) with AML and MDS receiving
found to be associated with primary poor graft function HHCT using PTCy for GVHD prophylaxis [64].
[50], and has negative impact survival post-transplant, not Although results from two other retrospective studies of
only in HHCT but also in other alternative donor transplants HHCT with PTCy platform did not show a significant
 S. O. Ciurea et al.

impact of donor age on transplant outcomes [65, 66], using relationship (mother donor) rather than donor gender has a
a younger donor might provide additional benefits, includ- stronger influence on transplant outcomes.
ing better CD34+ cell yield especially with a BM graft [67]
and lower likelihood of clonal hematopoiesis, which can Donor relationship and non-inherited maternal and
increase the risk of developing hematologic malignancies paternal antigens (NIMA/NIPA)
later in life in recipients of stem cells from older donors
[68]. Moreover, younger donors are more likely to be The effects of donor relationship on HHCT outcomes have
physically fit and better tolerate the stem cell collection been investigated in several studies [27, 65, 66, 73].
procedure and ensure that the procedure is perfectly safe for Focusing on TCR HHCT with PTCy, Solomon et al. [65]
the donor. found that a parent donor (either maternal or paternal)
resulted into a significantly higher risk of relapse and lower
Donor gender survival compared with a sibling or child donor, and the
impact of donor relationship on outcomes persisted after
It has been hypothesized that minor histocompatibility adjusting for donor age. Moreover, a recent study by
antigens (mHAgs) encoded on Y chromosome (H-Y) can be McCurdy and colleagues revealed a significantly higher risk
recognized by female donor T lymphocytes and may be of graft failure in patients who received haploidentical grafts
responsible to an increased risk of GVHD and NRM in a from their parent, while graft failure risk was not different
setting of female donor to male recipient transplantation. between sibling and offspring donors [66]. Taken together,
However, this risk can be counterbalanced by the benefit of these data suggest that an offspring or sibling donor is
increasing graft-versus-tumor effect and a lower risk of preferred over a parent donor for HHCT. However, con-
relapse, since H-Y antigen can also be expressed on tumor flicting results were seen when comparing outcomes with
cells. This is particularly important in HLA-matched different parental donors.
transplantation when minor HLAs are the main target of It has been speculated that the benefit of mother-to-
donor alloreactive T cells [69–71]. However, an adverse child transplantation may be the result of the maternal
impact of using a female donor to a male recipient seems to immune system exposure to paternal antigens from fetus
be more pronounced in HLA-haplotype matched trans- during pregnancy, which can enhance graft-versus-tumor
plants. Kasamon et al. found that transplantation using a effect in a mother graft [69]. Moreover, child exposure to
female donor to a male recipient resulted in lower survival maternal antigens during in utero development or nursing
after TCR HHCT using PTCy for GVHD prophylaxis. can lead to a lifelong immunologic tolerance, preventing
Although the negative impact on survival was not entirely alloimmunization against maternal HLA antigens that the
accounted for by a significantly increased risk of GVHD, patient did not inherit such as in a setting of mother to
this finding still suggests that a male donor should be a child or non-inherited maternal antigens (NIMA) mis-
preferred choice when selecting haploidentical donor for a matched sibling donor transplants [74, 75]. This evidence
male recipient, at least in a HHCT with PTCy platform [44]. was first observed in kidney transplants; indeed
The effect of donor gender on HHCT outcomes has also kidney graft from haploidentical sibling mismatched
been explored outside the female to male transplant setting. for NIMA had similar graft survival with graft from an
Using the Beijing protocol of unmanipulated HHCT, Wang HLA-identical sibling donor [76]. In TCR HHCT, some
et al. showed that transplantation using a female donor was studies have shown a lower risk of GVHD and TRM in
associated with a higher rate of severe acute GVHD, NRM patients receiving stem cell graft from a NIMA mis-
and inferior survival. However, this negative impact was matched sibling donor than from a non-inherited paternal
lost when mother donors were excluded from the analysis antigens (NIPA) mismatched sibling [27, 73, 77, 78]. The
[27]. Mothers seem to be a poor donor choice for child Chinese group found that NIMA mismatched sibling
recipients when using the Beijing protocol of HHCT as it donor was associated with less acute GVHD when com-
was shown to be associated with higher rate of GVHD, pared with NIPA mismatched sibling. Althogh NRM and
NRM, and poor survival. In contrast, Stern et al. found that survival were not influenced by NIMA/NIPA mismatch-
relapse rate and NRM were lower, resulting into better EFS ing, NIMA mismatched siblings may be preferred over
in acute leukemia young patients who received TCD HHCT NIPA mismatched ones when using the Beijing protocol,
from a mother than from a father donor. The protective at least to avoid the higher risk of acute GVHD [27].
effect from using a mother donor was seen in both female However, whether this immunologic tolerance is asso-
and male recipients, while in a control cohort of patients ciated with better outcomes in TCD and TCR HHCT
who received transplants from haploidentical siblings, using PTCy remains unclear.
donor sex had no influence on outcome [72]. These Another aspect is the use of one-haplotype match
apparently conflicting results suggest that perhaps donor second-degree related donors, especially younger donors, if
The European Society for Blood and Marrow Transplantation (EBMT) consensus recommendations for donor. . .

no first degree related donor exists or the donor is too old or mismatched graft for TCR haploidentical donor transplants
too young for donation. The Hopkins group has recently with PTCy. A peripheral blood graft is preferred in case of
showed feasibility of using second-degree related donors transplant from a major ABO incompatible donor when
with their non-myeloablative PTCy-based protocol [79]. other donors are not available.
Correspondingly, the Chinese group reported comparable
survival outcome among recipients of a collateral and NK cell alloreactivity
immediate haploidentical family donor using their trans-
plant platform [80]. NK cells are an important component of human innate
immunity, recover early post-transplant and provide antitumor
ABO compatibility and antiviral effects during the period of severe lymphopenia.
NK cell alloreactivity can potentially provide better antitumor
The impact of donor–recipient ABO compatibility on effect, as documented by lower relapse rates and better sur-
transplant outcomes has been evaluated in different trans- vival in patients with higher NK cell numbers early post-
plant settings, and has shown different results [81–84]. In transplant [88, 89]. Cytotoxic activity of NK cells is mediated
HLA matched related donor transplants, results from a primarily by a balance between inhibitory and activating
meta-analysis revealed that ABO mismatched transplanta- receptors expressed on the cell surface, the former being
tion did not impact overall survival. However, minor and bi- mainly accounted by killer-cell immunoglobulin-like recep-
directional ABO mismatched graft was associated with poor tors (KIRs) that recognize HLA class I molecules on surface
overall survival in patients receiving unrelated AHCT [81]. of target cells. However, understanding of the biological
Additionally, the impact of ABO mismatch on transplant determinants of anti-tumor effects of NK cells remains
outcomes appears to be different in some studies, when incomplete and conflicting evidence exists in the transplan-
using peripheral blood or bone marrow stem cell source. tation literature. Several models of donor–recipient NK cell
Logan et al., using data from Stanford University and the alloreactivity have been proposed and studied in different
Center for International Blood and Marrow Transplant settings of AHCT especially in HHCT, which may explain, at
Research (CIBMTR), showed that ABO minor mismatched least in part, different results. The KIR ligand incompatibility
transplantation was associated with higher NRM and (ligand–ligand) model, in which NK cells will react and kill
negatively affected survival only in patients receiving bone host cells that lack the HLA class I ligand(s) for inhibitory
marrow but not peripheral blood stem cell grafts [85]. KIR, was first proposed by the Perugia group [90]. Using this
In HHCT setting, a large retrospective study from the model in a clinical study of TCD HHCT, Ruggeri et al. [91]
ALWP of the EBMT demonstrated inferior engraftment rate found that alloreactive NK cells in the graft-versus-host
in HHCT recipients who received a major ABO mismatch direction helped promote engraftment and graft-versus-tumor
graft compared with ABO matched HHCT, whereas effect, resulted in reduced risk of leukemia relapse and better
bi-directional ABO mismatching was found to be associated survival in adults with acute myeloid leukemia (AML)
with a significantly increased risk of grade II–IV acute without increasing the rate of GVHD. Leung et al. proposed
GVHD. Patients with major ABO mismatched grafts had an alternative model called the receptor-ligand or missing-self
decreased OS only when bone marrow-derived stem cell model, according to which NK cells will react if at least one
grafts were used, while ABO compatibility had no impact in KIR gene expressed in the donor’s NK cell repertoire does not
patients who received peripheral blood grafts [86], in recognize any of the HLA molecules in the recipient’s ligand
agreement with findings from the above-mentioned study repertoire. In a study of pediatric patients with high-risk
by Logan et al. [85]. These results suggest that, at least in leukemia given CD34+ selected haploidentical graft, the
TCR HHCT with PTCy, patients with major ABO mis- authors found that NK alloreactivity based on this model
matched grafts should receive PB stem cells. more accurately predicted the lower risk of leukemia relapse
In addition to an adverse effect on survival, major ABO than the ligand–ligand model [92].
mismatch can also lead to hemolytic anemia, delayed red KIR genes are organized in haplotypes and, although
cell engraftment as well as pure red cell aplasia. Therefore a more than 80 different KIR haplotypes have been reported,
major ABO mismatched graft requires graft manipulation to two distinct groups (termed A and B) have been identified.
decrease the amount of incompatible RBCs and to prevent The A haplotypes (found in around 20–25% of subjects) are
hemolytic complications. This process could reduce the characterized by a fixed number of KIR genes including
number of mononuclear cells, CD34+ and total nucleated several inhibitory KIR (KIR3DL3, KIR2DL3, KIR2DL1,
cells in a bone marrow graft and perhaps negatively affect KIR2DL4, KIR3DL1, and KIR3DL2), only one activating
transplant outcomes [87]. KIR (KIR2DS4), and the two pseudogenes (KIR2DP1 and
In summary, the available evidence supports the use of KIR3DP1). In contrast, B haplotypes have variable and
an ABO compatible over a minor and/or a major ABO greater gene content, and are characterized by the presence
 S. O. Ciurea et al.

of at least one of the following genes: KIR2DS2, KIR2DL2, addition, the Japanese group reported a similar relapse rate,
KIR2DL5B, KIR3DS1, KIR2DL5A, KIR2DS3, KIR2DS5, NRM and OS between TCR HHCT patients receiving graft
and KIR2DS1. All individuals can be categorized as having from either a KIR haplotype A/A or B/x donor, while using
1 of 2 KIR genotypes: homozygous group A KIR haplotype a donor with KIR haplotype B/x was associated with a
(A/A) or having at least one group B haplotype (B/x). higher incidence of severe acute GVHD [100]. The reasons
Michealis et al. [93] demonstrated a significantly reduced for these conflicting results perhaps come from the hetero-
incidence of relapse in recipients of TCD HHCT receiving geneity in transplant protocols employed and differences in
stem cell graft from a KIR haplotype Bx donor when inclusion criteria, as well as model used to describe NK cell
compared with haplotype AA donor. A similar result was alloreactivity.
reported in a study of TCD HHCT for pediatric patients However, taken together, a donor with alloreactive NK
with ALL, confirming the survival benefit of using donor cells appears to be a preferred choice for patients receiving
with KIR B haplotype [94, 95]. Mancusi and colleagues TCD HHCT, while more studies are needed to clarify this
also showed a reduction of NRM in patients transplanted issue in TCR HHCT, especially when PTCy-based GVHD
using a KIR B haplotype donor in comparison to those prophylaxis is employed. Recent work by Russo et al. [88]
given a KIR A haplotype donor HHCT [92]. All above- suggests that the majority of mature NK cells infused with
mentioned studies showing the benefit of NK alloreactivity unmanipulated grafts are lost upon PTCy administration
using different models and of KIR B haplotype donors were likely resulting in the blunting NK cell alloreactivity in this
conducted in TCD HHCT platforms, where donor T cells do setting.
not obscure the importance of the role played by NK cells,
whereas the benefit of donor–recipient NK alloreactivity in Donor–recipient CMV serostatus
TCR HHCT setting remains unclear since conflicting results
have been recently reported. Solomon and colleagues CMV infection/reactivation is a common complication after
showed that KIR mismatch using receptor-ligand model and AHCT, which sometimes can be fatal and may negatively
group B KIR haplotype with the presence of KIR2DS2 were influence post-transplant outcomes [101]. Although the
associated with reduced relapse rate and improvements in incidence of symptomatic CMV diseases has decreased
survival post-transplant [65]. Likewise, another recent study significantly because of preemptive therapy [102–104], this
by Wanquet et al. revealed that the presence of donor- infectious complication still develops in a significant pro-
recipient KIR-ligand mismatch was associated with a lower portion of all AHCT recipients, and it is influenced partly
incidence of relapse, which led to a significantly improved by the mismatch between donor and recipient CMV ser-
progression-free survival (PFS) and a trend for improved ostatus [105]. This issue may be more concerning in HHCT
OS, while rate of acute and chronic GVHD did not sig- as more patients reactivate CMV in the setting of an HLA-
nificantly increase. However, this benefit was seen only in a disparate donor transplant, and more potent immunosup-
subgroup of patients with active disease, but not in patients pression is needed to overcome the HLA barrier. Interest-
who were in remission at time of transplant [96]. Also, ingly, the use of a CMV positive donor in AHCT has been
Symons et al. showed that recipients of inhibitory KIR shown to prevent CMV reactivation and improve outcome
gene-mismatched grafts had an improved OS, EFS and when administered to a CMV positive recipient [101, 106].
relapse rate in TCR HHCT with PTCy. Moreover, the This donor–recipient combination may be particularly
authors also found that patients homozygous for the KIR A important when used in the context of transplant strategies
haplotype had an improved OS, EFS, and NRM if their to eliminate T cells as encountered in TCD HHCT.
donor expressed at least one KIR B haplotype [97]. Col- Indeed, the immediate availability of T cells with anti-CMV
lectively, results from these studies revealed beneficial reactivity may be useful to overcome CMV viral load early
effects of NK cell alloreactivity, suggesting that selection of post-transplant when T cells are only present in low
donors based upon NK cell alloreactivity may be warranted. numbers.
On the contrary, a study by the EBMT group demonstrated However, conflicting results on the impact of donor–
that KIR ligand mismatching described by “the ligand- recipient CMV serostatus match on TCR HHCT outcomes
ligand” model was associated with a trend for higher relapse have been reported to date. In a recent study, Solomon et al.
and significantly lower OS in recipients of TCR HHCT [65] found that donor CMV-negative serostatus was asso-
[98]. In accordance with these findings, Huang et al. [99] ciated with inferior survival, while a protective effect of a
demonstrated that use of donors with KIR match rather than CMV-seropositive donor was limited to CMV-seropositive
mismatch was associated with an improved NK-cell recipients. On the contrary, two retrospective studies failed
reconstitution quantitatively and functionally, resulting in to demonstrate any significant clinical impact of donor
a lower incidence of GVHD, relapse rate and a better sur- CMV serostatus after TCR HHCT [66, 107]. Moreover, a
vival in the setting of HHCT using the Beijing protocol. In report restricted to 983 CMV seropositive recipients of TCR
The European Society for Blood and Marrow Transplantation (EBMT) consensus recommendations for donor. . .

HHCT with PTCy from the EBMT group revealed that psychological evaluation and will necessitate an increased
donor CMV serostatus did not influence NRM or OS [108]. training of caregiver teams. With the shift from unrelated
Due to these conflicting results, it is difficult to conclude to family donors, family dynamics and dormant tensions
and make recommendations on TCR haploidentical donor may be reactivated. Indeed, the transplant is very often
selection based on donor–recipient CMV serostatus. experienced by the patient as an upheaval, not just in his
or her own body, but also in relation to others, especially
Degree of HLA-mismatch the nuclear family. From the donor’s point of view, giving
is a gift of self and an investment, especially in time but
Higher degree of HLA-mismatch between donor and reci- also symbolically. The challenge of choosing between
pient has been associated with a significantly increased several potential haploidentical related donors—mother,
TRM and poor survival after AHCT from both related and father, brother, sister or cousin, niece, nephew—will open
unrelated donors using conventional GVHD prophylaxis up particularly complex elaborations and exchanges:
[109–111]. However, the adverse effect of donor–recipient teams will have to explain their choice and justify them. It
HLA disparity appears to be reduced with the will be important for the transplant team to establish a
new approaches used for GVHD prophylaxis in HHCT. personal relationship with the donor and carefully/cau-
Kasamon and colleagues found that, in TCR HHCT using tiously manage the psychological repercussions of com-
non-myeloablative conditioning with PTCy for GVHD plications occurring either during or after the transplant,
prophylaxis, the presence of a greater number of HLA especially in case of failure. Children who die of com-
mismatches at either the antigen or allele level did not plications of a transplant of stem cells from their mother
worsen overall outcomes with regards to GVHD, relapse or a father, or patients who must live with chronic GVHD
and NRM. Besides that, having three or more HLA- after a transplant of their child’s cells might become
mismatches in the host-versus-graft (HVG) direction was common but new situations and inevitably, Oedipal
associated with superior EFS [44]. These results suggest updates will insistently color the dynamics of this type of
that greater HLA mismatch between the donor and the transplant.
recipient is not associated with worse outcomes in HHCT. One of the major aspects regarding a minor donor
Similar findings were also reported in other studies of TCR for parents or siblings as recipients is the potential
HHCT using both PTCy and with the Beijing protocol. In conflict of interest related to such donation. In this cir-
these studies, the total number of HLA mismatches either cumstance, several ethical challenging questions arise
bidirectional or in the GVH/HVG direction did not influ- such as “are parents capable to make fair decisions
ence transplant outcomes [27, 65, 112–114]. Regarding the regarding the donation in the best interests of their donor
specific HLA allele and antigen mismatch, the most recent child, and not determined by interests of themselves or
data from the EBMT demonstrated that an antigenic but not other family members?” or “should mature and immature
allelic mismatch at the HLA-DRB1 locus was an indepen- children be treated differently regarding consent or assent
dent risk factor for severe acute GVHD in PTCy, but not in to donate?” While regulations regarding minor donors
ATG regimens, suggesting that the role of HLA matching in differ between countries and regions, it is fundamental
HHCT might be modulated by GVHD prophylaxis [113]. that practice recommendations and standards focusing on
Other studies found that the presence of an HLA-DRB1 medical and psychological assessments and follow-up
mismatch in the graft-versus-host direction and HLA-DPB1 care for the donors are established by multi-disciplinary
non-permissive mismatch were associated with an teams to ensure that donor’s best interests in case of
improvement in survival [65]. children are fully considered and acted upon. According
Taken together, these data do not support selection of to the FACT-JACIE international standards, a donor
haploidentical donors based on the degree of HLA mis- advocate different from the transplant recipient’s primary
match. More data are needed to clarify the impact of spe- treating physician should be available to represent
cific HLA antigens/alleles on outcomes of HHCT as allogeneic donors who are minors or who are mentally
conflicting results have been reported to date. incapacitated, to help the donor understand the risks
and benefits of donation, ensure that the consent is
Special considerations regarding using minors as made without time pressure and with full information,
donors for haploidentical transplantation— and to aid in the resolution of subsequent problems
Psychological aspects and potential conflict of both physically and psychologically [115]. In cases
interest of using children as donors, in addition to evaluation by
a Pediatrician, a medical ethicist should probably be
It is clear that the increasing use of haploidentical donors involved to provide an unbiased assessment and help
will have to be accompanied by a strengthening of the facilitation the donation.
 S. O. Ciurea et al.

Table 1 Summary of
T cell depleted haploidentical transplants T cell replete haploidentical transplants
characteristics considered in
selecting donors for -No DSAs (MFI < 1000) -No DSAs (MFI < 1000)
haploidentical hematopoietic
cell transplantation -NK cell alloreactive donor -Younger donor over older donor
-Younger donor over older donor -Male donor for a male recipient
-Male donor for a male recipient -Sibling or offspring donor over parent donor
-First degree relative over second degree HLA -Between parent donors, father is preferred over mother
half-matched donor donor
-Between parent donors, mother is preferred -ABO matched is preferred to minor ABO mismatch to
over father major ABO mismatched donor
-ABO matched donor -Donor with KIR ligand match for a recipient of HHCTa
-CMV seropositive donor for CMV -First degree relative over second degree HLA half-
seropositive recipients matched donora
-Donor with NIMA mismatch over NIPA mismatch for a
recipient of HHCTa
DSA donor-specific anti-HLA antibodies, NK natural killer cells, HHCT haploidentical hematopoietic cell
transplantation, NIMA non-inherited maternal antigens, ABO blood group
a
Conclusive data available for the TCR Haploidentical transplants with GCSF-primed bone marrow and
enhanced GVHD prophylaxis (Beijing protocol)

Conclusions and summary 4. A male donor for a male recipient

recommendations 5. First degree relative over second degree HLA half-
matched donor
It is now clear that HHCT can provide the chance of a cure 6. Between parent donors, mother is preferred over father
for many patients who lack an HLA-matched donor, 7. ABO matched donor
including especially ethnic minorities, with similar results to 8. CMV seropositive donor for CMV seropositive
those reported using an HLA-matched donor. This devel- recipients
opment has become one of the most important success
stories in transplantation and probably in modern medicine.
Among several factors responsible for the success of HHCT, Summary of preferred donor characteristics
donor considerations are particularly important when more for T cell replete haploidentical transplants
than one potential HLA-haploidentical donor might be
available for transplantation, and multiple donor factors can
impact transplant outcomes. Therefore, the EBMT has 1. For a recipient with DSAs, a donor without correspond-
formed an expert panel charged to summarize the recom- ing HLA antigen is preferred
mendations for selection of a haploidentical donors based on 2. Younger donor over older donor
available published data for all HHCT platforms used in 3. A male donor for a male recipient
clinical practice (Table 1). Although it is likely that this field 4. Sibling or offspring donor over parent donor
will further evolve in the future, enough work has been done 5. Between parent donors, father is preferred over mother
to date to provide a comprehensive overview of this topic donor
right now. Below we have summarized our recommenda- 6. ABO matched to minor ABO mismatch to major ABO
tions in a still preliminary order of importance. mismatched donor
7. First degree relative over second degree HLA half-
matched donor (Beijing protocol)
Summary of preferred donor characteristics 8. Donor with KIR ligand match for a recipient of HHCT
for T-cell depleted haploidentical (Beijing protocol)
transplants 9. Donor with NIMA mismatch over NIPA mismatch for a
recipient of HHCT (Beijing protocol)

1. For a recipient with DSAs, a donor without correspond-

Compliance with ethical standards
ing HLA antigen is preferred
2. NK cell alloreactive donor if available Conflict of interest The authors declare that they have no conflict of
3. Younger donor over older donor interest.
The European Society for Blood and Marrow Transplantation (EBMT) consensus recommendations for donor. . .

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Affiliations

Stefan O. Ciurea1 Monzr M. Al Malki2 Piyanuch Kongtim3 Ephraim J. Fuchs4 Leo Luznik4 Xiao-Jun Huang 5
● ● ● ● ● ●

Fabio Ciceri6 Franco Locatelli7 Franco Aversa8 Luca Castagna9 Andrea Bacigalupo10 Massimo Martelli11
● ● ● ● ● ●

Didier Blaise 12 Patrick Ben Soussan13 Yolande Arnault13 Rupert Handgretinger14 Denis-Claude Roy15
● ● ● ● ●

Paul V. O’Donnell16 Asad Bashey17 Scott Solomon17 Rizwan Romee18 Jorge Gayoso19 Hillard M. Lazarus20
● ● ● ● ● ●

Karen Ballen21 Bipin N. Savani22 Mohamad Mohty23,24 Arnon Nagler24,25

● ● ●

1
The University of Texas MD Anderson Cancer Center, Therapie Cellulaire, Aix Marseille Univ, Inserm, CNRS, CRCM,
Houston, TX, USA Marseille, France
2 13
Department of Hematology and HCT, City of Hope National Departement de Psychologie Clinique, Institut Paoli Calmettes,
Medical Center, Duarte, CA, USA Marseille, France
3 14
Department of Medicine, Thammasat University, Department of Hematology and Oncology, Children’s University
Pathumthani, Thailand Hospital, Tubingen, Germany
4 15
Division of Hematologic Malignancies, Sidney Kimmel Blood and Marrow Transplantation Program, Hôpital
Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, Maisonneuve-Rosemont, Université de Montréal, Montreal, QC,
USA Canada
5 16
Institute of Hematology, Peking University People’s Hospital, Massachusetts General Hospital Cancer Center, Boston, MA, USA
Beijing, China 17
BMT Program at Northside Hospital, Atlanta, GA, USA
6
Hematology and BMT Unit, San Raffaele Scientific Institute, 18
Milan, Italy Dana Farber Cancer Institute, Boston, MA, USA
19
7
Department of Pediatric Hematology and Oncology, IRCCS Facultad de Medicina Universidad Complutense, HGU Gregorio
Ospedale Pediatrico Bambino Gesu, University La Sapienza, Maranon, Madrid, Spain
Rome, Italy 20
Case Western Reserve University, Cleveland, OH, USA
8
Hematology and BMT Unit, University of Parma, Parma, Italy 21
University of Virginia Health System, Charlottesville, VA, USA
9
Hematology Department, Humanitas Clinical and Research 22
Vanderbilt University Medical Center, Nashville, TN, USA
Center, Milan, Italy
23
10 Hopital Saint-Antoine, Paris, France
Instituto di Ematologia, Fondazione Policlinico Universitario
Gemelli, IRCCS, Universita’ Cattolica del Sacro Cuore, 24
Acute Leukemia Working Party of the EBMT, Hopital Saint-
Roma, Italy Antoine, Paris, France
11
University of Perugia, Perugia, Italy 25
Hematology Division, Chaim Sheba Medical Center,
12 Tel Hashomer, Israel
Departement D’Hematologie, Programme de Transplantation et de