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What compatibility in 2017 for the haematopoietic stem cell transplantation?
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State of the art
What compatibility in 2017 for the haematopoietic stem cell transplantation? Quelle compatibilité en 2017 pour la greffe de cellules souches hématopoïétiques ? X. Lafarge EFS Aquitaine Limousin, unité Inserm 1035, équipe cellules souches hématopoïétiques normales et leucémiques, place Amélie-Raba-Léon, CS 21010, 33075 Bordeaux cedex, France
Abstract The diversification of potential donors to perform stem cell allografts now enables to propose a compatible graft cell source adapted to the different clinical situations. Transplants with a geno-identical sibling donor, otherwise with the most HLA-compatible unrelated donor, remain the first-line solutions. Alternative transplants allow to graft patients having no donors in international registries, owing to the rarity of their HLA typing. They are carried out with fairly incompatible grafts and are therefore limited by the existence in the recipient of preformed anti-HLA antibodies which predispose to their rejection. The simple prevention of acute Graft-versus-host disease in haplo-identical transplants, as well as the availability of donors, explain why they have very often replaced placental stem cell transplants. These latter remain useful for pediatric patients or in the absence of family donors. © 2017 Elsevier Masson SAS. All rights reserved. Keywords: Immunogenetics; Histocompatibility; HLA; Allograft; Stem cells; Placental blood; Anti-HLA Antibodies
Résumé La diversification des donneurs potentiels pour la réalisation des allogreffes de cellules souches permet désormais de proposer une source cellulaire de greffon compatible adaptée aux différentes situations cliniques. Les greffes avec un donneur géno-identique issu de la fratrie ou à défaut avec un donneur non apparenté le plus HLA-compatible possible, demeurent les solutions de première intention. Les greffes alternatives à celles-ci permettent de greffer les patients n’ayant pas de donneurs sur les registres internationaux en raison de la rareté de leur typage HLA. Elles s’effectuent avec des greffons assez largement incompatibles et par conséquent sont limitées par l’existence chez le receveur d’anticorps anti-HLA préformés qui prédisposent à leur rejet. La prévention aisée post greffe de la réaction du greffon contre l’hôte dans les greffes haplo-identiques, ainsi que la disponibilité des donneurs, expliquent qu’elles aient remplacé très souvent les greffes de cellules souches placentaires. Ces dernières conservent une place pour les patients pédiatriques ou sans donneurs familiaux. © 2017 Elsevier Masson SAS. Tous droits réservés. Mots clés : Immunogénétique ; Histocompatibilité ; HLA ; Allogreffe ; Cellules souches ; Sang placentaire ; Anticorps anti-HLA
1. Introduction Allogeneic haematopoietic stem cells transplantation (HSCT) has become over the last 30 years a major therapeutical approach for numerous haematological diseases and immunodeficiencies, although impaired by numerous complications. Because of its important influence on post-graft clinical
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outcome, human leukocyte antigen (HLA) compatibility became the cornerstone of donor selection. Today, grafts with geno-identical or pheno-identical donors are still the first-line transplants for most clinical teams. If no sibling donors are available and if no acceptable unrelated donors can be found rapidly on registries, mismatched allo-HSCT with haploidentical related donors or with umbilical cord blood (UCB) units constitute a strong alternative. The histocompatibility laboratories must find and propose potential donors the more appropriate to a given situation, in the context of constant
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evolution of patient clinical management and technologies for HLA typing and antibodies determination, according to the accreditation standards edicted by the European Federation of Immunogenetics.
2. Geno-identical donors For patients needing an allo-HSCT, the first step in finding a suitable donor is usually to search HLA geno-identical individuals within the relatives. There are only 4 possible combinations of parental chromosomes in the progeny. As a consequence, there is a theoretical probability of 25% for an individual to have a sibling identical for all HLA genes, including class I to III, and non-classical HLA genes. Consanguinity between patient’s parents, and/or sharing common haplotypes can sometimes lead to identity between the patient and one parent, at least for locis HLA-A, B, C DRB1 and DQB1. Moreover, crossing overs may occur during the gametogenesis in parents, creating a new haplotype in the progeny and decreasing the probability to find an HLA-identical sibling. Monozygotic twins as potential donors, are generally not recruited, because these transplantions have similar results to autologous grafts. Globally, geno-identical sibling donors (SD) represent the source of cells for about one third of all the HSCT performed in France.
3. Marrow unrelated donors Nowadays, unavailability of SD can often be overcome by finding a compatible marrow unrelated donor (MUD) among the international registries. Specifically for patients with high risk of acute myeloid leukemias in primary relapse, HSCT with 10/10 MUD can be even associated to better outcome than with matched SD [1]. Globally, MUD represent the source of HSC for about half of all the graft performed in France. It is generally considered that the average probability for two unrelated individuals to be HLA-matched is about 1/1,000,000. By the end of 2016, more than 29 millions volunteer donors were available worldwide. The probability to find a compatible donor for a given patient exhibits considerable variations, between several hundreds of donors to. . . zero, depending on the frequency of patient’s HLA typing. The next generation of sequencing (NGS) recently introduced in several registries, allows to obtain for new donors a HLA typing at high or 4-digits resolution. This constitutes a great improvement since compatible donors can be identified immediately, whereas for previously registered donors, complementary typing are still required. Before the formal request of HSC collection, a verification of the compatibility must be performed by the laboratory affiliated with the transplant centre [2] on a new blood sample. This requirement is an opportunity to check the donor availability, but explains why finding a MUD is a challenge, in so far as the
time between the diagnosis and the transplantation influences the risk of relapse. 3.1. Molecular basis of HLA mismatches A mismatch (MM) could be defined as an incompatibility between two individuals due to differences in allelic polymorphisms. HLA compatibility can be determined at different levels of resolution [2]: • at 2 digits, the typing roughly corresponds to the antigenic level, i.e. determined by specific antibodies; • high resolution distinguishes alleles differing in the amino acid sequences of the peptide-binding domains (encoded by exons 2 and 3 for class I, by exon 2 for class II). High resolution, as defined by the EFI, requires also to identify/exclude non-expressed alleles, whatever the mechanism of this lack of expression; • 4-digit resolution concerns the whole amino acid sequence of HLA molecule, whatever the polymorphic positions. MM can be permissive (no impact in term of clinical outcome) or not, depending on their nature: MM can be at antigenic level, high or 4-digits resolution. First, MM can be linked to non-expressed (« null ») alleles. These null alleles can be due to polymorphisms situated in exons encoding premature stop codons, or situated in introns and perturbing the excision/splicing mechanisms. Owing to the absence of expression, these individuals must be considered as homozygous for the expressed allele for determining the compatibility. Secondly, MM can lead to different proteins with different functional properties in antigen presentation/protein–protein interactions, depending on the different polymorphisms positions (i.e. which exon). Thirdly, impacts of MM depend on the level of protein expression of each allele. The Next generation Sequencing is now the more informative method concerning the two first points (including in describing new alleles), but protein expression is not routinely evaluated. Endly, if the recipient is homozygous, the heterozygosity in the donor constitutes an acceptable MM in the host versus graft direction, without any real impact on clinical outcome. The exon 1 for HLA genes encodes for the leader peptide resulting from a cleavage after protein biosynthesis. HLA class I leader peptide has the particularity to be loaded by HLA-E molecules [3]. This non-classical HLA molecule is known to inhibit natural killer (NK) cells reactivity via CD94-NKG2A lectin-type NK cells inhibitory receptors. This system constitutes a global surveillance of HLA class I expression. It is not known if amino acid disparities for the peptide leader sequences influence the NK cells inhibition and consequently can generate a cellular response and have an impact on clinical outcome. However, some alleles can display stop codons in exon 1, leading to null alleles (for instance A*68:11N, B*18:17N, B*44:19N, C*03:20N [4]). These alleles are rare: on 13000 typings performed by NGS with OMIXON◦ kits, 2 such new null
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alleles were detected, for HLA-B and HLA-C [5]. These null alleles could not be detected by Sanger-type method, since exon 1 was not classicaly explored by this technique. Premature stop codons in exon 1 could also exist for class II but were never published. Exons 2–3 for class I, and 2 for class II encode for the peptidebinding groove. Consequently, MM are generally considered as non-permissive, except C*03:03 vs. C*03:04 [6], DRB1*11:01 vs. DRB1*11:04 [7], DQB1*03:01 vs. DQB1*03:02 [8] for which cohorts studies of patients have shown no pejorative effect. In contrast, certain incompatibilities must be avoided, particularly those involving a polymorphism located in the position116 of HLA class I molecules, located in site of attachment of peptides in particular for HLA-C and HLA-B [9–16]. Other exons (4–8 for class I; 3–6 for class II) are less polymorphic, and as a result were not systematically explored by the classical HLA typing methods (i.e. SBT, SSP, SSO). The use of NGS enables to detect new polymorphisms, in particular mutations in exon 3 for class II locis [5]. Because they are not implicated directly in the binding to peptides, their impact on the interaction with the T cell receptors might be questionnable. Meanwhile, exon 4 (class I) and 3 (class II) encodes for a domain interacting with CD8 or CD4 molecules, respectively. Therefore, polymorphisms on these exons could impact the global interaction between antigen presenting-cells and T lymphocytes. Functional studies have shown the absence of alloreactivity in case of incompatibilities located out of the peptides binding groove for B*44:02 vs. B*44:27, DRB1*14:01 vs. 14:54 [3,12–14]. Cohorts studies have shown no pejorative effect of certain incompatibilities: DRB1*14:01 vs. DRB1*14:54 [15]. Finally, some studies have shown that a low expression of molecules HLA-C and DP was associated with a decrease in the alloreactivity in HSCT [16–18].
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In case of incompatibility 9/10: • DQB1 incompatibility is preferable [24–30]; • for loci HLA-A, -B, -C, -DRB1: no consensus on the preferential incompatible locus [31–34], no difference between the 4-digits or antigenic level MM [30,32,33]. Others suggest to avoid MM at 4-digits level for the B locus [30,31]. Some advise to favor MM at 4-digits level to the locus C [25,33] but the beneficial impact in these studies is likely related to the effect of permissive incompatibility HLA-C*03:03 vs. *03:04 [6], which is common. If several mismatched donors are possible, it is better to choose a donor: • with a permissive MM and/or out of the peptide-binding domains; • with a MM in the host versus graft direction only (i.e. homozygous recipient/heterozygous donor) Conversely, it is important to avoid non-permissive incompatibilities (position 116 for HLA class I), 3.3.2. Locis DRB3/4/5/DPB1 Several studies propose to avoid the cumulative effect of more than 2 incompatibilities at the loci DRB3/4/5, DQB1 and DPB1 [25,27–30,33,35]. Concerning the HLA-DPB1 compatibility: • for malignant pathologies: if possible avoid MM [37], double MM [36], or non-permissive incompatibilities according to TCE4, even in 10/10 identical transplants [32,36,38,39]; • for non-malignant pathologies: seeking DPB1 identity; failing this, choose a permissive incompatibility [40].
3.2. Impact of other genes Some other genes were shown to impact the clinical outcome of HSCT, for instance MHC class I chain-related gene A [19], or killer cells Ig-like receptors. These interesting findings need to be confirmed and evaluated prospectively, but today no European nor national guidelines recommend using the typing of these genes to select donors. 3.3. Recommendations In 2016, the Société fran¸caise de greffe de moelle et de thérapie cellulaire (SFGM TC) [20] proposed these recommendations, mainly established from studies performed with myelo-ablative conditioning: 3.3.1. Compatibility on locis A, B, C, DRB1, DQB1 HLA matching considered on locis A, B, C, DRB1, and possibly DQB1, represents 8 to 10 specificities. A 10/10 should be preferred to a 9/10 compatible donor (However, in pediatric patients children, one HLA MM is less deleterious on overall survival in malignant or non-malignant pathologies [21–23]).
Differences between studies are likely due to different conditionings but also to different donor characteristics, particularly donor sex, since female donors are associated to a higher risk of acute graft-versus-host disease (GVHD) particularly in male patients. However, male patients with acute leukemia who received grafts from male MUD demonstrated an increased incidence of acute GVHD and leukemia-free survival same as when using HLA-identical female donors. As a result, SD are always preferable to MUD, whatever their sex [41]. 4. Haplo-identical donors 4.1. Haplomismatched donors: how is it possible? Haplo-identical transplantations were performed since years, but necessitated ex vivo T cell depletion in order to avoid the graft massive allogeneic response that would occur otherwise, directed against the recipient’s mismatched HLA. This requirement was resolved by the administration of high doses cyclophosphamide in vivo at day 2 after T-cells replete graft, inducing an in vivo depletion of alloreactive lymphocytes and preventing the acute GVHD occurrence.
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This opened up new possibilities for allogeneic transplantation, because probability of finding a haplo-identical donor in the relatives (theoretically 50% in the siblings, all parents, all children. . .) is high. These transplantations became a strong alternative and often replaced umbilical cord blood transplantation (UCBT), previously used for patients without SD or compatible MUD. 4.2. Mismatched antigens and donor-specific antibodies The main limitation impairing this type of transplantation is the presence in the recipient of preformed anti-HLA antibodies directed against the mismatched donor antigens. This concerns of course firstly female patients with available donors among their children, because pregnancy is the main physiological situation of anti-HLA production. Actually, these donor-specific antibodies (DSA) should contraindicate the graft because they constitute a significant risk of graft rejection. Despite the actual limitations of the anti-HLA antibodies detection methods, there is a consensus to use the Mean Fluorescence Intensity (MFI) obtained with the Luminex technique as a surrogate to seric antibodies concentration to help in treatment decisions. 4.3. Recommendations In 2016, the SFGM TC proposed these selection criterias, in a decreasing rank of priority [42]: • no DSA detected by a sensitive method (Luminex); • if only haplo-identical donors are available, choose the one with MFI < 1000; • if DSA MFI > 1000: a cross-match should be performed (by flow cytometry or complement dependent cytotoxicity). If the cross-match is negative: the transplantation can be organised. If the cross-match is positive: another type of transplantation should be prefered (9/10 MUD, UCB) or transplantation with the haplo-identical donor targeted by the DSA but after a desensitization protocol. If the MFI are >10,000, the desensitization will probably be ineffective to remove all the detectable antibodies. Desensitizations may be continued until the cross-match is negative by the CDC technique before the beginning of the conditioning. If the cross-match remains positive by CDC, it is recommended to cancel the HSCT with this donor. Other characteristics are considered secondarily: CMVnegative donor should be preferred to CMV-positive donors if possible for CMV-negative patients. Guidelines for ABO and donor sex is the same as geno-identical donors. Considering the recipient age: < 50 years, the related siblings are preferred to parents; > 50 years: select the younger donor. Concerning NIMA (non-inherited maternal antigens) and number of MM: there is no consistent data so far to support a specific recommendation.
5. Umbilical cord blood transplantation (UCBT) 5.1. Why UCBT can (still) help Haplo-identical donors are not always available or acceptable. Furthermore, if patient’s HLA typing is uncommon, he may not have compatible (even mismatched) MUD on the international registries. For this patient, UCBT is a good graft opportunity, for two reasons: • first, HLA polymorphism is much higher in UCB than in MUD: it increases the likelihood to find a graft matched even with a rare allele/haplotype, particularly for low-weight patients (children), since cell dose/kg recipient weight is critical (see below); • secondly, outcomes are similar with 9–10/10 HLA-identical donors, despite substantial MM between UCB and recipients. These finding was attributed to the naive status of the neonatal immune system. In addition, UCBT are a good opportunity for patients necessitating an urgent/rescue transplantation, because they are stored frozen and are rapidly available. On the other hand, no donor lymphocytes infusion is possible. 5.2. The cell dose issue Cell dose/kg recipient weight is a limiting point, particularly for adult patients. The total nucleated cells (TNC) count pre thawing (at banking) is mainly considered for cell dose determination, although they mostly are polymorphonuclear cells without any capacity to engraft. CD34+ cells count is usually available and logically should be more relevant for HSC estimation, but inter-laboratories variations for this quantification, in particular for “oldest” UCB, may explain why this parameter was considered as less reliable. However, important international centers consider now CD34+ cell dose as a critical factor in optimal unit selection [43]. TNC should exceed 2.5 [44] to 3.5 [45] or even 4 × 107 /kg [46], depending the HLA matching (see below). In obese patients, it is recommended to adapt the cell dose on the adjusted weight. [46]. If cell dose exceeds the indicated thresholds for several UCB, the best HLA-matched should be recruited. This cell dose can be achieved with a single or with two UCB, i.e. single (sUCBT) or double-UCBT (dUCBT). An alternative is to use a sUCBT after ex vivo HSC expansion, but it needs to master this technology. 5.3. Donor-specific antibodies Although there are conflicting data regarding HLA antibodies in the setting of UCBT [47,48], the presence of donor-specific anti-HLA antibodies (DSA) has been shown to adversely affect early haematopoietic reconstitution and survival [49,50]. Therefore, recipients must be screened with a sensitive technique (Luminex) prior to donor search, and UCB for which the recipient has high levels of DSA should be discarded. Most of the time, it is possible to find UCB not targeted by the recipient immunization as a result of the acceptable MM
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in UCBT and the possibility of a double-UCBT. In hyperimmunized patients, selecting homozygous UCB with a matched antigen for the locus concerned by the immunization can help to overcome this obstacle. Otherwise, it is better to consider a desensitization protocol before UCBT or a HSCT with adult donor. At present, there are currently insufficient data to make specific recommendations for the level at which DSA’s should be considered clinically relevant and what the optimal strategy (e.g. desensitization, plasma exchange or rituximab) should be used if such units cannot be avoided. The absence of DSA should be verified just before the beginning of conditioning, particularly if the patients were meanwhile transfused. 5.4. Histocompatibility in UCBT: HLA “rediscovered” in mismatched transplants The recommendations published by the SFGMTC in 2013 [46] proposed to consider HLA at antigenic level for HLA-A and HLA-B and allelic resolution or HLA-DRB1, defining 6 specificities. If a choice must be made between several 5/6 or 6/6 UCB, it was proposed to search a UCB identical for HLA-C because the transplant related mortality is diminished. Moreover matching on DRB1 should be favoured, and double MM on DRB1 or C + DRB1 should be avoided [51]. Transplant centers should give priority to GVH direction only-mismatched units (contrary to MUD), because better outcome was obtained in mismatched transplants with homozygous UCB [52]. This findings were not confirmed in an European study [53], consequently this recommendation now could be questioned. Single UCBT: • for malignant diseases: HLA 4–5/6: TNC > 3 × 107 /kg, HLA 6/6: TNC > 2.5 × 107 /kg; • for non-malignant diseases HLA 4–6/6 TNC > 4 × 107 /kg. Double-UCBT (all indications): HLA 4–6/6 is acceptable and cumulated TNC > 4 × 107 /kg (UCB1 > 2.0 × 107 /kg and UCB2 > 1.5 × 107 /kg) regardless the HLA compatibility. The compatibility between UCB and patients should be favoured rather than between both UCB. Matching criterias between both UCB should follow Minnesota team propositions, i.e. 4–6/6 compatibilities [54]. The importance of allelic matching, including HLA-A, B, C, DRB1 locis, was demonstrated in pediatric patients with malignant hemopathies, grafted with sUCB. Compared with 8/8 UCB, neutrophil recovery was lower with 3–5/8 UCB, and non-relapse mortality was higher with 3–7/8 UCB. The observed effects are independent of cell dose and patient age [44]. On this basis, G. Michel [55] proposed for sUCBT these selection criteria: HLA 5–8/8 UCB: TNC > 3 × 107 /kg (for 5/8 UCB, TNC > 5 × 107 /kg is better) and proposed to administer antithymocyte globulin in acute GVHD prevention in 5/8 UCBT only.
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5.5. dUCBT outcome Generally, only one “dominant” UCB sustains the long-term haematopoietic reconstitution, but the “looser” UCB’s presence is beneficial and participates to the early reconstitution, as demonstrated by a transient mixed unit chimerism in the first weeks post-graft. An immune rejection developping from dominant UCB against the looser unit may be responsible for its failure to engraft [56]. More rarely (4%), a mixed unit chimerism persists for at least 1 year after transplantation. It was proposed to be more likely if both units are closely HLA-matched to each other [57] but it was not confirmed [58]. Compared to sUCBT, results concerning the dUCBT clinical outcome are controversial: more frequent extensive chronic GVHD [59], or lower relapse rate and higher overall and leukemia-free-survival [60]. 5.6. Other considerations Thus far, data regarding ABO compatibility, non-inherited maternal antigens and Killer immunoglobulin receptor ligand matching are conflicting and therefore guidance on the routine incorporation of these factors into unit selection cannot be currently made. 6. Conclusion The diversification of the potential donors in recent years now enables to propose a suitable graft for most patients. New immunotherapies (CAR T-cells, immune checkpoints inhibitors) constitute promising therapeutic tools but it is too early to estimate what position they will take as treatments for malignant hemopathies, from the cost/effectiveness/toxicity point of view. Additionally, HSCT are necessary to treat nonmalignant diseases; as a result, we still must try to ameliorate the HSCT outcome; in particular, it is necessary to specify more precisely: • the clinical support of patients with DSA (MFI thresholds, desensitization protocols); • the selection criterias for haplo-identical donors as for UCB, in the light of recent published data. Moreover, haplo-identical HSCT leaves the field open to cyclophosphamide-based protocols as a GVH prophylaxis in other mismatched transplantations. Disclosure of interest The author declare that they have no competing interest. References [1] Ruggeri A, Battipaglia G, Labopin M, Ehninger G, Beelen D, et al. Unrelated donor versus matched sibling donor in adults with acute myeloid leukemia in first relapse: an ALWP-EBMT study. J Hematol Oncol 2016;9:89.
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State of the art
What compatibility in 2017 for the haematopoietic stem cell transplantation? Quelle compatibilité en 2017 pour la greffe de cellules souches hématopoïétiques ? X. Lafarge EFS Aquitaine Limousin, unité Inserm 1035, équipe cellules souches hématopoïétiques normales et leucémiques, place Amélie-Raba-Léon, CS 21010, 33075 Bordeaux cedex, France
Abstract The diversification of potential donors to perform stem cell allografts now enables to propose a compatible graft cell source adapted to the different clinical situations. Transplants with a geno-identical sibling donor, otherwise with the most HLA-compatible unrelated donor, remain the first-line solutions. Alternative transplants allow to graft patients having no donors in international registries, owing to the rarity of their HLA typing. They are carried out with fairly incompatible grafts and are therefore limited by the existence in the recipient of preformed anti-HLA antibodies which predispose to their rejection. The simple prevention of acute Graft-versus-host disease in haplo-identical transplants, as well as the availability of donors, explain why they have very often replaced placental stem cell transplants. These latter remain useful for pediatric patients or in the absence of family donors. © 2017 Elsevier Masson SAS. All rights reserved. Keywords: Immunogenetics; Histocompatibility; HLA; Allograft; Stem cells; Placental blood; Anti-HLA Antibodies
Résumé La diversification des donneurs potentiels pour la réalisation des allogreffes de cellules souches permet désormais de proposer une source cellulaire de greffon compatible adaptée aux différentes situations cliniques. Les greffes avec un donneur géno-identique issu de la fratrie ou à défaut avec un donneur non apparenté le plus HLA-compatible possible, demeurent les solutions de première intention. Les greffes alternatives à celles-ci permettent de greffer les patients n’ayant pas de donneurs sur les registres internationaux en raison de la rareté de leur typage HLA. Elles s’effectuent avec des greffons assez largement incompatibles et par conséquent sont limitées par l’existence chez le receveur d’anticorps anti-HLA préformés qui prédisposent à leur rejet. La prévention aisée post greffe de la réaction du greffon contre l’hôte dans les greffes haplo-identiques, ainsi que la disponibilité des donneurs, expliquent qu’elles aient remplacé très souvent les greffes de cellules souches placentaires. Ces dernières conservent une place pour les patients pédiatriques ou sans donneurs familiaux. © 2017 Elsevier Masson SAS. Tous droits réservés. Mots clés : Immunogénétique ; Histocompatibilité ; HLA ; Allogreffe ; Cellules souches ; Sang placentaire ; Anticorps anti-HLA
1. Introduction Allogeneic haematopoietic stem cells transplantation (HSCT) has become over the last 30 years a major therapeutical approach for numerous haematological diseases and immunodeficiencies, although impaired by numerous complications. Because of its important influence on post-graft clinical
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outcome, human leukocyte antigen (HLA) compatibility became the cornerstone of donor selection. Today, grafts with geno-identical or pheno-identical donors are still the first-line transplants for most clinical teams. If no sibling donors are available and if no acceptable unrelated donors can be found rapidly on registries, mismatched allo-HSCT with haploidentical related donors or with umbilical cord blood (UCB) units constitute a strong alternative. The histocompatibility laboratories must find and propose potential donors the more appropriate to a given situation, in the context of constant
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evolution of patient clinical management and technologies for HLA typing and antibodies determination, according to the accreditation standards edicted by the European Federation of Immunogenetics.
2. Geno-identical donors For patients needing an allo-HSCT, the first step in finding a suitable donor is usually to search HLA geno-identical individuals within the relatives. There are only 4 possible combinations of parental chromosomes in the progeny. As a consequence, there is a theoretical probability of 25% for an individual to have a sibling identical for all HLA genes, including class I to III, and non-classical HLA genes. Consanguinity between patient’s parents, and/or sharing common haplotypes can sometimes lead to identity between the patient and one parent, at least for locis HLA-A, B, C DRB1 and DQB1. Moreover, crossing overs may occur during the gametogenesis in parents, creating a new haplotype in the progeny and decreasing the probability to find an HLA-identical sibling. Monozygotic twins as potential donors, are generally not recruited, because these transplantions have similar results to autologous grafts. Globally, geno-identical sibling donors (SD) represent the source of cells for about one third of all the HSCT performed in France.
3. Marrow unrelated donors Nowadays, unavailability of SD can often be overcome by finding a compatible marrow unrelated donor (MUD) among the international registries. Specifically for patients with high risk of acute myeloid leukemias in primary relapse, HSCT with 10/10 MUD can be even associated to better outcome than with matched SD [1]. Globally, MUD represent the source of HSC for about half of all the graft performed in France. It is generally considered that the average probability for two unrelated individuals to be HLA-matched is about 1/1,000,000. By the end of 2016, more than 29 millions volunteer donors were available worldwide. The probability to find a compatible donor for a given patient exhibits considerable variations, between several hundreds of donors to. . . zero, depending on the frequency of patient’s HLA typing. The next generation of sequencing (NGS) recently introduced in several registries, allows to obtain for new donors a HLA typing at high or 4-digits resolution. This constitutes a great improvement since compatible donors can be identified immediately, whereas for previously registered donors, complementary typing are still required. Before the formal request of HSC collection, a verification of the compatibility must be performed by the laboratory affiliated with the transplant centre [2] on a new blood sample. This requirement is an opportunity to check the donor availability, but explains why finding a MUD is a challenge, in so far as the
time between the diagnosis and the transplantation influences the risk of relapse. 3.1. Molecular basis of HLA mismatches A mismatch (MM) could be defined as an incompatibility between two individuals due to differences in allelic polymorphisms. HLA compatibility can be determined at different levels of resolution [2]: • at 2 digits, the typing roughly corresponds to the antigenic level, i.e. determined by specific antibodies; • high resolution distinguishes alleles differing in the amino acid sequences of the peptide-binding domains (encoded by exons 2 and 3 for class I, by exon 2 for class II). High resolution, as defined by the EFI, requires also to identify/exclude non-expressed alleles, whatever the mechanism of this lack of expression; • 4-digit resolution concerns the whole amino acid sequence of HLA molecule, whatever the polymorphic positions. MM can be permissive (no impact in term of clinical outcome) or not, depending on their nature: MM can be at antigenic level, high or 4-digits resolution. First, MM can be linked to non-expressed (« null ») alleles. These null alleles can be due to polymorphisms situated in exons encoding premature stop codons, or situated in introns and perturbing the excision/splicing mechanisms. Owing to the absence of expression, these individuals must be considered as homozygous for the expressed allele for determining the compatibility. Secondly, MM can lead to different proteins with different functional properties in antigen presentation/protein–protein interactions, depending on the different polymorphisms positions (i.e. which exon). Thirdly, impacts of MM depend on the level of protein expression of each allele. The Next generation Sequencing is now the more informative method concerning the two first points (including in describing new alleles), but protein expression is not routinely evaluated. Endly, if the recipient is homozygous, the heterozygosity in the donor constitutes an acceptable MM in the host versus graft direction, without any real impact on clinical outcome. The exon 1 for HLA genes encodes for the leader peptide resulting from a cleavage after protein biosynthesis. HLA class I leader peptide has the particularity to be loaded by HLA-E molecules [3]. This non-classical HLA molecule is known to inhibit natural killer (NK) cells reactivity via CD94-NKG2A lectin-type NK cells inhibitory receptors. This system constitutes a global surveillance of HLA class I expression. It is not known if amino acid disparities for the peptide leader sequences influence the NK cells inhibition and consequently can generate a cellular response and have an impact on clinical outcome. However, some alleles can display stop codons in exon 1, leading to null alleles (for instance A*68:11N, B*18:17N, B*44:19N, C*03:20N [4]). These alleles are rare: on 13000 typings performed by NGS with OMIXON◦ kits, 2 such new null
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alleles were detected, for HLA-B and HLA-C [5]. These null alleles could not be detected by Sanger-type method, since exon 1 was not classicaly explored by this technique. Premature stop codons in exon 1 could also exist for class II but were never published. Exons 2–3 for class I, and 2 for class II encode for the peptidebinding groove. Consequently, MM are generally considered as non-permissive, except C*03:03 vs. C*03:04 [6], DRB1*11:01 vs. DRB1*11:04 [7], DQB1*03:01 vs. DQB1*03:02 [8] for which cohorts studies of patients have shown no pejorative effect. In contrast, certain incompatibilities must be avoided, particularly those involving a polymorphism located in the position116 of HLA class I molecules, located in site of attachment of peptides in particular for HLA-C and HLA-B [9–16]. Other exons (4–8 for class I; 3–6 for class II) are less polymorphic, and as a result were not systematically explored by the classical HLA typing methods (i.e. SBT, SSP, SSO). The use of NGS enables to detect new polymorphisms, in particular mutations in exon 3 for class II locis [5]. Because they are not implicated directly in the binding to peptides, their impact on the interaction with the T cell receptors might be questionnable. Meanwhile, exon 4 (class I) and 3 (class II) encodes for a domain interacting with CD8 or CD4 molecules, respectively. Therefore, polymorphisms on these exons could impact the global interaction between antigen presenting-cells and T lymphocytes. Functional studies have shown the absence of alloreactivity in case of incompatibilities located out of the peptides binding groove for B*44:02 vs. B*44:27, DRB1*14:01 vs. 14:54 [3,12–14]. Cohorts studies have shown no pejorative effect of certain incompatibilities: DRB1*14:01 vs. DRB1*14:54 [15]. Finally, some studies have shown that a low expression of molecules HLA-C and DP was associated with a decrease in the alloreactivity in HSCT [16–18].
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In case of incompatibility 9/10: • DQB1 incompatibility is preferable [24–30]; • for loci HLA-A, -B, -C, -DRB1: no consensus on the preferential incompatible locus [31–34], no difference between the 4-digits or antigenic level MM [30,32,33]. Others suggest to avoid MM at 4-digits level for the B locus [30,31]. Some advise to favor MM at 4-digits level to the locus C [25,33] but the beneficial impact in these studies is likely related to the effect of permissive incompatibility HLA-C*03:03 vs. *03:04 [6], which is common. If several mismatched donors are possible, it is better to choose a donor: • with a permissive MM and/or out of the peptide-binding domains; • with a MM in the host versus graft direction only (i.e. homozygous recipient/heterozygous donor) Conversely, it is important to avoid non-permissive incompatibilities (position 116 for HLA class I), 3.3.2. Locis DRB3/4/5/DPB1 Several studies propose to avoid the cumulative effect of more than 2 incompatibilities at the loci DRB3/4/5, DQB1 and DPB1 [25,27–30,33,35]. Concerning the HLA-DPB1 compatibility: • for malignant pathologies: if possible avoid MM [37], double MM [36], or non-permissive incompatibilities according to TCE4, even in 10/10 identical transplants [32,36,38,39]; • for non-malignant pathologies: seeking DPB1 identity; failing this, choose a permissive incompatibility [40].
3.2. Impact of other genes Some other genes were shown to impact the clinical outcome of HSCT, for instance MHC class I chain-related gene A [19], or killer cells Ig-like receptors. These interesting findings need to be confirmed and evaluated prospectively, but today no European nor national guidelines recommend using the typing of these genes to select donors. 3.3. Recommendations In 2016, the Société fran¸caise de greffe de moelle et de thérapie cellulaire (SFGM TC) [20] proposed these recommendations, mainly established from studies performed with myelo-ablative conditioning: 3.3.1. Compatibility on locis A, B, C, DRB1, DQB1 HLA matching considered on locis A, B, C, DRB1, and possibly DQB1, represents 8 to 10 specificities. A 10/10 should be preferred to a 9/10 compatible donor (However, in pediatric patients children, one HLA MM is less deleterious on overall survival in malignant or non-malignant pathologies [21–23]).
Differences between studies are likely due to different conditionings but also to different donor characteristics, particularly donor sex, since female donors are associated to a higher risk of acute graft-versus-host disease (GVHD) particularly in male patients. However, male patients with acute leukemia who received grafts from male MUD demonstrated an increased incidence of acute GVHD and leukemia-free survival same as when using HLA-identical female donors. As a result, SD are always preferable to MUD, whatever their sex [41]. 4. Haplo-identical donors 4.1. Haplomismatched donors: how is it possible? Haplo-identical transplantations were performed since years, but necessitated ex vivo T cell depletion in order to avoid the graft massive allogeneic response that would occur otherwise, directed against the recipient’s mismatched HLA. This requirement was resolved by the administration of high doses cyclophosphamide in vivo at day 2 after T-cells replete graft, inducing an in vivo depletion of alloreactive lymphocytes and preventing the acute GVHD occurrence.
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This opened up new possibilities for allogeneic transplantation, because probability of finding a haplo-identical donor in the relatives (theoretically 50% in the siblings, all parents, all children. . .) is high. These transplantations became a strong alternative and often replaced umbilical cord blood transplantation (UCBT), previously used for patients without SD or compatible MUD. 4.2. Mismatched antigens and donor-specific antibodies The main limitation impairing this type of transplantation is the presence in the recipient of preformed anti-HLA antibodies directed against the mismatched donor antigens. This concerns of course firstly female patients with available donors among their children, because pregnancy is the main physiological situation of anti-HLA production. Actually, these donor-specific antibodies (DSA) should contraindicate the graft because they constitute a significant risk of graft rejection. Despite the actual limitations of the anti-HLA antibodies detection methods, there is a consensus to use the Mean Fluorescence Intensity (MFI) obtained with the Luminex technique as a surrogate to seric antibodies concentration to help in treatment decisions. 4.3. Recommendations In 2016, the SFGM TC proposed these selection criterias, in a decreasing rank of priority [42]: • no DSA detected by a sensitive method (Luminex); • if only haplo-identical donors are available, choose the one with MFI < 1000; • if DSA MFI > 1000: a cross-match should be performed (by flow cytometry or complement dependent cytotoxicity). If the cross-match is negative: the transplantation can be organised. If the cross-match is positive: another type of transplantation should be prefered (9/10 MUD, UCB) or transplantation with the haplo-identical donor targeted by the DSA but after a desensitization protocol. If the MFI are >10,000, the desensitization will probably be ineffective to remove all the detectable antibodies. Desensitizations may be continued until the cross-match is negative by the CDC technique before the beginning of the conditioning. If the cross-match remains positive by CDC, it is recommended to cancel the HSCT with this donor. Other characteristics are considered secondarily: CMVnegative donor should be preferred to CMV-positive donors if possible for CMV-negative patients. Guidelines for ABO and donor sex is the same as geno-identical donors. Considering the recipient age: < 50 years, the related siblings are preferred to parents; > 50 years: select the younger donor. Concerning NIMA (non-inherited maternal antigens) and number of MM: there is no consistent data so far to support a specific recommendation.
5. Umbilical cord blood transplantation (UCBT) 5.1. Why UCBT can (still) help Haplo-identical donors are not always available or acceptable. Furthermore, if patient’s HLA typing is uncommon, he may not have compatible (even mismatched) MUD on the international registries. For this patient, UCBT is a good graft opportunity, for two reasons: • first, HLA polymorphism is much higher in UCB than in MUD: it increases the likelihood to find a graft matched even with a rare allele/haplotype, particularly for low-weight patients (children), since cell dose/kg recipient weight is critical (see below); • secondly, outcomes are similar with 9–10/10 HLA-identical donors, despite substantial MM between UCB and recipients. These finding was attributed to the naive status of the neonatal immune system. In addition, UCBT are a good opportunity for patients necessitating an urgent/rescue transplantation, because they are stored frozen and are rapidly available. On the other hand, no donor lymphocytes infusion is possible. 5.2. The cell dose issue Cell dose/kg recipient weight is a limiting point, particularly for adult patients. The total nucleated cells (TNC) count pre thawing (at banking) is mainly considered for cell dose determination, although they mostly are polymorphonuclear cells without any capacity to engraft. CD34+ cells count is usually available and logically should be more relevant for HSC estimation, but inter-laboratories variations for this quantification, in particular for “oldest” UCB, may explain why this parameter was considered as less reliable. However, important international centers consider now CD34+ cell dose as a critical factor in optimal unit selection [43]. TNC should exceed 2.5 [44] to 3.5 [45] or even 4 × 107 /kg [46], depending the HLA matching (see below). In obese patients, it is recommended to adapt the cell dose on the adjusted weight. [46]. If cell dose exceeds the indicated thresholds for several UCB, the best HLA-matched should be recruited. This cell dose can be achieved with a single or with two UCB, i.e. single (sUCBT) or double-UCBT (dUCBT). An alternative is to use a sUCBT after ex vivo HSC expansion, but it needs to master this technology. 5.3. Donor-specific antibodies Although there are conflicting data regarding HLA antibodies in the setting of UCBT [47,48], the presence of donor-specific anti-HLA antibodies (DSA) has been shown to adversely affect early haematopoietic reconstitution and survival [49,50]. Therefore, recipients must be screened with a sensitive technique (Luminex) prior to donor search, and UCB for which the recipient has high levels of DSA should be discarded. Most of the time, it is possible to find UCB not targeted by the recipient immunization as a result of the acceptable MM
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in UCBT and the possibility of a double-UCBT. In hyperimmunized patients, selecting homozygous UCB with a matched antigen for the locus concerned by the immunization can help to overcome this obstacle. Otherwise, it is better to consider a desensitization protocol before UCBT or a HSCT with adult donor. At present, there are currently insufficient data to make specific recommendations for the level at which DSA’s should be considered clinically relevant and what the optimal strategy (e.g. desensitization, plasma exchange or rituximab) should be used if such units cannot be avoided. The absence of DSA should be verified just before the beginning of conditioning, particularly if the patients were meanwhile transfused. 5.4. Histocompatibility in UCBT: HLA “rediscovered” in mismatched transplants The recommendations published by the SFGMTC in 2013 [46] proposed to consider HLA at antigenic level for HLA-A and HLA-B and allelic resolution or HLA-DRB1, defining 6 specificities. If a choice must be made between several 5/6 or 6/6 UCB, it was proposed to search a UCB identical for HLA-C because the transplant related mortality is diminished. Moreover matching on DRB1 should be favoured, and double MM on DRB1 or C + DRB1 should be avoided [51]. Transplant centers should give priority to GVH direction only-mismatched units (contrary to MUD), because better outcome was obtained in mismatched transplants with homozygous UCB [52]. This findings were not confirmed in an European study [53], consequently this recommendation now could be questioned. Single UCBT: • for malignant diseases: HLA 4–5/6: TNC > 3 × 107 /kg, HLA 6/6: TNC > 2.5 × 107 /kg; • for non-malignant diseases HLA 4–6/6 TNC > 4 × 107 /kg. Double-UCBT (all indications): HLA 4–6/6 is acceptable and cumulated TNC > 4 × 107 /kg (UCB1 > 2.0 × 107 /kg and UCB2 > 1.5 × 107 /kg) regardless the HLA compatibility. The compatibility between UCB and patients should be favoured rather than between both UCB. Matching criterias between both UCB should follow Minnesota team propositions, i.e. 4–6/6 compatibilities [54]. The importance of allelic matching, including HLA-A, B, C, DRB1 locis, was demonstrated in pediatric patients with malignant hemopathies, grafted with sUCB. Compared with 8/8 UCB, neutrophil recovery was lower with 3–5/8 UCB, and non-relapse mortality was higher with 3–7/8 UCB. The observed effects are independent of cell dose and patient age [44]. On this basis, G. Michel [55] proposed for sUCBT these selection criteria: HLA 5–8/8 UCB: TNC > 3 × 107 /kg (for 5/8 UCB, TNC > 5 × 107 /kg is better) and proposed to administer antithymocyte globulin in acute GVHD prevention in 5/8 UCBT only.
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5.5. dUCBT outcome Generally, only one “dominant” UCB sustains the long-term haematopoietic reconstitution, but the “looser” UCB’s presence is beneficial and participates to the early reconstitution, as demonstrated by a transient mixed unit chimerism in the first weeks post-graft. An immune rejection developping from dominant UCB against the looser unit may be responsible for its failure to engraft [56]. More rarely (4%), a mixed unit chimerism persists for at least 1 year after transplantation. It was proposed to be more likely if both units are closely HLA-matched to each other [57] but it was not confirmed [58]. Compared to sUCBT, results concerning the dUCBT clinical outcome are controversial: more frequent extensive chronic GVHD [59], or lower relapse rate and higher overall and leukemia-free-survival [60]. 5.6. Other considerations Thus far, data regarding ABO compatibility, non-inherited maternal antigens and Killer immunoglobulin receptor ligand matching are conflicting and therefore guidance on the routine incorporation of these factors into unit selection cannot be currently made. 6. Conclusion The diversification of the potential donors in recent years now enables to propose a suitable graft for most patients. New immunotherapies (CAR T-cells, immune checkpoints inhibitors) constitute promising therapeutic tools but it is too early to estimate what position they will take as treatments for malignant hemopathies, from the cost/effectiveness/toxicity point of view. Additionally, HSCT are necessary to treat nonmalignant diseases; as a result, we still must try to ameliorate the HSCT outcome; in particular, it is necessary to specify more precisely: • the clinical support of patients with DSA (MFI thresholds, desensitization protocols); • the selection criterias for haplo-identical donors as for UCB, in the light of recent published data. Moreover, haplo-identical HSCT leaves the field open to cyclophosphamide-based protocols as a GVH prophylaxis in other mismatched transplantations. Disclosure of interest The author declare that they have no competing interest. References [1] Ruggeri A, Battipaglia G, Labopin M, Ehninger G, Beelen D, et al. Unrelated donor versus matched sibling donor in adults with acute myeloid leukemia in first relapse: an ALWP-EBMT study. J Hematol Oncol 2016;9:89.
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Please cite this article in press as: Lafarge X. What compatibility in 2017 for the haematopoietic stem cell transplantation? Transfusion Clinique et Biologique (2017), http://dx.doi.org/10.1016/j.tracli.2017.06.006