Articles de revues : « Non-permissive mismatche »

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Chiusolo, Patrizia, Teresa Lamparelli, Giuseppe Sapienza, Alida Dominietto, Anna Maria Raiola, Carmen Di Grazia, Sabrina Giammarco et al. « The Impact of Aminoacid Substitution at Position 116 Class I HLA, in Unrelated Donor Transplants ». Blood 134, Supplement_1 (13 novembre 2019) : 4620. http://dx.doi.org/10.1182/blood-2019-130614.

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Background : The role of aminoacid substitution at position 116 of class I HLA antigens, has been the subject of several contributions, suggesting the possibility of permissive or non permissive mismatches. Hypothesis. Permissive mismatched at position AA116, yield outcomes comparable to 10/10 matched grafts and superior to AA116 non permissive mismatches. Patients: We have analyzed 358 unrelated donor transplants (UD) to test this hypothesis. All donors were matched at class II for DRB1 and DQ alleles; 226 were also matched at high resolution for A,B and C alleles; 84 had 1 permissive AA116 mismatch (Pmm), and 48 had 1 non permissive mismatch (NPmm). The 3 groups were comparable for patients age (p=0.5), donors age (p=0.9), diagnosis (p=0.2) and intensity of the conditioning regimen (p=0.4); both NPmm and Pmm had more patients with advanced disease, as compared to matched patients. The stem cell source was peripjheral blood for the large majority of patients. Results. The cumulative incidence (CI) of acute GvHD grade II-IV (p=0.01) and III-IV (p=0.001) was greater in patients with 1 allele mismatch, compared to matched patients, irrespective of AA116 permissive substitution. The CI of non relapse mortality (NRM) at 5 years 29%, 35%, 50% respectively in patients grafted from 10/10 matched donors, 1 allele Pmm donors and 1 allele NPmm donors (p=0.005). GvHD with or without infections, as a cause of death was recorded in 19%, 23% and 33% of the three groups respectively (p=0.1). The CI of relapse was respectively 18%, 30%, 20% (p=0.1). The actuarial survival at 5 years was 68% for 10/10 matched patients, 63% for 1 allele Pmm patients and 47% for 1 allele NPmm patients. Conclusions. We confirm that aminoacid substitution at position 116 of class I HLA antigens, is a risk factor for non relapse mortality and survival. Patients with permissive mismatched AA116 donors have outcome comparable to patients grafted from matched donors. Figure Disclosures Angelucci: Novatis: Honoraria, Other: Chair Steering Committee TELESTO protocol; Celgene: Honoraria, Other: Participation in DMC; BlueBirdBio: Other: Local advisory board; Jazz Pharmaceuticals: Other: Local advisory board; Roche: Other: Local advisory board; Vertex Pharmaceuticals Incorp., and CRISPR Therapeutics: Other: Participation in DMC.

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Shaw, Bronwen E., Katharina Fleischhauer, Mari Malkki, Theodore Gooley, Elisabetta Zino, Stephen Spellman, Yasuo Morishima et al. « Permissive HLA-DPB1 Mismatching Compared to a Non-Permissive Mismatching Significantly Improves Overall Survival Following Allogeneic Transplantation In Patients with Both 10/10 and 9/10 Matched Unrelated Donors ». Blood 116, n^o 21 (19 novembre 2010) : 227. http://dx.doi.org/10.1182/blood.v116.21.227.227.

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Abstract Abstract 227 It is well established that the use of a donor matched for 9–10/10 alleles at HLA-A,-B,-C,-DRB1,-DQB1 significantly improves overall survival (OS) after unrelated donor (UD) haematopoietic stem cell transplantation (HSCT). Whilst the matching status for HLA-DPB1 alleles has been shown to influence transplant complications (relapse and graft-versus-host disease (GVHD), its impact on survival has not been well defined. The current unmet need in clinical practice is an approach to stratify selection criteria when a clinician is confronted with the choice between several 10/10 or 9/10 matched unrelated donors. There is now considerable interest in exploring different types of matching criteria to define permissive HLA-DPB1 mismatches which may be associated with an improved outcome. We have previously shown that HLA-DPB1 permissiveness can be functionally defined by the characterization of shared T cell epitopes (TCE) recognized by alloreactive T cells. In this model, allelic HLA mismatches are classified as permissive if they do not involve TCE disparities, and as non-permissive if they do. Using this concept, we developed two overlapping algorithms of permissivity for allelic HLA-DPB1 mismatches, on the basis of 3 (TCE3) or 4 (TCE4) groups of DPB1 alleles encoding immunogenic TCE. Data from relatively small prospective studies has shown a worse outcome to be associated with non-permissive DPB1 TCE disparities. Here, we present outcomes in 9123 UD-HSCT pairs, collected through the International Histocompatibility Working Group (IHWG). The cohort was comprised of 5809 10/10 matched transplant pairs and 3314 9/10 matched pairs. Within the 10/10 and 9/10 matched pairs three groups of patients were identified: 1. Zero DPB1 mismatches (i.e. allele matched), 2. Permissive DPB1 mismatch, 3. Non-permissive DPB1 mismatch. The model was adjusted for disease severity, source of stem cells, conditioning regimen, use of T-cell depletion, patient/donor gender and patient age. In line with DPB1 allele frequencies in worldwide populations, the number of transplants scored as permissive was higher for TCE3 (4398/7270 [60.4%]) than for TCE4 (2577/7270 [35.4%]). Using the DPB1 permissive mismatch transplants as the reference group (either 10/10 or 9/10 matched), we showed that DPB1 allelic matches resulted in similar survivals to DPB1 permissive mismatches, both in the 10/10 (HR 0.96, p=0.498 for TCE3 and HR 0.99, p=0.85 for TCE4) and the 9/10 setting (HR 0.97, p=0.70 for TCE3 and HR 0.99, p=0.96 for TCE4). In contrast, survival was significantly worse in the presence of a non-permissive TCE3 or TCE4 mismatch, both in the 10/10 (HR 1.15, p=0.0005 for TCE3 and HR 1.13, p=0.0035 for TCE4) and in the 9/10 matched setting (HR 1.13, p=0.0140 for TCE3 and HR 1.11, p=0.0448 for TCE4). The survival detriment appeared to be due to a significantly increased non-relapse mortality (TCE3: 10/10 HR 1.27, p<0.001 and 9/10 HR 1.21, p=0.0001; TCE4: 10/10 HR 1.24, p<0.001 and 9/10 HR 1.13, p=0.0514), as well as an increase in grades II-IV acute GVHD (TCE3: 10/10 HR 1.17, p<0.001 and 9/10 HR 1.29, p<0.001; TCE4: 10/10 HR 1.12, p=0.0035 and 9/10 HR 1.19, p<0.0001). There was no significant difference in disease relapse between permissive and non-permissive mismatched pairs. Finally, using the 10/10 DPB1 permissive mismatched group as a reference, we found survival to be similar for 10/10 DPB1 non-permissive (HR 1.15) and 9/10 DPB1 permissive (HR 1.20) or DPB1 allele matched (HR 1.17) transplants. In conclusion, our results suggest that extending donor selection to include HLA-DPB1 both allelic and functional TCE matching may result in better prediction of survival for patients. These findings provide an attractive new algorithm to stratify donor choice when several well-matched UD are identified. Disclosures: No relevant conflicts of interest to declare.

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Michallet, Mauricette, Mohamad Sobh, Hélène Labussière-wallet, Marie Balsat, Caroline Lejeune, Sophie Ducastelle-Leprêtre, Xavier Thomas et al. « Allogeneic Hematopoietic Stem Cell Transplantation from Unrelated Peripheral Blood or Bone Marrow Donors : The Impact of HLA Matching Including HLA-DPB1 Allele in a Multivariable Risk Model ». Blood 126, n^o 23 (3 décembre 2015) : 3213. http://dx.doi.org/10.1182/blood.v126.23.3213.3213.

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Abstract Introduction Allogeneic hematopoietic stem cell transplantation (allo-HSCT) from unrelated donors has been increasingly used worldwide in the last decade in patients with hematological malignancies when HLA-identical sibling donors are unavailable. Identification of the HLA locus matching at the allele level is important in optimizing transplantation outcomes by minimizing non-relapse mortality (NRM) as well as in enhancing the graft-versus-leukemia effect. It has been demonstrated that patients with HSC donors matched on HLA-A, -B, -C, -DRB1, and -DQB1 alleles can have different outcomes if considering matching on HLA-DPB1 allele. HLA-DPB1 mismatches based on T-cell-epitope groups could identify mismatches that might be tolerated (permissive) and those that would negatively impact transplantation outcomes (non-permissive). We conducted this study to evaluate the impact of HLA matching degree between patient and HSC donor including HLA-DPB1, taking into account the other impacting variables in the allo-HSCT settings. Material and methods A total of 235 patients who received allo-HSCT at our center between January 2005 and December 2014 with a full donor/recipient HLA class I and II locus available data were included, 131 (56%) were males, the median age at allo-HSCT was 50 years (range: 18-69). There was 123 (53%) acute leukemia (93 AML, 30 ALL), 24 (10%) MDS, 35 (15%) multiple myeloma, 20 (8%) NHL, 7 (3%) Hodgkin's disease, 10 (4%) myeloproliferative neoplasms, 13 (6%) CML, and 3 (1%) CLL. One hundred and nineteen patients (51%) received myeloablative conditioning (MAC) and 116 (49%) received reduced intensity conditioning (RIC). Disease status at allo-HSCT was complete remission (CR) in 144 (61%) patients and less than CR in 91 (39%). HSC donor was 10/10 HLA matched unrelated (MUD) for 162 (69%) (80 PBSC and 93 BM), among them 21 (9%) were matched for HLA-DPB1, 41 (18%) had permissive mismatch and 100 (42%) had non-permissive mismatch; while 73 (31%) had 9/10 HLA mismatched donor MMUD (48 PBSC and 25 BM), among them, 7 (3%) were matched for HLA-DPB1, 12 (5%) had permissive mismatch and 54 (23%) had non-permissive mismatch; 110 (47%) were ABO compatible, 58 (24%) had minor incompatibility and 67 (29%) had major incompatibility. For sex mismatching, in 33 (14%) cases, it was female donor to a male patient. Results After a median follow-up for surviving patients of 29 months (range: 4-108), patients with 10/10 HLA MUD had better overall survival (OS) than those with 9/10 MMUD without considering the HLA-DPB1 matching, with 2 years OS probability of 51% vs 35% respectively (p=0.09), which was reflected by a lower NRM at 2 years of 29% vs 42% (p=0.07). When considering the HLA-DPB1 matching, we found comparable outcomes in terms of OS and NRM for: 1) 10/10 HLA MUD - DPB1 matched vs 10/10 HLA MUD - DPB1 permissive mismatched, 2) 10/10 HLA MUD - non-permissive DPB1 mismatched vs 9/10 HLA MMUD - DPB1 matched, 3) 9/10 HLA MMUD - DPB1 matched vs 9/10 HLA MMUD - DPB1 permissive mismatched; all these 3 groups were not significantly different between each other expect for a last group which included 9/10 HLA MMUD with non-permissive DPB1 mismatch, this group had worse OS and NRM compared to all others with 2 years rates of 34% vs 49% (p=0.05) and 47% vs 29% (p=0.04) respectively. In multivariate analysis, patient age (>50 years), disease status (less than CR), HLA matching (9/10 HLA MUD non-permissive DPB1) and sex mismatching (female donor to male patient) were significantly impacting OS and NRM. We included all these variables in a risk score: age < 50 years= 0, > 50 years= 1; CR= 0, less than CR= 1; HLA 10/10 (matched on DPB1) or HLA 10/10 with permissive MM on DPB1= 0; HLA 10/10 with non-permissive MM on DPB1 or HLA 9/10 (matched on DPB1 or with permissive MM on DPB1)=1; HLA 9/10 with non-permissive MM on DPB1=2; for sex matching, female donor to male patient=1, all other= 0. The risk score distinguished low risk patients (total score=0), intermediate (total score=1 or 2) and high risk (total score >2) with 2 years OS and NRM rates of 66%, 52%, 30% (p=0.003) and 22%, 29% 48% (p=0.004) respectively. Conclusion MMUD with non-permissive T-cell-epitope mismatch at HLA-DPB1 should be avoided due to increased rates of NRM. The risk score combining HLA matching with age, disease status and sex matching is very helpful for daily clinical practice offering patients better treatment strategy. Figure 1. Figure 1. Disclosures Nicolini: Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Arrieta-Bolanos, Esteban, Pietro Crivello, Meilun He, Tao Wang, Shahinaz M. Gadalla, Sophie Paczesny, Steven G. E. Marsh et al. « A Refined Model of HLA-DP Permissiveness Improves Stratification of Acute Graft-Versus-Host Disease Risks after Unrelated Hematopoietic Cell Transplantation : A Retrospective Study from the CIBMTR ». Blood 138, Supplement 1 (5 novembre 2021) : 2890. http://dx.doi.org/10.1182/blood-2021-146957.

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Abstract Introduction: Permissive HLA-DPB1 mismatches defined by the T-cell epitope (TCE) model are an established selection criterion for unrelated donors in allogeneic hematopoietic cell transplantation (alloHCT) (Dehn et al. Blood 2019). Based on biological evidence, the TCE model has classified HLA-DPB1 alleles into at least three functional groups, one of which (TCE group 3; TCE3) houses a large number of alleles with different structural and functional characteristics. We have recently shown that structurally close HLA-DP allotypes have similar peptide-binding motifs and share a significant proportion of their immunopeptidomes, the latter being fundamental for permissiveness (Meurer & Crivello et al. Blood 2021). Hence, we hypothesized that HLA-DPB1 mismatches involving alleles that encode structurally distant allotypes within TCE3 could be less permissive than those involving alleles that encode structurally closer allotypes, and thus have a differential impact on clinical outcomes. Methods: Multidimensional scaling techniques were used to compare 28 polymorphic positions (amino acids 8-215) among 51 alleles present in a cohort of 5,140 10/10 matched patient-donor pairs who received a first alloHCT for AML, ALL, or MDS between 2008-2017. Based on these analyses, TCE3-permissive mismatches (N=2,216) were further stratified into those involving structurally close or more distant combinations and compared with HLA-DPB1-matched (N=785) and non-permissively mismatched (N=2,023) pairs. These models were tested in parallel to the "classical" TCE model considering permissive mismatches (N=2,332) as a whole, to determine their association with overall survival (OS), disease-free survival (DFS), treatment-related mortality (TRM), primary disease relapse, and acute (a) and chronic (c)GVHD. Kaplan-Meier analysis and log-rank testing were used to compare the median OS and DFS. The incidences of GVHD, relapse and TRM were compared using competing risks and Gray's test. The effect of HLA-DPB1 mismatch on time-to-event outcomes was modelled by Cox regression after adjusting for confounders and testing for the proportional hazards assumption. Results: Within TCE3, we identified a subgroup of 4 frequent and structurally as well as functionally closely related alleles (i.e. DPB1*02:01, 04:01, 04:02, 23:01) that form a separate cluster (Figure 1A). These "core" alleles have similar bound-peptide motifs (van Balen et al. J Immunol 2020) and can be distinguished from other alleles in TCE3 in terms of the strength of in vitro alloreactive responses elicited from permissive responders (Meurer et al. Front Immunol 2018). Moreover, principal component analysis identified the HLA-DP 84-87 DEAV/GGMP motif as a major factor driving structural variability among TCE3 alleles (not shown). We used these observations to stratify TCE3 permissive mismatches in the allo-HCT cohort into "core" (N=930) and "non-core" (N=1,286) or into DEAV/GGPM-matched (N=1,209) and mismatched (N=1,007) pairs (Figure 1B). Multivariable analysis confirmed the association of aGVHD2-4 for the classical TCE model of non-permissive mismatching (p<.0001) and revealed a trend in DEAV/GGPM and "core"/"non-core" TCE3-permissive models. When compared to HLA-DPB1 allele matched pairs the risks of aGVHD2-4 increased progressively with "core" TCE3-permissive (HR 1.12 [0.98-1.28]; p=0.1012), "non-core" TCE3-permissive (HR 1.24 [1.06-1.46]; p= 0.0082), and non-permissive mismatches (HR 1.32 [1.16-1.50]; p<.0001) (Figure 1C, "core" vs. "non-core" HR 0.90 [0.80-1.01]; p=0.062). Similar albeit less significant results were obtained with the DEAV/GGPM model. The "core"/"non-core" TCE3 model was also associated with TRM with alloHCT from "core" TCE3-permissive donors showing lower risks of TRM than "non-core" TCE3-permissive (HR 0.82 [0.70-0.96]; p=0.0118) and non-permissive donors (HR 0.78 [0.68-0.88]; p=0.0002). Conclusion: Our results suggest that structural differences within TCE3 that reflect functional divergence and differential immunogenicity of alleles in this group associate with the risks of aGVHD and TRM after alloHCT. Hence, within the population of 10/10 matched donors, selection of "core" TCE3-permissive donors might reduce patient morbidity after transplantation. Figure 1 Figure 1. Disclosures Paczesny: Medical University of South Carolina: Patents & Royalties: inventor on the ST2 bispecific antibody patent application. Lee: AstraZeneca: Research Funding; Incyte: Research Funding; Janssen: Other; Kadmon: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Syndax: Research Funding; Takeda: Research Funding; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding.

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Oran, Betul, Rima M. Saliba, Yudith Carmazzi, Elizabeth J. Shpall, Katayoun Rezvani, Marcos De Lima, Marcelo Fernández-Viña, Richard E. Champlin et Kai Cao. « Increased Disease Progression in HLA-a, -B, -C, -DRB1 and -DBP1 Matched Recipients of Unrelated Donor Transplants with Peripheral Blood Is Independent of Risk Groups By Disease Risk Index ». Blood 126, n^o 23 (3 décembre 2015) : 2005. http://dx.doi.org/10.1182/blood.v126.23.2005.2005.

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Abstract The use of unrelated donors matched in all alleles of HLA-A, -B, -C, and -DRB1 loci has been associated with superior outcomes compared with those having 1 or more mismatches. Recent studies showed increased transplant-related mortality (TRM) with the use of HLA-DPB1 mismatched donors supporting the notion that the ideal volunteer unrelated donor should fully match at HLA-A, -B, -C, and -DRB1 and lack -DPB1 mismatches. The issue of the effect of HLA-DPB1 mismatch on the disease progression rate is still controversial and we aimed to investigate the impact of HLA-DPB1 mismatch in the graft versus host direction on transplant outcomes in patients categorized according to the recently defined disease risk index (DRI) for disease risk classification. Our study cohort included 1,211 transplant patients with hematological malignancies whohave received an hematopoietic stem cell transplant (HSCT) from an unrelated HLA-A, -B, -C,-DRB1 matched donor by high resolution typing (8/8 matched) after 2005 through 2014. The study cohort had a median age of 55 (range, 19-77); the hematopoietic stem cell source was peripheral blood (PB) in 698 and bone marrow (BM) in 513 patients. Disease risk index (DRI) at HSCT was high or very high in 382 (33%), intermediate in 598 (51%), low in 185 (16%) patients. Of the pairs, 1,154 (95%) were matched atHLA-DQB1 and 1,116 (92%) at HLA- DRB3/4/5 by high resolution testing. However, 633 (52%) had mismatch at one of the DPB1 alleles and 208 (17%) had two mismatches. There was association between matching for DPB1and matching for DRB3/4/5 (p=0.002) but not with DQB1. In PB recipients, there was a highly significant decreaseof disease progression in DPB1 mismatched pairs (one and two allele; HR=0.7, p=0.01 and HR=0.6, p=0.01 respectively) as compared tothose pairs with DPB1 matched. The impact of mismatches at one or two alleles were not different on disease progression (HR=1.2, p=0.4). However, the impact of DPB1 mismatch on disease progression was not uniform in different disease risk groups by DRI. Mismatch at DPB1 significantly decreased disease progression only in the intermediate risk group (HR=0.5, p=0.002) but not in low risk and high/very high disease groups by DRI (HR=0.9, p=0.8 and HR=0.7, p=0.1 respectively) (Figure 1a-c). In BM recipients, increasing number of DPB1 incompatibilities decreased disease progression (HR=0.9, p=0.4 and HR=0.6, p=0.1 for 1 and 2 allele mismatches respectively) but did not reach significance. Mismatches at HLA-DQB1 and -DRB3/4/5 had no impact on disease progression in both PB and BM recipients. Pairs with one or two allele-level DPB1 mismatches increased TRM compared with DPB1 matched pairs in PB (HR=1.5, p=0.04 and HR=1.9, p=0.006 respectively) and BM recipients (HR=1.8, p=0.03 and HR=1.9, p=0.05). There was no difference between two and one allele DPB1 mismatched for TRM in PB and BM recipients. Multivariate analyses revealed that the negative impact of DPB1 mismatch on TRM was not uniform in younger or (?) older patients. Interestingly, DPB1 mismatches increased TRM only in younger (aged<55) patients (HR=2.3, p=0.02) if they were PB recipients but only in older patients (HR=2.03, p=0.046) if they were BM recipients. We next analyzed the impact of DPB1 matching on progression free survival (PFS) and did not observe any impact of DPB1 mismatches on PFS in PB (HR=0.9, p=0.9) and BM (HR=1.12, p=0.6) recipients. Subgroup analyses by DRI to identify a specific risk group that the use of HLA-A, -B, -C and -DRB1 matched but DPB1 mismatched unrelated donor might lead to improved PFS did not reveal any particular risk group in both PB and BM recipients. Thus, in recipients of HLA-A, -B-C and DRB1 allele-level matched unrelated donors a mismatch for DPB1 is associated with a significantlydecreased risk of disease progression with no impact on PFS in intermediate risk group by DRI. Further analysis permissive vs. non-permissive DPB1 mismatches would be warranted. Figure 1. The cumulative incidence of disease progression by DPB1 mismatch and Disease Risk Index in peripheral blood recipients. Figure 1. The cumulative incidence of disease progression by DPB1 mismatch and Disease Risk Index in peripheral blood recipients. Disclosures No relevant conflicts of interest to declare.

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Metzing, Maximilian, Pietro Crivello, Thuja Meurer, Michel G. D. Kester, Dominik Megger, Weiqiang Chen, Peter Van Balen et al. « HLA-DM Mediates Permissiveness of HLA-DPB1 T Cell Epitope Mismatches in Unrelated HCT ». Blood 134, Supplement_1 (13 novembre 2019) : 3211. http://dx.doi.org/10.1182/blood-2019-129921.

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Introduction: In 8/8 matched unrelated donor (UD) hematopoietic cell transplantation (HCT), permissive HLA-DPB1 (DP) mismatches within the same functional T Cell Epitope (TCE) group are associated with better outcomes compared to non-permissive mismatches across different TCE groups (Fleischhauer, Blood 2017). This clinical advantage has been shown to be associated with limited in vitro T cell alloreactivity (Meurer, Front Immunol 2019), which in turn is dependent on polymorphic peptide contact amino acids in the DP molecule (Crivello, Biol Blood Marrow Transplant 2015). The HLA class II immunopeptidome is shaped by the peptide editor HLA-DM (DM), and its natural antagonist HLA-DO (DO). Here we investigated the effect of DM/DO activity on the DP immunopeptidome, the breadth of the overall alloresponse to and immunogenicity of permissive and non-permissive DP mismatches, in healthy individuals and in patients after UD-HCT. Methods: HeLa cells expressing single DP alleles in the presence or absence of DM, or in the presence of DM and DO (Rutten, BBMT 2008), were generated for HLA-DPB1*04:02 (DP4) and *10:01 (DP10) as prototypes for 2 distinct TCE groups. The DP immunopeptidomes were analyzed by mass spectrometry. Alloresponses against DP were quantified by CD137 up-regulation assays after co-culture of irradiated HeLa cells with CD4+ responder T cells from 14 healthy blood donors permissive to DP4 and non-permissive to DP10, or from 2 patients referring to the University Hospital Essen, Germany, the latter alive and well >9 months after 8/8 matched UD-HCT with a permissive DP4 or a non-permissive DP10 mismatch, respectively. The breadth of the responding T cell receptor beta (TCRb) repertoire was determined by immunosequencing (Adaptive Biotechnologies, Seattle, USA). The study was performed under informed consent according to the declaration of Helsinki. Results: Reflecting their association with different TCE groups, DP4 and DP10 presented peptidomes with limited (<4%) overlap and different peptide motifs. These features were not changed by the presence or absence of DM. In contrast, the presence of DM resulted in a significant (>50%) shrinking of the peptide repertoire displayed by the same DP antigen in the absence of DM, with approximately 30% peptides shared by the same allele in the two conditions, both for DP4 and for DP10 (Figure 1A). In the presence of DM, the magnitude of the T cell alloresponse to non-permissive DP10 was significantly higher than to permissive DP4, both in healthy individuals (40.7% vs 16.3%, respectively, p<0.0001) and in the informative transplanted patients (Figure 1B). Neither the absence of DM (40.7% vs 45.3%, p=ns) nor the presence of DM with DO (71.6% vs 77.4%, p=ns) altered the magnitude of the non-permissive alloresponse to DP10. Compellingly, both the absence of DM (16.3% vs 39.0%, p<0.001) and the co-expression of DM and DO (21.6% vs 59.5%, p<0.001) significantly increased the response to permissive DP4, again both in healthy individuals and in the informative transplanted patients. The strength of the overall alloresponse was associated with the breadth of the corresponding TCRb repertoire, with significantly higher diversity (1-clonality) in response to non-permissive DP10 (mean 0.68) compared to permissive DP4 (mean 0.48) in the presence of DM, and similar high diversity against both DP antigens in its absence (mean 0.74 vs 0.75 against DP4 and DP10, respectively) in healthy individuals. In the transplanted patients, the permissive alloresponse to DP4 was dominated by a single TCRb that could be retrieved at high frequency also in ex-vivo follow-up samples from the same patient from day +195 and +363, while the non-permissive alloresponse to DP10 was polyclonal (mean 0.62 and 0.61 in the presence and absence of DM, respectively) (Figure 1C). Conclusion: Permissiveness of HLA-DPB1 TCE mismatches is dependent on the peptide editing by DM, and converted into non-permissiveness in its absence or in the presence of its antagonist DO. Permissiveness is associated with the immunopeptidomes of mismatched HLA-DP alloantigens on the MHC side, and with TCRb diversity on the alloreactive T cell side, both in healthy individuals and in patients after UD-HCT. These new mechanistic insights suggest that expression of DM and DO by leukemia or healthy tissues might modulate graft-versus-leukemia and graft-versus-host disease after permissively DP mismatched UD HCT. Disclosures No relevant conflicts of interest to declare.

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Ruggeri, Annalisa, Carlheinz Mueller, Liesbeth C. de Wreede, Junfeng Wang, Lotte Wieten, Luca Vago, Jorinde Hoogenboom et al. « Association of Donor-Recipient HLA Matching with Outcome of Unrelated Donor Hematopoietic Stem Cell Transplantation : A Study from the Cellular Therapy and Immunobiology Working Party (CTIWP) of the European Society for Blood and Marrow Transplantation (EBMT) ». Blood 134, Supplement_1 (13 novembre 2019) : 3281. http://dx.doi.org/10.1182/blood-2019-125369.

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Introduction: Optimal HLA matching is associated with clinical outcome of unrelated donor (UD) hematopoietic cell transplantation (HCT)(Pidala, Blood2014, Morishima, Blood2015, Fürst, Blood2013), but a comprehensive analysis addressing this question in European transplant centers has not yet been performed. Within the CTIWP of EBMT, we have addressed this issue in adultsreceiving an UD-HCT from 2000 to 2015. Methods: All consecutive cases of UC-HCT with available 6-loci high resolution (2nd field) HLA-A, -B, -C, -DRB1, -DQB1, -DPB1 typing for both patient and donor and ARD-level matching for at least 7/8 HLA-A,B,C,DRB1 alleles reported to the EBMT were selected. Further inclusion criteria were first allogeneic HCT for hematological malignancies, patient age >=18 years, availability of donor age and use of either bone marrow or peripheral blood (PB) as stem cell source. Overall, 9575 patient-donor pairs were included from 29 countries and 198 transplant centers. Median follow-up was of 28.3 months, main diagnosis was acute leukemia (AL)(51.5%), disease stage was early in 44.1% of cases. UD-HCT were performed with PB in 84.7%, in vivo T cell depletion (TCD) in 64.4% and reduced intensity conditioning regimen in 57.3% of cases, and mostly standard graft-versus-host-disease (GvHD) prophylaxis with calcineurin inhibitors. HLA data were validated using the HLAcore library and a haplotype based probability check from the German Donor Registry. Pairs were stratified by: 1) In the overall cohort, according to HLA-A, -B, -C, -DRB1 matching status (8/8 N=7724 and 7/8 N=1851) and 2) in informative 8/8 matched pairs (N=7480), according to HLA-DPB1 matching status as identical (23.7%), permissive (26.6%) or non-permissive (32.9%) by the 3-group T Cell Epitope (TCE3) model, or by the 4-group TCE4 model (Fleischhauer, Blood2017). Primary endpoint was overall survival (OS), secondary endpoints were non-relapse mortality (NRM), relapse and acute GvHD grade II-IV, and relapse free survival (RFS). Results: At 5 years, OS and RFS in the entire cohort were 47% and 40.5%. The cumulative incidence of 5-y NRM, relapse and 1-y grade II-IV aGvHD was 28.1%, 31.4% and 19.4%, respectively. In multivariate analysis, a single mismatch at HLA-A, -B, -C, -DRB1 (7/8) was associated with a significantly higher risk of death compared to full match (8/8; HR 1.16, p<0.001). Other variables significantly associated with OS were patient (HR 1.14, p<0.001) and donor age (HR 1.08, p<0.001) per decade, CMV serostatus (HR 1.10, p=0.007), diagnosis of AL (HR 1.14, p<0.001), disease status (HR 1.22, p<0.001) and year of HCT (HR 0.98, p<0.001). The hazards of NRM, grade II-IV aGvHD and RFS were also significantly higher in 7/8 compared to 8/8 group (HR 1.34, p<0.001, HR 1.18, p<0.001 and HR 1.13, p<0.001, respectively) but not with lower risks of relapse (HR 0.96, p=0.51). In 8/8 matched HCT, when comparing with the HLA-DPB1 TCE3 permissive group, NRM were significantly higher in the non-permissive but not in the allele matched group (HR 1.17, p<0.001 and HR 0.90, p=0.15). Permissive HLA-DPB1 mismatches were associated with significantly lower relapse risks compared to allele matches but not compared to non-permissive mismatches (HR 0.85, p<0.01 and HR 0.96, p=0.433, respectively). OS was not significantly different between permissively HLA-DPB1 mismatched and allele matched pairs (HR 0.98, p=0.678.) or non-permissively mismatched pairs (HR 1.07, p=0.08). RFS was similar between the 3 groups. Stratification according to the TCE4 group model resulted in similar outcome associations. Conclusion: In this large independent cohort of UD-HCT from EBMT performed mostly from PB with in vivo TCD, a single allele mismatch at HLA-A, -B, -C, -DRB1 was independently associated with lower OS, and RFS, higher risk of NRM and aGvHD and no difference in relapse. The latter outcome was improved by permissive HLA-DPB1 mismatches in the 8/8 setting, which carried a significantly lower risk of NRM compared to non-permissive mismatches. The results from this new dataset validate current paradigms in donor selection and provide an important new platform for donor selection and HCT immunobiology. Figure: OS and RI relapse in UD-HCT. Pairs were stratified according to A) 8/8 (N=7724) and 7/8 (N=1851) HLA-A,B,C,DRB1 allele mismatches, or B) HLA-DPB1 allele matches (N=2045), TCE3 permissive mismatches (N=3743) and TCE3 non-permissive mismatches (N=2838) in the 8/8. Figure Disclosures Vago: Moderna Therapeutics: Research Funding; GenDx: Research Funding. Socie:Alexion: Consultancy. Kröger:Celgene: Honoraria, Research Funding; DKMS: Research Funding; JAZZ: Honoraria; Medac: Honoraria; Neovii: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Riemser: Research Funding; Sanofi-Aventis: Research Funding. Leleu:Takeda: Honoraria; Oncopeptide: Honoraria; Karyopharm: Honoraria; Amgen: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria; BMS: Honoraria; Merck: Honoraria; Sanofi: Honoraria. Bonini:Novartis: Consultancy; -: Patents & Royalties: Adoptive T cell therapy field; Intellia Therapeutics: Research Funding; Molmed: Consultancy; Intellia Therapeutics: Consultancy; TxCell: Consultancy; GSK: Consultancy; Allogene: Consultancy; Kite/Gilead: Consultancy. Chabannon:EBMT: Other: Working Party Chair, Board member; Fresenius Kabi: Other: research support; Miltenyi Biotech: Other: research support; Terumo BCT: Other: speaker's fees; Celgene: Other: speaker's fees; Novartis: Other: speaker's fees; Gilead: Other: speaker's fees, hospitalities; Sanofi SA: Other: research support, speaker's fees, hospitalities.

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Lee, Yoo Jin, Joon Ho Moon, In Hee Lee, Jae-Ho Yoon, Byung-Sik Cho, Jae-Sook Ahn, Hyeoung Joon Kim et al. « Killer Cell Immunoglobulin-like Receptor Ligand Matching Determines the Post-Transplant High Risk Groups Among Patients with Permissive HLA Mismatch in Unrelated Donor Hematopoietic Cell Transplantation ». Blood 128, n^o 22 (2 décembre 2016) : 4566. http://dx.doi.org/10.1182/blood.v128.22.4566.4566.

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Abstract Background: Human leukocyte antigen (HLA) matching between donor and recipient is a key part of successful allogeneic hematopoietic cell transplantation (allo-HCT). The HCT from the unrelated donor (UD) with one allele/antigen mismatch (MM) can be as beneficial as HCT from perfectly matched donor. For the remaining patients, the donors with permissive mismatches may be the option. In HLA-mismatched transplantation, the patient and donor can also be mismatched for their killer cell immunoglobulin-like receptor (KIR) ligands that recognize allotypic determinants shared by certain HLA class I allele groups. Recent research has accumulated evidence of the role of each HLA locus and KIR ligand MM on clinical outcomes for UD-HCT. However, HCT outcomes of the patients with permissive MM depending on KIR ligand MM (KIR-L-MM) status remain obscure in UD-HCT. In the current study, we identified permissive and nonpermissive MM allele combinations and analyzed the effects of these mismatches in combination of KIR ligand mismatches in patients with acute myeloid leukemia (AML). Methods: A total of 438 patients with AML who underwent allo-HCT from UD from 2007 to 2014 were analyzed. Alleles of patients and donors at the HLA-A, -B, -C, and -DRB1 loci were identified by the high resolution DNA typing. Nonpermissive HLA allele combinations were defined as a significant HLA risk factor for severe acute graft-versus-host disease (aGVHD). KIR-L-MM among patient-donor pairs were searched in the Immuno Polymorphism Database available at www.ebi.ac.uk/ipd/kir. Results: Median age of the patients was 45 (range 15-60) years and 117 patients (40.4%) were female. Eighty-five (19.4%) patients were high risk at the time of HCT. Reduced intensity conditioning was performed in 131 patients (29.9%) and anti-thymocyte globulin was used in 324 patients (74.0%). Primary graft source was peripheral blood stem cells (n=369, 84.2%) and median 6.0 x 106/kg cells were infused. Severe aGVDH occurred in 43 patients (9.8%) and chronic GVHD (cGVHD) in 193 (44.1%). With median follow-up duration of 19 (range, 2-96) months, treatment-related mortality (TRM) occurred in 111 patients (25.3%), relapse in 119 (27.2%) and death in 214 (48.9%). Two-hundred sixty-four patients (60.3%) were HLA full matched in the 4 loci. Mismatches in HLA-A loci observed in 64 patients, HLA-B in 35, HLA-C in 98, and HLA-DRB1 in 60. Five nonpermissive MM pairs in 33 patients were identified as donor/patient pair: A*02:06/A*02:01, C*03:03/C*08:01, C*08:01/C03:04, C*08:01/C*15:02, and DRB1*04:03/DRB1*04:05. Among 98 patients with HLA-C loci MM, 16 patients showed KIR ligand MM (KIR-L-MM) as GvH direction, which was observed in the permissive MM group. Severe aGVHD occurred in 30.4%, 22.4%, 13.4%, and 10.8% in nonpermissive, permissive MM and KIR-L-MM, permissive MM and KIR-L-M, and full match group, respectively (p=0.003). The 3-year overall survival (OS) rate was inferior in permissive MM and KIR-L-MM group (30.0%) compared to full match (53.5%), permissive MM and KIR-L-M (51.8%), and nonpermissive (42.4%) group (p=0.067). The 3-year TRM was higher in permissive MM and KIR-L-MM group (57.5%) than full match (21.0%), permissive MM and KIR-L-M (27.7%), and nonpermissive (33.3%) group (p=0.006). In the multivariate analysis, high risk at HCT (HR 2.087, p<0.001), severe aGVHD (HR 3.851, p<0.001), and cGVHD (HR 0.321, p<0.001) were identified as variables affecting the OS. The following variables adversely affected on TRM: permissive MM and KIR-L-MM group (HR 2.699, p=0.007), severe aGVDH (HR 2.204, p=0.001), and cGVHD (HR 2.052, p<0.001). Non-permissive MM (HR 7.487, p=0.001) and CD34+ cells >6x106/kg (HR 4.113, p=0.017) were high risk factors on severe aGVHD. Conclusion: Permissive MM for HLA could be further classified into high risk groups with regard to TRM by KIR-L matching in UD-HCT. The evaluation of KIR-L matching is warranted to reduce unfavorable outcomes among the patients with permissive MM in UD-HCT. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

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Sandhu, Karamjeet S., Ketevan Gendzekhadze, Dongyun Yang, Ryotaro Nakamura, Sally Mokhtari, Monzr M. Al Malki, Haris Ali et al. « Prediction of Graft-Versus-Host Disease in Recipients of Single Mismatched Unrelated Hematopoietic Cell Transplantation Donor Using a Highly Multiplexed Proteomic Assay, MHC-Pepseq ». Blood 138, Supplement 1 (5 novembre 2021) : 1808. http://dx.doi.org/10.1182/blood-2021-153597.

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Abstract Graft-versus-host disease (GVHD) remains a major cause of treatment failure after allogeneic hematopoietic cell transplantation (alloHCT). In HLA-mismatched donor setting, indirect presentation of allogeneic peptides from recipient's mismatched HLA class I or II proteins by donor or recipient antigen presenting cells can be an immunogenic driver of GVHD. However, the potential diversity of such antigens is large, and predicting them in a systematic manner has proven challenging. Using a novel, highly-multiplexed peptide-MHC binding assay (MHC-PepSeq) we sought to 1) identify allogeneic peptides derived from mismatched HLA protein that can be efficiently presented by HLA-DR, and 2) explore the possibility that the frequency of these HLA-DRB1 binding allopeptides may be predictive of clinical GVHD in HLA-DPB1 mismatched donor/recipient pairs. Using publicly-available population allele frequency data (allelefrequencies.net), we identified a set of class I and II sequences that cover >95% of alleles at each of 9 human HLA-loci (-A, -B, -C, -DRA1,-DRB1, -DQA1, -DQB1, -DPA1, -DPB1) in 3 major US populations (European Caucasian, African American, Mexican Chicano). When represented in the form of densely overlapping tiled 15-mer peptides, 7,744 unique 15mers were identified. We encoded these peptides into DNA oligonucleotides and used the PepSeq parallel synthesis protocol to generate a library of the corresponding DNA-barcoded peptides. The library was incubated with recombinantly-expressed full-length HLA proteins, washed, eluted, amplified, and sequenced to identify the various HLA-derived peptides that bind to the assayed HLA proteins (Figure 1). In the current study, DPB1-derived allopeptides in the setting of HLA-A, B, C, DRB1, and DQB1 (10/10) matched unrelated (MUD) HCT donors with a mismatch in DPB1 were investigated. The peptide library was assayed for binding to the DRB1*07:01 protein, selected since it was the common allele in this cohort. We identified 327 patients who were transplanted at our center and met these criteria. For each case, we used comprehensive in silico tiling to identify HLA-DPA and DPB-derived peptides present in the recipient but absent in the donor. This set was intersected with the peptides identified as binders to HLA-DRB1*07:01 in the 7,744-plex MHC-PepSeq assay, to arrive at a donor-recipient pair-specific set of 'allopeptides' Overall, we identified such allopeptide at the median of 0 (range: 0-8) across the 327 cases. Next, we examined an association between the number of allopeptides and acute GVHD in the cohort of 94 patients with positive HLA-DRB1*07:01. Median age at alloHCT was 60 years (range: 19-78), 53% males, 1.% bone marrow graft and only 7% female to male donors. Ablative (TBI) conditioning was delivered to 34%) pts. 83% received Tacrolimus/Sirolimus-based, and 9% received post-transplant cyclophosphamide-based GVHD prophylaxis. Patient/HCT characteristics are summarized in Table 1. In this cohort, 18% had no DPB1 mismatch, 54% had a single and 28% had double mismatches, with 21% pts carrying non-permissive DPB1 mismatches. Allopeptide score was 0 in 75% of pts. Non-permissive mismatch 9 (39%) vs. 11 (16%) were more likely to have allopeptide score ≥1 and similarly double mismatches 11 (48%) vs. 15 (21%) were more likely to have allopeptide score of ≥1. Among pts with ≥1 allopeptide score 14 (61%) had DPB1 matched or permissive mismatch. The cumulative incidence of grade 2-4 acute GVHD was 40.8% (range: 29-52) in pts with no allopeptides from DPB1 compared with 56% (range: 34-74) in those with ≥1 allopeptides (p=0.259) (Figure 2). The cumulative incidence of grade 3-4 acute GVHD and chronic GVHD were similar between allopeptide 0 vs. ≥1. Together, we show that the "MHC-PepSeq" assay can identify novel candidate HLA-derived allopeptides in 10/10 MUD HCTs. The number of such peptides are relatively low - with a majority having no allopeptide. In an exploratory analysis in a selected cohort of patients with HLA-DRB1*0701 in the setting of 10/10 MUD HCT, the number of allopeptides in our assay may be predictive of GVHD. The expanded analyses on other HLA-DRB1 restriction elements are underway. Figure 1 Figure 1. Disclosures Al Malki: CareDx: Consultancy; Hansa Biopharma: Consultancy; Neximmune: Consultancy; Jazz Pharmaceuticals, Inc.: Consultancy; Rigel Pharma: Consultancy. Ali: BMS: Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees. Forman: Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company; Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Allogene: Consultancy.

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Beelen, Dietrich W., Pietro Crivello, Andreas Heinold, Sabine Riebschläger, Falko M. Heinemann, Vera Rebmann, Monika Lindemann, Hellmut Ottinger, Peter Horn et Katharina Fleischhauer. « The Functional Distance Between Mismatched HLA-DPB1 Increases Risks of Relapse and Mortality after Unrelated Donor Hematopoietic Cell Transplantation for AML, ALL and MDS : A Refinement of the T Cell Epitope Group Algorithm for Permissive Mismatches ». Blood 126, n^o 23 (3 décembre 2015) : 4288. http://dx.doi.org/10.1182/blood.v126.23.4288.4288.

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Abstract Background: We and others have previously shown that non-permissive T cell epitope (TCE) group mismatches at HLA-DPB1 are associated with the risks of mortality after hematopoietic cell transplantation (HCT) from 10/10 HLA-matched unrelated donors (Fleischhauer et al, Lancet Oncol 2012; Pidala et al, Blood 2014). Moreover, we recently reported that TCE groups are reflected by a numerical score assignable to each HLA-DPB1 allele based on the combined median impact of 12 naturally occurring amino acid substitutions (AAS) on allorecognition of HLA-DPB1*09:01 as reference, termed functional distance (FD) (Crivello et al, Biol Blood Marrow Transplant 2015). Here we studied the association between the Delta in FD scores of HLA-DPB1 alleles present in the patient and in the donor (Delta-FD), and the clinical outcome of unrelated HCT. Methods: 417 consecutive adult patients transplanted from a 10/10 HLA-matched unrelated donor AML (n=302 [72%]), ALL (n=58 [8%]), or MDS (n=57 [14%]) at the University Hospital Essen between the years 2005 and 2014 were included in the analysis. 37 pairs were matched for both HLA-DPB1 alleles (12/12 HLA matches) while the remaining 380 pairs were HLA-DPB1 mismatched. Among the latter, Delta-FD scores were calculated as the absolute number of [FDpatient-FDdonor] on the basis of previously described FD scores for each HLA-DPB1 allele (Crivello et al, Biol Blood Marrow Transplant 2015). Results: The median Delta-FD score of HLA-DPB1 mismatched pairs was 1.64 (0.01-7.46). Receiver Operator Curves indicated stratification into 2 subgroups with Delta-FD scores <=2.665 (n=253 [66%]) and >2.665 (n=127 [34%]) as the best predictor of overall survival (OS). The 2 subgroups showed no significant differences for the distribution of major variables including diagnosis, disease status at transplant, immune prophylaxis and conditioning regimen, except for the percentage of permissive HLA-DPB1 TCE mismatches which was significantly higher in the subgroup with Delta-FD scores <=2.665 (p<0.0001). With a median follow-up of 4 yrs for surviving pts, the 5-yrs OS in the entire HLA-DPB1 mismatched cohort was 48%. In the 2 Delta-FD subgroups, the Kaplan-Meier (KM) probabilities of OS were 52% for Delta-FD <=2.665 and 38% for Delta-FD >2.665 (p<0.008), compared to 50% and 44% (p=0.31) for permissive and non-permissive TCE mismatches, respectively. In multivariate analysis, independent predictors of OS were time-dependent acute GvHD (HR 3.41, p<0.0001) and chronic GvHD (HR 0.41, p<0.0001), the use of anti-thymocyte globulin (HR 0.58, p=0.0006), disease status at transplant (HR 1.27, p<0.007), patient age (HR 1.63 p<0.007), and the stratified Delta-FD score (HR 1.51, p<0.007). Moreover, Delta-FD scores >2.665 were associated with lower probability of event-free survival (HR 1.48, p<0.007), due to significantly higher risks of disease relapse (HR 1.52, p<0.03) and NRM (HR 1.50, p<0.045), but not of acute or chronic GvHD. No significant differences were observed for any of the endpoints between 12/12 HLA-matched and 10/10 HLA-matched pairs with Delta-FD <=2.665. Conclusion: Stratification of HLA-DPB1 mismatches according to Delta-FD scores between donor and recipient represents a refinement of our previously published TCE algorithm of non-permissive mismatches with significant overlaps. In comparison to the latter, Delta-FD scores showed improved associations with the risks of mortality and relapse after 10/10 HLA-matched unrelated HCT in the patient cohort analyzed. If confirmed, these findings could provide a refined tool for donor-recipient matching for HLA-DPB1, and suggest that the combined impact of key AAS on T-cell alloreactivity, rather than AAS at individual positions, are relevant parameters for risk prediction in HLA-DPB1 mismatched HCT. Disclosures No relevant conflicts of interest to declare.

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Iwasaki, Makoto, Junya Kanda, Hidenori Tanaka, Takero Shindo, Noriko Doki, Takahiro Fukuda, Yukiyasu Ozawa et al. « Impact of Human Leukocyte Antigen Epitope Matching on Outcomes after Unrelated Bone Marrow Transplantation ». Blood 138, Supplement 1 (5 novembre 2021) : 3914. http://dx.doi.org/10.1182/blood-2021-145686.

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Abstract Background The immunological effect of human leukocyte antigen (HLA) disparity has not been fully elucidated by the number and locus of HLA antigens or alleles. Several methods to predict epitopes recognized by the immune system have been developed to understand the immunogenicity of amino acid sequences in mismatched HLA pairs. We investigated the association between mismatching of HLA antibody-identified epitopes and hematopoietic stem cell transplantation (HSCT) outcomes. Patients and Methods This was a retrospective cohort study with 9,991 patients who underwent their first HSCT for hematologic malignancies from unrelated bone marrow donors in the Transplant Registry Unified Management Program (TRUMP). HLA epitope mismatches (EMM) were quantified using HLA-matchmaker (HLAMM). We conducted a multivariate analysis using Cox proportional hazard regression for the overall survival and the Fine-Gray regression model for competing risks. Statistical analyses were performed with Stata version 15.1 and R version 4.0.2. Results The median follow-up period for survivors was 6.3 years (interquartile range [IQR], 2.5-9.2 years). The most common indication for HSCT was acute myeloid leukemia (n=3,917, 39.2%), followed by acute lymphoblastic leukemia (n=1,913, 19.2%), and mature lymphoid malignancies (n=1,906, 19.1%). HSCT from HLA-matched, HLA 1 allele mismatched, and HLA 2 or more allele mismatched donors was received by 6,200, 2660, and 1131 patients, respectively. The number of EMM in recipient-donor pairs in our study population ranged from 0 to 37 in HLA class I (median, 0) and 0 to 60 in HLA class II (median, 1). Patients were categorized into two groups, low and high EMM, using the median value for each epitope matching as the threshold. Higher HLA class I EMM in the graft-versus-host (GVH) direction was associated with a significantly higher risk of grade III-IV acute GVHD (aGVHD) (hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.21-2.36). Higher EMM for both class I and class II in the host-versus-graft (HVG) direction was associated with a significantly longer time to neutrophil engraftment (HR 0.78, 95% CI 0.65-0.95). In subgroup analysis limited to HLA 1 allele mismatch, class I high EMM group in the GVH direction had a significant association with higher risk for grade II-IV and grade III-IV aGVHD compared with both class I and class II low-EMM group (HR 1.69, 95% CI 1.16-2.47). Patients with HLA-C EMM accounted for 94.5% (n=1,603) of patients with HLA class I EMM. We further investigated the impact of HLA-C on severe aGVHD in relation to other known high-risk mismatch patterns. All killer immunoglobulin-like receptor (KIR)-ligand mismatched recipient-donor pairs (n=376) had HLA-C EMM. In multivariate analysis, patients with KIR-ligand mismatches and EMM did not show a higher incidence of grade III-IV aGVHD compared with KIR-ligand-matched patients with EMM (HR 0.96, 95% CI 0.74-1.25). In addition to the known high-risk mismatch patterns in the Japanese cohort (Kawase et al. Blood. 2007, Morishima et al. Haematologica. 2016), EMM was associated with a higher risk for grade III-IV aGVHD (Figure 1A, compared with HLA-C allele-matched patients (Match), HLA-C allele-mismatched patients without antigen mismatches, and EMM (group A): HR 0.78, 95% CI 0.41-1.48; HLA-C antigen-mismatched patients without EMM (group B): HR 0.56, 95% CI 0.28-1.15; HLA-C epitope-mismatched patients without high-risk mismatches (group C): HR 1.67, 95% CI 1.44-1.95; Patients with high-risk mismatches other than patient mismatched HLA-C*14:02 (group D): HR 2.01, 95% CI 1.50-2.69; Patients with patient mismatched HLA-C*14:02 (group E): HR 3.38, 95% CI 2.39-4.78). HLA-C epitope-mismatched patients without high-risk mismatches also showed a higher incidence of non-relapse mortality (NRM) and lower overall survival (OS) than HLA-C allele-matched patients (NRM (Figure 1B): HR 1.39, 95% CI 1.25-1.54; OS (Figure 1C): HR 1.20, 95% CI 1.10-1.30). Conclusion HLAMM-based epitope matching might be useful for identifying high-risk groups who can develop serious complications after HSCT from HLA-mismatched unrelated donors. In the HLA-C locus, epitope-mismatched recipient-donor pairs are non-permissive mismatched patterns along with known high-risk amino acid substitutions. Our findings might be helpful for clinicians in selecting permissive donors from alternative donor options. Figure 1 Figure 1. Disclosures Iwasaki: Amgen Astellas BioPharma: Honoraria; Astellas Pharma Inc.: Consultancy, Honoraria; Bristol-Myers Squibb Co: Honoraria; CHUGAI PHARMACEUTICAL Co., Ltd.: Honoraria; DAIICHI SANKYO Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; Janssen Pharmaceutical K.K.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin Co., Ltd.: Honoraria; Megakaryon Co: Honoraria, Membership on an entity's Board of Directors or advisory committees; NextGeM Inc: Patents & Royalties; Novartis Pharma K.K.: Honoraria; Ono Pharma Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Sanofi K.K.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; SymBio Pharmaceuticals, Ltd.: Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceutical Company Limited: Honoraria, Membership on an entity's Board of Directors or advisory committees; TEIJIN PHARMA LIMTED.: Honoraria. Uchida: Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Novartis Pharma Inc.: Honoraria. Kataoka: Ono Pharmaceutical: Honoraria, Research Funding; Celgene: Honoraria; Eisai: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; AstraZeneca: Honoraria; Sumitomo Dainippon Pharma: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Janssen Pharmaceutical: Honoraria; Takeda Pharmaceutical: Honoraria, Research Funding; Otsuka Pharmaceutical: Honoraria, Research Funding; Asahi Genomics: Current holder of individual stocks in a privately-held company; Shionogi: Research Funding; Teijin Pharma: Research Funding; Japan Blood Products Organization: Research Funding; Bristol-Myers Squibb: Research Funding; Mochida Pharmaceutical: Research Funding; JCR Pharmaceuticals: Research Funding; MSD: Research Funding. Kanda: MSD: Honoraria; Sanofi: Research Funding; Otsuka Pharmaceutical: Honoraria, Research Funding. Ichinohe: Daiichi Sankyo: Research Funding; Bristol-Myers Squibb: Honoraria; Chugai Pharmaceutical: Research Funding; CSL Behring: Honoraria, Research Funding; Eisai Co.: Honoraria, Research Funding; FUJIFILM Wako Chemicals.: Honoraria, Research Funding; Kyowa Kirin Co.: Honoraria, Research Funding; Ono Pharmaceutical Co.: Honoraria, Research Funding; Nippon Shinyaku Co: Research Funding; Otsuka Pharmaceutical Co.: Research Funding; Sumitomo Dainippon Pharma Co.: Honoraria, Research Funding; Taiho Pharmaceutical Co.: Research Funding; Takara Bio Inc.: Research Funding; Zenyaku Kogyo Co.: Research Funding; Celgene: Honoraria; Novartis Pharma K.K.: Honoraria; Repertoire Genesis Inc.: Honoraria, Research Funding; AbbVie Pharma: Research Funding; Astellas Pharma: Honoraria, Research Funding; Takeda Pharmaceutical Co.: Honoraria. Atsuta: Mochida Pharmaceutical Co., Ltd.: Speakers Bureau; Astellas Pharma Inc.: Speakers Bureau; AbbVie GK: Speakers Bureau; Kyowa Kirin Co., Ltd: Honoraria; Meiji Seika Pharma Co, Ltd.: Honoraria.

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Crocchiolo, Roberto, Elisabetta Zino, Nicoletta Sacchi, Jessica Marcon, Simona Pollichieni, Rosi Oneto, Giuseppe Bandini, Andrea Bacigalupo, Fabio Ciceri et Katharina Fleischhauer. « NON-Permissive HLA-DPB1 T CELL Epitope Disparities Correlate with Engraftment and Survival after Unrelated Stem Cell Transplantation ». Blood 112, n^o 11 (16 novembre 2008) : 562. http://dx.doi.org/10.1182/blood.v112.11.562.562.

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Abstract Over 80% of stem cell transplantations (SCT) from unrelated donors (UD) are performed across allelic HLA-DPB1 disparities which have been associated with acute graft-versus-host disease (aGvHD) and, in 10/10 matched pairs, protection from disease relapse, while no significant correlation with overall survival (OS) could be revealed so far. We have previously developed an algorithm for non-permissive HLA-DP disparities involving an immunogenic T cell epitope (TCE) encoded by DPB1*0901, *1001 and *1701 (group 1), and, in a weaker form, by DPB1*0301, *1401 and *4501 (group 2) (Zino et al, Blood 2004). Here we report on the analysis of this algorithm in 627 UD SCT facilitated through the Italian Bone Marrow Donor Registry (IBMDR) and the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) between 1999 and 2006, performed for malignant disorders including acute myeloid or lymphoid leukaemia (n=320; 51%) and Hodgkin’s or non-Hodgkin’s lymphoma (n=86; 13.7%). 242 pairs (38.5%) were matched at the allelic level for HLA-A, B, C, DRB1 and DQB1 (10/10 allele-matched pairs), while the remaining 385 pairs (61.5%) presented at least one mismatch at either of these loci (<10/10 matched pairs). Non-permissive DPB1 TCE disparities were determined by either considering both group 1 and group 2 DPB1 alleles (“2-group model”), or group 1 alleles only (“1-group model”). In line with DPB1 allelic frequencies in the Italian population, non-permissive DPB1 TCE disparities were present in 40% of pairs according to the 2-group model, and in 16% of pairs according to the 1-group model. In the 10/10 matched pairs, the Cox regression probability of engraftment was significantly reduced by the presence of non-permissive TCE disparities in the 2-group model (HR=0.23; C.I. 0.07–0.70, p=0.01) and in the 1-group model (HR=0.25; C.I. 0.08–0.75, p=0.01). Importantly, in the 10/10 matched pairs, the adjusted Cox regression hazards of transplant related mortality (TRM) were significantly increased by the presence of non-permissive TCE disparities in the 2-group model (HR=1.72; C.I. 1.09–2.70, p=0.02) and in the 1-group model (HR=1.71; C.I. 1.01–2.92, p=0.05), resulting in a significant increase in the hazards of overall mortality in the 1-group model (HR=1.66; C.I. 1.07–2.58, p=0.02) which was marked but not statistically significant in the 2-group model (HR=1.38; C.I. 0.96–1.98, p=0.08). These effects of non-permissive TCE DPB1 disparities were completely abrogated by the additional presence of one or more mismatches at either of the other five HLA loci in the <10/10 matched group. Interestingly, the estimated cumulative incidence probability of TRM and OS was similar in the 10/10 matched pairs with non-permissive DPB1 TCE disparities according to the 2-group model and in the <10/10 matched pairs regardless of DPB1 matching status, and worse in the presence of DPB1 TCE disparities according to the 1-group model. No impact of non-permissive DPB1 disparities on the hazards of aGvHD grade 2–4 or disease relapse were observed in neither of the two models. Taken together, our data show, for the first time, a significant association between HLA-DP matching status and survival in UD SCT, suggesting that the avoidance of non-permissive DPB1 TCE disparities according to the 2-group model and, even more so, according to the 1-group model, could significantly improve the clinical success of this treatment by reducing transplant mortality.

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Solomon, Scott R., Michael A. Aubrey, Xu Zhang, Allison Piluso, Brian M. Freed, Stacey Brown, Katelin C. Jackson et al. « Selecting the Best Donor for T Cell-Replete Haploidentical Transplantation : Importance of HLA Disparity, NK Alloreactivity, and Other Clinical Variables ». Blood 130, Suppl_1 (7 décembre 2017) : 670. http://dx.doi.org/10.1182/blood.v130.suppl_1.670.670.

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Abstract Lack of a matched sibling or unrelated donor can be a significant barrier to allogeneic hematopoietic cell transplantation (HCT). Haploidentical (haplo) donors are readily available for nearly all such patients. However, donor selection criteria to determine the optimal haplo donor are not readily available. In order to determine which donor characteristics are most important in predicting transplant success, we retrospectively analyzed 208 consecutive donor-recipient pairs receiving haplo HCT with post-transplant cyclophosphamide for hematologic malignancy. Donor characteristics were evaluated by multivariate Cox analysis and correlated with overall survival (OS), disease-free survival (DFS), relapse/progression, and non-relapse mortality (NRM), while controlling for significant patient and transplant-related factors. Donor variables analyzed included age, sex, relationship to recipient, CMV status, ABO compatibility, HLA disparity and several NK alloreactivity models (KIR receptor-ligand, ligand-ligand, haplotype, B content, activating KIR-based education systems, Sekine donor licensing model). Median (range) recipient and donor age was 52 (19-75) and 38 (15-73) years respectively, and 41% of donor-recipient pairs were non-Caucasian. Patients were transplanted for AML (34%), MDS/MPS/CML (20%), ALL (17%), NHL/HD/CLL (25%). PBSC was used as the stem cell source in 66% of patients, and conditioning intensity was myeloablative in 41%. The donor was a child, sibling, or parent in 47%, 38%, and 14% respectively. Median (range) follow-up for surviving patients was 33 (7-130) months. In multivariate Cox analysis, patient/transplant characteristics associated with improved OS and DFS included recipient age <55 years, black race, CMV seronegativity, low/intermediate disease risk index (DRI), and more recent transplant year. When adjusting for significant patient/transplant variables, donor characteristics independently associated with improved overall survival included presence of HLA-DR mismatch [GVH direction] (HR 0.35, p=0.010), the presence of HLA DP non-permissive mismatch [GVH direction] (HR 0.51, p=0.033), KIR receptor-ligand mismatch (HR 0.56, p=0.023), the presence of KIR B/x haplotype with KIR2DS2 (HR 0.38, p=0.005 vs. B/x without KIR2DS2; HR 0.47, p=0.013 vs. A/A), donor CMV positivity (HR 0.49, p=0.009) and donor relation (child vs. parent - HR 0.31, p=0.016; sibling vs. parent - HR 0.48, p=0.087). Donor characteristics independently associated with reduced risk of disease relapse/progression included the presence of KIR receptor-ligand mismatch (HR 0.39, p=0.001), KIR B/x haplotype with KIR2DS2 (HR 0.43, p=0.023 vs. B/x without KIR2DS2), the presence of ≥4 (out of 10) HLA allelic mismatches [GVH direction] (HR 0.29, p=0.001), the presence of a non-permissive HLA-DP mismatch (HR 0.25, p<0.001) and the use of a non-parental donor (child vs. parent - HR 0.26, p=0.010; sibling vs. parent - HR 0.37, p=0.039). Donor characteristics associated with increased NRM included higher HLA disparity (HR 7.86, p=0.016), HLA-DR match (HR 15.99, p<0.001), absence of KIR B/x haplotype with KIR2DS2 (A/A haplotype - HR 5.03, p=0.003; B/x without KIR2DS2 - HR 3.92, p=0.034), CMV seronegativity (HR 2.99, p=0.026), and female donor-male recipient (HR 2.35, p=0.071). Adjusted 3-yr OS was improved in patients with the presence of KIR R-L mm (66% vs 50%, p=0.013), KIR B/x with KIR2DS2 (69% vs. 55% [A/A] or 43% [B/x without KIR2DS2, p=0.052 and 0.007, respectively]), HLA-DR mm (64% vs. 45%, p=0.071), and HLA-DP non-permissive mm (72% vs. 56%, p=0.026), emphasizing the importance of donor HLA and KIR typing for optimal donor selection (see figure). This large, single institution analysis demonstrates the significance of HLA-DR/HLA-DP disparity, NK alloreactivity, and other clinical variables in the donor selection process for haplo HCT. These results suggest that HLA-DP and donor KIR typing should be performed routinely in T cell-replete haplo HCT to assist in donor selection and risk stratification. Disclosures Solh: ADC Therapeutics: Research Funding; Amgen: Speakers Bureau; Celgene: Speakers Bureau.

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Arrieta-Bolaños, Esteban, Maryam Mohamaddokht, Thuja Meurer, Pietro Crivello, Amin T. Turki, Peter A. Horn, Dietrich W. Beelen, J. H. Frederik Falkenburg et Katharina Fleischhauer. « Relative Contribution of Naïve and Memory T Cells to Alloreactivity in Hematopoietic Cell Transplantation ». Blood 134, Supplement_1 (13 novembre 2019) : 1923. http://dx.doi.org/10.1182/blood-2019-130273.

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Introduction: Graft-versus-host disease (GvHD) is a major impediment to the cure of blood disorders by hematopoietic cell transplantation (HCT). GvHD is mediated by alloreactive T cells recognizing histocompatibility antigen (HAg) mismatches between patient and donor. Naïve T cells are thought to be the main mediators of alloreactive responses since, theoretically, memory T cells would have never been exposed to and selected by alloantigens, except in multiparous women or transfused individuals. Accordingly, clinical trials using naïve T cell-depleted allografts are being conducted with the aim to reduce GvHD after human leukocyte antigen (HLA)-matched HCT. However, several groups have shown that memory T cells can also mediate alloreactive responses, in particular against mismatched HLA. We hypothesized that the relative importance of naïve vs. memory T cell alloreactivity depends on the matching status of the patient-donor pair. Specifically, we reasoned that naïve-depletion strategies will be most efficient in HLA-identical sibling HCT, where minor (m)HAg presented by self-HLA are the only targets of T cell alloreactivity, but less so in HLA-matched unrelated HCT, where HLA-DPB1 mismatches (mmDPB1) are frequent and potentially recognized through molecular mimicry by both naïve and memory T cells. Methods: In order to model T cell alloreactivity to mHAg and to major HLA mismatches post HCT, we used a quantitative in vitro assay based on co-culture of responder and stimulating cells. Naïve (CD45RA+CD45RO-) and memory (CD45RA-CD45RO+) CD4+ T cells were enriched from peripheral blood mononuclear cells from healthy individuals using microbead technology to >95% purity and used as responders. Irradiated transduced HeLa cells engineered to express single HLA-DP antigens and the necessary machinery for HLA class II antigen presentation were used to stimulate CD4+ T cells. HeLa transductants expressing the autologous (i.e. DP-matched, response restricted to mHAg) or an allogeneic (mmDPB1) DP antigen were used to challenge naïve and memory CD4+ cells from each responder. After 14 days of culture, T cells were restimulated overnight and the levels of T cell response were quantified by cell surface expression of the activation marker CD137. Results: In 36 independent T cell cultures from 8 different individuals, the overall levels of alloreactivity against mHAg were significantly lower than those against mmDPB1 (mean 50.3% vs 20.7%, p<0.0001) (Figure 1A). Consistent with current concepts, alloreactivity to mHAg was significantly higher in the naïve than in the memory subset (mean 27.7% vs 10.5%, p=0.015) (Figure 1B). This was most evident in 5/8 responders (mean 38.4% vs 13.3%, p=0.016), in particular in females under 40 years of age. In 3 of the 8 responders, mHAg alloreactivity was generally low and not significantly different between the naïve and the memory subsets (mean 10.3% vs 12.9%, p=0.73). In contrast, alloreactivity against mmDPB1 was evenly distributed between the naïve and the memory subset (mean 52.1% vs 48.5%, p=0.62) in all responders, independent of age, sex or cytomegalovirus serostatus of the responder (Figure 1C). Interestingly, naïve DPB1*04:01-restricted mHAg alloreactive CD4+ T cells were able to cross-recognize the structurally similar (i.e. permissive) DPB1*04:02 (mean 43.3%) but not the dissimilar (i.e. non-permissive) DPB1*09:01 (mean 14.1%) (Figure 1D). Moreover, when purified CD4+ cells from self-DPB1*04:01 homozygous donors were challenged with DPB1*04:02 or DPB1*09:01, naïve CD4+ T cells were the main source of alloreactive responses against the permissive mmDPB1 (mean 25.0% vs 7.4% for naïve and memory cells, respectively), while both memory (mean 50.0%) and naïve (mean 46.0%) CD4+ cells elicited strong alloresponses against the non-permissive mmDPB1. Conclusion: Our data provide the first direct experimental evidence that alloreactivity against mmDPB1 is stronger than against mHAg, and importantly that it is mediated equally by naïve and memory CD4+ T cells while the mHAg response is mediated mainly by the naïve subset. However, our data also suggests that some mmDPB1 involving structurally (and hence functionally) similar alleles (in general permissive) might behave similarly to DPB1 matches. These observations should be taken into account in clinical trials aimed at improving the outcome of unrelated HCT by selective depletion of naïve T cells. Disclosures Turki: Jazz Pharmaceuticals, CSL Behring, MSD.: Consultancy; Neovii Biotech, all outside the submitted work: Other: Travel subsidies. Beelen:Medac GmbH Wedel Germany: Consultancy, Honoraria.

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Rutten, Caroline E., Simone A. P. van Luxemburg-Heijs, Edith D. van der Meijden, Marieke Griffioen, Roelof Willemze et J. H. Frederik Falkenburg. « HLA-DPB1 Mismatching Results in the Generation of a Full Repertoire of HLA-DPB1 Specific T Cell Responses Showing Immunogenicity of All HLA-DPB1 Alleles ». Blood 112, n^o 11 (16 novembre 2008) : 3504. http://dx.doi.org/10.1182/blood.v112.11.3504.3504.

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Abstract In unrelated donor hematopoietic stem cell transplantation (URD-SCT) patients are preferably transplanted with stem cells from a fully HLA matched donor, usually defined as identical for HLA-class I, -DR and -DQ. Since HLA-DPB1 is often not taken into consideration in donor selection, 80–90% of URD-SCTs are mismatched for HLA-DPB1. The role of HLA-DPB1 as transplantation antigen has been unclear, since clinical reports on the impact of matching for HLA-DPB1 on transplant outcome showed conflicting results. HLA-DPB1 mismatching has been associated with an increased risk of graft versus host disease (GVHD). However, we recently demonstrated that HLA-DPB1 specific T cells can mediate a potent graft versus leukemia effect without inducing GVHD. It has been suggested that the controversial effects of matching for HLA-DPB1 in URD-SCT could partly be explained by the assumption that not all HLA-DPB1 differences are immunogenic. This theory was based on the cross-reactive recognition of two HLA-DPB1* 09 specific T cell clones that recognized other HLA-DPB1 alleles sharing amino acids (aa) in position 8–11 of HLA-DPB1 (Zino et al, blood 2004). It was hypothesized that there would be no induction of T cell responses between individuals expressing HLA-DPB1 molecules sharing this aa sequence. This was translated into a classification of permissive and non-permissive HLA-DPB1 mismatches in order to allow a broader donor selection. To investigate whether cross-reactive recognition of other HLA-DPB1 molecules by our previously generated HLA-DPB1*02 or *03 specific CD4+ T cell clones depended on the presence of specific aa sequences we tested recognition of a panel of 14 EBV-LCL expressing 9 different HLA-DPB1 molecules. All HLA-DPB1*02 as well as all *03 specific T cell clones showed cross-reactivity with other HLA-DPB1 alleles and each T cell clone exhibited its own pattern of cross-reactivity. Two HLA-DPB1*0201 specific T cell clones with different TCR-Vβ showed also recognition of EBV-LCL expressing HLA-DPB1*1001 and *1701 or HLA-DPB1*1001, *0901 and *1601 respectively. Five HLA-DPB1*03 reactive T cells clones with different TCR-Vβ showed differential cross-recognition of EBV-LCL expressing HLA-DPB1*0101, *0601, *1101, *1301 and *1401. To identify immunogenic differences the aa sequences of the HLA-DPB1 molecules recognized by the various T cell clones were compared. The HLA-DPB1 molecules recognized by the HLA-DPB1*02 specific T cell clones shared an aa substitution at position 69 compared to the responder cell. However, HLA-DPB1*0601,*0901 and *1901 with the same substitution were not recognized by both T cell clones. This phenomenon was also observed for the HLA-DPB1*03 specific T cell clones, indicating that the cross-reactive recognition of HLA-DPB1 could not be predicted by aa sequences. Next, we analyzed the immunogenicity of various HLA-DPB1 alleles in different stimulator/responder combinations to verify the classification of permissive and non-permissive mismatches. We developed a model to generate allo-HLA-DP responses by transducing HLA-class II negative HELA cells with various HLA-DP molecules and used these cells to stimulate purified CD4+ T cells from HLA-DPB1 homozygous donors. HELA cells transduced with HLA-DPB1*0101, *0201, *0301, *0401, *0402, *0501, *0601, *0901, *1101, *1301, *1401 or *1701 were used as stimulator cells. Responder CD4+ T cells were typed HLA-DPB1* 0201, *0301, *0401 or *0402. 14 days after stimulation, CD4+ T cells were tested for recognition of the stimulator cells and of HELA cells transduced with the responder HLA-DPB1 molecule as a negative control. For these 4 responders, stimulation with 12 different HLA-DP transduced HELA cell lines resulted in specific IFN-γ production in response to the stimulator cells in 47 out of 48 stimulations. 28 CD4+ T cell lines also showed cross-reactive recognition of HELA cells transduced with at least one other HLA-DPB1 molecule. In conclusion, we showed that cross-reactive recognition of various HLA-DPB1 molecules by HLA-DPB1 specific T cells is a common observation. However, we demonstrated that cross-reactivity between HLA-DPB1 molecules by allo-HLA-DPB1 specific T cells does not exclude the generation of immune response between individuals expressing these HLA-DPB1 molecules. By generating multiple allo-HLA-DP specific T cell lines, we showed that all HLA-DPB1 mismatch combinations are immunogenic.

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Solomon, Scott R., Michael T. Aubrey, Xu Zhang, Melhem Solh, Lawrence E. Morris, H. Kent Holland, Katelin C. Jackson, Brian M. Freed, Christina L. Roark et Asad Bashey. « Optimizing Donor Selection for Haploidentical Transplantation Utilizing the Four-Group T Cell Epitope (TCE-4) Algorithm for Prediction of HLA-DPB1 Non-Permissive Mismatches ». Blood 138, Supplement 1 (5 novembre 2021) : 420. http://dx.doi.org/10.1182/blood-2021-149289.

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Abstract An HLA-DPB1 non-permissive mismatch (npmm) has been associated with higher risks of acute graft-versus-host disease and non-relapse mortality after matched unrelated donor transplantation (MUDT) and thus avoiding HLA-DPB1 npmm is important in unrelated donor selection. In contrast, HLA-DPB1 npmm by the 3-group T cell epitope algorithm (TCE-3) has been shown to be protective in the context of haploidentical donor transplantation (HIDT) using post-transplant cyclophosphamide (PTCy) (Solomon et al. BBMT 2018). Additional HLA-DPB1 "permissiveness" models, also based on cross-reactive patterns of alloreactive T cells against HLA-DPB1 alleles, include the TCE-4 (based on 4 TCE groups) and functional distance (FD, based on net difference in distance between key amino acid polymorphisms) algorithms. Lastly, an expression model is based on the surface expression of the recipient mismatched HLA-DPB1 (RDP) allele according to variants of a biallelic SNP. The present analysis had 2 major aims: to 1) determine which HLA-DPB1 permissiveness model (TCE-3, TCE-4, FD, expression) provides the best tool for haploidentical donor selection and 2) analyze the role of vector (GVH vs. HVG direction) on the effect of an HLA-DPB1 npmm. A total of 322 patients with acute leukemia, MDS, lymphoma, CLL or CML, receiving a HIDT-PTCy from a single institution were evaluated with a median follow-up time of 45 months [range 6, 184]. Baseline characteristics included a median age of 50 years [19, 80], 47% non-white, HCT-CI ≥3 in 50%, PBSC graft in 80%, and myeloablative conditioning in 49%. The number of donor-recipient pairs having an HLA-DPB1 npmm according to the TCE-3, TCE-4, FD and expression was 82 (25%), 130 (40%), 54 (17%) and 99 (31%) respectively. In univariate analysis, HLA-DPB1 npmm identified by the TCE-3 and TCE-4 models were statistically associated with improved overall survival (OS) (p=0.041 and p=0.004 respectively), whereas FD risk and RDP expression were not (see figure). For disease-free survival (DFS), only the TCE-4 model showed a statistically significant association (p=0.022). Directionality of the HLA-DP npmm (GVH vs. HVG vector) had no significant impact on survival following HIDT-PTCy, a finding similar to the context of MUDT (Fleischhauer BMT 2017). In multivariate Cox analysis, adjusting for patient/donor age, gender, race, HLA-DR mismatch and transplant year, HLA-DPB1 npmm by the TCE-4 model had the most significant association with improved OS (HR 0.59, p=0.012), with TCE-3 being less predictive (HR 0.65, p=0.07) (see figure). Furthermore, HLA-DPB1 npmm by TCE-4 led to improved DFS (HR 0.69, p=0.046) and trends for lower cumulative incidences of relapse/progression (HR 0.73, p=0.16) and NRM (HR 0.54, p=0.09). In summary, the presence of an HLA-DP npmm in either the GVH or HVG direction continues to be associated with improved survival following HIDT-PTCy in a large single institution retrospective analysis with extended follow-up. Compared to the original TCE-3 model, a TCE-4-predicted HLA-DPB1 npmm is more strongly associated with overall survival. This fact, combined with the larger number of HLA-DPB1 npmm donors identified by the TCE-4 model, suggests that it may be a better selection tool for optimal haploidentical donor identification. Figure 1 Figure 1. Disclosures Solh: Partner Therapeutics: Research Funding; Jazz Pharmaceuticals: Consultancy; BMS: Consultancy; ADCT Therapeutics: Consultancy, Research Funding.

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Morishima, Yasuo, Takakazu Kawase, Keitaro Matsuo, Koichi Kashiwase, Hidetoshi Inoko, Hiroh Saji, Shunichi Kato, Takeo Juji, Yoshihisa Kodera et Takehiko Sasazuki. « Identification of Non-Permissive HLA Allele Mismatch Combinations and Amino Acid Substitution Responsible for Acute Graft-Versus-Host Disease in Unrelated Allogeneic Bone Marrow Transplantation. » Blood 108, n^o 11 (16 novembre 2006) : 170. http://dx.doi.org/10.1182/blood.v108.11.170.170.

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Abstract Background: In the allogenic hematopoietic stem cell transplantation from unrelated donors (UR-HSCT), an effect of HLA locus mismatch in allele level on clinical outcome has been clarified. However, the effect of each HLA allele mismatch combinations is little known, and its molecular mechanism to induce acute graft versus host disease (aGVHD) remained to be elucidated. Methods: Consecutive 4866 patients transplanted with T cell replete marrow from a serologically HLA-A, -B and -DR antigen-matched donor through Japan Marrow Donor Program were registered in this cohort study. All HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1 alleles were retrospectively typed in 2171 pairs, and partly in the other pairs. The impact of the HLA allele mismatch combinations in HLA six loci and amino acid substitution positions in HLA-C and HLA-DPB1 locus on aGVHD and survival was analyzed using a multivariable Cox regression model. Results: Significant high-risk HLA allele mismatch combinations compared with match for severe aGVHD were identified; four in HLA-A allele (donor A*0206- patient A*0201 (n=108) hazard ratio (HR): 1.77, A*0206-A*0207 (n=20) : 3.24, A*2601-A*2603 (n=32): 1.96, A*2602-A*2601 (n=24): 2.18), six in HLA-B (B*1507-B*1501 (n=14): 2.95, B*4002-B*4003 (n=14): 2.44, B*4002-B*4006 (n=85): 1.69, B*4003-B*4006 (n=7): 3.85, B*4006-B*4002 (n=60): 1.62, B*4403-B*4402 (n=4) : 5.78), 11 in HLA-C, six in HLA-DRB1, zero in HLA-DQB1 and two in HLA-DPB1. Amino acid substitutions of position 80 of HLA-C at which donor had Asp80 and patient Lys80 (Asp80-Lys80) and Ser77-Asp77 were first elucidated as significant risk factors for severe aGVHD. These two amino acid substitutions were completely linked, and HR for severe aGVHD was 1.49 (1.01–2.21). As position 80 is ligand for NK cell receptor KIR2DL as a result, further analysis was performed in the KIR2DL ligand match in the GVH vector population. Notably, particular amino acid substitution at positions 95, 156 and 163 of HLA-C was a significant risk factor for severe aGVHD. HR of Leu95-Ile95, Arg156-Leu156, Leu156-Trp156, Trp156-Leu156 and Thr163-Leu163 substitutions were 1.74 (95%CI: 1.06–2.86), 2.10 (1.16–3.81), 5.22 (1.65–16.4), 4.64 (1.04–20.7) and 1.82 (1.11–2.99), respectively. The amplitude of hydropathy scales were 0.7, 8.3, 4.7, 4.7 and 4.7, respectively. Amino acid substitutions of any other positions of HLA-C were not significant risk factors. When analyzing the location of amino acid substitution in HLA-C, residues located in the T-cell receptor contact have marginal impact on severe aGVHD (HR: 1.45 trend P=0.096), and no other locations were significant. In HLA-DPB1 mismatch combinations, there was no obvious tendency to associate the positons of amino acid substitutions with severe aGVHD and grades 2–4 aGVHD. Conclusion: These findings provide evidences to elucidate the mechanism of aGVHD on the base of HLA molecule. Furthermore, the identification of non-permissive and possible permissive mismatch would be beneficial for the selection of suitable donor and international donor exchange for UR-HSCT.

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Pingel, Julia, Camila J. Hernandez Frederick, Tao Wang, Emmanuelle Polge, Michael D. Haagenson, Stephanie J. Lee, Mohamad Mohty et al. « Evaluation of the Impact of Non-Inherited Maternal Antigens on the Outcome of HLA Mismatched Unrelated Donor Hematopoietic Stem Cell Transplantation for Hematological Malignancies on Behalf of the ALWP of the EBMT and the CIBMTR ». Blood 126, n^o 23 (3 décembre 2015) : 3226. http://dx.doi.org/10.1182/blood.v126.23.3226.3226.

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Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) offers a potential cure for a variety of hematological malignancies. Patients without an HLA matched sibling donor can turn to unrelated donor registries to identify a suitably HLA matched donor. In the case where a fully HLA-A, -B, -C, -DRB1 and -DQB1 (10/10) matched donor is unavailable, there are often multiple 9/10 matched donors to select from. However, the prioritization and identification of permissive HLA mismatches in the 9/10 matched setting have proven elusive. Fetal exposure to non-inherited maternal antigens (NIMA) imparts lifelong immune modulating effects leading to tolerance to these antigens. Prior studies have found that matching for non-inherited maternal antigens (NIMA) can lead to lower rates of acute graft versus host disease (aGVHD) and lower treatment-related mortality (TRM) in cord blood HSCT (J.J. van Rood et al., Blood 2002; J. J. van Rood et al., PNAS, 2009; V. Rocha et al., BBMT, 2012). Patients undergoing mismatched HSCT with adult unrelated donors could benefit from NIMA matching by introducing maternal HLA testing during confirmatory typing of the donor and using NIMA matching as a criterion for mismatched donor selection. This joint EBMT-CIBMTR retrospective analysis was designed to evaluate the influence of NIMA matching in HSCT with mismatched adult unrelated donors. Matching criteria were based on HLA-A, -B, -C, -DRB1, -DQB1 at high resolution. Included donor-recipient pairs had 5 loci HLA typing and a minimum of one year follow-up recorded at EBMT or CIBMTR and donors were registered with DKMS German Bone Marrow Donor Center. To obtain maternal HLA typing information, DKMS contacted the respective donors by mail to inform about the study and to provide detailed information, a buccal swab kit and an informed consent form to the donor's mother that the donor could send on. SBT-based HLA typing was performed at the DKMS Life Science Lab, Dresden, Germany once signed informed consent and samples were received. A total of 1735 donors were contacted and maternal samples could be retrieved for 803 cases (46%). A total of 50 NIMA matches (6%) were found reflecting the rate expected from previous studies. Multivariate analyses were performed using Cox proportional hazards models adjusting for significant co-variates for overall survival (OS), disease free survival (DFS), relapse, TRM and acute and chronic GVHD comparing NIMA matched to NIMA mismatched cases. The final analysis population was restricted to 9/10 matched cases (N=452) transplanted for acute myeloid leukemia (N=307) and acute lymphoblastic leukemia (N=145) using myeloablative (N=307) or reduced intensity (N=145) conditioning from 1999-2013. The NIMA matched (N=32) and mismatched (N=420) groups were well balanced for all disease, patient, transplant and donor characteristics. The groups differed by mismatched HLA locus with the NIMA matched group skewed towards more HLA-C mismatches (66% vs. 35%). Univariate analyses did not find any significant differences between the NIMA matched and mismatched groups for any outcomes. TRM rates were similar between the groups at 1 year with 23% (95% CI: 10-40%) and 23% (95% CI: 19-28%) in the NIMA matched and mismatched groups, respectively. No significant associations were observed in multivariate analyses of the NIMA matched versus mismatched groups (Table). In contrast to prior studies of NIMA matched HSCT, no significant associations were found between NIMA matching and any outcomes. However, our findings may be due to the fact that the current study was underpowered to detect the expected difference in TRM observed in prior studies. Investigation on a larger cohort or a prospective trial would be needed. We thank Carlheinz Müller from the German unrelated donor registry ZKRD for providing additional HLA information and the donors and their mothers for their cooperation in this study. Table. Multivariate analysis results of NIMA matched versus mismatched (used as reference) HSCT Table 1.OutcomeHR95% CIp-valueOS0.890.54-1.480.653DFS0.880.53-1.430.598TRM0.740.35-1.600.447Relapse0.890.45-1.750.737aGVHD II-IV0.970.53-1.800.935aGVHD III-IV0.590.19-1.910.382cGVHD1.770.99-3.160.053 Disclosures Lee: Bristol-Myers Squibb: Consultancy; Kadmon: Consultancy. Nagler:Biokine LTD: Consultancy.

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Zino, Elisabetta, Luca Vago, Simona Di Terlizzi, Benedetta Mazzi, Luigi D’ Amato, Silvano Rossini, Fabio Ciceri, Maria G. Roncarolo, Claudio Bordignon et Katharina Fleischhauer. « Epitope-Specific Typing (EST) for HLA-DPB1 Matching : Proof of Principle for an Innovative Approach to Unrelated Hematopoietic Stem Cell Donor Selection. » Blood 108, n^o 11 (16 novembre 2006) : 3130. http://dx.doi.org/10.1182/blood.v108.11.3130.3130.

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Abstract Background. Conventional matching of patients and their unrelated donor (UD) hematopoietic stem cells (HSC) by 4-digit molecular HLA typing is associated with lengthy donor searches and elevated social costs. 80% of UD transplants are performed across DPB1 mismatches which, if involving disparity in host versus graft (HvG) direction for an immunogenic T cell epitope, have been shown to be associated with poor clinical outcome of transplantation for hematopoietic malignancies and beta-thalassemia. In this study we have developed an innovative approach of DPB1 epitope- rather than allele-specific matching, by only two PCR reactions (epitope-specific typing; EST). Moreover, we have determined allelic DPB1 frequencies in Italy, confronted them with the ones previously reported for other ethnic groups, and calculated the probability of finding non-permissive DPB1 mismatches in unrelated HSC donor searches. Methods. High resolution genomic DPB1 typing and EST were performed in parallel on blood samples taken from 112 healthy unrelated Italian blood donors. Results. EST of DPB1 alleles encoding the immunogenic T cell epitope yielded 100% concordant results with high resolution DPB1 typing in all 112 samples studied, and is therefore suitable to univocally determine the presence or absence of non-permissive DPB1 disparities. The overall frequency of DPB1 alleles encoding the shared T cell epitope in the Italian population was 23.15%. Importantly, we show that based on DPB1 allelic polymorphism in the four ethnic groups representative of the world-wide UD registries, over 75% of UD matched for the other HLA loci will not present a DPB1 epitope disparity in HvG direction, demonstrating that prospective UD-recipient DPB1 matching by EST does not significantly limit the number of suitable donors, and has a negligible impact on the time and cost of the search. Conclusions. EST is a challenging alternative to conventional tissue typing which, if applied more broadly to HLA loci other than DPB1, could fundamentally change current approaches to UD searches.

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Fuchs, Ephraim J., Shannon R. McCurdy, Scott R. Solomon, Tao Wang, Michelle Kuxhausen, Yvette L. Kasamon, MHD Monzr Al Malki et al. « Improving Donor Selection for Haploidentical Stem Cell Transplantation with Post-Transplant Cyclophosphamide through Selective HLA-Mis/Matching ». Blood 136, Supplement 1 (5 novembre 2020) : 24–26. http://dx.doi.org/10.1182/blood-2020-140433.

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Background HLA-haploidentical (haplo) blood or marrow transplantation (BMT) with post-transplantation cyclophosphamide (PTCy) is widely used, but few factors that inform donor selection have been identified. Based on prior observations for HLA-B leader (EW Petersdorf et al. Lancet Haematol 2020), HLA-DRB1 (YL Kasamon et al. BBMT 2010), and HLA-DPB1 (SR Solomon et al. BBMT 2018), we hypothesized that mismatching at individual HLA loci may influence BMT outcomes, but single and additive HLA gene effects have not been evaluated systematically in the context of haploBMT with PTCy. Methods The Center for International Blood and Marrow Transplant Research (CIBMTR) identified 1,434 patients who underwent T-cell-replete haploBMT with PTCy for acute leukemia or myelodysplastic syndrome (MDS) between 2008-2017. Multivariable models assessed transplant outcomes associated with 3 HLA-factors: (1) B-leader dimorphism (MM, MT, TT) matching; (2) HLA-DRB1 mismatching in the graft-versus-host (GVH) direction; and (3) nonpermissive HLA-DPB1 mismatching in the GVH direction using the T-cell epitope-3 model, which classifies HLA-DPB1 mismatches into permissive or non-permissive. All final models contained the HLA factors and adjusted for other significant clinical covariates at p<.05 in univariate analysis. P-values were not adjusted for multiple testing. Results Diagnoses were 58% AML, 23% ALL, 19% MDS. 22% of AML patients were in advanced disease stage (relevant analyses were stratified for disease stage for both acute leukemia and MDS). Median recipient age was 54 (range 1-78) years. Median follow up among survivors was 12 (range 2-119) months. Marrow was the graft source in 43% of recipients. Myeloablative conditioning was used in 45% of recipients. Fifty percent of recipients had hematopoietic cell transplantation-comorbidity index (HCT-CI) scores of ≥3. HLA-DP typing was missing in 52% of cases and thus all models had a "missing" category for HLA-DP. Mismatching in the GVH direction at HLA-A, HLA-C, or HLA-DQ was not associated with study outcomes [overall survival (OS), disease-free survival (DFS), relapse, nonrelapse mortality (NRM), or grade II-IV acute, grade III-IV acute, or chronic graft-versus-host disease (gr2-4a or cGVHD)]. When compared to leader-matched patients, HLA-B leader-mismatching was associated with worse OS and DFS (hazard ratio [HR] 1.25 [95% CI, 1.09 to 1.44]; P=.002, and HR 1.18 [95% CI, 1.03 to 1.34]; P=.01, respectively), and higher risk of NRM (HR 1.38 [95% CI, 1.10 to 1.74]; P=.005), but was not associated gr2-4a or cGVHD, or relapse. In contrast, when compared to matching at HLA-DRB1, the presence of any GVH direction mismatch at HLA-DRB1 was associated with improved DFS (HR 0.80 [95% CI, 0.68 to 0.94]; P=.007) and lower risk of relapse (HR 0.69 [95% CI, 0.56 to 0.86]; P=.0008), but with no effect on OS, gr2-4a or cGVHD, or NRM. Similarly, any nonpermissive GVH mismatching at HLA-DPB1 was also associated with improved DFS (HR 0.72 [95% CI, 0.55-0.94], p=.015) and OS (HR 0.59 [95% CI, 0.43-0.82], p=.002), with a tendency towards lower relapse (HR 0.75 [95% CI, 0.54-1.05], p=.09), but with no effect on gr2-4a or cGVHD, or NRM. When combining the effects of leader matching at HLA-B and mismatching at HLA-DRB1 there was an additive improvement in both DFS and OS (Figure 1 A and B) with significantly lower NRM (p=0.03) and relapse (p=0.008) when compared to other groups. Within this unselected large cohort, favorable haplo donors based on B-leader matching and HLA-DRB1 mismatching were used for 48.5% of recipients and had improved DFS (HR 0.68 [95% CI, 0.52 to 0.88], p=.004) when compared to B-leader mismatched and HLA-DRB1 matched pairs, suggesting that with intentional selection of donors based on these factors, even more could receive a favorable combination. Conclusion HLA-B leader mismatching is a risk factor for NRM and worse OS and DFS, whereas either HLA-DRB1 or nonpermissive HLA-DPB1 mismatch is associated with reduced relapse and improved DFS, after haploBMT with PTCy. PTCy dissociates the graft-versus-leukemia effect of HLA-DRB1 and nonpermissive HLA-DPB1 mismatching from GVHD. The best outcomes after haploBMT with PTCy are seen when a donor is HLA-B leader matched and HLA-DRB1 mismatched. When there is more than one potential haplo donor for an acute leukemia or MDS patient, selection based on HLA considerations may improve DFS and OS. Figure Disclosures Shaw: Orca Bio: Consultancy. Lee:Takeda: Research Funding; AstraZeneca: Research Funding; Novartis: Research Funding; Incyte: Consultancy, Research Funding; Syndax: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Research Funding; Kadmon: Research Funding.

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Lorentino, Francesca, Nicoletta Sacchi, Elena Oldani, Valeria Miotti, Alessandra Picardi, Anna Maria Gallina, Paolo Bernasconi et al. « Permissive HLA-DPB1 Mismatch and Survival after Unrelated Donor Allogeneic Stem Cell Transplantation for Hematological Malignancies : A Comparative Analysis of Different Immunogenetic Models on 422 Patients from GITMO and IBMDR ». Blood 132, Supplement 1 (29 novembre 2018) : 482. http://dx.doi.org/10.1182/blood-2018-99-115216.

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Abstract Introduction: Hematopoietic Stem Cell Transplantation (HSCT) from unrelated donors (UD) is a curative therapy for many hematologic malignancies. HLA matching plays a major role in determining HSCT outcome but the relative role of incompatibilities at the different HLA loci is still debated. In particular, over 80% of UD-HSCT are performed across HLA-DPB1 mismatches (mm): a number of previous studies have devised immunogenetic models to elucidate the impact of HLA-DPB1 mm on HSCT outcome, but a comparative analysis of these models in a recent and well-characterized cohort is lacking. Methods: We selected 422 adult patients (pts) who received an 8/8 (HLA-A, B, -C and -DRB1) allele level-matched UD-HSCT from 2012 to 2015: of them, 382 (90%) had a mm at one or both HLA-DPB1 alleles. We classified functional HLA-DPB1 matching by four models, on the basis of: I) differential immunogenicity of alleles belonging to 3 groups of T-cell epitopes (TCE), as defined by functional studies (Zino, Blood, 2004) and refined by in silico prediction (Crivello, BBMT 2015); II) a similar model subdividing allelles in 4 TCE groups (TCE4, Crocchiolo, Blood 2009); III) differences in "delta functional distance" scores between the alleles of donor and pt, based on 12 polymorphic AA in HLA-DPB1 exon 2 (Crivello, Blood 2016); IV) mismatches in the rs9277534 single-nucleotide polymorphism in the HLA-DPB1 3′ UTR region, predicted on the basis of the DPB1 genotype (Schöne, Hum Immunol 2018), and previously shown to be associated to the expression levels of HLA-DPB1 molecules (HLAexp, Petersdorf, NEJM 2015). Indication for HSCT was acute leukemia (55%), lymphoma and multiple myeloma (29%), myelodysplastic and myeloproliferative syndromes (16%). According to EBMT score definition, 45% of pts were in early, 26% in intermediate, and 29% in advanced disease status. Conditioning regimens were myeloablative (64%) or reduced intensity (36%). Peripheral blood was the preferred stem cell source (81%). Graft-versus-host disease (GvHD) prophylaxis was based on anti-thymocyte globulin (ATG) in 91% of pts, mostly associated with cyclosporine and methotrexate (81%). Median follow-up was 3.2 y. Results: Among the four models adopted to classify functional HLA-DPB1 matching, the TCE4 provided the best results in predicting mm that were permissive (P) or non permissive (NP) for HSCT outcomes. By this model, P mismatched pairs (N=135) had a significantly superior 3-y overall survival (OS) and Graft-versus host disease and Relapse-Free Survival (GRFS) compared to NP pairs (N=247) (60±8% vs 49±7%, p .05; and 36±8% vs 29±5%, p .04). This was associated with a higher transplant-related mortality (TRM), 30±6% in NP mm and 21±6% in P mm, p .09 and a higher 3-y CI of extensive cGvHD in NP mm (12±4%) compared to P (4±2%), p .01 (Figure 1). No effect was found for relapse incidence. Cox multivariate analysis (adjusted for pt age, donor/host gender and CMV, disease status, Sorror score, conditioning intensity, stem cell source, ATG use, HLA matching on 5 loci, center effect), showed that a NP mm compared to P mm was associated with higher hazards for OS (HR 1.6, p .01), GRFS (HR 1.4, p .02), TRM (HR 1.9, p .01), cGvHD (HR 1.6, p .03) and extensive cGvHD (HR 3.6, p <.01). No interaction was found between HLA matching on 5 loci and HLA-DPB1 permissivity predicted by TCE4. Directionality of NP mm did not impact on clinical risk stratification. Of the 382 transplants with HLA-DPB1 mismatches, 229 had unidirectional mismatches in GvH direction and thus could be classified by the HLAexp model. The predicted expression level of the mismatched allele in the patient was associated with 100-d CI of grade≥2 aGvHD: 32±10% in high expression (N=76) versus 16±6% in low expression (N=153) mismatched alleles, p <.01. This was also confirmed in adjusted Cox multivariate analysis for grade≥2 aGvHD (HR 2.2, p <.01). However, this did not have a significant impact on severe aGvHD, TRM and OS. No significant associations with clinical outcomes were found for the "delta functional distance" or the TCE3 model, respectively. Conclusions: Our study provides further proof that functional HLA-DPB1 matching is crucially associated to UD-HSCT outcome also in recent transplants, and suggest that, at least in the cohort under analysis, mainly composed of Italian pts transplanted using an ATG-based prophylaxis, the TCE4 model appears superior to other models in stratifying risk groups and predicting survival. Figure. Figure. Disclosures Patriarca: Medac: Other: Travel, accommodations, expenses; Jazz: Other: Travel, accommodations, expenses; Celgene: Other: Advisory Role; Travel, accommodations, expenses; Janssen: Other: Advisory role; MSD Italy: Other: Advisory Role. Rambaldi:Italfarmaco: Consultancy; Roche: Consultancy; Omeros: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Amgen Inc.: Consultancy. Fleischhauer:GENDX: Research Funding. Vago:GENDX: Research Funding; Moderna TX: Research Funding.

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Ducreux, Stephanie, Valérie Dubois, Pascal Loiseau, Ibrahim Yakoub-Agha, Myriam Labalette, Mauricette Michallet, Marie t. Rubio et al. « Association Between Multiple Mismatches at the HLA-DPB1 and DRB3/4/5 Genes and Adverse Outcomes in HLA-a, -B, -C, -DRB1 and -DQB1 Identical Hematopoietic Stem Cell Transplantation : A Study on Behalf of the Francophone Society of Stem Cell Transplantation and Cellular Therapy (SFGM-TC) and the Francophone Society for Histocompatibility and Immunogenetics (SFHI) ». Blood 128, n^o 22 (2 décembre 2016) : 4660. http://dx.doi.org/10.1182/blood.v128.22.4660.4660.

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Abstract Background: Matching for all alleles of the HLA-A, -B, -C, and -DRB1 loci (8/8 match) is associated with the highest overall survival (OS) rates after unrelated donor (URD) hematopoietic stem cell transplantation (HSCT). In Europe, patients (pts) are also matched at the HLA-DQB1 loci (10/10 match) with no overall evidence of improved OS. HLA-DPB1 mismatching has been associated with a higher risk of acute graft-versus-host disease (aGvHD) and a decreased risk of relapse. A detrimental role of additional HLA-DQB1, HLA-DPB1 and HLA-DRB3/4/5 mismatches (MM) has been recently identified on OS but only in 7/8 HLA-A, -B, -C, and -DRB1 loci URDs HSCT. We investigated the impact of HLA-DPB1 and HLA-DRB3/4/5 MM on outcomes in a large cohort of 10/10 matched URD HSCTs. Patients and methods: 2,393 pts who received an initial HSCT from a 10/10 matched URD in 35 French centers were included between January 2000 and October 2012. Informed consent was obtained in accordance with the Declaration of Helsinki. High-resolution typing was performed for HLA-A, -B, -C, -DRB1, -DQB1, -DPB1 and -DRB3/4/5 loci for all donor/recipient pairs. Clinical data were obtained through ProMISe (Project Manager Internet Server), an internet-based system shared by all French transplantation centers. Impact of HLA-DRB3/4/5 and -DPB1 MM was quantitatively and qualitatively evaluated. For quantitative evaluation, patients were classified into 5 different groups according to their global matching level for the 7 considered loci (14/14, 13/14, 12/14, 11/14, 10/14). For qualitative evaluation, MM type and directionality (GvH and host versus graft (HvG) directions) were evaluated. HLA-DPB1 MM were classified as permissive or non-permissive (K Fleischhauer, Lancet Oncol. 2012). The primary composite endpoint for the analysis was GvHD-free and relapse-free survival (GRFS). We defined early GRFS as being alive at 3 months after HSCT with no previous grade III-IV aGvHD and no relapse and late GRFS as being alive >3 months with no previous grade III-IV aGvH, no relapse and no moderate or severe chronic GvHD (cGvHD). Late GRFS was evaluated at months 6, 12, 24 and 36 after HSCT. Acute GvHD, cGvHD, relapse and OS were also studied. Models were adjusted for HSCT period, disease risk, age, sex matching, stem cell source, and conditioning regimen. Results: Table 1showspopulation characteristics and distribution of cumulative MM. The median follow-up was 59 months. Compared to 14/14 pairs, quantitative evaluation showed a significantly lower early GRFS for pts who received a 10-11/14 (Hazard Ratio HR 2.0, 95% CI 1.4 to 2.9, p=0.0003) or a 12/14 URD HSCT (HR 1.4, 95% CI 1.1 to 1.8, p=0.01). This was related to a significantly increased risk of grade III-IV aGVHD associated with 10-11/14 (HR 2.3, 95% CI 1.5 to 3.7, p=0.0004) and 12/14 pairs (HR 1.7, 95% CI 1.2 to 2.4, p=0.003). 10-11/14 pairs were also associated with a higher risk of death at 3 months (HR 2, 95% CI 1.1 to 3.6, p=0.024). Qualitatively, in pts matched for HLA-DRB3/4/5 but MM for HLA-DPB1 (n=1846, 77.1%), 2 HLA-DPB1 MM and non-permissive HLA-DPB1 MM were associated with a lower early GRFS (HR 1.4, 95% CI 1.1 to 1.9, p=0.01 and HR 1.3, 95% CI 1.0 to 1.7, p=0.02 respectively) due to an increased risk of aGvHD (HR 1.7, 95% CI 1.2 to 2.5, p=0.002 and HR 1.50, 95% CI 1.08 to 2.08, p= 0.017 respectively). Outcomes were not influenced by either GvHD or HvG mismatch directions. Late GRFS analyses once adjusted were not significantly different according to MM numbers, type and directions. Only 19 pairs (0.8%) were DPB1 matched and DRB3/4/5 mismatched (high linkage disequilibrium between DRB3/4/5 and DRB1); HLA-DRB3/4/5 MM could thus not be qualitatively analyzed. Conclusion: MultipleHLA-DPB1 and HLA-DRB3/4/5 MM have an early impact after 10/10 matched URDs HSCT. The best outcomes are seen in 13 and 14/14 pairs. Early GRFS is significantly impacted by 10-11/14, 12/14, 2 DPB1 MM as well as non-permissive HLA-DPB1 MM URD HSCT which is related to an increased risk of grade III-IV aGvHD. There is a significantly increased risk of mortality for 10-11/14 pairs at 3 months. Prospective evaluation of matching for HLA-DPB1 and HLA-DRB3/4/5 is warranted to reduce early post-HSCT toxicity in donor-recipient 10/10 matched pairs. Disclosures Michallet: Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Astellas Pharma: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria. Peffault De Latour:Pfizer: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Research Funding.

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Fleischhauer, K., K. W. Ahn, H. L. Wang, L. Zito, P. Crivello, C. Müller, M. Verneris et al. « Directionality of non-permissive HLA-DPB1 T-cell epitope group mismatches does not improve clinical risk stratification in 8/8 matched unrelated donor hematopoietic cell transplantation ». Bone Marrow Transplantation 52, n^o 9 (5 juin 2017) : 1280–87. http://dx.doi.org/10.1038/bmt.2017.96.

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Gaziev, Javid, Antonella Isgro, Katia Paciaroni, Marco Marziali, Gioia De Angelis, Michela Ribersani, Cecilia Alfieri et Marco Andreani. « Outcomes of Unrelated Bone Marrow Transplantation in Patients with Thalassemia ». Blood 132, Supplement 1 (29 novembre 2018) : 5777. http://dx.doi.org/10.1182/blood-2018-99-109764.

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Abstract Introduction. Bone marrow transplantation from an HLA-matched related or unrelated donor remains the only curative treatment for patients with thalassemia. Although one third of patients with thalassemia can find a matched unrelated donor (MUD) few patients were treated by MUD transplantation. Early experience with the use of MUD transplant in class 3 patients with thalassemia resulted in high rates of graft rejection and transplant-related mortality with thalassemia-free (TFS) survival of 53% (La Nasa G et al. Blood 2002). Significant improvements in MUD transplantation in recent years have prompted us to consider it also for high risk patients with thalassemia. Methods . All patient-donor pairs were typed at high resolution for HLA-A, -B, -C, -DRB1, -DQA1, -DQB1, and DPB1. Fourteen consecutive patients with a median age of 5 years (range, 2-17.2) received unrelated bone marrow transplantation for thalassemia. Four patients were in class 1, 2 were in class 2 and 8 were in class 3 of risk. All patients were treated with the conditioning regimen consisting of weight-based IV Bu, thiotepa (10 mg/kg/d), CY (200 mg/kg) and thymoglobulin (10 mg/kg) preceded by preconditioning with hydroxyurea (30 mg/kg/d), azathioprine (3 mg/kg/d) from D −45, and fludarabine (30 mg/m2/d) from D −16 through D −12. Patients received CSA, methylprednisolone and a short course of MTX as GVHD prophylaxis. Results. Between May 2009 and December 2017 un unrelated donor search was performed for 47 patients at our Institute. Forty one patients were Caucasian and 6 patients black African origin. Among Caucasians 16/41 (39%) found a 10/10 and 5/41 (12%) a 9/10 HLA allele-matched unrelated donor, while 1 of 6 black African patients (16.6%) found a 10/10 HLA-matched donor. Among 22 patients with a suitable donor (10/10 or 9/10 HLA allele-matched) 14 received transplantation, 2 patients withdrew consent, 1 patient's donor refused donation, and the remaining 5 patients are awaiting transplant. Twelve patients received 10/10 and 2 patients 9/10 HLA allele-matched grafts. Eight patients had permissive DPB1 mismatches while 2 patients had non-permissive mismatches in the HvG direction and 4 patients in the GvH direction. Median TNC/kg and CD34+/kg infused were 7.2x108 (range, 3.95-12.5) and 7.75x106 (range, 3.47-16.4), respectively. Sustained engraftment occurred in all patients. The median time to neutrophil and platelet recovery was 20 days (range, 15-27) and 19 days (range, 15-28), respectively. All but one patient showed 100% donor chimerism. The patient with stable mixed chimerism (48% donor DNA) has remained transfusion independent for over 3 years with hemoglobin levels >13.5-14 g/dL. Grade 2 and 3-4 acute GVHD occurred in 3 (21%) and 2 (14%) patients, respectively. Two patients developed mild (skin) or severe (skin, gut and liver) chronic GVHD. There was no association between non permissive DPB1 mismatches in the GvH direction and GVHD. All but one patient are alive and are off immunosuppressive therapy. One patient died due to chronic GVHD-related complications. The median follow-up among surviving patients was 2.8 years (range, 0.8-8.6). The 5-year OS and TFS probabilities were 90% (95% CI 47 to 99%) (Figure 1). Patients showed suboptimal CD4+ recovery within the first year: absolute (mean±SEM) cells/ul of CD4+ at 6 months was 223±48. At 12 and 24 months recovery of CD4+, CD8+, CD19+ and CD56+ were 597±122, 1077±228, 331±75, 229±64 and 812±284, 1067±405, 218±82, 112±22, respectively. One patient developed mild to moderate hepatic sinusoidal obstruction syndrome which resolved with supportive care. CMV reactivation occurred in 9 patients and none developed CMV disease. One patient developed adenovirus gastroenteritis. EBV reactivation occurred in 4 patients; one developed posttransplant lymphoproliferative disorder that was successfully treated with Rituximab. Bacterial infections were common: 5 (38%) patients developed gram negative or gram positive sepsis and 4 (29%) patients pneumonia. Probable invasive fungal infections occurred in 2 (14%) patients. Conclusions. This study showed that unrelated donor BMT can successfully cure a proportion of patients with thalassemia. Remarkably, despite 57% of patients were in class 3 of risk the 5-year OS and TFS rates were 90%. We conclude that class 3 patients with thalassemia who have a suitably matched unrelated donor should not be denied the option of transplantation. Disclosures No relevant conflicts of interest to declare.

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Bárcena, A., A. H. Galy, J. Punnonen, M. O. Muench, D. Schols, M. G. Roncarolo, J. E. de Vries et H. Spits. « Lymphoid and myeloid differentiation of fetal liver CD34+lineage- cells in human thymic organ culture. » Journal of Experimental Medicine 180, n^o 1 (1 juillet 1994) : 123–32. http://dx.doi.org/10.1084/jem.180.1.123.

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In this article, we report that the human fetal thymus contains CD34bright cells (< 0.01% of total thymocytes) with a phenotype that resembles that of multipotent hematopoietic progenitors in the fetal bone marrow. CD34bright thymocytes were CD33-/dull and were negative for CD38, CD2, and CD5 as well as for the lineage markers CD3, CD4, and CD8 (T cells), CD19 and CD20 (B cells), CD56 (NK cells), glycophorin (erythrocytes), and CD14 (monocytes). In addition, total CD34+ lineage negative (lin-) thymocytes contained a low number of primitive myeloid progenitor cells, thus suggesting that the different hematopoietic lineages present in the thymus may be derived from primitive hematopoietic progenitor cells seeding the thymus. To investigate whether the thymus is permissive for the development of non-T cells, human fetal organ culture (FTOC) assays were performed by microinjecting sorted CD34+lin- fetal liver cells into fragments of HLA-mismatched fetal thymus. Sequential phenotypic analysis of the FTOC-derived progeny of CD34+lin- cells indicated that the differentiation into T cells was preceded by a wave of myeloid differentiation into CD14+CD11b+CD4dull cells. Donor-derived B cells (CD19+CD20+) were also generated, which produced immunoglobulins (IgG and IgM) when cultured under appropriate conditions, as well as functional CD56+CD3- NK cells, which efficiently killed K562 target cells in cytotoxicity assays. These results demonstrate that the microinjection of fetal liver hematopoietic progenitors into fetal thymic organ fragments results in multilineage differentiation in vitro.

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Abrams, Thomas Adam, Syed Mohammad Ali Kazmi, Ira Seth Winer, Vivek Subbiah, Gerald Steven Falchook, Matthew Reilley, Paul Raymond Kunk et al. « A phase 1b multitumor cohort study of cabozantinib plus atezolizumab in advanced solid tumors (COSMIC-021) : Results of the colorectal cancer cohort. » Journal of Clinical Oncology 40, n^o 4_suppl (1 février 2022) : 121. http://dx.doi.org/10.1200/jco.2022.40.4_suppl.121.

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121 Background: Cabozantinib, a multiple receptor tyrosine kinase inhibitor, promotes an immune-permissive environment which may enhance the activity of immune checkpoint inhibitors. COSMIC-021 (NCT03170960) is evaluating the combination of cabozantinib with atezolizumab, an anti-PD-L1 inhibitor, in patients with advanced solid tumors. Outcomes in patients (pts) with metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidine-containing therapy are presented. Methods: Pts with mCRC and an ECOG PS of 0–1 who progressed during or following systemic chemotherapy including fluoropyrimidine plus oxaliplatin or irinotecan were eligible. Up to 2 prior lines of anti-cancer therapy including EGFR-targeted therapy were allowed. Microsatellite instability high (MSI-H) and/or mismatch repair (MMR)-deficient pts were excluded. Pts received cabozantinib 40 mg PO QD plus atezolizumab 1200 mg IV Q3W. The primary endpoint was objective response rate (ORR) per RECIST 1.1 by investigator. Other endpoints included safety, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). CT/MRI scans were performed Q6W for the first year and Q12W thereafter. Results: 31 pts received cabozantinib plus atezolizumab (median age, 60 y [range 31, 79]; male, 58%; ECOG PS 1, 61%; 2 prior lines of therapy, 71%; prior EGFR inhibitor, 16%; ≥3 tumor sites, 52%; tumors in left colorectum, 71%). Median follow-up was 28.1 mo (range, 24.2, 31.3) as of July 21, 2021. Cabozantinib plus atezolizumab demonstrated clinical activity in pts with mCRC (Table). Patients with wild-type RAS (n = 12) had numerically longer PFS and OS and higher ORR vs those with mutations (n = 19) (Table). Treatment-related adverse events (TRAEs) of any grade occurred in 28 (90%); the most common were diarrhea (52%), fatigue (42%), and nausea (35%). Grade 3-4 TRAEs occurred in 16 (52%); the most common were hypertension (10%), fatigue (6%), and lipase increased (6%); no Grade 5 events were reported. Conclusions: Cabozantinib plus atezolizumab demonstrated encouraging clinical activity with manageable toxicity in pts with previously treated advanced non-MSI-H/MMR-proficient CRC. Clinical trial information: NCT03170960. [Table: see text]

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Lindner, Sarah, Tobias Berg, Christian Seidel, Franziska Kalensee, Michael A. Rieger, Hubert Serve, Gesine Bug, Joachim Schwaeble et Evelyn Ullrich. « Impact of KIR/HLA Incompatibilities after Posttransplant Cyclophosphamide Based T Cell-Replete Haploidentical Hematopoietic Stem Cell Transplantation ». Blood 134, Supplement_1 (13 novembre 2019) : 3340. http://dx.doi.org/10.1182/blood-2019-125243.

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Introduction: Posttransplantation cyclophosphamide (PTCy) based T cell-replete haploidentical (haplo) hematopoietic stem cell transplantation (HSCT) is a valid option for patients with indication for allogeneic HSCT without a human leucocyte antigen (HLA) matched donor. However, selection criteria to determine the optimal among several available haplo donors are still a matter of debate. Especially, the impact of killer cell immunoglobulin-like receptor (KIR)/human leukocyte antigen (HLA) incompatibilities (inc) in the setting of PTCy T cell-replete haplo HSCT is unclear. PTCy has been reported to eliminate most mature donor NK cells infused with the graft, including single KIR+ NK cells, thereby blunting NK cell alloreactivity in this setting (Russo et al., Blood 2018). Willem et al. (J Immunol 2019) reported (i) a significant loss of KIR2DL2/3+ NK cells at day +30 in patients with inhibitory KIR/HLA incompatibility (inc.) suggesting that PTCy might target responsive KIR NK cells and (ii) a correlation of genetic KIR2DL/HLA inc. with less relapse, but more graft-versus-host-disease (GvHD). Similarly, NK alloreactivity defined as KIR receptor-ligand mismatch or group B KIR haplotype with the presence of KIR2DS2 has been correlated with improved survival (Salomon et al., BBMT 2018). Aims of our study were to evaluate the impact of (i) HLA/KIR inc, (ii) donor KIR genotype and (iii) HLA-DP mismatch status on survival and incidence of relapse, acute and chronic GvHD in our homogeneously treated, independent patient cohort. Patients and methods: We retrospectively analyzed the outcome of 51 consecutively transplanted patients (AML/MDS (n=28/5), ALL (n=9), HD (n=2), NHL (n=5), CML (n=1), PMF (n=1)) receiving a PTCy based T cell-replete haplo HSCT between 01/2011-12/2018. All patients received a myeloablative conditioning regimen (fludarabine/total body irradiation (FTBI) or thiotepa/busulfan/fludarabine (TBF)) with unmanipulated bone marrow (98%) as the preferred graft (median CD34+ cells: 3.02 x 106/kg (range, 1.50-6.90) and median CD3+ T cells: 3.54 x 107/kg (range 1.52-43.74)). GvHD prophylaxis with ciclosporin A started on day 0, mycophenolate-mofetil on day +1, PTCy was applied on day +3 and +5. Results: Patient, donor and transplant characteristics as detailed in table 1 were well balanced between the inh. KIR/HLA inc. group (n=29) vs. no inh. KIR/HLA inc. group (n=22) with the exception of the median donor age (41.7 (range, 23.4-73.7) vs. 33.6 years (range, 19.0-56.2), resp. All patients engrafted. At day +28 (range, 20-29; n=26) CD3+ cells were 88.5/nL (range, 3-665), CD3+CD4+ cells 22.5/nL (range, 0-277.0), CD3+CD8+ cells 117.0/nL (range, 7-478), CD19+ cells 1.0/nL (range, 0-12), CD56bright cells 74.4/nL (range11.1-93.4), CD56dim cells 25.5/nL (range, 6.4-88.9) measured by flow cytometry and without differences between the inh. KIR/HLA inc. group vs. no inh. KIR/HLA inc. group. Cytomegalovirus (CMV) reactivation occurred in 73.3% of patients at risk and median time of occurrence was 32 days (range, 12-97) without difference between groups. Median follow-up for surviving patients was 26.1 months (range, 2.8-92.8) and we found no significant differences in 2-year overall survival (OS; 65.3±10.3 vs. 89.6±7.0, p=0.311), 2-year relapse-free survival (RFS; 66.0±9.4 vs 77.8±10.2, p=0.235), GvHD- and relapse-free survival (GRFS; 48.4±9.8 vs 60.5±12.0, p=0.182) as well as cumulative incidence (CI) of relapse (23.3% vs 16.2%, p= 0.283), acute GvHD grade 2-4 (27.6% vs 31.8, p=0.563), moderate-severe chronic GvHD (22.2% vs. 9.9%, p=0.227) and NRM (16.3% vs 5.3%, p=0.283) between the inh. KIR/HLA inc. group vs. no inh. KIR/HLA inc. group. This was also the case for donor KIR genotype AA vs AB (n=46; 2-y OS: 74.9±13.0% vs. 73.0±9.9%, p=0.844; 2-y RFS: 60.0±14.8% vs 74.5±8.4%, p=0.645) and HLA-DP-identical/permissive mismatch (MM) vs non permissive MM (n=45; 2-y OS: 70.7±10.0% vs 72.7±13.4%, p=0.945; 2-y RFS: 73.2±8.2% vs 63.6.0±14.5%, p=0.798) Conclusion: Our outcome data support the hypothesis of PTCy eliminating mature donor NK cells infused with the graft and thereby reducing the impact of alloreactivity in this setting. However, our patient number is quite small and the findings need to be validated in larger cohorts and preferably prospective studies. Disclosures Lindner: Celegene, Sanofi, Neovii: Honoraria, Research Funding. Berg:Riemser Pharma GmbH: Consultancy, Honoraria; Incyte, Abbvie, Astellas, Alexion and Celgene: Other: travel support. Bug:Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene Neovii: Other: travel grant; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; Hexal: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Sanofi: Other: travel grants. Schwaeble:Uniqure BV: Research Funding. Ullrich:CellGenix: Honoraria, Research Funding; Novartis: Research Funding.

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Luft, Thomas, Katharina Schmidt, Karl-Heinz Kellner, Aleksandar Radujkovic, Nicola Lehners, Mark-Alexander Schwarzbich, Ute Hegenbart, Anthony D. Ho et Peter Dreger. « ATG and Statins Reduce Incidence of Severe Chronic Gvhd By Distinct Mechanisms Involving CXCL9 and Kynurenine Catabolism ». Blood 126, n^o 23 (3 décembre 2015) : 856. http://dx.doi.org/10.1182/blood.v126.23.856.856.

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Abstract Introduction: Severe chronic graft versus host disease (cGVHD) causes debilitating morbidity due to fibrotic and inflammatory changes in connective tissues mainly of skin, lungs, eyes and the gastrointestinal tract. In contrast, mild cGVHD is strongly associated with better overall survival due to lower relapse rates, so that permissive immunosuppressive drug management is actively pursued by many clinicians. Although alloreactive T lymphocytes are clearly involved in the induction of both grades of cGVHD, it is unpredictable which patients are prone to develop severe rather than mild chronic disease. Monokine induced by interferon gamma (MIG, CXCL9) has been correlated with cGVHD. CXCL9 is a member of the CXCR3 ligand family, which plays a role in other fibrotic diseases such as systemic sclerosis. Anthranilic acid (AA) reduced the severity of acute GVHD in mice. AA is the product of a complex metabolic pathway involving indoleamine 2,3-dioxygenase (IDO), (Trp), kynurenine (Kyn), and Vitamin B6. Based on our observation that anti-thymocyte globulin (ATG) and statins independently reduce the incidence of severe cGVHD, we investigated if MIG, IDO, Trp, Kyn and Vitamin B6 serum levels are correlated with cGVHD. Patients and methods: The incidence of cGVHD was evaluated in 554 patients who consented to participate in this observational study and who survived the first 6 months after alloSCT. Median age was 53 years, 333 were male. The underlying conditions were AML (157), ALL (49), MPN/ MDS (95), lymphoma (203), and multiple myeloma (99). Donors were matched related (194), matched unrelated (227), mismatched unrelated (113), or haploidentical (15). Myeloablative or aplasia conditioning was administered in 101, reduced intensity conditioning in 453 patients. 325 patients received ATG and 244 patients received pravastatin at a dose of 20 mg/d starting from day-1 of alloSCT as per institutional policy. 176 patients received both, ATG and pravastatin, whereas 159 patients received neither. Chronic GVHD was diagnosed and graded as severe or non-severe applying the National Institutes of Health's 2005 consensus criteria. Day +100 serum samples for measuring CXCL9, IDO, Trp and Kyn by ELISA were available for 350 patients and at onset of cGVHD for 185 patients. Furthermore, VitB6 was measured by HPLC on day +100 in 194 patients. Results: Chronic GVHD occurred in 295 patients (54%), 58 (11%) of whom developed severe cGVHD of skin, lungs or eyes, 40 (7%) isolated severe cGVHD of the gastrointestinal tract, and 197 (36%) developed non-severe cGVHD. ATG and statin were associated with reduced incidence of of severe cGVHD. In contrast, only ATG reduced mild chronic GVHD whereas statins did not (Figure 1). Increased levels of CXCL9 were observed for both mild and severe cGVHD at disease onset and on day+100 after alloSCT. In contrast, highest Kyn levels were measured at disease onset of patients with severe cGVHD of lung, skin and eyes. Patients who received ATG prior to transplantation showed significantly lower serum levels of CXCL9 at cGVHD onset, but not on d+100. In contrast, statins did not influence CXCL9 levels, but were associated with lower serum levels of Trp and Kyn and increased IDO levels on day+100. Higher Trp and Kyn serum levels on day+100 despite statin usage predicted higher incidence of severe cGVHD. The reduction of both, Trp and Kyn serum levels in the context of IDO activation suggested that Kyn catabolism is enhanced by statins. Indeed, higher Vitamin B6 serum levels compensated for statin failure and protected against severe cGVHD. Conclusions: Ourdata suggest that ATG and statins minimize severe cGVHD by distinct mechanisms. The fact that ATG associates with reduced immune activation markers (CXCL9) at cGVHD onset, but has no impact on homeostatic serum markers on day +100 is consistent with initial depletion of alloreactive T cells during the early post-transplant period, resulting in weaker immune activation after tapering immunosuppressive therapy. In contrast, statin intake seems to induce IDO and reduce Trp serum levels on day+100 along with activation of Kyn catabolism, pointing to a pathophysiological role of this pathway in the prevention of cGVHD. Accordingly, Vitamin B6 levels could reduce severe cGVHD incidence in patients who failed to lower Trp and Kyn levels in the context of statins. The synergism of statin and Vitamin B6 is clinically relevant and warrants further studies. Figure 1. Figure 1. Disclosures Luft: Immundiagnostik AG: Research Funding. Kellner:Immundiagnostik AG: Equity Ownership. Hegenbart:Janssen: Honoraria, Other: travel support.

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Shaw, Bronwen E., Brent R. Logan, Stephen R. Spellman, Steven GE Marsh, James Robinson, Joseph Pidala, Carolyn Hurley et al. « Analysis of 10,462 8/8 HLA- Matched Unrelated Donor Transplants Could Not Identify a Donor Selection Score, As Younger Age Is the Only Significant Donor Characteristic Associated with Survival ». Blood 130, Suppl_1 (7 décembre 2017) : 848. http://dx.doi.org/10.1182/blood.v130.suppl_1.848.848.

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Abstract Background. There is no hierarchical algorithm that weights the characteristics of individual donors against each other in a quantitative manner to facilitate donor selection when multiple potential equally HLA-matched unrelated donors (URD) are available. Donor factors, such as age, sex, CMV status, ABO type, and matching of secondary HLA loci (DQB1, DPB1), have been associated with recipient survival in URD hematopoietic cell transplantation (HCT) although the impact of specific factors has varied among studies. The goal of this study was to develop and validate a donor selection score that prioritizes donor characteristics associated with better survival in 8/8 HLA-matched URD transplantation. Methods. Two large CIBMTR patient datasets were studied: HCT from 1999-2011 (n=5952) and 2012-2014 (n=4510). Patients were adults (>18), transplanted for acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), or myelodysplastic syndrome (MDS). Each dataset was randomly split for the analysis. Cohort 1 (c1): 2/3 (n=3969) for modeling/score development (training) and 1/3 (n=1983) for testing and similarly for cohort 2 (c2): 2/3 (n=3051) and 1/3 (n=1459). Thus, two independent models were built and tested, adjusting for significant patient characteristics associated with survival. Interactions between donor characteristics, and donor and recipient characteristics were tested. The following donor characteristics were considered for the donor score: HLA-DQB1 matching, HLA-DPB1 matching (using the T-cell epitope matching categorization), age, sex matching, parity, CMV matching, ABO matching and race matching. Results. In the final survival model (training set from 1999-2011, c1) we found significant negative associations with survival for three donor risk factors: non-permissive DPB1 matching (HR 1.13; 95% CI 1.01, 1.26; p-value=0.032), older donor age (as a linear effect, HR 1.07 per decade increase in age; 95% CI 1.02, 1.12, p-value=0.004), and CMV mismatching for CMV+ recipients (HR 1.14; 95% CI 1.02, 1.27; p-value=0.022). For CMV- recipients, a CMV+ donor was not significantly associated with an increase in mortality (HR=1.03; 95% CI 0.89-1.20; p-value=0.68), so this was not included in the score. ABO mismatching (any type: major, minor or bidirectional) was associated with mortality in initial modelling, but the effect was not present in more recent transplants (HR for ABO mismatch among patients transplanted since 2007: 1.04; 95% CI 0.91-1.19; p-value=0.638), so it was not included in the final model and donor score. Based on these results a donor risk score was constructed, however this score was not validated in the testing set (c1), nor were any of the individual component donor factors significantly associated with worse overall survival. In the second cohort (c2), only donor age was significantly associated with worse survival, and it validated in the independent test set from c2. Since donor age was significant in 3 of the 4 cohorts, we quantified the impact of donor age in the validation set of the most recent cohort, c2. We found that choosing a donor 2, 5, 10 or 20 years older was associated with a 1%, 2%, 3% or 7% decrease in 2 year OS, adjusted for patient characteristics. Conclusion. Despite data on over 10,000 URD transplants, we were unable to develop a valid donor selection score. The only donor characteristic associated with better survival was younger age, with 2-year survival being 3% better when a donor is 10 years younger. We did not test other endpoints; it is possible that separate scores could be generated to predict the risk of other outcomes (e.g. graft failure, graft-versus-host disease), however, unless the adverse donor characteristics are identical for these outcomes, centers will still have to prioritize the various donor characteristics to select from a pool of potential donors. This large data set shows that none of the other easily available donor clinical and genetic factors tested were reproducibly associated with survival and hence, flexibility in selecting URD based on these characteristics is justified. These data support a simplified URD selection process and have significant implications for URD registries. Disclosures Porter: Incyte: Honoraria; Genentech/Roche: Employment, Other: Family member employment, stock ownship - family member; Servier: Honoraria, Other: Travel reimbursement; Novartis: Honoraria, Patents & Royalties, Research Funding; Immunovative Therapies: Other: Member DSMB. Lee: Amgen: Other: One-time advisory board member; Bristol-Myers-Squibb: Other: One-time advisory board member; Mallinckrodt: Honoraria; Kadmon: Other: One-time advisory board member.

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Mytilineos, Daphne, Chrysanthi Tsamadou, Christine Neuchel, Uwe Platzbecker, Donald Bunjes, Natalie Schub, Eva Wagner-Drouet et al. « The Human Leukocyte Antigen-DPB1 Degree of Compatibility Is Determined by Its Expression Level and Mismatch Permissiveness : A German Multicenter Analysis ». Frontiers in Immunology 11 (25 janvier 2021). http://dx.doi.org/10.3389/fimmu.2020.614976.

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T-cell epitope matching according to the TCE3 algorithm classifies HLA-DPB1 mismatches in permissive and non-permissive. This classification has been shown to be predictive for mortality and acute GvHD (aGvHD) events in large international cohorts. We retrospectively genotyped HLA-DPB1 in 3523 patients transplanted in Germany between 2000 and 2014 and in their unrelated donors using an Illumina amplicon-NGS based assay. Aim of the study was to evaluate DP-compatibility beyond the established TCE3 algorithm by assessing the combined effect of several DP-mismatch parameters on post-transplant outcome. We implemented an extended DP-mismatch assessment model where TCE3, DP allotype expression with respect to rs9277534, mismatch vector and number of mismatches were conjointly taken into consideration. In this model, non-permissive HLA-DPB1 mismatches showed significantly increased aGvHD risk if they were accompanied by two HLA-DPB1 mismatches in GvH direction (HR: 1.46) or one mismatched highly expressed patient allotype (HR: 1.53). As previously reported, non-permissive HLA-DPB1 mismatches associated with a significantly higher risk of aGvHD and non-relapse mortality (HR 1.36 and 1.21, respectively), which in turn translated into worse GvHD and relapse free survival (HR 1.13). Effects on GvL and GvHD appeared strongest in GvH-directed non-permissive mismatches. Our study results support the consideration of additional HLA-DPB1 mismatch parameters along with the established TCE3 matching algorithm for refinement of future donor selection. In particular, our findings suggest that DP non-permissiveness associated with two HLA-DPB1 mismatches or at least on highly expressed mismatched patient allotype should be avoided.

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Arrieta-Bolaños, Esteban, Pietro Crivello, Meilun He, Tao Wang, Shahinaz M. Gadalla, Sophie Paczesny, Steven G. E. Marsh et al. « A core group of structurally similar HLA-DPB1 alleles drives permissiveness after hematopoietic cell transplantation ». Blood, 24 mai 2022. http://dx.doi.org/10.1182/blood.2022015708.

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Clinically tolerable, permissive HLA-DPB1 mismatches defined by the T-cell epitope (TCE) model improve the selection of unrelated donors in allogeneic hematopoietic cell transplantation (HCT). Mechanistically, overlapping immunopeptidomes in structurally close HLA-DP allotypes with similar peptide-binding motifs are fundamental for permissiveness in vitro, but their relevance in vivo is still unknown. Here, we hypothesized that a similarity measure reflecting the peptide-binding region of HLA-DPB1 alleles could constitute a proxy for immunopeptidome overlap and hence predict permissive mismatches in the clinical setting. To test this, we used multidimensional scaling techniques based on 28 polymorphic amino acid positions, resulting in the stratification of HLA-DPB1 alleles from the heterogeneous TCE group 3 (TCE3) into a subgroup of four frequent, structurally related, and less immunogenic "core" TCE3 alleles compared to the remaining "non-core" alleles. In a CIBMTR cohort of 5140 10/10-matched patients transplanted for AML, ALL, or MDS from 2008-2017, the risks of aGVHD II-IV increased progressively from "core" TCE3 permissive (N=930; HR 1.12 [0.98-1.28]; p=0.1012) to "non-core" TCE3-permissive (N=1286; HR 1.24 [1.06-1.46]; p= 0.0082), and non-permissive mismatches (N=2023; HR 1.32 [1.16-1.50]; p<.0001) compared to allele-matched patients (N=785). "Core" TCE3-permissive pairs (HR 0.78 [0.68-0.88]; p=0.0002), but not "non-core" TCE3-permissive pairs (HR 0.95 [0.83-1.09]; p=0.4578) showed significantly lower risks of TRM when compared to non-permissive pairs. Our results suggest that frequent mismatches between structurally similar "core" HLA-DPB1 alleles are the main drivers of permissiveness after HCT, and provide evidence for a role of immunopeptidome differences between mismatched HLA-DPB1 alleles in the clinical outcome of HCT.

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Iwasaki, Makoto, Junya Kanda, Hidenori Tanaka, Takero Shindo, Takahiko Sato, Noriko Doki, Takahiro Fukuda et al. « Impact of HLA Epitope Matching on Outcomes After Unrelated Bone Marrow Transplantation ». Frontiers in Immunology 13 (3 mars 2022). http://dx.doi.org/10.3389/fimmu.2022.811733.

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The significance of antibody-identified epitopes stimulating humoral alloimmunity is not well understood in the identification of non-permissive human leukocyte antigen (HLA) mismatching patterns in hematopoietic stem cell transplantation (HSCT). This was a retrospective study in a cohort of 9,991 patients who underwent their first HSCT for hematologic malignancies from unrelated bone marrow donors in the Transplant Registry Unified Management Program (TRUMP). HLA eplet mismatches (EMM) were quantified using HLAMatchmaker (HLAMM). The median age of patients was 48 years (range, 16 to 77). The number of EMM in recipient-donor pairs in our study population ranged from 0 to 37 in HLA class I (median, 0) and 0 to 60 in HLA class II (median, 1). In addition to the known high-risk mismatch patterns in the Japanese cohort, HLA-C EMM in the GVH direction was associated with a significantly higher risk for grade III-IV aGVHD, leading to a higher risk of non-relapse mortality and lower overall survival (compared with HLA-C matched patients, HR 1.67, 95% CI 1.44–1.95; HR 1.39, 95% CI 1.25–1.54; HR 1.20, 95% CI 1.10–1.30, respectively). HLAMM-based epitope matching might be useful for identifying patients who are at high risk for serious complications after HSCT from HLA mismatched unrelated donors.

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Meurer, Thuja, Pietro Crivello, Maximilian Frederik Metzing, Michel Kester, Dominik A. Megger, Weiqiang Chen, PA van Veelen et al. « Permissive HLA-DPB1 mismatches in HCT depend on immunopeptidome divergence and editing by HLA-DM ». Blood, 6 septembre 2020. http://dx.doi.org/10.1182/blood.2020008464.

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In hematopoietic cell transplantation (HCT), permissive HLA-DPB1 mismatches between patients and their unrelated donors (UD) are associated with improved outcomes compared to non-permissive mismatches, but the underlying mechanism is incompletely understood. Here we used mass spectrometry, T-cell receptor-beta (TCRb) deep sequencing, and cellular in vitro models of alloreactivity to interrogate the HLA-DP immunopeptidome and its role in alloreactive T cell responses. We find that permissive HLA-DPB1 mismatches display significantly higher peptide repertoire overlaps compared to their non-permissive counterparts, resulting in lower frequency and diversity of alloreactive TCRb clonotypes in healthy individuals and transplanted patients. Permissiveness can be reversed by the absence of the peptide editor HLA-DM, or the presence of its antagonist HLA-DO, through significant broadening of the peptide repertoire. Our data establish the degree of immunopeptidome divergence between donor and recipient as the mechanistic basis for the clinically relevant permissive HLA-DPB1 mismatches in HCT, and show that permissiveness is dependent on HLA-DM-mediated peptide editing. Its key role for harnessing T-cell alloreactivity to HLA-DP highlights HLA-DM as a potential novel target for cellular and immunotherapy of leukemia.

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