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895 Interindividual HLA Evolutionary Divergence in Single HLA-Mismatched Unrelated Donor Hematopoietic Cell Transplantation for Malignant Hematological Disorders: A Report on Behalf of the Cellular Therapy and Immunobiology Working Party of the EBMT

Program: Oral and Poster Abstracts
Type: Oral
Session: 732. Allogeneic Transplantation: Disease Response and Comparative Treatment Studies: Modern Challenges in Transplantation
Hematology Disease Topics & Pathways:
Research, Clinical Research, registries
Monday, December 11, 2023: 2:45 PM

Simona Pagliuca, MD, PhD1, Jarl Mooyaart2*, Nicolaus Kröger, MD3*, Jürgen Finke, MD4, Victoria Potter5*, Peter Dreger, MD6, Inken Hilgendorf, MD7*, Wolfgang Andreas Bethge, MD8*, Regis Peffault De Latour9,10*, Alessandro Rambaldi11, Henrik Sengeloev12*, Jakob Passweg13*, Tobias Gedde-Dahl14*, David Burns, MD, PhD15*, Kim Orchard16*, Stephan Mielke, MD17, Matthias Edinger, MD18*, Marco Andreani19*, Pietro Crivello, PhD20*, Pietro Merli, MD21*, Jorinde D. Hoogenboom2*, Liesbeth C. de Wreede, PhD22*, Christian Chabannon, MD, PhD23, Jurgen Kuball, MD24, Carmelo Gurnari, MD25,26, Katharina Fleischhauer, MD27*, Annalisa Ruggeri, MD, PhD28* and Tobias Lenz29*

1Department of Hematology, Centre Hospitalier Régional Universitaire (CHRU), Vandœuvre-lès-Nancy, France, France
2EBMT Leiden Study Unit, Leiden, Netherlands
3Department of Stem Cell Transplantation with Research Department Cell and Gene Therapy University Medical Center Hamburg-Eppendorf, Hamburg, Germany
4Department of Hematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, University of Freiburg, Freiburg, Germany
5Department of Haematological Medicine, King's College Hospital NHS, London, United Kingdom
6Department of Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany
7Universitätsklinikum Jena, Klinik für Innere Medizin II, Abteilung für Hämatologie und Internistische Onkologie, Jena, Germany
8Department of Internal Medicine II, Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany
9French Référence Center for Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria, Paris, France
10Hôpital Saint-Louis,, Paris, France
11Department of Oncology-Hematology, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
12Rigshospitalet, Copenhagen, Denmark
13University Hospital Basel, Basel, CHE
14Rikshospitalet, Oslo University Hospital, Oslo, Norway
15University Hospital Birmingham NHS Trust, Stoke, United Kingdom
16Southampton General Hospital,, Southampton, United Kingdom
17Department of Cellular Therapy and Allogeneic Stem Cell Transplantation, Karolinska Institute & University Hospital, Stockholm, Stockholms Laen, Sweden
18Internal Medicine III - Hematology and Oncology, University Hospital Regensburg, Regensburg, DEU
19Bambino Gesù Children's Hospital, Rome, ITA
20Essen University Hospital, Essen, NRW, DEU
21Department of Pediatric Hematology and Oncology, IRCCS Bambino Gesù Children’s Hospital, Catholic University of the Sacred Heart, Rome, Italy
22Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, Netherlands
23Institut Paoli Calmettes CLCC Provence-Alpes-Cote d'Azur, Marseille, FRA
24Utrecht University, University Medical Centre, Utrecht, Netherlands
25Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
26Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
27University Hospital Duisburg-Essen, Essen, Germany
28Hematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milan, Italy
2927. Research Unit for Evolutionary Immunogenomics, Department of Biology, University of Hamburg, Hamburg, Germany

In allogeneic hematopoietic cell transplantation (allo-HCT), alloreactive T-cell responses (graft versus leukemia - GvL and graft versus host disease - GvHD) are mediated by the interaction between recipient antigens and donor lymphocytes via human leukocyte antigen (HLA) molecules.

HLA evolutionary divergence (HED) is a metric recently implemented as a functional proxy for the structural variability between two homologous HLA alleles at their peptide binding sites, mirroring quantitative differences in pathogen and cancer-related immunopeptidomes (A).1

Here, we hypothesize that differences in and between donor and recipient HEDs at given loci may modulate the direction and the intensity of alloreactivity, informing on post-transplant outcomes. We tested this hypothesis in onco-hematologic patients undergoing allo-HCT from a single HLA-A, -B, -C, -DRB1, or –DQB1 (9/10) mismatched unrelated donor (MMUD) at EBMT centers.

We included patients with selected hematological malignancies, receiving a thymoglobulin-based T cell depletion, for whom complete clinical and HLA information was available in the EBMT database. We deployed individual locus-specific recipient/donor HED (HED-R, HED-D) metrics as previously described1, and conceptualized two novel interindividual HED scores accounting for functional differences at the mismatched HLA loci (A). The latter were considered as: 1) DeltaHED, quantifying the relative directional difference between HED-D and HED-R and informing on differences in immunopeptidome sizes, potentially capturing the direction and the intensity of the alloreactive response (GvH or HvG); 2) HEDmismatch, describing the HED of the mismatched locus as a proxy for the qualitative differences in immunopeptidomes between donor and recipient (B).

Using multivariable Cox regression (cause-specific) models adjusted for relevant clinical variables, we investigated the associations of HED-R, DeltaHED and HEDmismatch, analyzed as continuous variables, with relapse free survival (RFS), overall survival (OS), non-relapse mortality (NRM), relapse and grade II-IV acute and chronic GvHD. For each outcome and in each mismatched subgroup, we built separate models for these immunogenetic parameters and checked for proportional hazards assumption (PHA). To account for multiple comparisons, only p-values <0.01 were considered significant.

Overall, 4639 adult patients, with available HLA data, received a 9/10 MMUD allo-HCT between 2010 and 2019 for acute leukemia (N=3853, 83%), myelodysplastic syndromes or myeloproliferative neoplasms (N=786, 17%). Median recipient age was 53.5 (IQR 40.2-61.9) with a male/female ratio of 1.28, whilst median donor age was 33.1 (IQR 24.5-40). Majority of patients (90%) received peripheral blood stem cells and were mismatched with their donors for locus A (33%), followed by C (21%), B (15%), DQB1 (14%) and DRB1 (6%). When analyzing the impact of HED-related parameters in each model, we observed that most recurrent associations with outcomes occurred with DRB1-related metrics. In the DRB1-mismatched subgroup (N=276), a time-varying association was found for HEDmismatch of DRB1 locus with higher HEDmismatch leading to worse RFS [HR:1.25 at t=0, (95% CI 1.1-1.42), p<0.001] and lower OS [HR:1.23 at t=0, (95%CI 1.08-1.41), p=0.002]. The strength of this associations declined over time for both endpoints (respectively RFS: HR:0.91, 95% CI 0.86-0.97, p=0.005 and OS: HR:0.93, 95% CI 0.88-0.98, p=0.013). The (directional) DeltaHED DRB1 measure instead did not display any impact on outcomes. In the same subgroup, higher HED-R in the locus C showed also a time-varying association with NRM at transplant [HR:1.89, (95% CI 1.29-2.85), p=0.002], progressively declining over time (HR:0.77, 95% CI 0.65-0.92, p=0.003). Furthermore, DRB1 HED-R modulated the probability of survival in B-mismatched subgroup, being higher scores associated with reduced OS [HR:1.03, (95%CI 1.01-1.06), p=0.009].

Here, we provide an immunogenetic benchmark to explore donor-recipient interactions in MMUD allo-HCT, demonstrating how different HLA configurations within the mismatched loci, in particular for DRB1 genes, can influence post-transplant outcomes. Given the peculiar associations observed, HED may have a role in driving early GvL effects, informing on future donor selection strategies in high-risk patients.

Disclosures: Finke: Gilead Sciences: Current holder of stock options in a privately-held company; AbbVie: Current holder of stock options in a privately-held company; Riemser: Honoraria, Research Funding, Speakers Bureau; Neovii: Honoraria, Research Funding, Speakers Bureau; Medac: Honoraria, Research Funding; Roche: Current holder of stock options in a privately-held company. Dreger: Novartis: Consultancy, Speakers Bureau; Riemser: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria; Gilead: Consultancy, Speakers Bureau; Beigene: Consultancy, Honoraria; AstraZeneca: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Miltenyi: Consultancy. Hilgendorf: Medac: Honoraria; AbbVie: Honoraria; Novartis: Consultancy, Honoraria; Takeda: Honoraria; Amgen: Honoraria; Fondatione Internationale Menarini: Honoraria; BeiGene: Honoraria; Jazz: Honoraria; Janssen: Honoraria. Peffault De Latour: Jazz Pharmaceuticals: Honoraria. Rambaldi: ABBVIE: Honoraria; Incyte: Honoraria; Roche: Honoraria; Janssen: Honoraria; Celgene-BMS: Honoraria; Novartis: Honoraria; Kite-Gilead: Honoraria; Jazz: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Agmen: Honoraria; Omeros: Honoraria. Mielke: Celgene/BMS, Novartis, Janssen, Gilead/KITE, JSMO, Pfizer: Speakers Bureau; Immunicum/Mendes, Miltenyi: Other: Participation on a Data Safety Monitoring Board or Advisory Board; SWECARNET: Other: Founder/Leadership (via my institution) ; ScientifyResearch: Other: Founder (spouse) . Merli: Sobi: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Miltenyi: Speakers Bureau; Amgen: Speakers Bureau.

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