-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

2178 HLA Class I Mismatches Reduce Survival after HCT in the Ptcy Era: A Study By the EBMT Cellular Therapy and Immunobiology Working Party

Program: Oral and Poster Abstracts
Session: 722. Allogeneic Transplantation: Acute and Chronic GVHD, Immune Reconstitution: Poster I
Hematology Disease Topics & Pathways:
ALL, Lymphoid Leukemias, Hodgkin lymphoma, Research, Acute Myeloid Malignancies, AML, MDS, Biological therapies, adult, non-Hodgkin lymphoma, Lymphomas, MPN, B Cell lymphoma, Clinical Research, Chronic Myeloid Malignancies, Diseases, immune mechanism, Therapies, Immunotherapy, immunology, registries, Lymphoid Malignancies, Adverse Events, Myeloid Malignancies, survivorship, Biological Processes, Study Population, Human, Transplantation
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Esteban Arrieta-Bolanos1,2*, Edouard F. Bonneville, PhD3,4*, Marie Robin, MD, PhD5*, Tobias Gedde-Dahl, MD6*, Urpu Salmenniemi7*, Nicolaus Kröger, MD8*, Ibrahim Yakoub-Agha, MD, PhD9*, Charles Crawley, MD10*, Goda Choi, MD11*, Annoek E. C. Broers, MD12*, Edouard Forcade, MD, PhD13*, Martin Carre, MD14*, Xavier Poiré, MD, PhD15*, Anne Huynh, MD16*, Péter Reményi, MD17*, Stig Lenhoff, MD18*, Fabio Ciceri19*, Eleni Tholouli, MD20*, Thomas Schröder, MD21*, Eric Deconinck22, Kristina Elisabet Carlson, MD, PhD23, Liesbeth C. de Wreede, PhD3*, Jorinde D. Hoogenboom4*, Florent Malard, MD, PhD24*, Annalisa Ruggeri, MD, PhD19* and Katharina Fleischhauer, MD2,25*

1Institute for Experimental Cellular Therapy, Essen University Hospital, Essen, Germany
2German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Essen, Germany
3Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, Netherlands
4EBMT Leiden Study Unit, Leiden, Netherlands
5Department of Hematology, Transplantation Division, Hopital Saint-Louis, Paris Cedex 10, France
6Oslo University Hospital, Rikshospitalet, Clinic for Cancer Medicine, Hematology Department, Section for Stem Cell Transplantation, Oslo, Norway
7Dept of Hematology, Helsinki University Hospital Comprehensive Cancer Center and University of Helsinki, Helsinki, Finland
8University Medical Center Hamburg, Hamburg, Germany
9CHU de Lille, Université de Lille, INSERM U1286, Infinite, 59000, Lille, France
10Addenbrookes Hospital, Cambridge, United Kingdom
11University of Groningen, University Medical Center Groningen (UMCG), Groningen, Netherlands
12Erasmus MC Cancer Institute, Rotterdam, Netherlands
13Service d'Hématologie Clinique et Thérapie Cellulaire, CHU Bordeaux, Hopital Haut-Leveque, Pessac, France
14Clinical Hematology Department, CHU Grenoble Alpes - Université Grenoble Alpes, Grenoble, France
15Section of Hematology, Institut Roi Albert II, Cliniques Universitaires St-Luc, Brussels, Belgium
16Institut Universitaire du Cancer Toulouse - Oncopole, Toulouse, France
17Department of Hematology and Stem Cell Transplantation, South-Pest Central Hospital, Budapest, Hungary
18Skanes University Hospital, Lund, Sweden
19Hematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milan, Italy
20Manchester Royal Infirmary, Clinical Haematology Department, Manchester, United Kingdom
21Department of Hematology and Stem Cell Transplantation, West German Cancer Center, University Hospital Essen, Essen, Germany
22Besançon University Hospital, Besançon, France
23Department of Medical Sciences, University Hospital Uppsala, Uppsala, Sweden
24Department of Clinical Hematology and Cellular Therapy, Sorbonne University, Saint Antoine Hospital, Assistance Publique - Hôpitaux de Paris, INSERM UMRs 938, Centre de Recherche Saint-Antoine (CRSA), PARIS, France
25Institute for Experimental Cellular Therapy, University Hospital Essen, Essen, Germany

Introduction: Human leukocyte antigen (HLA) compatibility between patient and donor is a mainstay in allogeneic hematopoietic cell transplantation (HCT) to reduce the risk of potentially fatal graft-versus-host disease (GvHD). Traditionally, mismatches at HLA class I (HLA-A, HLA-B, HLA-C) and class II (HLA-DRB1) have been associated with significantly reduced overall survival (OS) and increased risks of non-relapse mortality (NRM) and acute (a)GvHD compared to fully matched donors (Lee et al. Blood 2007). This has resulted in a preference for 8/8 (10/10 in Europe) HLA-matched donors in unrelated HCT (Dehn et al. Blood 2019). More recently, interest in expanding the donor pool to patients lacking a fully matched donor (Shaw et al. JCO 2021 & TCT 2023) and advances in the management and prevention of GvHD, in particular with post-transplant cyclophosphamide (PTCy) (Bolaños-Meade et al. NEJM 2023), are increasing the use of mismatched (i.e. <10/10) unrelated donors. However, the role of HLA mismatches in current HCT practice, including new strategies for GvHD prophylaxis, remains unclear. Here, we evaluated the effects of mismatching at the major HLA loci in a large contemporary cohort of patients transplanted for hematological malignancies.

Methods: We studied outcomes in 17,276 adult patients transplanted from unrelated donors between 2005-2020 reported to the EBMT Registry. 67.5% of the patients were treated for acute myeloid or lymphoblastic leukemia, or myelodysplastic or myeloproliferative neoplasms. 23.5% of the transplants were performed across one (9/10; n=3,561) or two (8/10; n=499) high-resolution HLA mismatches. Reduced-intensity conditioning was used in 56% of the patients, with 76% having in vivo T-cell depletion, and 91% receiving peripheral blood stem cells. Standard GvHD prophylaxis based on calcineurin inhibitors alone or in combination with other drugs was used in all patients. PTCy was used in 7% of the 10/10 (n=924) vs 15% (n=599) of the <10/10 transplants. Univariable and multivariable models were constructed to analyze the effect of the number, class, and locus of HLA mismatches compared to 10/10 transplants in the presence or absence of PTCy.

Results: In the whole cohort, the presence of one or two mismatches at the five main HLA loci significantly reduced OS (45% [95% CI 40-50%] and 47% [95% CI 45-49%] in 8/10 and 9/10, respectively, vs 52% [95% CI 51-53%] in 10/10 at 60 months; p<0.001; Figure 1A). In multivariable analysis adjusted for the most relevant clinical and transplant-related variables including the use of PTCy, the presence of one (HR 1.24 [99% CI 1.15-1.34]; p<0.001) or two (HR 1.29 [99% CI 1.09-1.54]; p<0.001) HLA mismatches was confirmed to be associated with a higher risk of mortality when compared to 10/10 transplants. When the type of mismatch was taken into account, results showed that only HLA class I (HR 1.31 [99% CI 1.20-1.42]; p<0.001) and not HLA class II (HR 1.07 [99% CI 0.93-1.22]; p=0.23) single mismatches were significantly associated with worse survival. For HLA class I, these associations were stronger for HLA-A (HR 1.37 [99% CI 1.21-1.54]; p<0.001) and HLA-B (HR 1.44 [99% CI 1.23-1.69]; p<0.001) than for HLA-C (HR 1.16 [99% CI 1.01-1.33]; p=0.005). Similar associations were observed for other endpoints, including GvHD-free, relapse-free (GRFS), and relapse-free (RFS) survival, NRM, and aGVHD grades II-IV and III-IV. In contrast, no significant differences were observed for the risks of relapse or chronic (c)GvHD. The use of PTCy significantly reduced the risks of aGvHD and mortality compared to transplants performed with standard prophylaxis. However, the effects of HLA mismatches were similar regardless of the administration of PTCy (non-significant interaction; p=0.22), with a single mismatch conferring significantly increased risks of mortality both in the presence (HR 1.38 [99% CI 1.14-1.68]; p<0.001) and in the absence (HR 1.23 [99% CI 1.13-1.33]; p<0.001) of PTCy (Figure 1B).

Conclusion: In contemporary HCT, HLA disparity is associated with increased risks of mortality, mainly driven by HLA class I mismatches. These associations are present even under GvHD prophylaxis with PTCy, challenging the notion that GvHD prophylaxis can completely overcome the effects of histocompatibility, and highlighting the need to continue defining better tolerated mismatches to provide the best possible outcome for all patients.

Disclosures: Salmenniemi: Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Immedia Pharma AB: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Viatris: Consultancy. Yakoub-Agha: Novartis: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria. Huynh: Medac: Other: Advisory board; Astellas: Other: Advisory board; Servier: Other: Advisory board; Pfizer: Other: advisory board; Jazz: Other: travel fees, advisory board; Novartis: Other: travel fees, advisory board; Neovii: Other: Advisory board. Deconinck: STEMLINE MENARINI: Consultancy; NOVARTIS: Research Funding; Immunogen Inc.: Honoraria; GILEAD KITE: Other: Hospitality, Research Funding.

*signifies non-member of ASH