Donor Selection and Human Leukocyte Antigen Loss Leukemia Relapse After Hematopoietic Cell Transplantation

PURPOSE For patients with hematologic malignancies, relapse is the leading cause of death after allogeneic hematopoietic cell transplantation (allo-HCT). Frequently, relapses are explained by immune evasion through alterations of human leukocyte antigens (HLAs), but determinants and clinical consequences remain poorly defined. METHODS We analyzed 533 relapses of hematologic cancers after allo-HCT from different donor types, conducted at 27 centers worldwide. Genomic loss of mismatched HLA (HLA loss) was assessed using a newly developed next-generation sequencing pipeline. Clinical and immunogenetic factors associated with HLA loss were evaluated. Using HLA data from approximately 5 million individuals, a web-based tool to infer HLA incompatibility phasing was developed. RESULTS HLA loss occurred in 15.6% of relapses, with significant variation according to donor type (28.7% haploidentical family, 7.2% unrelated adult, 2.7% cord blood, P < .0001). The distribution of HLA mismatches across the patient's haplotypes, predicted through the phasing tool, was strongly associated with HLA loss, with an incidence of 27.6% when HLA mismatches were in the same haplotype, compared with 5.4% if present on different haplotypes ( P < .0001). HLA loss affected postrelapse outcomes, abrogating the efficacy of original donor lymphocyte infusions, with significant survival advantage by second allo-HCT from a different donor. CONCLUSION The likelihood of HLA loss varies significantly according to the number and positioning of HLA mismatches between patient and donor. A newly developed phasing tool enables reliable prediction of its risk, supporting informed donor selection. Routine assessment of HLA loss at relapse is warranted, as it critically affects the success of immunologic salvage therapies.

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Journal
Journal of Clinical Oncology
Published
2026-06-25
DOI
https://doi.org/10.1200/jco-26-00113
Primary Topic
Hematopoietic Stem Cell Transplantation
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article
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article

Donor Selection and Human Leukocyte Antigen Loss Leukemia Relapse After Hematopoietic Cell Transplantation

Ivetta Danylesko, Maria Teresa Lupo Stanghellini, Heidi Altmann, Jürgen Sauter et al.
Journal of Clinical Oncology
Hematopoietic Stem Cell Transplantation
article

Donor Selection and Human Leukocyte Antigen Loss Leukemia Relapse After Hematopoietic Cell Transplantation

Ivetta Danylesko, Maria Teresa Lupo Stanghellini, Heidi Altmann, Jürgen Sauter, Marco Andreani, Vinzenz Lange, Éolia Brissot, Miguel Waterhouse, Kathrin Nachtkamp, Dolores Grosso, Luisa Betke, Cristina Toffalori, Dietrich W. Beelen, Mohamad Mohty, Alessandra Carotti, Akifumi Takaori‐Kondo, Alessandra Picardi, Fabio Ciceri, Martin Bornhäuser, Alexander H. Schmidt, Katharina Fleischhauer, Francesca Lorentino, Luca Vago, Federica Cugnata, Benedetto Bruno, G Orofino, Loredana Ruggeri, Jaime Sanz, Alessandro Busca, Takanori Teshima, Monica Zanussi, Antonio Pierini, Anita Badbaran, Ivana Gojo, Lucia Brunello, Friedrich Stölzel, Stéfania Bramanti, Monzr M. Al Malki, Desireé Kunadt, Max Jan, Masahiro Onozawa, Margherita Ursi, Esther Schuler, Annalisa Imovilli, Raffaella Cerretti, Shukaib Arslan, Guillermo Sanz, Daniele Mannina, Norbert Vey, Amin T. Turki, Florent Malard, Filippo Milano, Riccardo Saccardi, Arnon Nagler, Raynier Devillier, Neal Flomenberg, Robert J. Soiffer, Francesco Zallio, Kathrin Putke, Haris Ali, Junya Kanda, Ismael Buño, Claudia Wehr, Pietro Crivello, Robert Coleman Lindsley, Jacopo Peccatori, Francesca Bonifazi, Luisa Giaccone, Robert Zeiser, Massimo Pini, Andrea Bacigalupo, Carlheinz Müller, Guido Kobbe, Clelia Di Serio, Esteban Arrieta‐Bolaños, Esperanza Such, Carolina Martínez Laperche, Ron Patrick Cadeddu, Didier Blaise, Giulio Caravagna, Jan A. Hofmann, Ketevan Gendzekhadze, Mi Kwon, Francis Ayuk, Juan Montoro, Mizuki Watanabe, Hideki Goto, Patrizia Chiusolo, Müberra Ahci-Hanci, Zixuan Wang, Ralph Wäsch, Benedetta Mazzi, Jerome Ritz, Luca Facchini, Nicolaus Kröger, Giovanni Rombolà, Leo Luznik, Brandon Hadland
article en

Abstract

PURPOSE For patients with hematologic malignancies, relapse is the leading cause of death after allogeneic hematopoietic cell transplantation (allo-HCT). Frequently, relapses are explained by immune evasion through alterations of human leukocyte antigens (HLAs), but determinants and clinical consequences remain poorly defined. METHODS We analyzed 533 relapses of hematologic cancers after allo-HCT from different donor types, conducted at 27 centers worldwide. Genomic loss of mismatched HLA (HLA loss) was assessed using a newly developed next-generation sequencing pipeline. Clinical and immunogenetic factors associated with HLA loss were evaluated. Using HLA data from approximately 5 million individuals, a web-based tool to infer HLA incompatibility phasing was developed. RESULTS HLA loss occurred in 15.6% of relapses, with significant variation according to donor type (28.7% haploidentical family, 7.2% unrelated adult, 2.7% cord blood, P < .0001). The distribution of HLA mismatches across the patient's haplotypes, predicted through the phasing tool, was strongly associated with HLA loss, with an incidence of 27.6% when HLA mismatches were in the same haplotype, compared with 5.4% if present on different haplotypes ( P < .0001). HLA loss affected postrelapse outcomes, abrogating the efficacy of original donor lymphocyte infusions, with significant survival advantage by second allo-HCT from a different donor. CONCLUSION The likelihood of HLA loss varies significantly according to the number and positioning of HLA mismatches between patient and donor. A newly developed phasing tool enables reliable prediction of its risk, supporting informed donor selection. Routine assessment of HLA loss at relapse is warranted, as it critically affects the success of immunologic salvage therapies.

Journal of Clinical Oncology
Università Cattolica del Sacro Cuore (IT), City Of Hope National Medical Center (US), Harvard University (US), Johns Hopkins University (US), Thomas Jefferson University (US), Vita-Salute San Raffaele University (IT), Inserm (FR), Universität Hamburg (DE), University of Freiburg (DE), German Cancer Research Center (DE), Hokkaido University (JP), Kyoto University (JP), University of Perugia (IT), Sheba Medical Center (IL), University Medical Center Freiburg (DE), Instituto de Salud Carlos III (ES), Agostino Gemelli University Polyclinic (IT), San Raffaele University of Rome (IT), Hospital General Universitario Gregorio Marañón (ES), Hospital Universitari i Politècnic La Fe (ES), Christian-Albrechts-Universität zu Kiel (DE), Sorbonne Université (FR), Azienda Ospedaliera Citta' della Salute e della Scienza di Torino (IT), Düsseldorf University Hospital (DE), Fred Hutch Cancer Center (US), Azienda Sanitaria Unità Locale di Reggio Emilia (IT), Assistance Publique – Hôpitaux de Paris (FR), Advanced Radiation Therapy (United States) (US), Hôpital Saint-Antoine (FR), Sidney Kimmel Cancer Center (US), University Medical Center Hamburg-Eppendorf (DE), National Center for Tumor Diseases (DE), University Hospital Schleswig-Holstein (DE), Azienda Ospedaliero-Universitaria Careggi (IT), Dana-Farber Cancer Institute (US), Azienda USL di Bologna (IT), Essen University Hospital (DE), Bambino Gesù Children's Hospital (IT), German National Bone Marrow Donor Registry (DE), Centre de Recherche Saint-Antoine (FR), Hokkaido University Hospital (JP), Centre de Recherche en Cancérologie de Marseille (FR), Azienda Ospedaliera Nazionale SS. Antonio e Biagio e Cesare Arrigo (IT), Deutsche Knochenmarkspenderdatei (DE), IRCCS Humanitas Research Hospital (IT), Klinik und Poliklinik für Psychotherapie und Psychosomatik (DE), Sidney Kimmel Comprehensive Cancer Center (US), Nationales Centrum für Tumorerkrankungen Dresden (DE), Heinrich Heine University Düsseldorf (DE), University of Turin (IT), University of Lübeck (DE)
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Hematopoietic Stem Cell Transplantation
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