DOI: 10.1200/jco-26-00113 ISSN: 0732-183X

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

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