Donor Selection and Human Leukocyte Antigen Loss Leukemia Relapse After Hematopoietic Cell Transplantation.
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Fleischhauer Katharina, Toffalori Cristina, Cugnata Federica, Hofmann Jan A, Orofino Giorgio, Lorentino Francesca, Ahci-Hanci Müberra, Lange Vinzenz, Müller Carlheinz R, Kunadt Desiree, Bornhäuser Martin, Sanz Guillermo, Soiffer Robert, Waterhouse Miguel, Giaccone Luisa, Ali Haris, Nachtkamp Kathrin, Bacigalupo Andrea, Bonifazi Francesca, Luznik Leo, Facchini Luca, Bramanti Stefania, Nagler Arnon, Saccardi Riccardo, Milano Filippo, Zallio Francesco, Pierini Antonio, Mohty Mohamad, Flomenberg Neal, Takaori-Kondo Akifumi, Vey Norbert, Teshima Takanori, Kröger Nicolaus, Laperche Carolina Martinez, Andreani Marco, Lupo Stanghellini Maria Teresa, Peccatori Jacopo, Di Serio Clelia, Kobbe Guido, Al Malki Monzr M, Bruno Benedetto, Zeiser Robert, Lindsley Robert Coleman, Sanz Jaime, Beelen Dietrich, Stölzel Friedrich, Sauter Jürgen, Schmidt Alexander H, Ciceri Fabio, Vago Luca, HLALOSS Consortium
Аннотация
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.