Donor Selection and Human Leukocyte Antigen Loss Leukemia Relapse After Hematopoietic Cell Transplantation
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.
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (98)
Katharina Fleischhauer
9Institute for Experimental Cellular Therapy, University Hospital Essen, Essen, Germany
Cristina Toffalori
IRCCS San Raffaele Scientific Institute, Milano, Italy
Federica Cugnata
Jan A. Hofmann
Giorgio Orofino
1IRCCS San Raffaele Hospital Scientific Institute, Hematology and Bone Marrow Transplantation Unir, Milan, Italy
Francesca Lorentino
Hematology and Bone Marrow Transplantation Unit, I.R.C.C.S. San Raffaele Scientific Institute, Milano, Italy
Müberra Ahci-Hanci
Experimental Cellular Therapy, University Hospital Essen, Essen, Germany
Vinzenz Lange
DKMS Life Science Lab, Dresden, Germany
Carlheinz R. Müller
Zentrales Knochenmarkspender-Register Deutschland (ZKRD), Ulm, Germany
Desiree Kunadt
27Medizinische Klinik und Poliklinik I, University Hospital Carl Gustav Carus Dresden, Technical University of Dresden, Dresden, Germany
Martin Bornhäuser
Guillermo Sanz
26Hospital Universitario y Politécnico La Fe, Hematology Department, Valencia, Spain
Robert Soiffer
1Dana Farber Cancer Institute, Boston, United States
Miguel Waterhouse
Department of Internal Medicine I, Hematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany
Luisa Giaccone
Haris Ali
Kathrin Nachtkamp
Andrea Bacigalupo
10Rome, Rome, Italy
Francesca Bonifazi
Leo Luznik
2Baylor College of Medicine, Medicine, Houston, United States
Luca Facchini
Hematology Department, Azienda U.S.L., I.R.C.C.S. di Reggio Emilia, Reggio Emilia, Italy
Stefania Bramanti
7Bone Marrow Transplant Unit, Humanitas Clinical and Research Center - IRCCS, Humanitas Cancer Center, Rozzano, Italy
Arnon Nagler
3Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel HaShomer, Ramat Gan, Israel
Riccardo Saccardi
Cellular Therapies and Transfusion Medicine Unit, Careggi University Hospital, Firenze, Italy
Filippo Milano
Francesco Zallio
Unità trapianti midollo, Azienda Ospedaliera SS Antonio e Biagio e C. Arrigo, Alessandria, Italy
Antonio Pierini
21Institute of Hematology, Centro Ricerche Emato-Oncologiche, Ospedale S. Maria della Misericordia, University of Perugia, Perugia, Italy
Mohamad Mohty
Neal Flomenberg
Sidney Kimmel Cancer Center at Thomas Jefferson University, Philadelphia, PA
Akifumi Takaori-Kondo
Norbert Vey
7Department of Hematology, Institut Paoli-Calmettes, Marseille, France
Takanori Teshima
Nicolaus Kröger
From the Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Carolina Martinez Laperche
Department of Hematology, Gregorio Marañón General University Hospital (H.G.U.G.M.), Madrid, Spain
Marco Andreani
Laboratory of Immunogenetics and Transplant, Department of Oncohematology and Cell and Gene Therapy, I.R.C.C.S. Bambino Gesù Pediatric Hospital, Roma, Italy
Maria Teresa Lupo Stanghellini
IRCCS San Raffaele Scientific Institute, Italy
Jacopo Peccatori
1San Raffaele Scientific Institute, Lymphoma Unit, Milan, Italy
Clelia Di Serio
Guido Kobbe
Monzr M. Al Malki
1City of Hope, Duarte, United States
Benedetto Bruno
Robert Zeiser
Robert Coleman Lindsley
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
Jaime Sanz
2Hospital Universitari i Politècnic La Fe, Valencia Departament de Medicina Universitat de Valencia, CIBERONC, Instituto Carlos III, Madrid, Spain, Hematology Department, Valencia, Spain
Dietrich Beelen
2University Hospital Essen, Essen, Germany
Friedrich Stölzel
8Department of Internal Medicine II, Hematology and Oncology, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany
Jürgen Sauter
Alexander H. Schmidt
Fabio Ciceri
Vita-Salute San Raffaele University, Milan
Luca Vago
Vita-Salute San Raffaele University, Italy
Juan Montoro
Max Jan
Broad Institute of Harvard and MIT
Claudia Wehr
1University of Freiburg, Hematology, Oncology and Stem Cell Transplantation, Department of Medicine I, Faculty of Medicine, Freiburg, Germany
Alessandro Busca
Ketevan Gendzekhadze
1City of Hope, Duarte, United States
Esther Schuler
Kathrin Putke
Monica Zanussi
Benedetta Mazzi
Pietro Crivello
Luisa Betke
Esteban Arrieta-Bolanos
3University Hospital Essen, Institute for Experimental Cellular Therapy, Essen, Germany
Amin T. Turki
Alessandra Picardi
Mi Kwon
Francis Ayuk
From the Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Masahiro Onozawa
20Hokkaido University Hospital, Sapporo, Japan
Raynier Devillier
10Institut Paoli-Calmettes, Service d’hématologie, Marseille, France
Junya Kanda
Dolores Grosso
Florent Malard
1Sorbonne Université, AP-HP, Centre de Recherche Saint-Antoine INSERM UMRs938, Paris, France
Loredana Ruggeri
Heidi Altmann
Esperanza Such
Laboratory of Cytogenetics and Molecular Biology. Hospital Universitari i Politècnic La Fe, Valencia, Spain
Jerome Ritz
Dana–Farber Cancer Institute, Boston
Ralph Wäsch
18Department of Medicine I, Hematology, Oncology and Stem Cell Transplantation, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Lucia Brunello
Shukaib Arslan
1City of Hope, Duarte, United States
Ron Patrick Cadeddu
Massimo Pini
Brandon Hadland
1Fred Hutchinson Cancer Center, Seattle, United States
Giovanni Rombolà
Ivetta Danylesko
1Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
Daniele Mannina
1IRCCS Humanitas Research Hospital, Department of Biomedical Sciences, Humanitas University, Rozzano, Italy
Annalisa Imovilli
Ivana Gojo
Johns Hopkins University, Baltimore, Maryland, United States
Margherita Ursi
Patrizia Chiusolo
6Section of Hematology, Department of Radiological and Hematological Sciences, Catholic University, Fondazione Policlinico Gemelli IRCCS, Rome, Italy
Raffaella Cerretti
8Fondazione Policlinico Tor Vergata, Rome, Italy
Ismael Buño
24Hospital General Universitario Gregorio Marañón. Instituto de Investigación Sanitaria Gregorio Marañón, Hematology Department, Madrid, Spain
Anita Badbaran
From the Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Hideki Goto
Didier Blaise
19Programme de Transplantation & Therapie Cellulaire, Marseille, France
Mizuki Watanabe
2Kyoto University Hospital, Department of Hematology, Kyoto, Japan
Zixuan Wang
Eolia Brissot
Alessandra Carotti
16Sezione di Ematologia, Perugia, Italy
Giulio Caravagna