title: Incidence, risk factors and clinical outcome of leukemia relapses with loss of the mismatched HLA after partially incompatible hematopoietic stem cell transplantation.
abstract: Genomic loss of the mismatched human leukocyte antigen (HLA) is a recently described mechanism of leukemia immune escape and relapse after allogeneic hematopoietic stem cell transplantation (HSCT). Here we first evaluated its incidence, risk factors and outcome in 233 consecutive transplants from partially HLA-mismatched related and unrelated donors (MMRD and MMUD, respectively). We documented 84 relapses, 23 of which with HLA loss. All the HLA loss relapses occurred after MMRD HSCT, and 20/23 in patients with acute myeloid leukemia. Upon MMRD HSCT, HLA loss variants accounted for 33% of the relapses (23/69), occurring later than their 'classical' counterparts (median: 307 vs 88 days, P<0.0001). Active disease at HSCT increased the risk of HLA loss (hazard ratio (HR): 10.16; confidence interval (CI): 2.65-38.92; P=0.001), whereas older patient ages had a protective role (HR: 0.16; CI: 0.05-0.46; P=0.001). A weaker association with HLA loss was observed for graft T-cell dose and occurrence of chronic graft-versus-host disease. Outcome after 'classical' and HLA loss relapses was similarly poor, and second transplantation from a different donor appeared to provide a slight advantage for survival. In conclusion, HLA loss is a frequent mechanism of evasion from T-cell alloreactivity and relapse in patients with myeloid malignancies transplanted from MMRDs, warranting routine screening in this transplantation setting.
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milano, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Crucitti
authors.affiliation: Humanitas Cancer Center, Rozzano, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Crocchiolo
authors.affiliation: Unit of Molecular and Functional Immunogenetics, Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milano, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Toffalori
authors.affiliation: Unit of Molecular and Functional Immunogenetics, Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milano, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Mazzi
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milano, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Greco
authors.affiliation: Department of Health Sciences, Section of Biostatistics, University of Genova, Genova, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Signori
authors.affiliation: San Raffaele Flow Cytometry Resource, Analytical Cytology Technical Applications Laboratory, IRCCS San Raffaele Scientific Institute, Milano, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Sizzano
authors.affiliation: Unit of Molecular and Functional Immunogenetics, Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milano, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Chiesa
authors.affiliation: Unit of Molecular and Functional Immunogenetics, Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milano, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Zino
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milano, Italy.
authors.forename: M T
authors.initials: MT
authors.lastname: Lupo Stanghellini
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milano, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Assanelli
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milano, Italy.
authors.forename: M G
authors.initials: MG
authors.lastname: Carrabba
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milano, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Marktel
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milano, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Marcatti
authors.affiliation: 1] Università 'Vita-Salute San Raffaele', Milano, Italy [2] MolMed SpA, Milano, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Bordignon
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milano, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Corti
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milano, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Bernardi
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milano, Italy.
authors.forename: J
authors.initials: J
authors.lastname: Peccatori
authors.affiliation: Experimental Hematology Unit, Division of Immunology, Transplantation and Infectious Disease, IRCCS San Raffaele Scientific Institute, Milano, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Bonini
authors.affiliation: 1] Unit of Molecular and Functional Immunogenetics, Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milano, Italy [2] Institute for Experimental Cellular Therapy, University of Essen, Essen, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Fleischhauer
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milano, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Ciceri
authors.affiliation: 1] Hematology and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milano, Italy [2] Unit of Molecular and Functional Immunogenetics, Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milano, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Vago
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology; D006680:HLA Antigens / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006650:Histocompatibility Testing; D006801:Humans; D015994:Incidence; D015470:Leukemia, Myeloid, Acute / Q000453:epidemiology / Q000276:immunology* / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016016:Proportional Hazards Models; D012008:Recurrence; D012189:Retrospective Studies; D012307:Risk Factors; D055815:Young Adult
chemical_list: D006680:HLA Antigens