Impact of Graft-Versus-Graft Natural Killer Cell Alloreactivity on Single Unit Dominance After Double Umbilical Cord Blood Transplantation

Rettman, Pauline; Willem, Catherine; Volteau, Christelle; Legrand, Nolwenn; Chevallier, Patrice; Lodé, Laurence; Esbelin, Julie; Cesbron, Anne; Bonneville, Marc; Moreau, Philippe; Senitzer, David; Retière, Christelle; Gagne, Katia

doi:10.1097/tp.0000000000001545

Cited by 6 publications

(5 citation statements)

References 51 publications

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“…Conventional allogeneic hematopoietic stem cell transplantation (HSCT) yields long-term survival in only 7% to 24% of patients with refractory acute lymphoblastic leukemia and in only 10% to 40% of those with late-stage acute myelogenous leukemia (AML) [1][2][3][4][5][6]. Although several recent studies of allogeneic HSCT using 2 grafts (ie, double-umbilical cord blood [UCB] transplantation [dUCBT]) and haploidentical cord blood (haplo-cord) HSCT have shown an enhanced graft-versus-leukemia (GVL) effect along with a graft-versus-graft (GVG) response [4,[7][8][9][10][11][12][13][14][15][16][17], this finding remains controversial [9,14,18,19]. The outcomes of previous studies were strongly influenced by the extent of HLA mismatching and patient selection [20,21].…”

Section: Introductionmentioning

confidence: 99%

Cord Haploidentical Non-In Vitro T Cell Depletion Allogeneic Hematopoietic Stem Cell Transplantation Reduces Relapse of Refractory Acute Leukemia

Wang

Wei

et al. 2019

Biology of Blood and Marrow Transplantation

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Whether a graft-versus-graft (GVG) response in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) is associated with an enhanced graft-versus-leukemia (GVL) effect remains highly controversial. Furthermore, it is unknown if the GVG response overwhelms the impact of refractory acute leukemia. We aimed to compare the characteristics and therapeutic outcomes between patients undergoing a modified haploidentical cord blood (cord-haplo) HSCT protocol (n = 97) and those undergoing haploidentical HSCT (n = 42) for refractory acute leukemia. A reliable and stable predominant haploidentical donor chimerism was established. The 2-year relapse rate was more favorable in patients undergoing cord-haplo HSCT than in those undergoing haploidentical HSCT (25.9% versus 53.2%; P = .007), as was progression-free survival (PFS; 35.5% versus 17.9%; P = .049). Meanwhile, nonrelapse mortality at 2years was not significantly different (38.0% versus 24.6%; P = .367). We also found that a higher number of mutual haploidentical donor-mismatched antigens, a concept similar to HLA mismatching, was associated with better disease control. Multivariate analysis identified cord-haplo HSCT as an independent significant predictor of reduced relapse (hazard ratio [HR], .44; P = .028) and improved PFS (HR, .58; P = .033), as was chronic graft-versus-host disease (GVHD) (relapse: HR, .42; P = .013; PFS: HR, .63: P = .052). However, the incidences of neutrophil and platelet engraftment, GVHD, and virus reactivation were comparable in the 2 groups. This study demonstrates that cord-haplo HSCT significantly enhances the GVL effect and improves PFS, providing a reliable and efficient therapeutic platform for patients with refractory acute leukemia.

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Section: Introductionmentioning

confidence: 99%

Cord Haploidentical Non-In Vitro T Cell Depletion Allogeneic Hematopoietic Stem Cell Transplantation Reduces Relapse of Refractory Acute Leukemia

Wang

Wei

et al. 2019

Biology of Blood and Marrow Transplantation

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“…Also, the role of killer cell immunoglobulin-like receptor-HLA interactions on unit dominance is a matter of debate. Although an in vitro model suggested that unidirectional potential natural killer alloreactivity might play a role in unit dominance, 2 studies that evaluated the association of killer cell immunoglobulinlike receptor/HLA GVG mismatches and unit dominance in patients showed conflicting results [5,31,32]. In our study, we did not compare CD34 + cells viability between CBUs.…”

Section: Discussionmentioning

confidence: 75%

Cord Blood Unit Dominance Analysis and Effect of the Winning Unit on Outcomes after Double-Unit Umbilical Cord Blood Transplantation in Adults with Acute Leukemia: A Retrospective Study on Behalf of Eurocord, the Cord Blood Committee of Cellular Therapy, Immunobiology Working Party, and the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation

Tozatto-Maio

Giannotti

Labopin

et al. 2018

Biology of Blood and Marrow Transplantation

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Usually, after double umbilical cord blood transplantation (DUCBT), only 1 of the transplanted units persists in the long term. The characteristics of the winning cord blood unit (W-CBU) that determine unit dominance and how they influence the outcomes of DUCBT remain unclear. We retrospectively analyzed 347 patients with acute leukemia transplanted with a DUCBT (694 CBU) from 2005 to 2013 who had documented neutrophil engraftment and a W-CBU identified by chimerism analysis, to identify unit characteristics impacting on dominance. Median age at DUCBT was 40 years and median follow-up was 35 months. Among W-CBUs, 41% were ≥5/6 HLA matched to the recipient and 59% were ≤4/6. Multivariate analysis indicated that ≤4/6 HLA-matched W-CBUs led to lower leukemia-free survival (44% versus 56%; hazard ratio [HR], 1.5; P = .032) and overall survival (49% versus 62%; HR, 1.5; P = .028), increased nonrelapse mortality (26% versus 18%; HR, 1.9; P = .027), and acute graft-versus-host disease (46% versus 35%; HR, 1.7; P = .013). We were unable to predict unit dominance, but we demonstrated that outcomes were strongly influenced by the degree of HLA mismatch between W-CBU and recipient. Therefore, selection of both units with the lower number of HLA mismatches with the recipient is indicated.

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“…Recently, a retrospective study performed on a large cohort of AML patients reported that there was no impact of KIR3DL1/2DS1 or a haplotype-motif-based donor selection algorithm on OS and relapse after unrelated HLA matched HSCTs [151]. In line with HSCT protocols, the impact of KIR-L mismatches was investigated in adult patients after dUCBTs [152][153][154][155][156][157][158]. Once again, conflicting data were reported, which were linked either to the competing KIR models used or the heterogeneity of the patients and treatment modalities.…”

Section: Kir Models Used To Evaluate Nk Cell Alloreactivity and Clinical Outcomes After Allogeneic Hsctmentioning

confidence: 99%

Relevance of Polymorphic KIR and HLA Class I Genes in NK-Cell-Based Immunotherapies for Adult Leukemic Patients

Dubreuil

Chevallier

Retière

et al. 2021

Cancers

Self Cite

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Since the mid-1990s, the biology and functions of natural killer (NK) cells have been deeply investigated in healthy individuals and in people with diseases. These effector cells play a particularly crucial role after allogeneic hematopoietic stem-cell transplantation (HSCT) through their graft-versus-leukemia (GvL) effect, which is mainly mediated through polymorphic killer-cell immunoglobulin-like receptors (KIRs) and their cognates, HLA class I ligands. In this review, we present how KIRs and HLA class I ligands modulate the structural formation and the functional education of NK cells. In particular, we decipher the current knowledge about the extent of KIR and HLA class I gene polymorphisms, as well as their expression, interaction, and functional impact on the KIR+ NK cell repertoire in a physiological context and in a leukemic context. In addition, we present the impact of NK cell alloreactivity on the outcomes of HSCT in adult patients with acute leukemia, as well as a description of genetic models of KIRs and NK cell reconstitution, with a focus on emergent T-cell-repleted haplo-identical HSCT using cyclosphosphamide post-grafting (haplo-PTCy). Then, we document how the immunogenetics of KIR/HLA and the immunobiology of NK cells could improve the relapse incidence after haplo-PTCy. Ultimately, we review the emerging NK-cell-based immunotherapies for leukemic patients in addition to HSCT.

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Impact of Graft-Versus-Graft Natural Killer Cell Alloreactivity on Single Unit Dominance After Double Umbilical Cord Blood Transplantation

Abstract: Our unicentric study suggests, for the first time, the significant impact of KIR NK cell alloreactivity in the determination of which UCB unit will dominate in dUCBT.

Cited by 6 publications

References 51 publications

Cord Haploidentical Non-In Vitro T Cell Depletion Allogeneic Hematopoietic Stem Cell Transplantation Reduces Relapse of Refractory Acute Leukemia

Cord Haploidentical Non-In Vitro T Cell Depletion Allogeneic Hematopoietic Stem Cell Transplantation Reduces Relapse of Refractory Acute Leukemia

Relevance of Polymorphic KIR and HLA Class I Genes in NK-Cell-Based Immunotherapies for Adult Leukemic Patients

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