Severe adult hemophagocytic lymphohistiocytosis (HLHa) correlates with HLH-related gene variants

Coralie Bloch; Jean Philippe Jais; Marine Gil; Marouane Boubaya; Yves Lepelletier; Brigitte Bader-Meunier; Nizar Mahlaoui; Nicolas Garcelon; Olivier Lambotte; David Launay; Claire Larroche; Estibaliz Lazaro; Francois Liffermann; Olivier Lortholary; Marc Michel; Jean-Marie Michot; Pierre Morel; Morgane Cheminant; Felipe Suarez; Louis Terriou; Geoffrey Urbanski; Jean-Francois Viallard; Alexandre Alcais; Alain Fischer; Geneviève de Saint Basile; Olivier Hermine; French HLH Study Group

doi:10.1016/j.jaci.2023.07.023

Severe adult hemophagocytic lymphohistiocytosis (HLHa) correlates with HLH-related gene variants

J Allergy Clin Immunol. 2024 Jan;153(1):256-264. doi: 10.1016/j.jaci.2023.07.023. Epub 2023 Sep 9.

Authors

Coralie Bloch¹, Jean Philippe Jais², Marine Gil³, Marouane Boubaya⁴, Yves Lepelletier⁵, Brigitte Bader-Meunier⁶, Nizar Mahlaoui⁷, Nicolas Garcelon³, Olivier Lambotte⁸, David Launay⁹, Claire Larroche¹⁰, Estibaliz Lazaro¹¹, Francois Liffermann¹², Olivier Lortholary¹³, Marc Michel¹⁴, Jean-Marie Michot¹⁵, Pierre Morel¹⁶, Morgane Cheminant¹⁷, Felipe Suarez¹⁷, Louis Terriou⁹, Geoffrey Urbanski¹⁸, Jean-Francois Viallard¹⁹, Alexandre Alcais², Alain Fischer²⁰, Geneviève de Saint Basile²¹, Olivier Hermine²²; French HLH Study Group

Collaborators

French HLH Study Group:
Coralie Bloch²³, Jean Philippe Jais²⁴, Francois Liffermann²⁵, Pierre Morel¹⁶, Morgane Cheminant²⁶, Felipe Suarez²⁶, Olivier Hermine²⁶, Fabrice Bonnet²⁷, Pascal Godemer²⁸, Damaj Gandhi²⁹, Olivier Fain³⁰, Olivier Lambotte⁸, David Launay³¹, Louis Terriou³¹, Claire Larroche¹⁰, Estibaliz Lazaro¹¹, Jean-Francois Viallard¹¹, Francois Liffermann²⁵, Olivier Lortholary³², Marc Michel³³, Jean-Marie Michot¹⁵, Pierre Morel¹⁶, Frederic Pene³⁴, Antoinette Perlat³⁵, Geoffrey Urbanski³⁶

Affiliations

¹ Clinical Research Unit, Avicenne University Hospital, AP-HP, Bobigny, France; Paris 13 University, Sorbonne Paris Cité, Paris, France; Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, INSERM UMR1163/CNRS URL 8254, Paris, France; French National Center for Primary Immunodeficiencies, Necker University Hospital, AP-HP, Paris, France; Imagine Institute, Université Paris Cité, Paris, France. Electronic address: coralie.bloch-queyrat@aphp.fr.
² Imagine Institute, Université Paris Cité, Paris, France; Biostatistic Unit, Necker University Hospital, AP-HP, Paris, France; Human Genetics of Infectious Diseases: Complex Predisposition, INSERM UMR1163, Paris, France.
³ Imagine Institute, Université Paris Cité, Paris, France.
⁴ Clinical Research Unit, Avicenne University Hospital, AP-HP, Bobigny, France.
⁵ Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, INSERM UMR1163/CNRS URL 8254, Paris, France; Imagine Institute, Université Paris Cité, Paris, France.
⁶ Imagine Institute, Université Paris Cité, Paris, France; Department of Pediatric Immunology and Rheumatology, Necker University Hospital, AP-HP, Paris, France.
⁷ French National Center for Primary Immunodeficiencies, Necker University Hospital, AP-HP, Paris, France; Imagine Institute, Université Paris Cité, Paris, France; Department of Pediatric Immunology and Rheumatology, Necker University Hospital, AP-HP, Paris, France.
⁸ University Paris Saclay, AP-HP, Hôpital Bicêtre, IMVAHB UMR1184, INSERM, CEA, Le Kremlin Bicêtre, France.
⁹ Université de Lille, CHU Lille, Département de Médecine Interne et Immunologie Clinique, Centre de Référence des Maladies Auto-immunes Systémiques Rares du Nord et Nord-Ouest de France, Lille, France; INSERM INFINITE U1286, Lille, France.
¹⁰ Internal Medicine Unit, Avicenne Hospital, AP-HP, Bobigny, France.
¹¹ Internal Medicine Department, Bordeaux Hospital University, Bordeaux, France; CNRS-UMR 5164 Immuno ConcEpT, Bordeaux, France.
¹² Service de medecine interne-hematologie, Centre hospitalier de Dax, Dax, France.
¹³ French National Center for Primary Immunodeficiencies, Necker University Hospital, AP-HP, Paris, France; Imagine Institute, Université Paris Cité, Paris, France; Service de Maladies Infectieuses et Tropicales, Centre d'Infectiologie Necker Pasteur, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France.
¹⁴ Department of Internal Medicine, Centre de Référence maladies rares sur les Cytopénies Auto-Immunes de l'adulte, Hôpitaux Universitaires Henri Mondor, AP-HP, Université Paris-Est Créteil, Créteil, France.
¹⁵ Gustave Roussy, University Paris Saclay, Drug Development Department, Villejuif, France.
¹⁶ Service d'Hématologie Clinique, Hôpital Schaffner de Lens, Lens Cedex, France.
¹⁷ Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, INSERM UMR1163/CNRS URL 8254, Paris, France; French National Center for Primary Immunodeficiencies, Necker University Hospital, AP-HP, Paris, France; Imagine Institute, Université Paris Cité, Paris, France; Clinical Hematology, Necker University Hospital, AP-HP, Paris, France.
¹⁸ Department of Internal Medicine and Clinical Immunology, University Hospital, Angers, France; MitoLab Team, MITOVASC Institute, UMR CNRS 6015, INSERM U1083, University of Angers, Angers, France.
¹⁹ Internal Medicine Department, Bordeaux Hospital University, Bordeaux, France.
²⁰ French National Center for Primary Immunodeficiencies, Necker University Hospital, AP-HP, Paris, France; Imagine Institute, Université Paris Cité, Paris, France; Department of Pediatric Immunology and Rheumatology, Necker University Hospital, AP-HP, Paris, France; Laboratory of Normal and Pathological Homeostasis of the Immune System, INSERM UMR1163, Paris, France; Necker University Hospital, AP-HP, Paris, France; College de France, Paris, France.
²¹ French National Center for Primary Immunodeficiencies, Necker University Hospital, AP-HP, Paris, France; Imagine Institute, Université Paris Cité, Paris, France; Laboratory of Normal and Pathological Homeostasis of the Immune System, INSERM UMR1163, Paris, France.
²² Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, INSERM UMR1163/CNRS URL 8254, Paris, France; French National Center for Primary Immunodeficiencies, Necker University Hospital, AP-HP, Paris, France; Imagine Institute, Université Paris Cité, Paris, France; Clinical Hematology, Necker University Hospital, AP-HP, Paris, France. Electronic address: ohermine@gmail.com.
²³ Clinical Research Unit, Avicenne University Hospital, AP-HP, Bobigny, France; Paris 13 University, Sorbonne Paris Cité, Paris, France; Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, INSERM UMR1163/CNRS URL 8254, Paris, France; Center for the Study of Primary Immunodeficiencies, Necker University Hospital, AP-HP, Paris, France; Imagine Institute, Paris University, Paris, France; Biostatistic Unit, Necker University Hospital, AP-HP, Paris, France.
²⁴ Imagine Institute, Paris University, Paris, France; Biostatistic Unit, Necker University Hospital, AP-HP, Paris, France; Human Genetics of Infectious Diseases: Complex Predisposition, INSERM UMR1163, Paris, France.
²⁵ Service de medecine interne-hematologie, Centre hospitalier de DAX, Dax, France.
²⁶ Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, INSERM UMR1163/CNRS URL 8254, Paris, France; Center for the Study of Primary Immunodeficiencies, Necker University Hospital, AP-HP, Paris, France; Imagine Institute, Paris University, Paris, France; Biostatistic Unit, Necker University Hospital, AP-HP, Paris, France; Clinical Hematology, Necker University Hospital, AP-HP, Paris, France.
²⁷ Internal Medicine and Infectious Disease Unit, Saint Andre Hospital, Bordeaux, France; Bordeaux University, ISPED, INSERM U1219, Bordeaux, France.
²⁸ Hematology, CH Bretagne Atlantique, Vannes Cedex, School of Medicine, Caen, AP-HP, Paris, France.
²⁹ University Hospital, Hematology Institute, Normandy University, School of Medicine, Caen, AP-HP, Paris, France.
³⁰ Internal Medicine Unit, Sorbonne University, Saint Antoine University, AP-HP, Paris, France.
³¹ Université de Lille, Lille, CHU Lille, Département de Médecine Interne et Immunologie Clinique, Centre de Référence des Maladies Auto-immunes Systémiques Rares du Nord et Nord-Ouest de France, Lille, France; CeRAINO, LIRIC INSERM U995, Lille, France.
³² Center for the Study of Primary Immunodeficiencies, Necker University Hospital, AP-HP, Paris, France; Imagine Institute, Paris University, Paris, France; Biostatistic Unit, Necker University Hospital, AP-HP, Paris, France; Service de Maladies Infectieuses et Tropicales, Centre d'Infectiologie Necker Pasteur, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France.
³³ Department of Internal Medicine, Centre de Référence maladies rares sur les Cytopénies Auto-Immunes de l'adulte, Hôpitaux Universitaires Henri Mondor, AP-HP, Créteil, Université Paris-Est Créteil, Créteil, France.
³⁴ Medical ICU, Hôpital Cochin, Hôpitaux Universitaires Paris Centre, AP-HP and University Paris Descartes, Paris, France.
³⁵ Internal Medicine and Clinical Immunology Unit, Rennes University Hospital, Rennes, France.
³⁶ Internal Medicine Department, University Hospital, Angers, France; MitoLab Team, MITOVASC Institute, UMR CNRS 6015, INSERM U1083, University of Angers, Angers, France.

PMID: 37678575
DOI: 10.1016/j.jaci.2023.07.023

Abstract

Background: The contribution of genetic factors to the severity of adult hemophagocytic lymphohistiocytosis (HLHa) remains unclear.

Objective: We sought to assess a potential link between HLHa outcomes and HLH-related gene variants.

Methods: Clinical characteristics of 130 HLHa patients (age ≥ 18 years and HScore ≥ 169) and genotype of 8 HLH-related genes (LYST, PRF1, UNC13-D, STX11, STXBP2, RAB27A, XIAP, and SAP) were collected. A total of 34 variants found in only 6 genes were selected on the basis of their frequency and criteria predicted to impair protein function. Severity was defined by refractory disease to HLH treatment, death, or transfer to an intensive care unit.

Results: HLHa-associated diseases (ADs) were neoplasia (n = 49 [37.7%]), autoimmune/inflammatory disease (n = 33 [25.4%]), or idiopathic when no AD was identified (n = 48 [36.9%]). Infectious events occurred in 76 (58.5%) patients and were equally distributed in all ADs. Severe and refractory HLHa were observed in 80 (61.5%) and 64 (49.2%) patients, respectively. HScore, age, sex ratio, AD, and infectious events showed no significant association with HLHa severity. Variants were identified in 71 alleles and were present in 56 (43.1%) patients. They were distributed as follows: 44 (34.4%), 9 (6.9%), and 3 (2.3%) patients carrying 1, 2, and 3 variant alleles, respectively. In a logistic regression model, only the number of variants was significantly associated with HLHa severity (1 vs 0: 3.86 [1.73-9.14], P = .0008; 2-3 vs 0: 29.4 [3.62-3810], P = .0002) and refractoriness (1 vs 0: 2.47 [1.17-5.34], P = .018; 2-3 vs 0: 13.2 [2.91-126.8], P = .0003).

Conclusions: HLH-related gene variants may be key components to the severity and refractoriness of HLHa.

Trial registration: ClinicalTrials.gov NCT02113917.

Keywords: HLH-related gene variants; Hemophagocytic lymphohistiocytosis (HLH); adult secondary HLH; severe HLH in adults.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Alleles
Genotype
Humans
Lymphohistiocytosis, Hemophagocytic* / genetics
Lymphohistiocytosis, Hemophagocytic* / therapy
Signaling Lymphocytic Activation Molecule Associated Protein / genetics
X-Linked Inhibitor of Apoptosis Protein / genetics

Substances

Signaling Lymphocytic Activation Molecule Associated Protein
X-Linked Inhibitor of Apoptosis Protein

Associated data

ClinicalTrials.gov/NCT02113917