CXCL9 as a novel prognostic marker to identify high-risk adults with hemophagocytic lymphohistiocytosis
Abstract
Abstract Hemophagocytic lymphohistiocytosis (HLH) is an interferon gamma–driven hyperinflammatory syndrome with high morbidity and mortality. Identifying reliable prognostic biomarkers is challenging due to various predisposing conditions and triggers. C-X-C-motif ligand 9 (CXCL9) is a clinically validated biomarker and surrogate marker of interferon gamma–mediated inflammation. We aimed to identify the role of CXCL9 in predicting severe disease and death in adults with HLH using a multicenter retrospective cohort of consecutively hospitalized patients who underwent a clinical evaluation for HLH that included CXCL9 testing. Patients were classified as HLH if they met HLH-2004 and/or HScore criteria. Conditional inference decision trees and Cox regression models were used to identify which clinical variables associated with acute mortality in patients with HLH. Overall, 171 patients were reviewed, and 126 patients met HLH criteria. The median age was 55 years (interquartile range, 40-66), with 62% male and 51% White. CXCL9 was markedly elevated in patients with HLH. Unbiased decision tree modeling, incorporating all clinical laboratory values, identified only CXCL9 of >16 100 pg/mL as the optimal predictor of inpatient mortality. Cox regression models demonstrated that CXCL9 of >16 100 pg/mL was significantly associated with 90-day mortality when controlling for important covariates. This shorter time to death in the elevated CXCL9 subgroup remained significant even after subdividing patients into those with malignancy (n = 53) and nonmalignancy HLH (n = 73). Continuous increases in CXCL9 within the cohort strongly associated with greater mortality. CXCL9 is a novel clinical marker that identifies high-risk HLH independent of underlying disease and could be used to select patients for early and aggressive targeted immunomodulatory therapy.
Article Details
Authors (50)
Joseph M. Rocco
1National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
Joseph H. Oved
2Pediatric Transplant and Cellular Therapy Service, Memorial Sloan Kettering Kids, Memorial Sloan Kettering Cancer Center, New York, NY
Rikita J. Patel
3Department of Medicine, New York–Presbyterian Brooklyn Methodist Hospital, Brooklyn, NY
A. Zara Herskovits
4Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Namitha Nair
5Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA
Bita Shakoory
1National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
Thomas E. Robertson
6Medicine Institute, Allegheny Health Network, Pittsburgh, PA
Rachel Dileo
6Medicine Institute, Allegheny Health Network, Pittsburgh, PA
Max W. Jacobs
6Medicine Institute, Allegheny Health Network, Pittsburgh, PA
Christa S. Zerbe
Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Rachael A. Gordon
5Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA
Michael J. Ombrello
7National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD
Amanda K. Ombrello
8National Human Genome Research Institute, National Institutes of Health, Bethesda, MD
Nirali N. Shah
Dimana Dimitrova
Jennifer Kanakry
10Center for Immuno-Oncology, National Cancer Institute, National Institutes of Health, Bethesda, MD
Andrew D. Zelenetz
11Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Alison J. Moskowitz
3Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Robert Stuver
3Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Zachary D. Epstein-Peterson
11Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Paola Ghione
4Memorial Sloan Kettering Cancer Center, New York, NY
Elena Mead
12Cellular Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Zainab Shahid
13Infectious Disease Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Sandeep Raj
1Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Jae H. Park
Sergio A. Giralt
Cellular Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York
Ivan Maillard
Mark B. Geyer
Memorial Sloan Kettering Cancer Center
Wenbin Xiao
Ahmet Dogan
Hematopathology Service, Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York
Megan Lim
Jeffrey I. Zwicker
5Hematology Service, Memorial Sloan Kettering Cancer Center, New York, NY
Jodi Mones
18Hematology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Rehka Parameswaran
18Hematology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Lauren Banaszak
16Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Shamir Geller
19Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Bianca D. Santomasso
12Cellular Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Roni Shouval
1Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Kevin J. Curran
Ottavia Delmonte
1National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
Luigi D. Notarangelo
Jeffrey I. Cohen
2Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
Steven M. Holland
Gilles Salles
41Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY
Steven M. Horwitz
Cellular Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York
Santosha A. Vardhana
11Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Miguel-Angel Perales
1Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY
Daniella Schwartz
5Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA
Irini Sereti
William T. Johnson
1Lymphoma Service and Cellular Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY