Perspectives on the current diagnostic and treatment paradigms in secondary hemophagocytic lymphohistiocytosis (HLH)

Leonard Naymagon, Mount Sinai School of Medicine, Tisch Cancer Institute, 1470 Madison Avenue, New York, NY, 10029, USA. leonard.naymagon@mountsinai.org.
Philip Roehrs, Stem Cell Transplant and Cellular Therapies, Division of Hematology and Oncology, Department of Pediatrics, University of Virginia, Charlottesville, VA, USA.
Michelle Hermiston, Department of Pediatrics, UCSF Benioff Children's Hospital and the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
James Connelly, Division of Hematology and Oncology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.
Jeffrey Bednarski, Division of Hematology and Oncology, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.
Jaap-Jan Boelens, Department of Pediatrics, Transplantation and Cellular Therapies, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Shanmuganathan Chandrakasan, Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA.
Blachy Dávila Saldaña, Department of Pediatrics, George Washington University, Washington, DC, USA.
Michael M. Henry, Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, AZ, USA.
Prakash Satwani, Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Department of Pediatrics, Columbia University, New York, NY, USA.
Anish Ray, Cook Children's Medical Center, Fort Worth, TX, USA.
Kelly Walkovich, Division of Hematology and Oncology, Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA.
David Teachey, Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Edward M. Behrens, Division of Rheumatology, Children's Hospital of Philadelphia, Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA, USA.
Scott W. Canna, Division of Rheumatology, Children's Hospital of Philadelphia, Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA, USA.
Ashish Kumar, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.

Document Type

Journal Article

Publication Date

4-26-2025

Journal

Orphanet journal of rare diseases

Volume

20

Issue

1

DOI

10.1186/s13023-025-03698-0

Abstract

Improved awareness of hemophagocytic lymphohistiocytosis (HLH) among clinicians has led to an increase in its diagnosis. Often diagnosis is made based on the HLH- 2004 criteria. While these criteria have considerable strengths, they lack specificity and may be fulfilled in the setting of many pro-inflammatory disorders. Genetic defects affecting cellular cytotoxicity cause familial (primary) HLH. On the other hand, secondary HLH is more a pathophysiologic process common to many conditions, rather than a singular disease entity. Improved genetic, immunologic, and functional testing have changed not only the way we diagnose HLH, but also how we treat it. In 2004, there were few active agents and regimens. In 2024, there are multiple safe and effective targeted therapies. We have begun to understand that routine and immediate use of etoposide-based therapy in secondary HLH is likely not appropriate, and emerging cytokine-directed therapies may be more rational interventions. Moreover, it is recognized that identifying and treating the driver of secondary HLH is at least as important as treating the cytokine storm and immune dysregulation. Unfortunately, over-reliance on, and narrow interpretation of, the HLH- 2004 criteria can lead to overdiagnosis, misdiagnosis, and unneeded exposure to drugs that can be harmful. It is important that clinicians understand the limitations of the current diagnostic paradigms for secondary HLH, and the shortcomings of reflexive use of etoposide-based therapy. Herein we will discuss the pros and cons of the current paradigm for the recognition, diagnosis, and treatment of secondary HLH.

Department

Pediatrics

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