INTO-HLH: A Disease Registry for Patients With Hemophagocytic Lymphohistiocytosis (HLH)

INTO-HLH- Insight Into the Natural History and Treatment Outcomes of Hemophagocytic Lymphohistiocytosis (HLH): A Disease Registry for Patients With HLH

The purpose of this observational study is to collect data on the natural history of disease of patients with Hemophagocytic Lymphohistiocytosis (HLH) including diagnosis, treatments, responses, and outcomes.

Study Overview

• Status: Recruiting
• Conditions: Hemophagocytic Lymphohistiocytoses

Detailed Description

Hemophagocytic Lymphohistiocytosis (HLH) is a complex, hyperinflammatory syndrome resulting from the interplay of genetic predisposition and various environmental factors. Despite available treatment options for HLH, approximately 30% of patients do not respond to therapy. Moreover, the standard therapy is constrained by its toxicities, and safer treatments are pursued.

There is an unmet need for a deeper understanding of the natural history, clinical/etiologic diversity, complications, and treatment outcomes of patients with HLH, specifically from North America. The proposed study, a collaboration between Cincinnati Children's Hospital Medical Center (CCHMC), Texas Children's Hospital, and Sobi Inc. aims to establish a robust registry that will enable investigators to better define the natural history of HLH.

• Study Type: Observational
• Enrollment (Estimated): 200

Contacts and Locations

• Study Contact: Name: Michael Jordan, MD; Phone Number: (513) 803-9063; Email: Michael.Jordan@cchmc.org
• Study Contact Backup: Name: Adi Zoref Lorenz, MD; Email: Adi.Zoref.Lorenz@cchmc.org

Study Locations

• United States
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Recruiting
      • Cincinnati Children's Hospital Medical Center
      • Contact: Michael Jordan, MD; Phone Number: 513-803-9063; Email: Michael.Jordan@cchmc.org
      • Principal Investigator: Michael Jordan, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients with clinically suspected or confirmed HLH

Description

Inclusion Criteria:

• Patients with clinically suspected or confirmed HLH, including those meeting the HLH-2004 diagnostic criteria (primary or secondary forms, including malignancy) and other forms of HLH (macrophage activation syndrome [MAS], cytokine release syndrome [CRS], etc.)
• Signed and dated informed consent and assent (adolescents)

Exclusion Criteria:

• None

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Patients with clinically suspected or confirmed Hemophagocytic Lymphohistiocytosis; Multi-institutional cohort registry of patients with clinically suspected or confirmed Hemophagocytic Lymphohistiocytosis

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to HLH diagnosis from the initial presentation	Date of initial presentation and the date of HLH diagnosis as defined by HLH diagnostic criteria (HLH-2004/MAS classification criteria)	Interval between date of presentation, as defined as the day of appearance of initial HLH symptom, and the date of full HLH diagnosis, as defined by fulfilling the HLH diagnostic criteria, will be measured. Timeframes up to 6 months will be assessed.
Number of patients with an autoimmune disease at the time of HLH diagnosis	Presence of an autoimmune disease at the time of diagnosis (e.g., Systemic juvenile idiopathic arthritis, lupus)	Up to 1 month from HLH diagnosis
Number of patients with malignancy at the time of HLH diagnosis	Presence of hematologic and solid malignancies at the time of HLH diagnosis.	Up to 1 month from HLH diagnosis.
Number of patients treated with immune-activating agents before HLH diagnosis	The number of patients treated with immune-activating agents before initial diagnosis (checkpoint inhibitors, CAR-T constructs)	Up to 1 month before HLH diagnosis.
Number of patients with central nervous system (CNS) involvement during the HLH disease course.	CNS involvement as defined by elevated neopterin, white blood cells, or protein at a cerebrospinal fluid or changes in MRI	Up to 1 month from HLH diagnosis.
Frequency of a genetic diagnosis underlying the HLH.	Data on genetic testing will be gathered and investigators will summarize the number to calculate the frequency of a genetic diagnosis.	Up to 1 month from HLH diagnosis.
Number of patients with infections (e.g., EBV, CMV, HHV6, HIV, fungal, bacterial) at the time of diagnosis.	The presence of infections at HLH diagnosis (serology and polymerase chain reaction).	Up to 1 month from HLH diagnosis.
Number of patients with organ failure.	Data will be gathered on organ failure related to HLH (e.g., kidney, lung, CNS).	Up to 1 year from HLH diagnosis.
Number of patients with long-term disease-related complications.	Data on long-term complications (e.g., impaired growth, impaired cognitive development) will be gathered.	Up to 5 years from HLH diagnosis.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment response rate to HLH-related treatments.	The response of all treatments for all patients using the criteria used to assess the efficacy of anti-IFN treatment in the NI-0501-04 04 and NI-0501-14 clinical trials.	Week two from the start of treatment.
Time to response to HLH-related therapy for patients in the registry.	The response of all treatments for all patients using the criteria used to assess the efficacy of anti-IFN treatment in the NI-0501-04 04 and NI-0501-14 clinical trials.	Assessed up to 12 weeks from start of treatment.
The survival probability of patients in the registry	Data on the occurrence and date of death and the date of last documentation for living patients will be gathered.	From HLH diagnosis to last follow-up or death, whichever comes first, assessed up to 5 years post-HLH diagnosis.
Number of patients who received hematopoietic stem cell transplantation (HSCT)	Data on the frequency of HSCT will be gathered.	From HLH diagnoses up to 5 years post-HLH diagnosis.
Frequency of hematopoietic stem cell transplantation (HSCT) related complications	Investigators will gather data on the frequency of primary graft failure and reception of more than one cellular product, secondary graft failure, and chimerism post-HSCT. Primary graft failure is defined as the observed record of failure to achieve an absolute neutrophil count (ANC) of >500/µL by 42 days after HSCT. Secondary graft failure is defined as the observed record of cytopenia after initial engraftment (ANC <500/ µL) and is not related to infection or drug toxicity, loss of donor chimerism <5%. Mixed chimerism is defined as <80% donor cells after day +30.	From HSCT up to 5 years post HSCT.
Number of participants with treatment-related adverse events >/= 3 as assessed by CTCAE 5.0	Grade 3 and higher adverse events (per CTCAE 5.0) reported in the medical charts will be collected. The data will be summarized and described using descriptive statistics.	From initiation of HLH related treatment up to 30 days following discontinuation of treatment.

Collaborators and Investigators

• Sponsor: Children's Hospital Medical Center, Cincinnati
• Collaborators: Baylor College of Medicine; Sobi, Inc.
• Investigators: Study Chair: Michael Jordan, MD, Children's Hospital Medical Center, Cincinnati

Study record dates

Study Major Dates

• Study Start (Actual): December 31, 2021
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): January 1, 2027

Study Registration Dates

• First Submitted: December 29, 2021
• First Submitted That Met QC Criteria: March 9, 2022
• First Posted (Actual): March 14, 2022

Study Record Updates

• Last Update Posted (Actual): February 24, 2026
• Last Update Submitted That Met QC Criteria: February 23, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Lymphatic Diseases; Histiocytosis, Non-Langerhans-Cell; Histiocytosis; Hemic and Lymphatic Diseases; Lymphohistiocytosis, Hemophagocytic
• Other Study ID Numbers: 2021-0821; Sobi.HLH-RWE102 (Other Identifier: Sobi, Inc.)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data that will be shared include individual participant data that underlie the results reported in the article, after de-identification. Investigators whose proposed use of the data has been approved by an independent review committee ("learned intermediary") identified for this purpose. The types of analyses will include research on HLH.
• IPD Sharing Time Frame: Beginning three months and ending 5 years following article publication.
• IPD Sharing Access Criteria: Proposals should be directed to intohlh@cchmc.org. The requests will be considered by the INTO-HLH steering committee.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No