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FHL2/3 Study

If you wish to contribute a patient, please download the patient registration form here:
Patient Registration Form

Please complete, sign and
fax to 49 (0) 761 270 - 74 250
or send via email to: annette.uhlmann@uniklinik-freiburg.de 

Retrospective study on clinical manifestation, treatment and outcome in FHL2 and FHL3

Familial hemophagocytic lymphohistiocytoses (FHL) are a group of genetic disorders of cytotoxicity, which predispose to the life-threatening syndrome of HLH. FHL2 (Perforin deficiency) and FHL3 (MUNC13-4 deficiency) are the most frequent forms of the disease. Current therapies include control of the aberrant immune activation by immune-/chemotherapy followed by HSCT still show about 20 to 40% overall mortality.

It is our vision that major advances in FHL therapy will depend on early patient identification, ideally by newborn screening, followed by patient-tailored curative therapy. Due to their frequency and severity, FHL2 and FHL3 are attractive target diseases for gene therapy approaches. However, data on natural history, treatment and outcome of FHL have so far mostly been reported in collective studies on genetic diseases predisposing to HLH, usually also including XLP and albinism syndromes and a limited number of FHL2/3 patients. Detailed disease-specific information focussed on FHL2 and FHL3 would help to specifically define the clinical needs for these diseases with respect to their natural history, treatment and outcome using current standard of care. Such data are essential when approaching regulatory authorities with concepts of newborn screening and gene therapy.

Several groups with advanced pre-clinical programs in gene therapy for FHL2 (Claire Booth, London, Sujal Ghosh, Düsseldorf) and FHL3 (Despina Moshous/Marina Cavazzana, Paris and Stephan Ehl/Toni Cathomen, Freiburg) have therefore joined forces to develop new diagnostic and therapeutic strategies. To achieve this aim, detailed disease-specific data will be collected in a retrospective analysis of patients diagnosed with FHL2 and FHL3, respectively, within the time period 2010-2020. The study has been approved by the Inborn Errors Working Party of the EBMT, ESID and the Histiocyte Society and will cover both transplanted as well as non-transplanted patients. Patients will mainly be captured in Europe, since the data are intended to reflect the current situation in those countries, where gene therapy trials will be initiated. If individual countries or centers with similar HLH treatment standards outside Europe wish to contribute, participation will be discussed individually.

The study has two steps: The first step aims at patient identification at the contributing centers while avoiding double registrations. This has already started. The second step will be the actual data collection for which the framework (ethics, database) is currently being created. We will build on data in existing registries. The backbone for data collection will be the PROMISE database of the EBMT, where HSCT data are captured and a small additional pre-SCT dataset for FHL will be implemented. Pre-transplant data and data on non-transplanted patients will also be captured by the common HLH registry of ESID and the Histiocyte Society, with a few additions to the currently available core dataset. Through a common FHL2/3 study ID, we will be able to link data that are already available or will be entered into these different platforms. Data collection will be initiated in the second quarter of 2022.

We invite you to participate in this joint effort on FHL2 and FHL3, helping us as a community to pave the way for newborn screening and gene therapy for these life-threatening diseases. Two separate publications are planned based on this data collection and all physicians contributing data will be considered as authors.

Stephan Ehl, Despina Moshous, Claire Booth, Sujal Ghosh

Coordinating Investigators

Stephan Ehl, Freiburg, Germany, stephan.ehl@uniklinik-freiburg.de
Despina Moshous, Paris, France, despina.mosohus@inserm.fr


Claire Booth, London, UK, c.booth@ucl.ac.uk
Sujal Ghosh, Düsseldorf, Germany, sujal.ghosh@med.uni-duesseldorf.de

Collaborating Partners

  • Inborn Error Working Party (IEWP) of the European Society for Blood and Marrow Transplantation (EBMT)
  • European Society for Immunodeficiencies (ESID)
  • Histiocyte Society (HS)

Cooperation & Funding

The Medical Center - University of Freiburg - Center for Chronic Immonodeficiency (CCI) is member of the European Reference Network for Primary Immonodeficiencies, Autoinflammatory Disorders, Autoimmune Diseases, Paediatric Rheumatic Diseases (ERN RITA). In this context it cooperates with other members from different states in carrying out this study.

Further cooperation and funding partners

FHL2/3: Contact for support

Center for Chronic Immunodeficiency (CCI) and Institute for Immunodeficiency (IFI)
Breisacher Str. 115
D-79106 Freiburg

Dr. Sarah Salou
FHL3 Medical Coordinator

Dr. Kritika Chetty
FHL2 Medical Coordinator

Dr. Annette Uhlmann
FHL2/3 Project Coordinator