Familial lymphohistiocytosis (FHL) is a group of rare genetic diseases (around fifteen cases per year in France). The defect in T lymphocyte cytotoxicity resulting from this disease is responsible for hemophagocytic lymphohistiocytosis (HLH). Promptly treatment of HLH is essential for prognosis. These diseases are fatal without a bone marrow transplant, with an overall 5-year survival rate of no more than 80% for FHL. The genetic or acquired nature of HLH is not easy to determine. An infectious trigger can be confounding when it occurs in an FHL. But above all, functional biological tests demonstrating a T lymphocyte cytotoxicity defects are difficult to interpret. Genetic diagnosis is therefore essential for confirming the primary nature of HLH, and for initiating targeted treatments (first stage: putting HLH into remission with chemotherapy or immunotherapy; second stage: bone marrow transplant). Genetic diagnosis of FHL is therefore a matter of emergency, and is currently based on targeted gene panel exploration (fragmentation sequencing) requiring 6 to 8 weeks. Recently, the development of third-generation sequencing (TGS) has revolutionized genomic medicine, enabling unitary sequencing in real time. As a result of this innovation, certain private molecular diagnostic specialties can now access this new emergency genomic medicine.
Aim: the main aim of this study is to demonstrate the feasibility of a national circuit for ultra-rapid genetic diagnosis of pediatric HLH revealing familial lymphohistiocytosis. The secondary objective is to evaluate the impact of this early genetic diagnosis on the delay to remission of HLH and the delay to transplantation.
Methods: This prospective, multicenter study measures the time required for genetic diagnosis of FHL in pediatric HLH, using innovative TGS sequencing technology.
Perspectives: Fast genomic diagnosis of FHL will considerably shorten the time to confirm the diagnosis, to obtain HLH remission and, finally, to reach transplantation faster.
Children under 18 years old
Confirmed or suspected diagnosis of FHL or a related genetic syndrome predisposing to HLH (e.g. Griscelli Syndrome, Chédiak-Higashi Syndrome, XLP1, XLP2) or a family history of lymphohistiocytic activation syndrome
Fever
Splenomegaly
Age ≥ 18 years
Solid tumor, leukemia, lymphoma
Subjects covered by articles L1121-5 to 1121-8 of the public health code (patients under guardianship or curatorship, patient deprived of liberty, pregnant or breadtfeeding woman)
Persons who do not understand the French language
Single group
Third-generation sequencing
Diagnostic testBlood sample will be collected in order to perform the third-generation sequencing testing which sould give results in a 5 day delay, instead of 6-8 weeks (standard testing)
Time (in days) from clinical suspicion to hematopoietic stem cell transplantation
Proportion of patients completing the full diagnostic pathway
Time from clinical suspicion to receipt of the genetic result (in days)
Time from clinical suspicion to initiation of specific immunomodulatory therapy (in days)
Overall survival
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Assistance Publique Hopitaux De Marseille
Lead sponsor
Aix Marseille Université
Collaborator
Etablissement Français du Sang
Collaborator
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