Impact of Ultra-fast Genetic Diagnosis of Familial Lymphohistiocytosis on the Time to Bone Marrow Transplantation and Overall Survival

Official title

Impact of Ultra-rapid Genetic Diagnosis of Primary Haemophagocytic Lymphohistiocytosis on the Time to Haematopoietic Stem Cell Transplantation

Overview

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.

Interventions

• Diagnostic test Third-generation sequencing
  Blood 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)

Primary outcome measures

• Time (in days) from clinical suspicion to hematopoietic stem cell transplantation [Time frame: From enrollment until 24 months post transplantation]

Secondary outcome measures (9)

• Proportion of patients completing the full diagnostic pathway [Time frame: From enrollment until 24 months post transplantation]
• Time from clinical suspicion to receipt of the genetic result (in days) [Time frame: From enrollment until 24 months post transplantation]
• Time from clinical suspicion to initiation of specific immunomodulatory therapy (in days) [Time frame: From enrollment until 24 months post transplantation]
• Overall survival [Time frame: From enrollment until 6, 12 and and 24 months post transplation]
• Total length of hospital stays (in days) [Time frame: From enrollment until 24 months post transplantation]
• Number of days in intensive care [Time frame: From enrollment until 24 months post transplantation]
• Direct hospital and medical costs [Time frame: From enrollment until 24 months post transplantation]
• Number of inappropriate or unnecessary treatments avoided [Time frame: From enrollment until 24 months post transplantation]
• Progression-free survival [Time frame: From enrollment until 6, 12 and and 24 months post transplation]

Eligibility criteria

Inclusion criteria

• 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
• Presence of at least 5 of the 8 following criteria (diagnostic criteria according to the definition of the "Histiocyte Society" (1)):

• Fever
• Splenomegaly
• Hypertriglyceridemia ≥ 3 mmol/l and/or hypofibrinogenemia≤ 1.5g/l
• Hemophagocytosis found in a histological sample
• Decreased or absent NK function (<10% of the laboratory normal)
• Ferritin ≥ 500μg/l
• Soluble CD25 ≥ 2,400U/ml or presence of activated T cells in phenotyping
• Cytopenia (affecting at least two blood cell lines): Haemoglobin < 9.0 g/dl, Platelets <100 G/L, Neutrophils <1,0 G/L
• Patient benefiting from social security coverage
• The legal guardian(s) who have signed the informed consent form

Exclusion criteria

• 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
• Patient in the exclusion period of another research protocol at the time of signing the consent form

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Single group

Masking

Open label

Primary purpose

Diagnostic

Study locations

France · 1 center

• Assistance Publique - Hôpitaux de Marseille — Marseille

Identifiers

NCT: NCT07741747 · RCAPHM25_0567 · 2026-A00463-48

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗