Infections

Symptoms and General Pathology

All Conditions

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Blood and Lymph Conditions

Rare Diseases

Bacteremia

Hyperthermia

Neutropenia

Fever

Viremia

Fungemia

Granulocytopenia

Anti-Infective Agents

All Drugs and Chemicals

Anti-Bacterial Agents

Antibiotics, Antitubercular

Blood sample taken for metagenomic sequencing at inclusion visit.

Metagenomic diagnosis (mNGS, DISQVER)

Maxime PICHON

Corinne LORRAIN

CORENTIN ORVAIN, MD

ANNE-MARIE COUTURIER, MD

NIELS MOYA, MD

ALBAN VILATTE, MD

The development of targeted therapies and intensive protocols in oncohaematology has improved the survival of patients with haematological malignancies. The increase in the number of patients treated and their life expectancy has been accompanied by an increase in the incidence of infectious complications secondary to the immunosuppression induced by these therapies.

Febrile neutropenia (NF) is a complication that occurs in approximately 10% to 15% of patients treated for solid tumours and up to 100% of patients treated for haematological malignancies, particularly after bone marrow and/or haematopoietic stem cell transplantation.

In 25% to 30% of cases, NF leads to serious complications. The vast majority of NF cases are caused by microbial infections (bacteria, viruses, fungi, parasites, etc.), which can progress to severe sepsis or septic shock if appropriate treatment is not initiated rapidly (introduction of anti-infective molecules and implementation of associated procedures). If no pathogen is identified during the management of the most severe patients, the prognosis is poor, with a mortality rate of 10%.

The performance of diagnostic strategies is therefore an important factor in improving the prognosis of these patients. To date, the reference diagnosis of microorganisms is based on blood cultures, blood Polymerase Chain Reaction (PCR), β-D-glucan and aspergillosis serology. Identifying the pathogens responsible for NF from a blood sample without an a priori hypothesis and in an optimised timeframe could allow earlier treatment of high-risk NF with implications for management (possible modification of antimicrobial and/or immunosuppressive treatment).

The aim of this study is to evaluate the performance of the mNGS-DISQVER® tool in diagnosing pathogenic microorganisms from blood samples collected from patients being managed for high-risk NF.

1. Clinical context

   The development of targeted therapies and intensive protocols in oncohaematology has improved the survival of patients with haematological malignancies. The increase in the number of patients treated and their life expectancy has been accompanied by an increased incidence of infectious complications secondary to the immunosuppression induced by these therapies.

   Chemotherapy-induced febrile neutropenia (NF) is a common and serious complication occurring in approximately 10% to 15% of patients treated for solid tumours and up to 100% of patients treated for haematological malignancies, particularly after bone marrow transplantation. Febrile neutropenia is defined as a combination of :
   * Neutropenia: neutrophil count \<500 g/L or \<1000 g/L (if \<500 g/L is expected within 48 hours)
   * Fever: \>38.5°C on a single occasion or \>38°C for more than one hour. NF is associated with high morbidity and mortality (25-30% of serious complications and 10% of mortality). Its occurrence includes the need for hospitalisation with broad-spectrum antibiotic therapy, delayed chemotherapy and loss of opportunity for the patient. In the USA, an episode of NF requiring hospitalisation is associated with an estimated health economic impact of $19,110. A recent study in France estimated the clinical and economic impact of hospitalisation for NF, in terms of number of patients hospitalised, number of stays, in-hospital mortality and average cost per stay, to be €5,333 for haemopathies.

   A significant proportion of NF cases are caused by microbial infections that can progress to septicaemia if probabilistic broad-spectrum antibiotic therapy is not administered within an hour. Furthermore, microbiological documentation remains essential to optimise antibiotic therapy, with blood culture as the reference test. However, this test is limited for a number of reasons: difficulties or slowness in culture, antibiotic treatment prior to sampling, or insufficient sample quantity. Despite the recommended minimum of 3 or 4 pairs of blood cultures, 70% of cases of febrile neutropenia are not microbiologically documented, making it impossible to adapt probabilistic broad-spectrum antibiotic therapy. Another limitation is the time required to obtain results: 6 to 24 hours are required to obtain a positive blood culture, plus another 18 to 24 hours for bacteria to grow on solid media, and another 18 to 24 hours for susceptibility testing (antibiotic susceptibility testing).

   The absence of an identified pathogen in the management of the most severe patients is associated with a poor prognosis, with a mortality rate of 10%. As a result, the performance and timeliness of diagnostic strategies are important factors in improving the prognosis of these patients. In this context, the development of high-throughput sequencing technologies has led to the development of new diagnostic approaches based on the detection of circulating DNA (lcDNA, e.g. used in antenatal screening for trisomy 21). Although more recently democratised, the concept of microbial cDNA is well established in the field of infectious diseases. This technology, based on a blood sample obtained by simple venipuncture, could offer patients with febrile neutropenia an improved diagnosis, particularly in the case of negative blood cultures, and an adjustment in their management.
2. Identification and description of the IVDD

The DISQVERⓇ device is CE-IVD marked according to the In Vitro Diagnostic Directive (IVDD) classification approved until May 2026. The assessment file for its marking according to In-Vitro Diagnostic Regulation (IVDR) is in progress.

DISQVER® is a digital analytical solution developed by Noscendo for the rapid identification of microorganisms in a patient's blood sample from free circulating DNA, without any a priori hypothesis.

The test is based on metagenomic Next Generation Sequencing "mNGS" to identify, without a priori assumptions, the genomic sequences of micro-organisms (bacteria, DNA viruses, fungi and parasites) potentially present in the patient's plasma sample. The genomic sequences identified are then compared with Noscendo's proprietary database of over 16,000 microbial genome sequences, including 1,500 pathogens.

A report detailing all relevant pathogens detected in the sample is provided within a few hours (access to a pseudonymised pdf report according to the laboratory's guidelines, including the micro-organisms found in the highest concentration and the most likely pathogen present).

Metagenomic Sequencing for the Identification of Pathogens in Febrile Neutropenic Patients

Evaluation of the Diagnostic Performance of the DISQVER® Metagenomic Sequencing Tool for the Identification of Pathogens in Febrile Neutropenic Haemato-oncology Patients

Based on the microorganisms identified by the conventional work-up and the mNGS-DISQVER® tool, an adjudication committee consisting of a microbiologist, an infectiologist and a haematologist, independent of the study, will assess the presence of at least one pathogen requiring appropriate management. The interpretation of the conventional work-up and that provided by the mNGS-DISQVER® tool will be blinded.

The intrinsic diagnostic capabilities will be assessed by the sensitivity/specificity of the new mNGS-DISQVER® test, with the classification resulting from the conventional work-up as the reference.

The Youden index, the positive and negative predictive values of the new mNGS-DISQVER® test (with conventional work-up as reference) and the proportions of concordant and discordant pairs between the new test and conventional work-up.

The differences between the percentages of patient management modalities (escalation, maintenance, de-escalation or discontinuation of anti-infective treatment) using the mNGS-DISQVER® tool versus the conventional work-up.

The mean time taken for conventional assessment, the prevalence of microorganisms diagnosed in routine care (independent of the adjudication committee) and the percentage distribution of anti-infective adjustments according to microorganisms diagnosed in routine care.

Noscendo

Poitiers University Hospital

Neoplasms

Immune System Diseases

Syndrome

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Communicable Diseases

Cytomegalovirus Infections

Preleukemia

Myelodysplastic Syndromes

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Lymphoma

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Hodgkin Disease

Lymphoma, Non-Hodgkin

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Hematologic Diseases

Bone Marrow Diseases

Precancerous Conditions

Myeloproliferative Disorders

Chronic Disease

Disease Attributes

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Cytomegalic Inclusion Disease

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Chronic Graft Versus Host Disease

Lymphosarcoma

Chronic Myeloid Leukemia

Hodgkin Lymphoma

Acute Graft Versus Host Disease

Chronic Myeloproliferative Disorders

Vaccines

5 mg/mL, Intramuscular (IM.) 3 vaccinations for donors; 1 vaccination pretransplant, up to 3 vaccinations after transplant for recipients

VCL-CB01

1 mL, IM. 3 vaccinations for donors; 1 vaccination pretransplant, up to 3 vaccinations after transplant for recipients

Phosphate-buffered Saline (PBS)

Richard T. Kenney, MD

The purpose of this trial is to evaluate a CMV vaccine given to related donor/recipient pairs (donors prior to peripheral blood stem cell donation and CMV-seropositive recipients just before and after transplantation) and CMV-seropositive recipient-only subjects (related or unrelated) to determine incidence rates of CMV infection, disease, and other complications from immunosuppression and/or transplantation. The outcomes for the groups receiving CMV vaccine will be compared to the outcomes for the group that received the placebo vaccine to see if there is a clinical benefit. For this trial, donors and recipients must have matched HLA genotype (matched at 5/6 or 6/6 HLA loci).

This study was run by Vical and the record was transferred to Astellas on 1/8/2013.

Trial will enroll up to 240 subjects (160 recipients and 80 donors). Qualified donors and/or CMV-seropositive recipients (donor/recipient pairs or recipient-only subjects) will be assigned randomly to receive either a CMV vaccine or a placebo vaccine. Donors will receive 3 vaccines prior to donation and recipients will receive 1 vaccine pretransplant and up to three vaccines posttransplant. Recipients will be followed for up to 1 year after transplant to evaluate the safety of the vaccine and to see if there is a clinical benefit in the group that received the CMV vaccine. The incidence rates of CMV infection, disease, and other complications from immunosuppression and/or transplantation will be studied.

Cytomegalovirus (CMV) Vaccine in Donors and Recipients Undergoing Allogeneic Hematopoietic Cell Transplant (HCT)

A Phase 2 Clinical Trial to Evaluate the Safety, Immunogenicity, and Clinical Benefit of a CMV Immunotherapeutic Vaccine in Donors and CMV-Seropositive Recipients Undergoing Allogeneic, Matched Hematopoietic Cell Transplant (HCT)

Access to anonymized individual participant level data collected during the study, in addition to study-related supporting documentation, is planned for studies conducted with approved product indications and formulations, as well as compounds terminated during development. Studies conducted with product indications or formulations that remain active in development are assessed after study completion to determine if Individual Participant Data can be shared. Conditions and exceptions are described under the Sponsor Specific Details for Astellas on www.clinicalstudydatarequest.com.

Vical

Astellas Pharma Inc

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Metagenomic Sequencing for the Identification of Pathogens in Febrile Neutropenic Patients	NCT06075888	Immunodepressed...	Metagenomic dia...	18 Years -	Poitiers University Hospital
Cytomegalovirus (CMV) Vaccine in Donors and Recipients Undergoing Allogeneic Hematopoietic Cell Transplant (HCT)	NCT00285259	Acute Lymphobla... Chronic Myeloge... Acute Myelogeno... Hodgkin's Lymph... Non-Hodgkin's L... Myelodysplastic...	VCL-CB01 Phosphate-buffe...	18 Years - 65 Years	Astellas Pharma Inc

Spots Global Cancer Trial Database for viremia

Every month we try and update this database with for viremia cancer trials from around the world to help patients and their families find trials that might be right for them.
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Spots Global Cancer Trial Database for viremia

Every month we try and update this database with for viremia cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for viremia cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.