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CSF BIOMARKERS

I-BFM Initiative on CSF ALL Biomarkers is an international collaboration of research groups, working on advancing the research field of paediatric central nervous system (CNS) involvement of acute lymphoblastic leukaemia (ALL).

The very first meeting of physicians and researchers interested in the field was initiated by Prof. Christina Halsey in 2018 at the annual I-BFM conference in Helsinki. The initiative’s online meetings to tackle operative targets has been organised by Dániel Erdélyi since November 2020.

Participating work groups:

  • Arja Harila-Saari et al., – Uppsala University, Uppsala, Sweden, 
  • Chirstina Halsey et al., – University of Glasgow, Galsgow, United Kingdom, 
  • Cornelia Eckert et al., – Charité Universitatsmedizin, Berlin, Germany, 
  • Dániel Erdélyi et al., – Semmelweis University, Budapest, Hungary, 
  • Denis Schewe et al., – Universitatsklinikum Schleswig, Holstein, Germany, 
  • Deniz Yilmaz Karapinar et al., – Ege University Faculty of Medicine, İzmir, Turkey,
  • Geertruy De Krnonnie et al., – University of Padova, Padova, Italy, 
  • Janez Jazbec et al., – Ljubljana University Medical Centre, Ljubjana, Slovenia, 
  • Kjeld Schmiegelow et al., – Rigshospitalet, Copenhagen, Denmark, 
  • Lüder Meyer et al., – Universitatsklinikum, Ulm, Germany, 
  • Manuel Ramirez et al., – Hospital Universitario Nino Jesus, Madrid, Spain, 
  • Mervi Taskinen et al., – Helsinki Univeristy Central Hospital, Helsinki, Finland, 
  • Shai Izraeli et al., – Tel Aviv University, Tel Aviv, Israel, 
  • Sophia Polychronopoulou et al., Aghia Sophia Children’s Hospital, Athens, Greece
  • Wojciech Mlynarski et al., – Medical University of Lódz, Lódz, Poland, 
  • Veerle Mondelaers et al., Ghent University Hospital, Gent, Belgium 

Background

ALL is the most common malignant disease in children. In the last two decades, highly sensitive methods were developed to monitor minimal residual disease in the bone marrow (BM). These led to restructured treatment regimens, and consequently improved survival rates vastly. Patients who develop central nervous system (CNS) involvement, however, face inferior prognosis. Diagnostic methods of the cerebrospinal fluid (CSF) underperform compared to those of the BM. The current standards are all based on cell-detection methods in the CSF (automated or manual cell counting, light microscopy evaluation of cytocentrifuge smears, flow cytometry) acquired via lumbar puncture. These conventional methods were found to provide high rate (>40%) of false negative results among patients with proven CNS-involvement as per neuro imaging or autopsy. In fact, majority of tumour cells adhere to the meninges or specific areas of the brain parenchyma (e.g. chorioid plexus), therefore the number of leukaemic cells detected in CSF does not reflect accurately the leukaemic burden of the CNS compartment. Hence, new diagnostic tools are necessary to improve diagnostics.

The need for standardisation of diagnostic procedures

Selection of methods applied, technical details of these methods, cut off values, definitions of CSF diagnostics, CNS staging widely vary worldwide, even among nearby hospitals within a given country. Comparison of trial results are therefore based: it is difficult to compare CNS positive cohorts when the diagnostics differ how they were defined as CNS positive. Standardisation of these procedure sare not only important for research purposes, but changes in treatment elements will follow for the patients’ benefit.

In conclusion, advanced, standardised diagnostic procedures and definitions, plus new, hopefully more sensitive biomarkers could lead to the development of a more accurate treatment stratification of ALL patients, improving clinical outcome and reducing treatment toxicity.

Aims:

Virtual biobank:

  • To bank CSF at set time points, as per an agreed standard operating protocol (SOP).
  • To keep hold of CSF sample numbers available at participating groups for research projects

Research:

  • To share knowledge and experience among research groups
  • To conduct joint grant applications and research projects of participating groups.
  • To share data and samples among participating groups for individual smaller projects.

Unifying, standardising routine CSF diagnostics:

  • International survey on current practice (en route)
  • Evidence based review (planned)
  • Consensus guidance (planned)

CNS directed therapy:

  • To improve CNS-targeted anti-leukaemic therapy

Current projects:

Standard operating protocol for CSF biobanking

Due to the rarity of CNS positive cases, it is difficult to implement meaningful research projects on CNS leukaemia locally. Sharing samples across research groups could solve the problem, however sample collecting and storing protocols differ among centres. Therefore, we established an international standard operating protocol (SOP) for the collection, processing, and storage of CSF samples. The main aim is to collect supernatant for soluble biomarker (DNA, RNA, protein, metabolite) research purposes. Additionally, cells (cellular nucleic acids, proteins, etc.) and/or extracellular vesicles can be stored.

You can download the SOP and useful files for data collection at the bottom of this site.

Childhood ALL CSF Diagnostics Survey

A questionnaire has been created to explore how cerebrospinal fluid diagnostics of childhood lymphoblastic leukaemia works in everyday practice. We intend to investigate heterogeneities in clinical practice, laboratory methods and stratification of patient management. The survey has been sent out worldwide to interview a set of selected professionals per country. We hope to publish findings. These will also help to identify critical heterogeneities, towards developing a consensus guidance.

Events:

Closed Scientific Mini Symposium, March 2021

Among initiative members we have organised a mini symposium, an event where all participants were welcome to show the latest results of their research.

Programme:

  • Lennart Lenk, Denis Schewe: Molecular mechanisms of CNS infiltration in ALL – recent data on new diagnostic and therapeutic approaches
  • Vera Münch, Lüder Meyer: The role of VEGF in CNS-ALL
  • Chris Halsey: Discovery of prognostic biomarkers for CNS relapse in childhood ALL
  • Gábor Barna: CD49f expression of precursor B ALL blasts in CSF by flow cytometry
  • Maria Thastrup: Flow cytometric detection of CNS leukemia in relapsed ALL
  • Christian Mirian Larsen: Proteomic analysis of cerebrospinal fluid in CNS leukemia
  • Bálint Egyed, Dániel Erdélyi, Ágnes Semsei: MicroRNAs as CSF leukaemia biomarkers
  • Cecilia Arthur, Arja Harila-Saari: Personalized ddPCR for analysis of cell free leukemic DNA in CSF

3rd Annual meeting of The European Society for Paediatric Oncology, March 2022

The initiative organized a session on CNS leukaemia during the 2022 SIOP-E congress. This was held during the joint session of Biology & Disease, Genetic Variation and ALL I-BFM Committees on 23rd March. We introduced our work to a wider audience. The session collated topics on routine CSF diagnostics and CSF biomarker research.

Programme:

  • Dániel Erdélyi: I-BFM CSF Biomarker Initiative
  • Maria Thastrup: CSF Flow Cytometry
  • Cecilia Arthur: Personalized droplet digital PCR for detection of cell free DNA in CSF
  • Shai Izraeli: Metabolic adaptation of blasts to the central nervous system
  • Lennart T.N. Lenk, Denis Schewe: Overview on new pathways and immunotherapy targets in CNS leukemia

Join our group and activities if you share our interest!

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