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Granulocyte-Colony Stimulating Factor: Encouraging Outcome in Sporadic ALS - Modelling and Bioinformatics Identify Substantial Filgrastim Responders

48 Pages Posted: 26 Jun 2020

See all articles by Ulrich Bogdahn

Ulrich Bogdahn

affiliation not provided to SSRN

Siw Johannesen

Department of Neurology, University Hospital Regensburg

J. Russell Huie

Weil Institute of Neuroscience, Brain and Spinal Cord Injury Center, University of California

Bettina Budeus

Lifedatascience Consulting

Sebastian Peters

Department of Neurology, University Hospital Regensburg

Anna M. Wirth

Department of Neurology, University Hospital Regensburg

Sabine Iberl

Department of Hematology -Internal Medicine III, University Hospital Regensburg

Tina Kammermaier

Department of Neurology, University Hospital Regensburg

Ines Kobor

Department of Neurology, University Hospital Regensburg

Eva Wirkert

epartment of Neurology, University Hospital Regensburg

Sabrina Küspert

Department of Neurology, University Hospital Regensburg

Marlene Tahedl

Department of Psychiatry and Psychotherapy, University Hospital Regensburg

Jochen Grassinger

Department of Hematology -Internal Medicine III, University Hospital Regensburg,

Armin Schneider

Lifedatascience Consulting

Ludwig Aigner

Institute of Molecular Regenerative Medicine, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University

Wilhelm Schulte-Mattler

Department of Neurology, University Hospital Regensburg

Gerhard Schuierer

Center of Neuroradiology, University Hospital Regensburg & District Medical Center Regensburg

Winfried Koch

BDS Koch

Tim-Henrik Bruun

Department of Neurology, University Hospital Regensburg

Adam R. Ferguson

University of California, San Francisco (UCSF) - Weill Institute for Neurosciences

Ulrich Bogdahn

University Hospital Regensburg - Department of Neurology

More...

Abstract

Background: There is an urgent demand for therapeutic options in patients with amyotrophic lateral sclerosis (ALS). Filgrastim (Granulocyte-Colony Stimulating Factor, G-CSF) is a hematopoietic growth factor with excellent safety and tolerability, routinely applied in oncology, intensive care, and stem cell mobilization for bone marrow transplantation. Preliminary pre-clinical and clinical evidence indicated potential efficacy in ALS.  

Methods: We offered ALS patients filgrastim as a new treatment approach (mostly five days per month, median duration 17 cycles, up to 76 cycles) and analyzed disease course, survival, and potential biomarkers in a total of 36 patients (mean age 52 years, CI 48-56, 29·7% female). The PRO-ACT database, which collects outcome data from 23 clinical trials performed with ALS patients worldwide, served as historical control and reference for modelling in this observational study.  

Findings: Long-term filgrastim treatment was safe and well tolerated. All filgrastim treated patients progressed significantly slower and survived longer compared to patients from PRO-ACT, supported by different statistical approaches. Particularly, Cox proportional hazard (filgrastim versus PRO-ACT: Risk Ratio 0·52, p=0·0052) and matched pair analyses (filgrastim versus PRO-ACT, 596 versus 373 days of survival, p<0·001) revealed a significant survival benefit for filgrastim treated patients. Strong treatment response to filgrastim with a median survival of 3·8 years (n=15/36, p<0·001) was associated with younger age, increased hematopoietic stem cell mobilization, less aggressive inflammatory cytokine plasma profile, and reduced fractional anisotropy (1·5 Tesla cerebral MRI DTI). A non-linear principal component analysis (NLPCA)-based biomarker analysis discovered individual patient responses as early as within three months of starting filgrastim treatment.  

Interpretation: Filgrastim constitutes a safe and powerful treatment option in ALS patients. Strong responding patients were identified by cytokines, stem cell function, and brain MRI. Treatment benefit was associated with younger age, however, also apparent in some of the older patients.

Funding Statement: German Ministry of Research (GO-Bio; funding for biomarker development in ALS), donation by RB Leipzig.

Declaration of Interests: UB an LA hold patents for clinical application of G-CSF in ALS, Orphan Drug Status is granted for EU and US by EMA and FDA–all within NeuroVision Pharma GmbH, Murnau, Germany. All other authors declare that they do not have any conflicts of interest.

Ethics Approval Statement: The ethics committee of the University of Regensburg approved a retrospective analysis (ethics approval: 15- 101-0106 and 14-101-0011).

Keywords: Amyotrophic lateral sclerosis; granulocyte-colony stimulating factor; biomarker; cytokines; hematopoietic stem cells; hematopoietic progenitor cells; treatment; Filgrastim; Bioinformatics; Survival Modelling

Suggested Citation

Bogdahn, Ulrich and Johannesen, Siw and Huie, J. Russell and Budeus, Bettina and Peters, Sebastian and Wirth, Anna M. and Iberl, Sabine and Kammermaier, Tina and Kobor, Ines and Wirkert, Eva and Küspert, Sabrina and Tahedl, Marlene and Grassinger, Jochen and Schneider, Armin and Aigner, Ludwig and Schulte-Mattler, Wilhelm and Schuierer, Gerhard and Koch, Winfried and Bruun, Tim-Henrik and Ferguson, Adam R. and Bogdahn, Ulrich, Granulocyte-Colony Stimulating Factor: Encouraging Outcome in Sporadic ALS - Modelling and Bioinformatics Identify Substantial Filgrastim Responders (4/5/2020). Available at SSRN: https://ssrn.com/abstract=3571546 or http://dx.doi.org/10.2139/ssrn.3571546

Ulrich Bogdahn

affiliation not provided to SSRN

No Address Available

Siw Johannesen

Department of Neurology, University Hospital Regensburg

J. Russell Huie

Weil Institute of Neuroscience, Brain and Spinal Cord Injury Center, University of California

Bettina Budeus

Lifedatascience Consulting

Sebastian Peters

Department of Neurology, University Hospital Regensburg

Anna M. Wirth

Department of Neurology, University Hospital Regensburg

Sabine Iberl

Department of Hematology -Internal Medicine III, University Hospital Regensburg

Tina Kammermaier

Department of Neurology, University Hospital Regensburg

Ines Kobor

Department of Neurology, University Hospital Regensburg

Eva Wirkert

epartment of Neurology, University Hospital Regensburg

Sabrina Küspert

Department of Neurology, University Hospital Regensburg

Marlene Tahedl

Department of Psychiatry and Psychotherapy, University Hospital Regensburg

Jochen Grassinger

Department of Hematology -Internal Medicine III, University Hospital Regensburg,

Armin Schneider

Lifedatascience Consulting

Ludwig Aigner

Institute of Molecular Regenerative Medicine, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University

Wilhelm Schulte-Mattler

Department of Neurology, University Hospital Regensburg

Gerhard Schuierer

Center of Neuroradiology, University Hospital Regensburg & District Medical Center Regensburg

Winfried Koch

BDS Koch

Tim-Henrik Bruun

Department of Neurology, University Hospital Regensburg

Adam R. Ferguson

University of California, San Francisco (UCSF) - Weill Institute for Neurosciences

Third Avenue and Parnassus
San Francisco, CA 94143
United States

Ulrich Bogdahn (Contact Author)

University Hospital Regensburg - Department of Neurology ( email )

Regensburg
Germany

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