Granulocyte-Colony Stimulating Factor: Encouraging Outcome in Sporadic ALS - Modelling and Bioinformatics Identify Substantial Filgrastim Responders
48 Pages Posted: 26 Jun 2020More...
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
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