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 Kuspert, Sabrina and Tahedl, Marlene and Grassinger, Jochen and Pukrop, Tobias 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 (2021) Modeling and Bioinformatics Identify Responders to G-CSF in Patients With Amyotrophic Lateral Sclerosis. FRONTIERS IN NEUROLOGY, 12: 616289. ISSN 1664-2295,
Full text not available from this repository. (Request a copy)Abstract
Objective: Developing an integrative approach to early treatment response classification using survival modeling and bioinformatics with various biomarkers for early assessment of filgrastim (granulocyte colony stimulating factor) treatment effects in amyotrophic lateral sclerosis (ALS) patients. Filgrastim, a hematopoietic growth factor with excellent safety, routinely applied in oncology and stem cell mobilization, had shown preliminary efficacy in ALS. Methods: We conducted individualized long-term filgrastim treatment in 36 ALS patients. The PRO-ACT database, with outcome data from 23 international clinical ALS trials, served as historical control and mathematical reference for survival modeling. Imaging data as well as cytokine and cellular data from stem cell analysis were processed as biomarkers in a non-linear principal component analysis (NLPCA) to identify individual response. Results: Cox proportional hazard and matched-pair analyses revealed a significant survival benefit for filgrastim-treated patients over PRO-ACT comparators. We generated a model for survival estimation based on patients in the PRO-ACT database and then applied the model to filgrastim-treated patients. Model-identified filgrastim responders displayed less functional decline and impressively longer survival than non-responders. Multimodal biomarkers were then analyzed by PCA in the context of model-defined treatment response, allowing identification of subsequent treatment response as early as within 3 months of therapy. Strong treatment response with a median survival of 3.8 years after start of therapy was associated with younger age, increased hematopoietic stem cell mobilization, less aggressive inflammatory cytokine plasma profiles, and preserved pattern of fractional anisotropy as determined by magnetic resonance diffusion tensor imaging (DTI-MRI). Conclusion: Long-term filgrastim is safe, is well-tolerated, and has significant positive effects on disease progression and survival in a small cohort of ALS patients. Developing and applying a model-based biomarker response classification allows use of multimodal biomarker patterns in full potential. This can identify strong individual treatment responders (here: filgrastim) at a very early stage of therapy and may pave the way to an effective individualized treatment option.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ; amyotrophic lateral sclerosis; granulocyte-colony stimulating factor (G-CSF); filgrastim; biomarker; modeling; principal component analysis (PCA); cytokines; stem cell |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) Medicine > Lehrstuhl für Neurologie Medicine > Lehrstuhl für Psychiatrie und Psychotherapie Medicine > Zentrum für Neuroradiologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 09 Aug 2022 14:05 |
| Last Modified: | 09 Aug 2022 14:05 |
| URI: | https://pred.uni-regensburg.de/id/eprint/46254 |
Actions (login required)
 |
View Item |
