Biomarker Supervised G-CSF (Filgrastim) Response in ALS Patients
Biomarker Supervised G-CSF (Filgrastim) Response in ALS Patients
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DOI：
10.3389/fneur.2018.00971
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发表时间：
2018-11-26
影响因子：
3.4
通讯作者：
Bogdahn, Ulrich
中科院分区：
文献类型：
--
作者：
Johannesen, Siw;Budeus, Bettina;Bogdahn, Ulrich
目的：通过评估肌萎缩侧索硬化症（ALS）患者血清中动员的骨髓源性干细胞和细胞因子，评估粒细胞集落刺激因子（G-CSF）（一种众所周知的造血干细胞因子）长期治疗的安全性、耐受性和可行性。方法：36名ALS患者在指定的患者基础上和门诊环境中接受皮下注射G-CSF治疗。在中位13.7个月（范围为2.7 - 73.8个月）内，通过个体给药方案（平均4.64亿IU/月，范围为90- 21.60亿IU/月）给药。观察安全性、耐受性、存活率和ALSFRS-R的变化。通过流式细胞术分析循环CD 34（+）和CD 34（+）CD 38（-）细胞来监测造血干细胞，并通过电化学发光法评估整个干预期间的外周细胞因子。结果：长期和个体化的G-CSF治疗耐受性好，安全性高。G-CSF导致造血干细胞显著动员到外周血中。较高的动员能力与延长生存期相关。血清细胞因子如MDC、TNF-β、IL-7、IL-16和Tie-2的初始水平与存活率显著相关。持续应用G-CSF导致血清细胞因子的持续改变，持续测量揭示了G-CSF.Conclusions的多方面影响：G-CSF治疗ALS患者是可行和安全的。它可以通过神经保护和再生活性、造血干细胞的动员和促炎和抗炎细胞因子以及血管生成因子的调节发挥其有益作用。当在诊断时测量时，这些细胞因子可作为预后标志物。造血干细胞数量和细胞因子水平被持续的G-CSF应用改变，并且可能在未来的临床试验中作为早期监测G-CSF治疗ALS疗效的治疗生物标志物。
Objective: To evaluate safety, tolerability and feasibility of long-term treatment with Granulocyte-colony stimulating factor (G-CSF), a well-known hematopoietic stem cell factor, guided by assessment of mobilized bone marrow derived stem cells and cytokines in the serum of patients with amyotrophic lateral sclerosis (ALS) treated on a named patient basis.Methods: 36 ALS patients were treated with subcutaneous injections of G-CSF on a named patient basis and in an outpatient setting. Drug was dosed by individual application schemes (mean 464 Mio IU/month, range 90-2160 Mio IU/month) over a median of 13.7 months (range from 2.7 to 73.8 months). Safety, tolerability, survival and change in ALSFRS-R were observed. Hematopoietic stem cells were monitored by flow cytometry analysis of circulating CD34(+) and CD34(+)CD38(-) cells, and peripheral cytokines were assessed by electrochemoluminescence throughout the intervention period. Analysis of immunological and hematological markers was conducted.Results: Long term and individually adapted treatment with G-CSF was well tolerated and safe. G-CSF led to a significant mobilization of hematopoietic stem cells into the peripheral blood. Higher mobilization capacity was associated with prolonged survival. Initial levels of serum cytokines, such as MDC, TNF-beta, IL-7, IL-16, and Tie-2 were significantly associated with survival. Continued application of G-CSF led to persistent alterations in serum cytokines and ongoing measurements revealed the multifaceted effects of G-CSF.Conclusions: G-CSF treatment is feasible and safe for ALS patients. It may exert its beneficial effects through neuroprotective and -regenerative activities, mobilization of hematopoietic stem cells and regulation of pro- and anti-inflammatory cytokines as well as angiogenic factors. These cytokines may serve as prognostic markers when measured at the time of diagnosis. Hematopoietic stem cell numbers and cytokine levels are altered by ongoing G-CSF application and may potentially serve as treatment biomarkers for early monitoring of G-CSF treatment efficacy in ALS in future clinical trials.