Comparison of the efficacy of hematopoietic stem cell mobilization regimens: a systematic review and network meta-analysis of preclinical studies

Abstract

Background Mobilization failure may occur when the conventional hematopoietic stem cells (HSCs) mobilization agent granulocyte colony-stimulating factor (G-CSF) is used alone, new regimens were developed to improve mobilization efficacy. Multiple studies have been performed to investigate the efficacy of these regimens via animal models, but the results are inconsistent. We aim to compare the efficacy of different HSC mobilization regimens and identify new promising regimens with a network meta-analysis of preclinical studies. Methods We searched Medline and Embase databases for the eligible animal studies that compared the efficacy of different HSC mobilization regimens. Primary outcome is the number of total colony-forming cells (CFCs) in per milliliter of peripheral blood (/ml PB), and the secondary outcome is the number of Lin− Sca1+ Kit+ (LSK) cells/ml PB. Bayesian network meta-analyses were performed following the guidelines of the National Institute for Health and Care Excellence Decision Support Unit (NICE DSU) with WinBUGS version 1.4.3. G-CSF-based regimens were classified into the SD (standard dose, 200–250 μg/kg/day) group and the LD (low dose, 100–150 μg/kg/day) group based on doses, and were classified into the short-term (2–3 days) group and the long-term (4–5 days) group based on administration duration. Long-term SD G-CSF was chosen as the reference treatment. Results are presented as the mean differences (MD) with the associated 95% credibility interval (95% CrI) for each regimen. Results We included 95 eligible studies and reviewed the efficacy of 94 mobilization agents. Then 21 studies using the poor mobilizer mice model (C57BL/6 mice) to investigate the efficacy of different mobilization regimens were included for network meta-analysis. Network meta-analyses indicated that compared with long-term SD G-CSF alone, 14 regimens including long-term SD G-CSF + Me6, long-term SD G-CSF + AMD3100 + EP80031, long-term SD G-CSF + AMD3100 + FG-4497, long-term SD G-CSF + ML141, long-term SD G-CSF + desipramine, AMD3100 + meloxicam, long-term SD G-CSF + reboxetine, AMD3100 + VPC01091, long-term SD G-CSF + FG-4497, Me6, long-term SD G-CSF + EP80031, POL5551, long-term SD G-CSF + AMD3100, AMD1300 + EP80031 and long-term LD G-CSF + meloxicam significantly increased the collections of total CFCs. G-CSF + Me6 ranked first among these regimens in consideration of the number of harvested CFCs/ml PB (MD 2168.0, 95% CrI 2062.0−2272.0). In addition, 7 regimens including long-term SD G-CSF + AMD3100, AMD3100 + EP80031, long-term SD G-CSF + EP80031, short-term SD G-CSF + AMD3100 + IL-33, long-term SD G-CSF + ML141, short-term LD G-CSF + ARL67156, and long-term LD G-CSF + meloxicam significantly increased the collections of LSK cells compared with G-CSF alone. Long-term SD G-CSF + AMD3100 ranked first among these regimens in consideration of the number of harvested LSK cells/ml PB (MD 2577.0, 95% CrI 2422.0–2733.0). Conclusions Considering the number of CFC and LSK cells in PB as outcomes, G-CSF plus AMD3100, Me6, EP80031, ML141, FG-4497, IL-33, ARL67156, meloxicam, desipramine, and reboxetine are all promising mobilizing regimens for future investigation.

Platelet-derived circulating soluble P-selectin is sufficient to induce hematopoietic stem cell mobilization

“…Due to time consumption in collecting sufficient clinical paired donors, the convenience of collecting samples during G-CSF administrations, and the possibility of using gene-deficiency mice to confirm the importance of P-selectin in HSC mobilization, a mouse model for G-CSF-induced HSC mobilization was established on the basis of previous studies [ 62 – 66 ]. In the present study, male mice were used to rule out the influence of gender in HSC mobilization.…”

Efficacy of hematopoietic stem cell mobilization regimens in patients with hematological malignancies: a systematic review and network meta-analysis of randomized controlled trials

“…The Phase III RCT assessing the superiority of BL-8040 plus G-CSF versus placebo plus G-CSF still have no published data when this manuscript is completed [ 83 ]. We previously compared the mobilization efficacy of G-CSF alone, G-CSF plus plerixafor (AMD3100) and new regimens with a network meta-analysis of preclinical studies, and the results suggested that G-CSF plus plerixafor still has stable advantages even when several new CXCR4 antagonists and many new agents of different mechanisms have been developed [ 84 ]. In addition, most of the new CXCR4 antagonists and new agents of other mechanisms have not been used in humans.…”

Catching Them Early: Framework Parameters and Progress for Prenatal and Childhood Application of Advanced Therapies

“…Even though higher HSPC yields are obtained during harvest in children compared with adults, the scarcity of stem cells with long-term repopulating potential (present among large numbers of committed progenitors or mature blood cells) in the available sources requires the enrichment and expansion of those cells in cultures to achieve therapeutic doses of products. Improvement and innovation in every step of source cell processing, from mobilization (newer mobilizing regimens to maximize HSPC harvest) to apheresis (to increase cell yields and minimize associated risks) and cell culture procedures (to retain stemness and long-term repopulating capacity of cells) are needed for the industrial translation of HSPC-based therapies [277][278][279].…”