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(Filgrastim) on Bone Marrow Progenitor Cells Bone Marrow Transplantation, (1999) 23, 15–19 1999 Stockton Press All rights reserved 0268–3369/99 $12.00 http://www.stockton-press.co.uk/bmt Effects of short-term administration of G-CSF (filgrastim) on bone marrow progenitor cells: analysis of serial marrow samples from normal donors C Martı´nez, A Urbano-Ispizua, M Rozman, M Rovira, P Marı´n, N Montfort, E Carreras and E Montserrat Hematology Department, Postgraduate School of Hematology Farreras-Valentı´, Institut d’Investigacions Biome`diques August Pi i Sunyer, Hospital Clı´nic, University of Barcelona, Spain Summary: cells.1–4 A large amount of information about the effects of cytokines on the mobilization of progenitor cells in periph- To determine the effect of G-CSF administration on eral blood is available.5–10 Thus, it is well established that both the total number of CD34؉ cells and the primitive 4 to 5 days of G-CSF administration to patients or normal -CD34؉ subsets in bone marrow (BM), we have analyzed donors effectively increases the absolute number of circul BM samples serially obtained from 10 normal donors ating CD34+ cells, allowing the collection of sufficient in steady-state and during G-CSF treatment. Filgrastim quantities of progenitor cells to ensure sustained was administered subcutaneously at a dosage of 10 engraftment after transplantation.6–9 Data concerning the ␮g/kg/day (n = 7) or 10 ␮g/kg/12 h (n = 3) for 4 consecu- effects of G-CSF on bone marrow (BM), however, are tive days. Peripheral blood sampling and BM aspirates scarce. In fact, it has not been elucidated whether the PBSC were performed on day 1 (just before G-CSF mobilization schedules currently in use result in the simul- administration), day 3 (after 2 days of G-CSF), and day taneous enrichment of stem and progenitor cells in BM, or 5 (after 4 days of G-CSF). During G-CSF adminis- simply in a shift of these cells from BM to peripheral blood. tration, a significant increase in the total number of BM Some clinical trials have recently been conducted to deter- nucleated cells was observed. The percentage (range) of mine the progenitor cell content and engraftment capability -CD34؉ cells decreased in BM from a median of 0.88 of BM harvested after G-CSF administration, with contro (0.47–1.44) on day 1 to 0.57 (0.32–1.87), and to 0.42 versial results.11–16 The main aim of this study was to ana- (0.16–0.87) on days 3 and 5, respectively. We observed lyze, in a population of normal donors, the effects of G- ,a slight increase in the total number of BM CD34؉ cells CSF administration on the number of BM progenitor cells on day 3 (0.66 × 109/l (0.13–0.77)), and a decrease on with special emphasis on the immature cell subsets. day 5 (0.23 × 109/l (0.06–1.23)) as compared with steady-state (0.40 × 109/l (0.06–1.68)). The proportion of primitive BM hematopoietic progenitor cells Materials and methods (CD34؉CD38؊, CD34؉HLA-DR؊, CD34؉CD117؊) decreased during G-CSF administration. In parallel, a Donors and G-CSF administration significant increase in the total number of CD34؉ cells in peripheral blood was observed, achieving the Peripheral blood and BM samples were obtained from 10 maximum value on day 5. These results suggest that in healthy donors included in a program of allogeneic PBSC normal subjects the administration of G-CSF for 5 days transplantation. Donors were thoroughly informed about may reduce the number of progenitor cells in BM, the investigative nature of the procedure and gave their particularly the most primitive ones. written consent. The protocol and consent forms were Keywords: G-CSF; bone marrow CD34+ cells; normal approved by the Hospital Clinic Ethics Committee and by donors the Spanish Ministry of Health. Median age of the donors was 48 years (range 20–57 years). Recombinant human G- CSF (Filgrastim; Amgen, Thousand Oaks, CA, USA) was administered subcutaneously at a dosage of 10 ␮g/kg/day Peripheral blood stem cells (PBSC) are being increasingly (n = 7) or 10 ␮g/kg/12 h (n = 3) for 4 consecutive days. used for both autologous and allogeneic transplantation. Bone marrow aspirates from the sternum were performed Numerous studies have shown that mobilized PBSC result under local anesthesia on day 1 (just before G-CSF in a more rapid hematopoietic reconstitution after mye- administration), on day 3 (after 2 days of G-CSF), and on loablative therapy as compared with bone marrow stem day 5 (after 4 days of G-CSF). The samples were collected with EDTA. In order to minimize peripheral blood cell con- Correspondence: Dr C Martı´nez, Hematology Department, Hospital tamination, no more than 1–1.5 ml of BM were obtained Clinic, Villarroel 170, 08036 Barcelona, Spain from each aspiration. Peripheral blood samples were col- Received 17 June 1998; accepted 10 August 1998 lected by venipuncture from each donor on days 0, 3 and 5. Short-term administration of filgrastim on BMPC C Martı´nez et al 16 Quantification and phenotyping of CD34+ cells median (range) of 1.7 (0.6–5.5) in steady-state to 1.9 (0.8– Bone marrow samples were collected with EDTA and 7.2), and 7.5 (3.2–9.3) on day 3 and 5, respectively. Abnor- diluted 1:2 in phosphate-buffered saline (PBS). Cell counts mal cytoplasmic vacuolization of promyelocytes was found were performed on the whole BM and peripheral blood on days 3 and 5 in seven cases. using an automated cell counter (Sysmex F-800; Baxter Fenwal, Deerfield, IL, USA). CD34 quantification was per- T lymphocytes and NK cells in bone marrow formed on unfractioned peripheral blood and BM using The relative numbers of CD3+ T lymphocytes and FACS Lysing Solution (Becton Dickinson Immunocytome- + + try Systems (BDIS), San Jose, CA, USA) and staining with CD3 CD56 NK cells decreased from a median (range) of the CD34-specific phycoerythrin (PE)-conjugated mono- 7.7% (4–21) and 1.65% (1.26–3.26) on day 1 to a median clonal antibody (MAb) 8G12 (HPCA-2-PE) (BDIS). The of 3.7% (2.4–6.5) and 0.9% (0.3–1.65) on day 5, respect- following MAbs were obtained from BDIS: FTIC-labeled ively. The total number of T and NK cells did not change. and PE-labeled 8G12 against CD34, FTIC-labeled MAbs against CD3 (Leu-4), and CD19 (Leu-12), PE-labeled Nucleated and CD34+ cells in bone marrow MAbs against CD56 (Leu-19), CD33 (anti-Leu-M9), CD38 (anti-Leu-17), and HLA-DR (anti-HLA-DR). The PE-lab- An increase in the total number of nucleated BM cells was observed during G-CSF administration, from a median eled MAb against CD117 was obtained from Immunotech × 9 = SA (Marseilles, France). The Simultest control (IgG1 FTIC 10 /l (range) of 41.5 (13.5–104) to 48 (35.5–120.8) (P 0.06) on day 3, and 56 (36.4–176) (P = 0.02) on day 5. At + IgG2a PE) was purchased from BDIS. Flow cytometry + was performed on a FACScan (BDIS) equipped with an the same points in time, the percentage (range) of CD34 air-cooled argon ion laser tuned to 488 nm. Lysis II cells decreased from a median of 0.88 (0.47–1.44) to 0.57 (0.32–1.87) (P = 0.09) and to 0.42 (0.16–0.87) (P = 0.01) software was used for data acquisition and analysis. For × 9 + the purpose of CD34+ cell analyses, a gate for viable cells (Table 2). The total number 10 /l (range) of BM CD34 excluding erythrocytes and debris was set according to for- cells increased slightly on day 3 (0.66 (0.13–0.77)), and ward (FSC) and side light scatter (SCC). The CD34+ cells decreased on day 5 (0.23 (0.06–1.23)) as compared with were analyzed in a fluorescence vs SCC plot. Thus, only basal values (0.40 (0.06–1.68)) (Figure 1). These changes cells with low SCC were counted as CD34+ cells. To obtain were not statistically significant, probably due to the small sufficient CD34+ cells for analysis of CD34+ subsets, an number of cases included in the study. acquisition gate was set according to SSC and fluorescence intensity range comprising the cells with positive CD34 Nucleated and CD34+ cells in peripheral blood fluorescence signals. A minimum of 300 000 events were × 9 run through the cytometer per test, and 3000–5000 CD34+ The peripheral WBC count increased from a median 10 /l (range) of 5.2 (3.2–13.6) before G-CSF administration to cells within the acquisition gate were stored in listmode = = data files for further analysis. 25.3 (23.8–37.8) (P 0.02) and 39.4 (21.0–69.2) (P 0.01) on days 3 and 5 of cytokine administration, respectively. The percentage of CD34+ cells rose from a median (range) Statistics of 0.002 (0.001–0.003) to 0.023 (0.007–0.030) (P = 0.06) Median values and ranges for each parameter were determ- on day 3, and 0.115 (0.028–1.62) (P = 0.01) on day 5 ined. The Wilcoxon test (paired, nonparametric) was (Table 2). This resulted in a significant increment in the performed to compare the results of the different total number of CD34+ cells in the peripheral blood, the subpopulations. maximum value being achieved on day 5 (Figure 1).
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