The CXCR4-Antagonist AMD3100 Augments the Number of Mobilized Peripheral Blood Progenitor Cells (PBPC) When Added to a G-CSF Standard Mobilization Regime and AMD3100-Mobilized PBPC Result in Rapid Hematopoietic Reconstitution after Autologous Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1961-1961 ◽  
Author(s):  
Stefan Fruehauf ◽  
Timon Seeger ◽  
Julian Topaly ◽  
Doris Herrmann ◽  
Falk Dillmann ◽  
...  
Keyword(s):  
Stem Cell ◽  
Progenitor Cells ◽  
Peripheral Blood ◽  
Autologous Transplantation ◽  
T Cell Subsets ◽  
Cxcr4 Antagonist ◽  
Hematopoietic Reconstitution ◽  
Peripheral Blood Progenitor Cells ◽  
Cd34 Cells ◽  
Patient Reported

Abstract Sufficient mobilization of peripheral blood progenitor cells (PBPC) is pivotal for successful autologous transplantation. G-CSF has gained a confirmed and dominant role in standard mobilization regimens. Recent reports provided evidence for the importance of the SDF1/CXCR4 axis in hematopoietic stem cell trafficking. AMD3100 is a CXCR4 antagonist that induces rapid mobilization of CD34+ cells in healthy volunteers. We initiated a phase II study assessing the safety and potential of AMD3100 in patients with multiple myeloma (MM) and non-Hodgkin’s lymphoma (NHL). At the time of the report 6 patients with MM and 4 patients with NHL were enrolled (5 female, 5 male; age median 44, range 44–71 yrs; prior chemotherapy regimens median 3, range 1–8). All patients with MM were in stage IIA or IIIA. Patients with NHL were in stage IIB, IIIA, IIIE or IV. Mobilization treatment consisted of 5 days G-CSF (10 μg/kg, s.c. AM) and a single dose of AMD3100 (240 μg/kg, s.c.) in the evening of day 4, 10–11 hours prior to leukapheresis. As expected, following 4 days of G-CSF treatment the CD34+ cell count in the peripheral blood increased 22-fold (range 7,8–33) and there was a correlation between baseline and day 4 PB CD34+ counts (r=0,88). Addition of AMD3100 led almost to a tripling of circulating CD34+ cells within 10 h after administration (2,8-fold increase, range 1,85–4,74). On the other hand, there was no mobilization of B-cells (CD19) -thus giving no indication for the co-mobilization of tumor cells- and no mobilization of NK/T-cell subsets (CD2, CD3, CD4, CD8). Patients with low starting PB CD34+ counts profited most. There was no association between the SDF1 1-3A polymorphism and the mobilization efficiency following AMD3100+G-CSF vs. G-CSF mobilization: 21% of patients showed the heterozygous G/A phenotype and the remainder the G/G phenotype. Interestingly, SDF1-serum levels in patients increased significantly after addition of AMD3100. Per leukapheresis procedure 4,3 (range 2,6–12,1) * 10e6 CD34+ cells/kg body weight (bw) were collected. Adverse effects were mild, one patient reported of nausea and emesis, WHO grade I. To date, four patients have been transplanted after high-dose chemotherapy (Melphalan 200mg/m2 or BEAM) with 4,7 (range 2,4–6,05) * 10e6 CD34+ cells/kg bw. Hematopoietic reconstitution (leukocytes >1/nl and thrombocytes >20/nl) was observed within a median of 14 (range 12–17) and 13 (range 10–15) days, respectively and is sustained in all patients. Thus CD34+ cells mobilized with AMD3100 appear to be fully functional. In conclusion AMD3100 is a seminal new drug development in the field of stem cell transplantation with the highest potential in poorly mobilizing patients.

Quantitative assessment of retroviral transfer of the human multidrug resistance 1 gene to human mobilized peripheral blood progenitor cells engrafted in nonobese diabetic/severe combined immunodeficient mice

Blood ◽  
2000 ◽  
Vol 95 (4) ◽  
pp. 1237-1248 ◽  
Author(s):  
B. Schiedlmeier ◽  
K. Kühlcke ◽  
H. G. Eckert ◽  
C. Baum ◽  
W. J. Zeller ◽  
...  
Keyword(s):  
Stem Cell ◽  
Multidrug Resistance ◽  
Progenitor Cells ◽  
Peripheral Blood ◽  
Autologous Transplantation ◽  
Embryonic Stem ◽  
Scid Mice ◽  
Nonobese Diabetic ◽  
Peripheral Blood Progenitor Cells ◽  
Mobilized Peripheral Blood

Mobilized peripheral blood progenitor cells (PBPC) are a potential target for the retrovirus-mediated transfer of cytostatic drug-resistance genes. We analyzed nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse-repopulating CD34+ PBPC from patients with cancer after retroviral transduction in various cytokine combinations with the hybrid vector SF-MDR, which is based on the Friend mink cell focus-forming/murine embryonic stem-cell virus and carries the human multidrug resistance 1 (MDR1) gene. Five to 13 weeks after transplantation of CD34+ PBPC into NOD/SCID mice (n = 84), a cell dose-dependent multilineage engraftment of human leukocytes up to an average of 33% was observed. The SF-MDR provirus was detected in the bone marrow (BM) and in its granulocyte fractions in 96% and 72%, respectively, of chimeric NOD/SCID mice. SF-MDR provirus integration assessed by quantitative real-time polymerase chain reaction (PCR) was optimal in the presence of Flt-3 ligand/thrombopoietin/stem-cell factor, resulting in a 6-fold (24% ± 5% [mean ± SE]) higher average proportion of gene-marked human cells in NOD/SCID mice than that achieved with IL-3 alone (P < .01). A population of clearly rhodamine-123dull human myeloid progeny cells could be isolated from BM samples from chimeric NOD/SCID mice. On the basis of PCR and rhodamine-123 efflux data, up to 18% ± 4% of transduced cells were calculated to express the transgene. Our data suggest that the NOD/SCID model provides a valid assay for estimating the gene-transfer efficiency to repopulating human PBPC that may be achievable in clinical autologous transplantation. P-glycoprotein expression sufficient to prevent marrow aplasia in vivo may be obtained with this SF-MDR vector and an optimized transduction protocol.

scholarly journals Recombinant rat stem cell factor synergizes with recombinant human granulocyte colony-stimulating factor in vivo in mice to mobilize peripheral blood progenitor cells that have enhanced repopulating potential

Blood ◽  
1993 ◽  
Vol 82 (6) ◽  
pp. 1720-1723 ◽  
Author(s):  
RA Briddell ◽  
CA Hartley ◽  
KA Smith ◽  
IK McNiece
Keyword(s):  
Stem Cell ◽  
Progenitor Cells ◽  
Peripheral Blood ◽  
Stem Cell Factor ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Peripheral Blood Progenitor Cells ◽  
Stimulating Factor ◽  
Synergistic Increase

Abstract Splenectomized mice treated for 7 days with pegylated recombinant rat stem cell factor (rrSCF-PEG) showed a dose-dependent increase in peripheral blood progenitor cells (PBPC) that have enhanced in vivo repopulating potential. A dose of rrSCF-PEG at 25 micrograms/kg/d for 7 days produced no significant increase in PBPC. However, when this dose of rrSCF-PEG was combined with an optimal dose of recombinant human granulocyte colony-stimulating factor (rhG-CSF; 200 micrograms/kg/d), a synergistic increase in PBPC was observed. Compared with treatment with rhG-CSF alone, the combination of rrSCF-PEG plus rhG-CSF resulted in a synergistic increase in peripheral white blood cells, in the incidence and absolute numbers of PBPC, and in the incidence and absolute numbers of circulating cells with in vivo repopulating potential. These data suggest that low doses of SCF, which would have minimal, if any, effects in vivo, can synergize with optimal doses of rhG-CSF to enhance the mobilization of PBPC stimulated by rhG-CSF alone.

Mobilization of peripheral blood progenitor cells by sequential administration of interleukin-3 and granulocyte-macrophage colony- stimulating factor following polychemotherapy with etoposide, ifosfamide, and cisplatin [see comments]

Blood ◽  
1992 ◽  
Vol 79 (5) ◽  
pp. 1193-1200 ◽  
Author(s):  
W Brugger ◽  
K Bross ◽  
J Frisch ◽  
P Dern ◽  
B Weber ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Peripheral Blood ◽  
Standard Dose ◽  
Gm Csf ◽  
Peripheral Blood Progenitor Cells ◽  
Cd34 Cells ◽  
Sequential Administration ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract We report on the requirements that have to be met to combine a standard- dose chemotherapy regimen with broad antitumor activity with the mobilization of peripheral blood hematopoietic progenitor cells. Thirty- two cancer patients were given a 1-day course of chemotherapy consisting of etoposide (VP16), ifosfamide, and cisplatin (VIP; n = 46 cycles), followed by the combined sequential administration of recombinant human interleukin-3 (rhIL-3) and recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF). Control patients received GM-CSF alone or were treated without cytokines. Maximum numbers of peripheral blood progenitor cells (PBPC) were recruited on day 13 to 17 after chemotherapy, with a median of 418 CD34+ cells/microL blood (range, 106 to 1,841) in IL-3/GM-CSF-treated patients, 426 CD34+/microL (range, 191 to 1,380) in GM-CSF-treated patients, and 46 CD34+/microL (range, 15 to 148) in patients treated without cytokines. In parallel, there was an increase in myeloid (10,490 colony-forming unit-granulocyte-macrophage [CFU-GM]/mL blood; range, 1,000 to 23,400), as well as erythroid (10,660 burst-forming unit-erythroid [BFU-E]/mL blood; range, 3,870 to 24,300) and multipotential (840 CFU-granulocyte, erythrocyte, monocyte, megakaryocyte [GEMM]/mL blood; range, 160 to 2,070) progenitor cells in IL-3 plus GM-CSF-treated patients. In GM-CSF-treated patients, significantly less precursor cells of all lineages were mobilized, particularly multipotential progenitors (400 CFU-GEMM/mL blood; range, 200 to 2,150). Only small numbers of CD34+ cells and clonogenic progenitor cells could be recruited in intensively pretreated patients. Our data document that after standard-dose chemotherapy-induced bone marrow hypoplasia, IL-3 plus GM-CSF can be used to recruit PBPC, which might shorten the hematopoietic recovery after high-dose chemotherapy in chemosensitive lymphomas or solid tumors.

Ancestim (r-metHuSCF) Plus Filgrastim for the Mobilization and Collection of Peripheral Blood Progenitor Cells for Autologous Transplant after Failure of Prior Mobilization: The French Experience of Compassionate Use.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3281-3281
Author(s):  
Valerie Lapierre ◽  
Christian Chabannon ◽  
Caroline Makowski ◽  
Cecile Dumesnil ◽  
Dominique Valteau-Couanet ◽  
...  
Keyword(s):  
Stem Cell ◽  
Lymphocytic Leukaemia ◽  
Autologous Transplantation ◽  
Median Number ◽  
Compassionate Use ◽  
French Experience ◽  
Peripheral Blood Progenitor Cells ◽  
Cd34 Cells ◽  
Life Threatening ◽  
Cell Mobilization

Abstract Background: Ancestim (r-met human stem cell factor; Amgen Inc, CA, USA) is available in France for compassionate use in patients who have failed prior mobilization or an insufficient number of CD34+ cells for autograft. We retrospectively reviewed data from these patients to evaluate the efficacy of ancestim combined with filgrastim in achieving an adequate stem cell yield. Patients and methods: Between January 1998 and July 2007, permission for ancestim use was granted by the French health authority and Amgen to 550 patients (pts) at 82 sites (median age 55 yrs (range, 18–74); 50% male). Non-Hodgkin’s lymphoma (NHL) accounted for 50% of pts, multiple myeloma (MM) 28%, chronic lymphocytic leukaemia 6%, Ewing’s sarcoma 4%, neuroblastomas 3%, ovarian carcinoma 1%, osteosarcomas 1%, and other tumours 7%. Of the 508 pts for whom data were available and analysed, 378 had undergone prior mobilization and 117 were considered to have insufficient harvests; mobilization history was unknown for 13 pts. Fifty-eight percent of the pts were treated with ancestim (20 microg/kg/day s.c.) and filgrastim (10 microg/kg/day s.c.) alone for a median of 6 days (range, 2–21), while the other pts received chemotherapy followed by ancestim (20 microg/kg/day s.c.) and filgrastim (5 microg/kg/day s.c.) for a median of 11 days (range, 1–33). Results: The target threshold of 2x106 CD34+ cells/kg was reached in 198/508 pts (39%) (including 51% of the 144 MM pts and 31% of the 254 NHL pts) after a median of 2 leukaphereses (range, 1–6). 35% of pts with prior mobilization failure and 52% of pts with prior insufficient harvests reached the target of 2 x106 CD34+ cells/kg, with a median number of CD34+ cells harvested of 3.4 x106/kg (range, 0.5–39.5). Of these, 150 pts (76%) proceeded to autologous transplantation. Data on engraftment are available for 137 pts: the median times to reach 0.5 x 109/L neutrophils and 20 x 109/L platelets were 12 days (range, 6–40) and 13 days (range, 0–31), respectively. All pts receiving ancestim were premedicated and treatment was generally well tolerated. Four pts were reported to have experienced severe mast cell-mediated reactions, none of which were life-threatening. Conclusion: Ancestim plus filgrastim, alone or with chemotherapy, successfully rescued adequate CD34+ cell mobilization and collection in preparation for autologous transplantation in approximately 40% of pts.

The Tetraspanin CD9 Regulates Engraftment and Mobilization of Human CD34+ Hematopoietic Stem/Progenitor Cells and Modulates VLA-4 Activity

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1169-1169
Author(s):  
Kam Tong Leung ◽  
Karen Li ◽  
Yorky Tsin Sik Wong ◽  
Kathy Yuen Yee Chan ◽  
Xiao-Bing Zhang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Progenitor Cells ◽  
Peripheral Blood ◽  
Scid Mouse ◽  
Conflicts Of Interest ◽  
Chimeric Mice ◽  
Hematopoietic Stem ◽  
Cell Engraftment ◽  
Cd34 Cells

Abstract Migration, homing and engraftment of hematopoietic stem/progenitor cells depend critically on the SDF-1/CXCR4 axis. We previously identified the tetraspanin CD9 as a downstream signal of this axis, and it regulates short-term homing of cord blood (CB) CD34+ cells (Leung et al, Blood, 2011). However, its roles in stem cell engraftment, mobilization and the underlying mechanisms have not been described. Here, we provided evidence that CD9 blockade profoundly reduced long-term bone marrow (BM; 70.9% inhibition; P = .0089) and splenic engraftment (87.8% inhibition; P = .0179) of CB CD34+ cells (n = 6) in the NOD/SCID mouse xenotransplantation model, without biasing specific lineage commitment. Interestingly, significant increase in the CD34+CD9+ subsets were observed in the BM (9.6-fold; P < .0001) and spleens (9.8-fold; P = .0014) of engrafted animals (n = 3-4), indicating that CD9 expression on CD34+ cells is up-regulated during engraftment in the SDF-1-rich hematopoietic niches. Analysis of paired BM and peripheral blood (PB) samples from healthy donors revealed higher CD9 expressions in BM-resident CD34+ cells (46.0% CD9+ cells in BM vs 26.5% in PB; n = 13, P = .0035). Consistently, CD34+ cells in granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood (MPB) expressed lower levels of CD9 (32.3% CD9+ cells; n = 25), when compared with those in BM (47.7% CD9+ cells; n = 16, P = .0030). In vitro exposure of MPB CD34+ cells to SDF-1 significantly enhanced CD9 expression (1.5-fold increase; n = 4, P = .0060). Treatment of NOD/SCID chimeric mice with G-CSF decreased the CD34+CD9+ subsets in the BM from 79.2% to 62.4% (n = 8, P = .0179). These data indicate that CD9 expression is down-regulated during egress or mobilization of CD34+ cells. To investigate the possible mechanisms, we performed a VCAM-1 (counter receptor of the VLA-4 integrin) binding assay on BM CD34+ cells. Our results demonstrated that CD34+CD9+ cells preferentially bound to soluble VCAM-1 (17.2%-51.4% VCAM-1-bound cells in CD9+ cells vs 12.8%-25.9% in CD9- cells; n = 10, P ≤ .0003), suggesting that CD9+ cells possess higher VLA-4 activity. Concomitant with decreased CD9 expression, MPB CD34+ cells exhibited lower VCAM-1 binding ability (2.8%-4.0% VCAM-1-bound cells; n = 3), when compared to BM CD34+ cells (15.5%-37.7%; n = 10, P < .0130). In vivo treatment of NOD/SCID chimeric mice with G-CSF reduced VCAM-1 binding of CD34+ cells in the BM by 49.0% (n = 5, P = .0010). Importantly, overexpression of CD9 in CB CD34+ cells promoted VCAM-1 binding by 39.5% (n = 3, P = .0391), thus providing evidence that CD9 regulates VLA-4 activity. Preliminary results also indicated that enforcing CD9 expression in CB CD34+ cells could enhance their homing and engraftment in the NOD/SCID mouse model. Our findings collectively established that CD9 expression and associated integrin VLA-4 activity are dynamically regulated in the BM microenvironment, which may represent important events in governing stem cell engraftment and mobilization. Strategies to modify CD9 expression could be developed to enhance engraftment or mobilization of CD34+ cells. Disclosures No relevant conflicts of interest to declare.

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