Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma

Blood ◽  
2009 ◽  
Vol 113 (23) ◽  
pp. 5720-5726 ◽  
Author(s):  
John F. DiPersio ◽  
Edward A. Stadtmauer ◽  
Auayporn Nademanee ◽  
Ivana N. M. Micallef ◽  
Patrick J. Stiff ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Hematopoietic Stem Cells ◽  
Primary Endpoint ◽  
Controlled Study ◽  
Double Blind ◽  
Hematopoietic Stem ◽  
Injection Site Reactions ◽  
Cd34 Cells ◽  
Stimulating Factor

Abstract This phase 3, multicenter, randomized (1:1), double-blind, placebo-controlled study evaluated the safety and efficacy of plerixafor with granulocyte colony-stimulating factor (G-CSF) in mobilizing hematopoietic stem cells in patients with multiple myeloma. Patients received G-CSF (10 μg/kg) subcutaneously daily for up to 8 days. Beginning on day 4 and continuing daily for up to 4 days, patients received either plerixafor (240 μg/kg) or placebo subcutaneously. Starting on day 5, patients began daily apheresis for up to 4 days or until more than or equal to 6 × 106 CD34+ cells/kg were collected. The primary endpoint was the percentage of patients who collected more than or equal to 6 × 106 CD34+ cells/kg in less than or equal to 2 aphereses. A total of 106 of 148 (71.6%) patients in the plerixafor group and 53 of 154 (34.4%) patients in the placebo group met the primary endpoint (P < .001). A total of 54% of plerixafor-treated patients reached target after one apheresis, whereas 56% of the placebo-treated patients required 4 aphereses to reach target. The most common adverse events related to plerixafor were gastrointestinal disorders and injection site reactions. Plerixafor and G-CSF were well tolerated, and significantly more patients collected the optimal CD34+ cell/kg target for transplantation earlier compared with G-CSF alone. This study is registered at www.clinicaltrials.gov as #NCT00103662.

scholarly journals Yf-H-2015005, a New CXCR4 Antagonist, in the Mobilization of Hematopoietic Stem Cells in Patients with Non-Hodgkin Lymphoma: A Randomized-Controlled Phase 3 Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 590-590
Author(s):  
Weiping Liu ◽  
Yufu Li ◽  
Quanshun Wang ◽  
Kaiyang Ding ◽  
Hang Su ◽  
...  
Keyword(s):  
Stem Cells ◽  
Adverse Event ◽  
Placebo Group ◽  
Hematopoietic Stem Cells ◽  
Primary Endpoint ◽  
Phase Iii ◽  
Cxcr4 Antagonist ◽  
Hematopoietic Stem ◽  
Related Adverse Event ◽  
Cd34 Cells

Background: Autologous hematopoietic stem cell transplantation (AHSCT) is an important therapy for non-Hodgkin's lymphoma (NHL). This study evaluated the safety and efficacy of YF-H-2015005, a new CXCR4 antagonist, when used to mobilize hematopoietic stem cells in patients with NHL eligible for treatment with AHSCT. Methods: This phase III, multicenter, randomized (1:1), double-blind, placebo-controlled study enrolled patients (age range, 18 to 65 years) with NHL, and who were in their first or second complete or partial remission. The patients received granulocyte colony-stimulating factor (G-CSF, 10 mg/kg/day) each morning for up to 8 days. Treatment with YF-H-2015005 (0.24 mg/kg/day) or placebo was initialed during the evening of the fourth day of G-CSF administration, and then continued for up to 4 days. Starting on day 5, apheresis was performed for 9 to 10 hours after each dose of YF-H-2015005 or until ≥ 5 × 106 CD34+ cells/kg had been collected. The primary endpoint was the percentage of patients who collected ≥ 5 × 106 CD34+ cells/kg during the course of 4 or fewer apheresis days. The secondary endpoints were the percentage of patients who collected ≥ 2 × 106 CD34+ cells/kg during the course of 4 or fewer apheresis days, the number of apheresis days required to reach ≥ 2 × 106 CD34+ cells/kg, the number of apheresis days required to reach ≥ 5 × 106 CD34+ cells/kg, and patient safety. Results: A total of 101 patients with NHL were randomly assigned to the YF-H-2015005 group (n = 51or placebo group (n = 50), respectively. The percentage of patients who met the primary endpoint was 57% (29/51) in the YF-H-2015005 group and 12% (6/50) in the placebo group (P &lt; 0.001). A larger proportion of patients in the YF-H-2015005 group (86%) achieved the secondary endpoint of collecting ≥ 2 × 106 CD34+ cells/kg in 4 or fewer apheresis days when compared with the placebo group (38%, P &lt; 0.001). Patients in the YF-H-2015005 group required shorter time periods to collect ≥ 2 × 106 CD34+ cells/kg (1 days vs. 4 days) and ≥ 5 × 106 CD34+ cells/kg (3 days vs. not reached). Treatment-related adverse event were observed in 37 patients (20 in the YF-H-2015005 group and 17 in the placebo group). The most common adverse events in the YF-H-2015005 group were diarrhea (14%), hyperhidrosis(6%), elevated alkaline phosphatase (6%). No serious treatment-related adverse event occurred. Conclusions: The combination of YF-H-2015005 and G-CSF was a tolerable regimen for use in rapidly mobilizing and collecting CD34+ cells for transplantation in patients with NHL. Disclosures Zhu: Mundipharma: Research Funding.

scholarly journals Differential mobilization of myeloma cells and normal hematopoietic stem cells in multiple myeloma after treatment with cyclophosphamide and granulocyte-macrophage colony-stimulating factor

Blood ◽  
1996 ◽  
Vol 87 (2) ◽  
pp. 805-811 ◽  
Author(s):  
Y Gazitt ◽  
E Tian ◽  
B Barlogie ◽  
CL Reading ◽  
DH Vesole ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
High Dose ◽  
Colony Stimulating Factor ◽  
Hematopoietic Stem ◽  
Myeloma Cells ◽  
Cd34 Cells ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Peripheral blood stem cells (PBSCs) mobilized with high-dose chemotherapy and hematopoietic growth factors are now widely used to support myeloablative therapy of multiple myeloma and effect complete remissions in up to 50% of patients with apparent extension of event- free and overall survival. Because tumor cells are present not only in bone marrow, but also in virtually all PBSC harvests, it is conceivable that autografted myeloma cells contribute to relapse after autotransplants. In this study, the kinetics of mobilization of normal hematopoietic stem cells were compared with those of myeloma cells present in PBSC harvests of 12 patients after high-dose cyclophosphamide and granulocyte-macrophage colony-stimulating factor administration. CD34+ and CD34+Lin-Thy+ stem cell contents were measured by multiparameter flow cytometry, and myeloma cells were quantitated by immunostaining for the relevant Ig light chain and by a quantitative polymerase chain reaction for the myeloma-specific CDRIII sequence. Results indicated marked heterogeneity in the percentages of mobilized stem cells among different patients (0.1% to 22.2% for CD34+ cells and 0.1% to 7.5% for CD34+Lin-Thy+ cells, respectively). The highest proportions of hematopoietic progenitor cells were observed early during apheresis, with 9 of 12 patients mobilizing adequate amounts of CD34+ cells for 2 autotransplants (> 4 x 10(6)/kg) within the first 2 days, whereas peak levels (percent and absolute numbers) of myeloma cells were present on days 5 and 6 (0.5% to 22.0%). During the last days of collection, mobilized tumor cells exhibited more frequently high labeling index values (1% to 10%; median, 4.4%) and an immature phenotype (CD19+). The differential mobilization observed between normal hematopoietic stem cells and myeloma cells can be exploited to reduce tumor cell contamination in PBSC harvests.

scholarly journals Optimization of methods for collecting peripheral hematopoietic stem cells in children with cancer: literature review

2020 ◽  
Vol 7 (2) ◽  
pp. 78-85
Author(s):  
N. G. Stepanyan ◽  
N. V. Sidorova ◽  
M. V. Rubanskaya ◽  
N. N. Tupitsyn ◽  
N. V. Matinyan ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
High Dose Chemotherapy ◽  
Optimal Number ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Cd34 Cells ◽  
Cxcr4 Antagonists ◽  
Somatic State ◽  
Stimulating Factor

Autologous hematopoietic stem cell transplantation (auto-HSCT) is a standard for the treatment of oncological, hematologic, and also some immune diseases, ensuring the restoration of blood counts after high-dose chemotherapy. In children, the success of mobilization and collection of hematopoietic stem cells (HSCs) is especially important. Mobilization schemes for children are decided on an individual basis, which requires the development and implementation of recommendations for improving the efficiency of mobilization and collection of HSCs. Mobilization schemes include the use of granulocyte colony-stimulating factor in the form of monotherapy or in combination with CXCR4 antagonists. These schemes are ineffective in some children, which requires re-mobilization or rejection of transplantation, which negatively affects the prognosis. When preparing a patient for HSCs collection, it is necessary to take into account all previous therapy, the patient’s age, weight and height indicators, and general somatic state. Harvesting the required amount of HSCs will allow for high-dose therapy followed by auto-HSCT, and thereby increase the effectiveness of treatment. It is necessary to optimize the protocol for mobilization of HSCs with a large bias for pediatric patients, which will clearly define the criteria for mobilization, give indications for this procedure and determine the criteria for technical collection, which will allow to obtain the optimal number of CD34+ cells, which will ensure the success of the treatment.

scholarly journals YF-H-2015005, a CXCR4 Antagonist, for the Mobilization of Hematopoietic Stem Cells in Non-Hodgkin Lymphoma Patients: A Randomized, Controlled, Phase 3 Clinical Trial

2021 ◽  
Vol 8 ◽  
Author(s):  
Weiping Liu ◽  
Yufu Li ◽  
Quanshun Wang ◽  
Hang Su ◽  
Kaiyang Ding ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Hodgkin Lymphoma ◽  
Primary Endpoint ◽  
Phase Iii ◽  
Cxcr4 Antagonist ◽  
Double Blind ◽  
Hematopoietic Stem ◽  
Non Hodgkin Lymphoma

Background: YF-H-2015005, a novel CXCR4 antagonist, has been proven to increase the quantities of circulating hematopoietic stem cells (HSCs), which results in an adequate collection of HSCs in non-Hodgkin lymphoma (NHL) patients.Methods: This was a multicenter, double-blind, randomized (1:1), placebo-controlled phase III clinical trial. All patients received granulocyte colony-stimulating factor (G-CSF) for up to 8 consecutive days. YF-H-2015005 or placebo was administrated on the evening of day 4 and continued daily for up to 4 days. Apheresis was conducted 9–10 h after each dose of YF-H-2015005 or placebo. The primary endpoint was the proportion of NHL patients procuring ≥5 × 106/kg CD34+ HSCs within ≤4 apheresis sessions.Results: In total, 101 patients with NHL were enrolled. The proportions of patients achieving primary endpoint were 57 and 12% in YF-H-2015005 and placebo groups, respectively (P &lt; 0.001). Moreover, a higher proportion of YF-H-2015005-treated patients reached a minimum target collection of ≥2 × 106/kg CD34+ HSCs in ≤4 apheresis days compared to placebo-treated patients (86 vs. 38%, P &lt; 0.001). Furthermore, the median time to collect ≥2 or 5 × 106/kg CD34+ HSCs were 1 and 3 days in YF-H-2015005-treated patients, but 4 days and not reached in placebo-treated patients, respectively. No severe treatment emergent adverse events were observed in both YF-H-2015005 treatment and placebo groups.Conclusions: YF-H-2015005 plus G-CSF regimen was a tolerable combination with high efficacy, which might be used to rapidly mobilize and collect HSCs in NHL patients.

scholarly journals Subpopulations of mobilized hematopoietic stem cells in patients with hematological malignances and donors: expression of CD38, HLA-DR and CD143

2019 ◽  
Vol 14 (2) ◽  
pp. 48-58
Author(s):  
M. L. Kanaeva ◽  
I. V. Galtseva ◽  
E. N. Parovichnikova ◽  
Yu. O. Davydova ◽  
T. V. Gaponova ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Hematopoietic Stem Cells ◽  
Converting Enzyme ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Hematopoietic Stem ◽  
Cell Counts ◽  
Hla Dr ◽  
Stimulating Factor

The study objectiveis to investigate the features of subpopulational composition of mobilized hematopoietic stem cells in peripheral blood (PB) and leukocyte concentrates (LC) in adult patients with oncohematological pathology and donors.Materials and methods. In 80 patients with hemoblastoses, expression of CD38, HLA-DR and CD143 (angiotensin-converting enzyme) was measured in PB and LC CD34+CD45low cells. The control group included 10 PB and 14 LC samples from healthy donors. Analysis of PB was performed prior to mobilization of hematopoietic stem cells (HSC) and on the day of leukapheresis prior to HSC collection. LC samples were examined at day 1 after HSC collection.Results.CD143 is expressed on CD34+CD45low cells both prior to mobilization and after it in all patients and donors, but CD34+CD45lowCD143+ cell counts varied depending on diagnosis and mobilization regimen. CD143+ expression on CD34+CD45low cells was significantly higher in patients who received combination of chemotherapy and granulocyte colony-stimulating factor compared to donors and patients with multiple myeloma who received only granulocyte colony-stimulating factor. Along with elevated CD34+CD45low cell count after hematopoiesis stimulation, CD34+CD45lowCD143+ cell counts also increased. It was shown that mobilized HSC almost completely lacks a fraction of early CD34+CD45low progenitor cells not expressing CD38, HLA-DR. Prior to hematopoiesis stimulation among CD34+CD45low cells, CD38+HLADR–cell fractions are prevalent, but after mobilization CD38–HLA-DR+ cell counts increased. No differences between CD34+CD45lowCD143+cell counts in patients with multiple myeloma depending on disease status, sex, age or number of chemotherapy courses prior to HSC mobilizationwere observed.Conclusion. Expression of angiotensin-converting enzyme on CD34+ cells in PB before and after HSC mobilization and in LC was observed. The cell counts varied depending on diagnosis and mobilization regimen.

A Phase III, Multicenter, Randomized, Double-Blind, Placebo Controlled, Comparative Trial of AMD3100 (Plerixafor)+G-CSF vs. Placebo+G-CSF in Non-Hodgkin’s Lymphoma (NHL) Patients for Autologous Hematopoietic Stem Cell (aHSC) Transplantation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 601-601 ◽  
Author(s):  
John F. DiPersio ◽  
Ivana Micallef ◽  
Patrick J. Stiff ◽  
Brian J. Bolwell ◽  
Richard Thomas Maziarz ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Phase Iii ◽  
Controlled Study ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Evening Dose ◽  
Hematopoietic Stem ◽  
Double Blind Placebo ◽  
Transplant Patients ◽  
Cd34 Cells

Abstract AMD3100, Plerixafor (A)+G-CSF (G) have safely and effectively allowed aHSC mobilization in Phase I and II studies. This Phase III, multicenter, randomized, double-blind, placebo controlled study compared the safety and efficacy of A+G versus Placebo (P)+G to mobilize and transplant patients with NHL. Methods: Adult NHL patients requiring an aHSC transplant, in first or second CR or PR were eligible to participate. Patients received G (10μg/kg/day) subcutaneously (SQ) for 4 days. On the evening of Day 4, patients received either A (240μg/kg SQ) or P. Patients underwent apheresis on Day 5 after an AM dose of G and 10–11 hours after administration of study treatment. Patients continued to receive the evening dose of study treatment, followed by AM dose of G and apheresis for up to a total of 4 aphereses or until ≥5 x 106 CD34+cells/kg were collected. Only study cells were used for transplant. Patients who failed to mobilize ≥2 x 106 CD34+cells/kg could enter into a rescue arm of A+G, without unblinding of randomized treatment. The primary endpoint was the percentage of patients who achieved ≥5 x 106 CD34+cells/kg in 4 or less aphereses days. All patients will be followed for ≥12 months post-transplant. Results: 298 patients were enrolled and randomized. All patients have completed 100 days follow-up and are included in this intent-to-treat analysis. Baseline characteristics were similar between groups. The primary endpoint was met in 89/150 (59%) patients in the A+G group and 29/148 (20%) patients in the P+G group, p<0.0001. 130/150 (87%) patients in the A+G group and 70/148 (47%) patients in the P+G group collected ≥2 x 106 CD34+cells/kg in 4 or less aphereses days, p<0.0001. Kaplan-Meir Estimates of Time to Trget Collection of ≥ × 106 CD34 + cells/kg Kaplan-Meir Estimates of Time to Trget Collection of ≥ × 106 CD34 + cells/kg The figure shows that more patients in the A+G group reached target after 1 day of apheresis than patients in the P+G group after 4 days of apheresis. A+G rescue was successful in 33/52 rescue patients in the P+G group and 4/10 rescue patients in the A+G group. 135 patients (90%) in A+G group and 82 patients (55%) in P+G group underwent transplantation. Median time to engraftment was Day 10 for PMN and Day 20 for platelets in both groups. Through 100 days, grafts were durable in all but 2 A+G (133/135) patients and in all P+G (82) patients. A+G patients experienced a higher incidence of GI effects (mild to moderate) and injection site erythema than P+G patients. There were 2 drug related serious adverse events in the A+G group and 1 in the P+G group. Conclusions: In this study, the addition of AMD3100 to G-CSF is generally safe and well tolerated and is superior to G-CSF alone for aHSC mobilization in NHL patients. A+G patients were statistically significantly more likely to achieve target cell collection quicker and to achieve sufficient cells for successful transplant than P+G patients.

scholarly journals Basic fibroblast growth factor mediates its effects on committed myeloid progenitors by direct action and has no effect on hematopoietic stem cells

Blood ◽  
1995 ◽  
Vol 86 (6) ◽  
pp. 2123-2129 ◽  
Author(s):  
AC Berardi ◽  
A Wang ◽  
J Abraham ◽  
DT Scadden
Keyword(s):  
Stem Cells ◽  
Growth Factor ◽  
Hematopoietic Stem Cells ◽  
Fibroblast Growth Factor ◽  
Colony Formation ◽  
Fibroblast Growth ◽  
Colony Stimulating Factor ◽  
Hematopoietic Stem ◽  
Myeloid Progenitor ◽  
Stimulating Factor

Basic fibroblast growth factor or fibroblast growth factor-2 (FGF) has been shown to affect myeloid cell proliferation and hypothesized to stimulate primitive hematopoietic cells. We sought to evaluate the effect of FGF on hematopoietic stem cells and to determine if FGF mediated its effects on progenitor cells directly or through the induction of other cytokines. To address the direct effects of FGF, we investigated whether FGF induced production of interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha, IL-6, granulocyte colony- stimulating factor, or granulocyte-macrophage colony-stimulating factor by two types of accessory cells, bone marrow (BM) fibroblasts and macrophages. We further evaluated whether antibodies to FGF-induced cytokines affected colony formation. To determine if FGF was capable of stimulating multipotent progenitors, we assessed the output of different colony types after stimulation of BM mononuclear cells (BMMC) or CD34+ BMMC and compared the effects of FGF with the stem cell active cytokine, kit ligand (KL). In addition, a subset of CD34+ BMMC with characteristics of hematopoietic stem cells was isolated by functional selection and their response to FGF was evaluated using proliferation, colony-forming, and single-cell polymerase chain reaction (PCR) assays. We determined that FGF had a stimulatory effect on the production of a single cytokine, IL-6, but that the effects of FGF on colony formation were not attributable to that induction. FGF was more restricted in its in vitro effects on BM progenitors than KL was, having no effect on erythroid colony formation. FGF did not stimulate stem cells and FGF receptors were not detected on stem cells as evaluated by single-cell reverse transcription PCR. In contrast, FGF receptor gene expression was detected in myeloid progenitor populations. These data support a directly mediated effect for FGF that appears to be restricted to lineage-committed myeloid progenitor cells. FGF does not appear to modulate the human hematopoietic stem cell.

scholarly journals Inhibition of day-12 spleen colony-forming units by a monoclonal antibody to the murine macrophage/monocyte colony-stimulating factor receptor

Blood ◽  
1995 ◽  
Vol 85 (10) ◽  
pp. 2731-2734 ◽  
Author(s):  
GL Gilmore ◽  
RK Shadduck
Keyword(s):  
Stem Cells ◽  
Growth Factor ◽  
Hematopoietic Stem Cells ◽  
Growth Factor Receptor ◽  
Hematopoietic Growth Factor ◽  
Colony Stimulating Factor ◽  
Hematopoietic Stem ◽  
Colony Forming Units ◽  
Stimulating Factor ◽  
Specific Control

Primitive hematopoietic stem cells differentiate into committed progenitors that are thought to selectively express hematopoietic growth factor receptor(s), thereby acquiring hematopoietic growth factor responsiveness. To assess whether hematopoietic stem cells express hematopoietic growth factor receptors, the progenitor activity of bone marrow (BM) fractions, isolated by expression of receptors for macrophage/monocyte colony-stimulating factor (M-CSF), were examined. Recovery of day-12 spleen colony-forming units (CFU-S) is diminished in both M-CSF receptor-positive (M-CSFR+) and M-CSFR-fractions, indicating antibody inhibition of day-12 CFU-S. Incubation of BM cells with antibody without fractionation inhibits 50% to 60% of day-12 CFU-S. This inhibition is specific (control antibodies have no effect) and reversible by removal of bound antibody at low pH. Incubating BM cells with control or antireceptor antibody does not affect day-8 CFU-S, which are predominantly erythroid. Treating sublethally irradiated mice with antibody inhibits endogenous day-12 CFU-S. These results indicate that some early progenitors express M-CSFRs, and blocking M-CSFRs inhibits the ability of these progenitors to form colonies, possibly because of inactivation caused by prolonged receptor blockade.

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