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Biology of Blood and Marrow... Feb 2009We investigated the efficacy and toxicity of combining granulocyte-colony stimulating factor (G-CSF) at standard doses with plerixafor, a CXCR4 inhibitor, to mobilize... (Clinical Trial)
Clinical Trial
Treatment with plerixafor in non-Hodgkin's lymphoma and multiple myeloma patients to increase the number of peripheral blood stem cells when given a mobilizing regimen of G-CSF: implications for the heavily pretreated patient.
We investigated the efficacy and toxicity of combining granulocyte-colony stimulating factor (G-CSF) at standard doses with plerixafor, a CXCR4 inhibitor, to mobilize stem cells in patients with non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM). Patients with NHL and MM underwent mobilization with G-CSF (10 microg/kg/day) for up to 9 days and plerixafor (240 microg/kg/day), which started on the evening of day 4. Apheresis began on day 5 and continued daily until either >or= 5 x 10(6) CD34/kg were collected or to a maximum of 5 aphereses. Toxicities, increase in circulating CD34 cells/microL before and after the first dose of plerixafor, percentage of patients collecting >or= 5 x 10(6) CD34/kg, total CD34 cells/kg collected, engraftment, and exploratory efficacy analyses in heavily pretreated patients were examined. Six sites enrolled 49 patients (NHL, 23; MM, 26). All completed mobilization and 47 of 49 (96%) underwent transplant. Circulating CD34 cells/microL increased by 2.5-fold (1.3-6.0-fold) after the first plerixafor dose. The median CD34 cells/kg collected was 5.9 x 10(6) (1.5-22.5) in 2 (1-5) days of aphereses. Median days to neutrophil and platelet engraftment were 11 (8-16) and 14.5 (7-39) days, respectively. Adverse events primarily were mild nausea and diarrhea (n=24). Twenty-eight (57%) were identified as heavily pretreated patients. Their median fold increase in circulating CD34 cells/microL was 2.5 (1.4-5.0) after plerixafor, similar to minimally pretreated patients. Plerixafor and G-CSF increased circulating CD34 cells/microL and led to the adequate collection of stem cells for autotransplant in 96% of the patients. This combination may have particular value in heavily pretreated patients.
Topics: Adult; Aged; Antigens, CD34; Benzylamines; Blood Component Removal; Cell Count; Cyclams; Drug Therapy, Combination; Female; Graft Survival; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cells; Heterocyclic Compounds; Humans; Lymphoma, Non-Hodgkin; Male; Middle Aged; Multiple Myeloma; Receptors, CXCR4
PubMed: 19167685
DOI: 10.1016/j.bbmt.2008.11.028 -
Stem Cells (Dayton, Ohio) Jan 2023While supplemental angiopoietin-1 (Ang1) improves hematopoiesis, excessive Ang1 induces bone marrow (BM) impairment, hematopoietic stem cell (HSC) senescence, and...
While supplemental angiopoietin-1 (Ang1) improves hematopoiesis, excessive Ang1 induces bone marrow (BM) impairment, hematopoietic stem cell (HSC) senescence, and erythropoietic defect. Here, we examined how excessive Ang1 disturbs hematopoiesis and explored whether hematopoietic defects were related to its level using K14-Cre;c-Ang1 and Col2.3-Cre;c-Ang1 transgenic mice that systemically and locally overexpress cartilage oligomeric matrix protein-Ang1, respectively. We also investigated the impacts of Tie2 inhibitor and AMD3100 on hematopoietic development. Transgenic mice exhibited excessive angiogenic phenotypes, but K14-Cre;c-Ang1 mice showed more severe defects in growth and life span with higher presence of Ang1 compared with Col2.3-Cre;c-Ang1 mice. Dissimilar to K14-Cre;c-Ang1 mice, Col2.3-Cre;c-Ang1 mice did not show impaired BM retention or senescence of HSCs, erythropoietic defect, or disruption of the stromal cell-derived factor 1 (SDF-1)/CXCR4 axis. However, these mice exhibited a defect in platelet production depending on the expression of Tie2 and globin transcription factor 1 (GATA-1), but not GATA-2, in megakaryocyte progenitor (MP) cells. Treatment with Tie2 inhibitor recovered GATA-1 expression in MP cells and platelet production without changes in circulating RBC in transgenic mice. Consecutive AMD3100 administration not only induced irrecoverable senescence of HSCs but also suppressed formation of RBC, but not platelets, via correlated decreases in number of erythroblasts and their GATA-1 expression in B6 mice. Our results indicate that genetic overexpression of Ang1 impairs hematopoietic development depending on its level, in which megakaryopoiesis is preferentially impaired via activation of Ang1/Tie2 signaling, whereas erythropoietic defect is orchestrated by HSC senescence, inflammation, and disruption of the SDF-1/CXCR4 axis.
Topics: Mice; Animals; Cartilage Oligomeric Matrix Protein; Angiopoietin-1; Chemokine CXCL12; Mice, Transgenic; Anemia; Thrombocytopenia; Receptor, TIE-2
PubMed: 36368017
DOI: 10.1093/stmcls/sxac080 -
Biology of Blood and Marrow... Aug 2012Collection of adequate hematopoietic stem cells (HSCs) is necessary for successful autologous transplantation; however, a proportion of patients fail to collect the... (Review)
Review
Collection of adequate hematopoietic stem cells (HSCs) is necessary for successful autologous transplantation; however, a proportion of patients fail to collect the minimum number of cells required. We summarized the efficacy and safety of HSC mobilization strategies. We performed a systematic review of randomized controlled trials comparing HSC mobilization strategies before autologous transplantation for hematologic malignancies. The primary outcome was CD34+ cell yield. Secondary outcomes included number of aphereses, proportion of failures, rate of count recovery, and adverse events. We identified 28 articles within 3 broad strategies. Using a cyclophosphamide with growth factor strategy (10 articles), CD34+ cell yield is improved by addition of molgramostim to cyclophosphamide (1.4 vs 0.5 × 10(6)/kg; P = .0165), addition of cyclophosphamide to filgrastim (7.2 vs 2.5 × 10(6)/kg; P = .004), and addition of ancestim to cyclophosphamide and filgrastim (12.4 vs 8.3 × 10(6)/kg; P = .007). Within a growth factor-based strategy (6 articles), addition of plerixafor improves CD34+ cell yield over filgrastim alone in multiple myeloma (MM; 11.0 vs 6.2 × 10(6)/kg; P < .001) and non-Hodgkin lymphoma (5.69 vs 1.98 × 10(6)/kg; P < .01). With combination or noncyclophosphamide-based chemotherapy (12 articles), higher-dose filgrastim (8.2 vs 4.7 × 10(6)/kg for 16 vs 8/mcg/kg daily of filgrastim, respectively; P < .0001) and addition of rituximab to etoposide and filgrastim (9.9 vs 5.6 × 10(6)/kg; P = .021) improve CD34+ cell yield. Growth factor alone after chemotherapy, ancestim, or plerixafor provide adequate autologous HSC grafts for the majority of patients. Although some strategies result in higher CD34+ cell yield, this potentially comes at the expense of increased toxicity. As all strategies are reasonable, programmatic, and patient-specific considerations must inform the approach to autologous graft mobilization.
Topics: Antigens, CD34; Benzylamines; Cyclams; Cyclophosphamide; Hematologic Neoplasms; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Heterocyclic Compounds; Humans; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Transplantation, Autologous
PubMed: 22261379
DOI: 10.1016/j.bbmt.2012.01.008 -
Biology of Blood and Marrow... Jun 2018The purpose of this report is to analyze long-term clinical outcomes of patients exposed to plerixafor plus granulocyte colony-stimulating factor (G-CSF) for stem cell... (Randomized Controlled Trial)
Randomized Controlled Trial
The purpose of this report is to analyze long-term clinical outcomes of patients exposed to plerixafor plus granulocyte colony-stimulating factor (G-CSF) for stem cell mobilization. This was a study of patients with non-Hodgkin lymphoma (NHL; n = 167) and multiple myeloma (MM; n = 163) who were enrolled in the long-term follow-up of 2 pivotal phase III studies (NCT00741325 and NCT00741780) of 240 µg/kg plerixafor plus 10 µg/kg G-CSF, or placebo plus 10 µg/kg G-CSF to mobilize and collect CD34 cells for autologous hematopoietic stem cell transplantation. Overall survival (OS) and progression-free survival (PFS) were evaluated over a 5-year period following the first dose of plerixafor or placebo. The probability of OS was not significantly different in patients with NHL or MM treated with plerixafor or placebo (NHL: 64%; 95% confidence interval [CI], 56% to 71% versus 56%; 95% CI, 44% to 67%, respectively; MM: 64%; 95% CI, 54% to 72% versus 64%; 95% CI, 53% to 73%, respectively). In addition, there was no statistically significant difference in the probability of PFS over 5 years between treatment groups in patients with NHL (50%; 95% CI, 44% to 67% for plerixafor versus 43%; 95% CI, 31% to 54% for placebo) or those with MM (17%; 95% CI, 10% to 24% for plerixafor versus 30%; 95% CI, 21% to 40% for placebo). In this long-term follow-up study, the addition of plerixafor to G-CSF for stem cell mobilization did not affect 5-year survival in patients with NHL or patients with MM.
Topics: Adolescent; Adult; Aged; Benzylamines; Child; Cyclams; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Heterocyclic Compounds; Humans; Longitudinal Studies; Lymphoma, Non-Hodgkin; Middle Aged; Multiple Myeloma; Survival Analysis; Transplantation, Autologous; Young Adult
PubMed: 29410180
DOI: 10.1016/j.bbmt.2018.01.039 -
Biology of Blood and Marrow... Aug 2017Plerixafor, given subcutaneously with granulocyte colony-stimulating factor (G-CSF), improves autologous stem cell collection in patients with lymphoma and multiple...
Phase I/II Study of Intravenous Plerixafor Added to a Mobilization Regimen of Granulocyte Colony-Stimulating Factor in Lymphoma Patients Undergoing Autologous Stem Cell Collection.
Plerixafor, given subcutaneously with granulocyte colony-stimulating factor (G-CSF), improves autologous stem cell collection in patients with lymphoma and multiple myeloma. Intravenous (i.v.) administration of plerixafor allows administration of plerixafor on the same day as pheresis and it may improve stem cell collection. The primary objectives of this phase I/II study were to determine the maximum tolerated dose of i.v. plerixafor and the efficacy of i.v. plerixafor + G-CSF to mobilize ≥ 2 × 10 CD34 cells/kg from patients with lymphoma. In phase I, 25 patients were treated with G-CSF + i.v. plerixafor at escalating doses; in phase II, 36 patients were treated with G-CSF + plerixafor .40 mg/kg. The treatment was well tolerated. Fifty-nine of 61 patients (98%) met the collection goal and 47 of 61 patients (77%) collected ≥ 5.0 × 10 CD34 cells/kg in a median of 2 pheresis days. Analysis of CD34 hematopoietic stem and progenitor cells (HSPCs) revealed that G-CSF-mobilized grafts were enriched with CD34CD45RACD123 primitive HSPCs whereas plerixafor preferentially mobilized CD34CD45RACD123 plasmacytoid dendritic cell precursors. In conclusion, i.v. plerixafor is well tolerated and effective when added to G-CSF for the mobilization of stem cells from patients with lymphoma, with mobilization kinetics and stem cell collections that compare favorably with subcutaneous dosing.
Topics: Adolescent; Adult; Aged; Autografts; Benzylamines; Cyclams; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Heterocyclic Compounds; Humans; Lymphoma; Male; Middle Aged; Multiple Myeloma
PubMed: 28476490
DOI: 10.1016/j.bbmt.2017.04.024 -
Journal of Leukocyte Biology Jun 2020Treatment with the CXCR4 antagonist, plerixafor (AMD3100), has been proposed for clinical use in patients with WHIM (warts, hypogammaglobulinemia, infections, and...
Treatment with the CXCR4 antagonist, plerixafor (AMD3100), has been proposed for clinical use in patients with WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome and in pulmonary fibrosis. However, there is controversy with respect to the impact of plerixafor on neutrophil dynamics in the lung, which may affect its safety profile. In this study, we investigated the kinetics of endogenous neutrophils by direct imaging, using confocal intravital microscopy in mouse bone marrow, spleen, and lungs. Neutrophils are observed increasing their velocity and exiting the bone marrow following plerixafor administration, with a concomitant increase in neutrophil numbers in the blood and spleen, while the marginated pool of neutrophils in the lung microvasculature remained unchanged in terms of numbers and cell velocity. Use of autologous radiolabeled neutrophils and SPECT/CT imaging in healthy volunteers showed that plerixafor did not affect GM-CSF-primed neutrophil entrapment or release in the lungs. Taken together, these data suggest that plerixafor causes neutrophil mobilization from the bone marrow but does not impact on lung marginated neutrophil dynamics and thus is unlikely to compromise respiratory host defense both in humans and mice.
Topics: Animals; Benzylamines; Bone Marrow; Cell Tracking; Cyclams; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cells; Heterocyclic Compounds; Humans; Leukocyte Count; Lung; Mice, Inbred C57BL; Neutrophils; Radiopharmaceuticals; Single Photon Emission Computed Tomography Computed Tomography; Spleen; Technetium
PubMed: 32374077
DOI: 10.1002/JLB.1MA0420-571RR -
Transplantation and Cellular Therapy Jul 2021Growth factor and chemotherapy-based stem cell mobilization strategies are commonly used to treat patients with multiple myeloma. We retrospectively compared 398...
Stem Cell Mobilization in Multiple Myeloma: Comparing Safety and Efficacy of Cyclophosphamide +/- Plerixafor versus Granulocyte Colony-Stimulating Factor +/- Plerixafor in the Lenalidomide Era.
Growth factor and chemotherapy-based stem cell mobilization strategies are commonly used to treat patients with multiple myeloma. We retrospectively compared 398 patients mobilized between 2017 and 2020 using either cyclophosphamide (4 g/m) plus granulocyte colony-stimulating factor (G-CSF) or G-CSF alone, with on demand plerixafor (PXF) in both groups. Although total CD34 yield was higher after chemomobilization compared with G-CSF +/- PXF (median, 13.6 × 10/kg versus 4.4 × 10/kg; P < .01), achievement of ≥2 × 10 CD34 cells (95% versus 93.7%; P = .61) and rates of mobilization failure (5% versus 6.3%; P = .61) were similar. Fewer patients required PXF with chemomobilization (12.3% versus 49.5%; P < .01), and apheresis sessions were fewer (median, 1 [range, 1 to 4] versus 2 [range, 1 to 5]). The rate of complications, including neutropenic fever, emergency department visits, and hospitalizations, was higher after chemomobilization (30% versus 7.4%; P < .01). Previous use of ≤6 cycles of lenalidomide did not impair cell yield in either group. The median cost of mobilization was 17.4% lower in the G-CSF +/- PXF group (P = .01). Between group differences in time to engraftment were not clinically significant. Given similar rates of successful mobilization, similar engraftment time, and less toxicity and lower costs compared with chemomobilization, G-CSF with on-demand PXF may be preferable in myeloma patients with adequate disease control and limited lenalidomide exposure.
Topics: Antigens, CD34; Benzylamines; Cyclams; Cyclophosphamide; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Heterocyclic Compounds; Humans; Lenalidomide; Multiple Myeloma; Retrospective Studies
PubMed: 33915323
DOI: 10.1016/j.jtct.2021.04.016 -
Bone Marrow Transplantation Sep 2020This study (NCT01288573) investigated plerixafor's safety and efficacy in children with cancer. Stage 1 investigated the dosage, pharmacokinetics (PK), pharmacodynamics...
Plerixafor combined with standard regimens for hematopoietic stem cell mobilization in pediatric patients with solid tumors eligible for autologous transplants: two-arm phase I/II study (MOZAIC).
This study (NCT01288573) investigated plerixafor's safety and efficacy in children with cancer. Stage 1 investigated the dosage, pharmacokinetics (PK), pharmacodynamics (PD), and safety of plerixafor + standard mobilization (G-CSF ± chemotherapy). The stage 2 primary endpoint was successful mobilization (doubling of peripheral blood CD34+ cell count in the 24 h prior to first apheresis) in patients treated with plerixafor + standard mobilization vs. standard mobilization alone. In stage 1, three patients per age group (2-<6, 6-<12, and 12-<18 years) were treated at each dose level (160, 240, and 320 µg/kg). Based on PK and PD data, the dose proposed for stage 2 was 240 µg/kg (patients 1-<18 years), in which 45 patients were enrolled (30 plerixafor arm, 15 standard arm). Patient demographics and characteristics were well balanced across treatment arms. More patients in the plerixafor arm (24/30, 80%) met the primary endpoint of successful mobilization than in the standard arm (4/14, 28.6%, p = 0.0019). Adverse events reported as related to study treatment were mild, and no new safety concerns were identified. Plerixafor + standard G-CSF ± chemotherapy mobilization was generally well tolerated and efficacious when used to mobilize CD34+ cells in pediatric cancer patients.
Topics: Adolescent; Autografts; Benzylamines; Child; Cyclams; Hematopoietic Stem Cell Mobilization; Heterocyclic Compounds; Humans; Neoplasms
PubMed: 32127657
DOI: 10.1038/s41409-020-0836-2 -
Biology of Blood and Marrow... Jun 2019Allogeneic hematopoietic cell transplantation (HCT) is potentially curative for acute myelogenous leukemia (AML); however, a major cause of treatment failure is disease...
Mobilization of Leukemic Cells Using Plerixafor as Part of a Myeloablative Preparative Regimen for Patients with Acute Myelogenous Leukemia Undergoing Allografting: Assessment of Safety and Tolerability.
Allogeneic hematopoietic cell transplantation (HCT) is potentially curative for acute myelogenous leukemia (AML); however, a major cause of treatment failure is disease relapse. The purpose of this single-center Phase I study was to determine the safety and tolerability of administration of the CXCR4 inhibitor plerixafor (Mozobil; Sanofi Genzyme) along with myeloablative conditioning in patients with AML undergoing allogeneic HCT. The rationale was that plerixafor may mobilize leukemic stem cells, making them more susceptible to the conditioning chemotherapy (registered at ClinicalTrials.gov; identifier NCT01141543). Three patients were enrolled into each of 4 sequential cohorts (12 patients total). Patients in the first cohort received 1 dose of plerixafor (240 μg/kg s.c.) before the first dose of fludarabine and busulfan, and subsequent cohorts received injections before 2, 3, and 4 days of conditioning chemotherapy. The median age at HCT was 49 years (range, 38 to 58 years). All patients engrafted following HCT, with an absolute neutrophil count ≥.5 × 10/L observed at a median of 14 days (range, 11 to 18 days). Adverse events possibly related to plerixafor were transient and not severe. Main adverse events following the injection were nausea and dizziness in 4 patients (33%) and fatigue in 4 patients (33%). Among the 12 patients, 2 patients (17%) relapsed post-HCT and 6 (50%) were alive at the last follow-up. The median follow-up of survivors was 67 months (range, 53 to 82 months). In conclusion, plerixafor administration is safe and well tolerated when included in a myeloablative conditioning regimen for allogeneic HCT for AML. Further study in a larger cohort is warranted for the investigation of the impact of plerixafor on post-allogeneic HCT outcomes.
Topics: Adult; Anti-HIV Agents; Benzylamines; Cyclams; Female; Hematopoietic Stem Cell Mobilization; Heterocyclic Compounds; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Transplantation, Homologous
PubMed: 30654137
DOI: 10.1016/j.bbmt.2019.01.014 -
Cells Apr 2021In the context of hematopoietic stem cell (HSC) transplantation, conditioning with myelo- and immune-ablative agents is used to eradicate the patient's diseased cells,...
In the context of hematopoietic stem cell (HSC) transplantation, conditioning with myelo- and immune-ablative agents is used to eradicate the patient's diseased cells, generate space in the marrow and suppress immune reactions prior to the infusion of donor HSCs. While conditioning is required for effective and long-lasting HSC engraftment, currently used regimens are also associated with short and long-term side effects on extramedullary tissues and even mortality. Particularly in patients with severe combined immunodeficiency (SCID), who are generally less than 1-year old at the time of transplantation and often suffer from existing comorbidities. There is a pressing need for development of alternative, less toxic conditioning regimens. Hence, we here aimed to improve efficacy of currently used myeloablative protocols by combining busulfan with stem-cell niche-directed therapeutic agents (G-CSF or plerixafor) that are approved for clinical use in stem cell mobilization. T, B and myeloid cell recovery was analyzed in humanized NSG mice after different conditioning regimens. Increasing levels of human leukocyte chimerism were observed in a busulfan dose-dependent manner, showing comparable immune recovery as with total body irradiation in CD34-transplanted NSG mice. Notably, a better T cell reconstitution compared to TBI was observed after busulfan conditioning not only in NSG mice but also in SCID mouse models. Direct effects of reducing the stem cell compartment in the bone marrow were observed after G-CSF and plerixafor administration, as well as in combination with low doses of busulfan. Unfortunately, these direct effects on the stem population in the bone marrow were not reflected in increased human chimerism or immune recovery after CD34 transplantation in NSG mice. These results indicate moderate potential of reduced conditioning regimens for clinical use relevant for all allogeneic transplants.
Topics: Animals; Benzylamines; Busulfan; Cells, Cultured; Cyclams; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Immune Reconstitution; Mice; Mice, Inbred BALB C; Myeloablative Agonists; Transplantation Conditioning
PubMed: 33946560
DOI: 10.3390/cells10051077