-
Leukemia & Lymphoma Jun 2021Interactions between the bone marrow microenvironment and MDS tumor clones play a role in pathogenesis and response to treatment. We hypothesized G-CSF and plerixafor...
Interactions between the bone marrow microenvironment and MDS tumor clones play a role in pathogenesis and response to treatment. We hypothesized G-CSF and plerixafor may enhance sensitivity to azacitidine in MDS. Twenty-eight patients with MDS were treated with plerixafor, G-CSF and azacitidine with a standard 3 + 3 design. Subjects received G-CSF 10 mcg/kg D1-D8, plerixafor D4-D8, and azacitidine 75 mg/m D4-D8, but the trial was amended to reduce G-CSF dose to 5 mcg/kg for 5 days after 2 patients had significant leukocytosis. Plerixafor was dose escalated to 560 mcg/kg/day without dose limiting toxicity. Two complete responses and 6 marrow responses were seen for an overall response rate (ORR) of 36% in evaluable patients, and ORR of 53% in patients receiving the triplet. Evidence of mobilization correlated with a higher ORR, 60% vs. 17%. Plerixafor, G-CSF and azacitidine appears tolerable when given over 5 days and has encouraging response rates.KEY POINTSPlerixafor and G-CSF can be safely combined with azacitidine for 5 days in patients with MDS.The overall response rate of 53% for evaluable patients with this regimen is higher than expected and more responses were seen in patients with blast mobilization.
Topics: Azacitidine; Benzylamines; Cyclams; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Heterocyclic Compounds; Humans; Myelodysplastic Syndromes
PubMed: 33467957
DOI: 10.1080/10428194.2021.1872068 -
Blood Advances May 2021Recent studies suggest that plerixafor mobilization and apheresis in patients with sickle cell disease (SCD) is safe and can allow collection of sufficient CD34+...
Recent studies suggest that plerixafor mobilization and apheresis in patients with sickle cell disease (SCD) is safe and can allow collection of sufficient CD34+ hematopoietic stem cell (HSC) collection for clinical gene therapy applications. However, the quantities of plerixafor-mobilized CD34+ cells vary between different SCD patients for unknown reasons. Twenty-three participants with SCD underwent plerixafor mobilization followed by apheresis, processing, and HSC enrichment under a phase 1 safety and efficacy study conducted at 2 institutions. Linear regression or Spearman's correlation test was used to assess the relationships between various hematologic and clinical parameters with total CD34+ cells/kg collected. Median CD34+ cells/kg after 2 or fewer mobilization and apheresis cycles was 4.0 × 106 (range, 1.5-12.0). Similar to what is observed generally, CD34+ yield correlated negatively with age (P < .001) and positively with baseline (P = .003) and preapheresis blood CD34+ cells/µL (P < .001), and baseline white blood cell (P = .01) and platelet counts (P = .03). Uniquely for SCD, CD34+ cell yields correlated positively with the number of days hydroxyurea was held (for up to 5 weeks, P = .01) and negatively with markers of disease severity, including hospitalization frequency within the preceding year (P = .01) and the number of medications taken for chronic pain (P = .002). Unique SCD-specific technical challenges in apheresis were also associated with reduced CD34+ cell collection efficiency and purification. Here, we describe factors that impact plerixafor mobilization success in patients with SCD, confirming known factors as described in other populations in addition to reporting previously unknown disease specific factors in patients with SCD. This trial was registered at www.clinicaltrials.gov as #NCT03226691.
Topics: Anemia, Sickle Cell; Benzylamines; Cyclams; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Heterocyclic Compounds; Humans; Severity of Illness Index
PubMed: 33956057
DOI: 10.1182/bloodadvances.2021004232 -
Biochemical Society Transactions Jun 2021The chemokine system plays a fundamental role in a diverse range of physiological processes, such as homeostasis and immune responses. Dysregulation in the chemokine... (Review)
Review
The chemokine system plays a fundamental role in a diverse range of physiological processes, such as homeostasis and immune responses. Dysregulation in the chemokine system has been linked to inflammatory diseases and cancer, which renders chemokine receptors to be considered as therapeutic targets. In the past two decades, around 45 drugs targeting chemokine receptors have been developed, yet only three are clinically approved. The challenging factors include the limited understanding of aberrant chemokine signalling in malignant diseases, high redundancy of the chemokine system, differences between cell types and non-specific binding of the chemokine receptor antagonists due to the broad ligand-binding pockets. In recent years, emerging studies attempt to characterise the chemokine ligand-receptor interactions and the downstream signalling protein-protein interactions, aiming to fine tuning to the promiscuous interplay of the chemokine system for the development of precision medicine. This review will outline the updates on the mechanistic insights in the chemokine system and propose some potential strategies in the future development of targeted therapy.
Topics: Animals; Antibodies, Monoclonal, Humanized; Benzylamines; Chemokines; Cyclams; Humans; Inflammation; Maraviroc; Molecular Targeted Therapy; Neoplasms; Protein Binding; Receptors, Chemokine; Signal Transduction
PubMed: 34060588
DOI: 10.1042/BST20201114 -
Blood Reviews May 2021Hematopoietic cell transplantation (HCT) has become a primary treatment for many cancers. Nowadays, the primary source of hematopoietic cells is by leukapheresis... (Review)
Review
Hematopoietic cell transplantation (HCT) has become a primary treatment for many cancers. Nowadays, the primary source of hematopoietic cells is by leukapheresis collection of these cells from peripheral blood, after a forced egress of hematopoietic cells from marrow into blood circulation, a process known as "mobilization". In this process, mobilizing agents disrupt binding interactions between hematopoietic cells and marrow microenvironment to facilitate collection. As the first essential step of HCT, poor mobilization, i.e. failure to obtain a desired or required number of hematopoietic cell, is one of the major factors affecting engraftment or even precluding transplantation. This review summarizes the available mobilization regimens using granulocyte-colony stimulating factor (G-CSF) and plerixafor, as well as the current understanding of the factors that are associated with poor mobilization. Strategies to mobilize patients or healthy donors who failed previous mobilization are discussed. Multiple novel agents are under investigation and some of them have shown the potential to enhance the mobilization response to G-CSF and/or plerixafor. Further investigation of the risk factors including genetic factors will offer an opportunity to better understand the molecular mechanism of mobilization and help develop new therapeutic strategies for successful mobilizations.
Topics: Benzylamines; Cyclams; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cells; Humans; Risk Factors; Stem Cell Niche
PubMed: 33213986
DOI: 10.1016/j.blre.2020.100771 -
Cell Communication and Signaling : CCS Mar 2023Matrix metalloproteinases (MMPs) play important roles in remodeling the extracellular matrix and in the pathogenesis of idiopathic pulmonary fibrosis (IPF). MMP19, which...
BACKGROUND
Matrix metalloproteinases (MMPs) play important roles in remodeling the extracellular matrix and in the pathogenesis of idiopathic pulmonary fibrosis (IPF). MMP19, which is an MMP, was significantly upregulated in hyperplastic alveolar epithelial cells in IPF lung tissues and promoted epithelial-mesenchymal transition (EMT). Recent studies have demonstrated that endothelial-to-mesenchymal transition (E(nd)MT) contributes to pulmonary fibrosis. However, the role of MMP19 in pulmonary vascular injury and repair and E(nd)MT remains unclear.
METHODS
To determine the role of MMP19 in E(nd)MT and pulmonary fibrosis. MMP19 expressions were determined in the lung endothelial cells of IPF patients and bleomycin (BLM)-induced mice. The roles of MMP19 in E(nd)MT and endothelial barrier permeability were studied in the MMP19 cDNA-transfected primary human pulmonary microvascular endothelial cells (HPMECs) and MMP19 adenoassociated virus (MMP19-AAV)-infected mice. The regulatory mechanism of MMP19 in pulmonary fibrosis was elucidated by blocking its interacting proteins SDF1 and ET1 with AMD3100 and Bosentan, respectively.
RESULTS
In this study, we found that MMP19 expression was significantly increased in the lung endothelial cells of IPF patients and BLM-induced mice compared to the control groups. MMP19 promoted E(nd)MT and the migration and permeability of HPMECs in vitro, stimulated monocyte infiltration into the alveolus, and aggravated BLM-induced pulmonary fibrosis in vivo. SDF1 and Endothelin-1 (ET1) were physically associated with MMP19 in HPMECs and colocalized with MMP19 in endothelial cells in IPF patient lung tissues. AMD3100 and bosentan alleviated the fibrosis induced by MMP19 in the BLM mouse model.
CONCLUSION
MMP19 promoted E(nd)MT by interacting with ET1 and stimulated monocyte infiltration into lung tissues via the SDF1/CXCR4 axis, thus aggravating BLM-induced pulmonary fibrosis. Vascular integrity regulated by MMP19 could be a promising therapeutic target for suppressing pulmonary fibrosis. Video abstract.
Topics: Animals; Humans; Mice; Bleomycin; Bosentan; Endothelial Cells; Epithelial-Mesenchymal Transition; Idiopathic Pulmonary Fibrosis; Lung; Monocytes; Matrix Metalloproteinases, Secreted
PubMed: 36915092
DOI: 10.1186/s12964-023-01040-4 -
Frontiers in Bioscience (Scholar... Jan 2012Currently, nearly all the autologous stem cell transplantation and majority of allogeneic stem cell transplantation are performed using circulating peripheral blood stem... (Review)
Review
Currently, nearly all the autologous stem cell transplantation and majority of allogeneic stem cell transplantation are performed using circulating peripheral blood stem cells. At steady conditions, less than 0.05 percent of the peripheral white cells are believed to be CD34+, a surrogate marker for stem cells. The content of hematopoietic CD34+ cells in the blood can be increased dramatically following recovery from myelosuppressive chemotherapy and/or the administration of hematopoietic growth factors (GM-CS or G-CSF), and an engrafting dose of stem cells can be collected by large volume apheresis following hematopoietic cytokine treatment. However these strategies fail to result in an adequate number of hematopoietic cells in 5-30 percent of the cases, limiting the ability of patients to receive high dose chemotherapy and stem cell transplantation in the treatment of their cancer. Plerixafor, a CXCR4 antagonist has been found to be a potent stem cell mobilizer and it's superiority used in combination with G-CSF over G-CSF alone has been seen in non-Hodgkin's lymphoma and multiple myeloma in double blind randomized phase III clinical trials, leading to FDA (Food and Drug Administration) approval. This review article describes the development of plerixafor to mobilize stem cells and optimal strategies for stem cell collection from peripheral blood.
Topics: Animals; Benzylamines; Clinical Trials, Phase III as Topic; Cyclams; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Heterocyclic Compounds; Humans; Lymphoma, Non-Hodgkin; Multiple Myeloma; Randomized Controlled Trials as Topic; Receptors, CXCR4
PubMed: 22202080
DOI: 10.2741/s288 -
Journal of Clinical Apheresis Aug 2022Peripheral blood stem cells (PBSCs) are the predominant graft source for adult allogeneic hematopoietic stem cell transplantation (HSCT). In poorly mobilized autologous...
BACKGROUND
Peripheral blood stem cells (PBSCs) are the predominant graft source for adult allogeneic hematopoietic stem cell transplantation (HSCT). In poorly mobilized autologous donors, plerixafor improves collection outcomes. We examine plerixafor use in allogeneic donors who mobilize poorly with granulocyte colony-stimulating factor (G-CSF) in those who are healthy and those with pre-existing medical conditions, and determine the optimal threshold to add plerixafor.
STUDY DESIGN/METHODS
We retrospectively examined all allogeneic PBSC collections from January 2013 to October 2020 at our center. Donors received G-CSF 10 mcg/kg daily for 4 days before undergoing apheresis collection on day 5. Plerixafor was added based on poor CD34+ cell collection yield after the first or second collection day.
RESULTS
Of the 1008 allogeneic donors, 41 (4.1%) received one dose of plerixafor in addition to G-CSF due to poor collection yield. After starting plerixafor there was a 0.75- to 7.74-fold (median 2.94) increase in CD34+ yield from the previous day. No donors with G-CSF-only mobilization who collected <2.0 × 10 CD34+ cells/kg recipient weight on day one achieved the goal of ≥4.0 × 10 CD34+ cells/kg recipient weight total over 2 days but 59.2% of donors who used rescue plerixafor did.
CONCLUSION
Donors both healthy and those with pre-existing disease responded well to plerixafor with minimal side effects. If the first-day collection yield is less than ~63% of the collection goal, addition of plerixafor may be necessary to reach the collection goal and limit the number of collection days in allogeneic donors.
Topics: Adult; Antigens, CD34; Benzylamines; Cyclams; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Heterocyclic Compounds; Humans; Peripheral Blood Stem Cells; Retrospective Studies
PubMed: 35633513
DOI: 10.1002/jca.21992 -
Bone Marrow Transplantation Aug 2021Given the availability and efficacy of the mobilizing agent plerixafor in augmenting hematopoietic progenitor cell mobilization with granulocyte colony-stimulating...
Given the availability and efficacy of the mobilizing agent plerixafor in augmenting hematopoietic progenitor cell mobilization with granulocyte colony-stimulating factor (G-CSF), there is a strong case for comparing the cost-effectiveness of mobilization with G-CSF + cyclophosphamide versus G-CSF alone. This study investigated the cost and effectiveness (i.e., successful 4 million-CD34 collection) of G-CSF alone versus high-dose cyclophosphamide (4 g/m) + G-CSF mobilization (± on-demand plerixafor) in patients with multiple myeloma (MM) eligible for autograft in Italy. A decision tree-supported cost-effectiveness analysis (CEA) model in MM patients was developed from the societal perspective. The CEA model compared G-CSF alone with cyclophosphamide 4 g/m + G-CSF (± on-demand plerixafor) and was populated with demographic, healthcare and non-healthcare resource utilization data collected from a questionnaire administered to six Italian oncohematologists. Costs were expressed in Euro (€) 2019. The CEA model showed that G-CSF alone was strongly dominant versus cyclophosphamide + G-CSF ( ± on-demand plerixafor), with incremental savings of €1198.59 and an incremental probability of a successful 4 million-CD34 apheresis (+0.052). Sensitivity analyses confirmed the robustness of the base-case results. In conclusion, chemotherapy-free mobilization (± on-demand plerixafor) is a "good value for money" option for MM patients eligible for autograft.
Topics: Benzylamines; Cost-Benefit Analysis; Cyclams; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Heterocyclic Compounds; Humans; Italy; Multiple Myeloma
PubMed: 33753907
DOI: 10.1038/s41409-021-01251-8 -
Haematologica May 2024High-dose melphalan plus autologous stem cell transplantation (ASCT) is a standard of care for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM),... (Observational Study)
Observational Study
A prospective, multicenter study on hematopoietic stemcell mobilization with cyclophosphamide plus granulocyte colony-stimulating factor and 'on-demand' plerixafor in multiple myeloma patients treated with novel agents.
High-dose melphalan plus autologous stem cell transplantation (ASCT) is a standard of care for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM), and adequate hematopoietic stem cell (HSC) collection is crucial to ensure hematologic recovery after ASCT. In this prospective, observational study we evaluated HSC mobilization with granulocyte colony-stimulating factor (G-CSF), cyclophosphamide, and 'on-demand' plerixafor (in patients with <20×106 CD34+ cells/L after at least 4 days of G-CSF or failing to collect ≥1×106 CD34+ cells/kg after the first apheresis) in NDMM patients treated with novel agent-based induction therapy. The primary endpoint was the rate of poor mobilizers (patients collecting <2×106 CD34+ cells/kg or requiring plerixafor rescue to reach an adequate HSC harvest). Secondary endpoints included the rate of patients collecting ≥2×106 CD34+ cells/kg after plerixafor administration and the identification of factors predicting mobilization failure or plerixafor need. Overall, 301 patients (median age 60 years) were enrolled. Two hundred and eighty-seven of 301 (95%) and 274 of 301 (93%) patients collected ≥2×106 and ≥4×106 CD34+ cells/kg, respectively, with a median of 9.9×106 CD34+ cells/kg collected. Poor mobilizers were 48 of 301 (16%): 34 of 301 (11%) required plerixafor rescue, and 14 of 301 (5%) failed HSC collection regardless of plerixafor. Thirty-four of 38 (90%) patients receiving plerixafor collected ≥2×106 CD34+ cells/kg. Bone marrow plasmacytosis at diagnosis >60% (odds ratio [OR]=4.14), lenalidomide use (OR=4.45), and grade 3-4 hematologic toxicities during induction (OR=3.53) were independently associated with a higher risk of mobilization failure or plerixafor need. Cyclophosphamide plus G-CSF and 'on-demand' plerixafor is an effective strategy in NDMM patients treated with novel agents, resulting in a high rate of HSC collection and high HSC yield (clinicaltrials gov. identifier: NCT03406091).
Topics: Humans; Multiple Myeloma; Hematopoietic Stem Cell Mobilization; Cyclams; Benzylamines; Middle Aged; Male; Cyclophosphamide; Female; Granulocyte Colony-Stimulating Factor; Aged; Prospective Studies; Heterocyclic Compounds; Adult; Hematopoietic Stem Cell Transplantation; Antineoplastic Combined Chemotherapy Protocols; Transplantation, Autologous; Treatment Outcome
PubMed: 37981892
DOI: 10.3324/haematol.2023.284023 -
Experimental Hematology Jul 2011Several stem cell mobilization strategies have been employed in the past 2 decades, including chemotherapy, hematopoietic growth factors, and chemotherapy plus growth... (Review)
Review
Several stem cell mobilization strategies have been employed in the past 2 decades, including chemotherapy, hematopoietic growth factors, and chemotherapy plus growth factors. Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage CSF are standard agents approved for peripheral blood stem cell mobilization since the early 1990s. Between 5% and 20% of patients, however, fail to mobilize a sufficient numbers of peripheral blood stem cells in response to G-CSF with or without chemotherapy. Recent advances in defining the basic mechanisms regulating the interactions between hematopoietic stem cells and their marrow niche had led to the discovery that CXCR4 and stromal-cell-derived factor 1α axis play a significant role. Plerixafor, an antagonist of the CXCR4-stromal-cell-derived factor 1α axis has been shown to result in a significant mobilization of hematopoietic stem cells. Numerous clinical trials have demonstrated that the combination of G-CSF and AMD3100 (G+A) resulted in a significant increase in CD34(+) cell yield as compared to the administration of G-CSF alone. In particular, the progenitors mobilized have been shown to comprise a significantly higher proportion of primitive and possibly more potent CD34(+)/CD38(-) subpopulation. Transplantation of PBSC mobilized by G+A administration have led to a rapid and sustained neutrophil and platelet engraftment. Another prospective role of this new class of agents might lie in the mobilization of dormant leukemia stem cells that are well protected by the niche. The future role of CXCR4 antagonists in treatment of hematologic malignancies includes mobilization of hematopoietic stem cells for transplantation and mobilization of leukemia-initiating cells for long-term cure.
Topics: Benzylamines; Bone Marrow Cells; Chemokine CXCL12; Cyclams; Drug Synergism; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Heterocyclic Compounds; Humans; Peripheral Blood Stem Cell Transplantation; Receptors, CXCR4; Stem Cell Niche
PubMed: 21624427
DOI: 10.1016/j.exphem.2011.05.004