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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 -
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 -
Relevance and clinical implications of tumor cell mobilization in the autologous transplant setting.Biology of Blood and Marrow... Jul 2011Autologous transplantation of peripheral blood (PB) hematopoietic stem cells (HSCs) is a widely used strategy for reconstitution of blood cells following high-dose... (Review)
Review
Autologous transplantation of peripheral blood (PB) hematopoietic stem cells (HSCs) is a widely used strategy for reconstitution of blood cells following high-dose chemotherapy for hematologic malignancies such as multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and acute myeloid leukemia (AML), among others. Stem cells for transplantation are usually obtained from PB after treatment with chemotherapy with or without cytokine, usually granulocyte-colony stimulating factor (G-CSF), or after treatment with cytokine alone. The use of autologous peripheral blood stem cells (PBSCs) for transplantation is associated with the risk of contamination of the graft with tumor cells; whether this impacts response rates, progression-free survival (PFS), and overall survival (OS) is still debatable. This review summarizes the controversy surrounding tumor cell mobilization (TCM), the complexity of detection of minimal residual diseases, the available diagnostic tools, differences in TCM with available mobilization regimens, and the potential effect of TCM on clinical outcome. Collectively, these data suggest that new treatment paradigms to manage hematologic malignancies, such as MM, NHL, and AML, are needed and should focus on increasing the chemosensitivity of the tumor and eliminating residual disease.
Topics: Antineoplastic Combined Chemotherapy Protocols; Benzylamines; Biomarkers, Tumor; Combined Modality Therapy; Cyclams; Cytokines; DNA, Neoplasm; Flow Cytometry; Granulocyte Colony-Stimulating Factor; Hematologic Neoplasms; Hematopoietic Stem Cell Mobilization; Heterocyclic Compounds; Humans; Neoplasm, Residual; Neoplastic Cells, Circulating; Neoplastic Stem Cells; Peripheral Blood Stem Cell Transplantation; Polymerase Chain Reaction; Recurrence; Risk; Translocation, Genetic; Transplantation, Autologous; Treatment Outcome
PubMed: 20971201
DOI: 10.1016/j.bbmt.2010.10.018 -
Molecular Oncology Dec 2018Head and neck squamous cell carcinomas (HNSCC) are associated with poor morbidity and mortality. Current treatment strategies are highly toxic and do not benefit over...
Head and neck squamous cell carcinomas (HNSCC) are associated with poor morbidity and mortality. Current treatment strategies are highly toxic and do not benefit over 50% of patients. There is therefore a crucial need for predictive and/or prognostic biomarkers to allow treatment stratification for individual patients. One class of biomarkers that has recently gained importance are microRNA (miRNA). MiRNA are small, noncoding molecules which regulate gene expression post-transcriptionally. We performed miRNA expression profiling of a cohort of head and neck tumours with known clinical outcomes. The results showed miR-9 to be significantly downregulated in patients with poor treatment outcome, indicating its role as a potential biomarker in HNSCC. Overexpression of miR-9 in HNSCC cell lines significantly decreased cellular proliferation and inhibited colony formation in soft agar. Conversely, miR-9 knockdown significantly increased both these features. Importantly, endogenous CXCR4 expression levels, a known target of miR-9, inversely correlated with miR-9 expression in a panel of HNSCC cell lines tested. Induced overexpression of CXCR4 in low expressing cells increased proliferation, colony formation and cell cycle progression. Moreover, CXCR4-specific ligand, CXCL12, enhanced cellular proliferation, migration, colony formation and invasion in CXCR4-overexpressing and similarly in miR-9 knockdown cells. CXCR4-specific inhibitor plerixafor abrogated the oncogenic phenotype of CXCR4 overexpression as well as miR-9 knockdown. Our data demonstrate a clear role for miR-9 as a tumour suppressor microRNA in HNSCC, and its role seems to be mediated through CXCR4 suppression. MiR-9 knockdown, similar to CXCR4 overexpression, significantly promoted aggressive HNSCC tumour cell characteristics. Our results suggest CXCR4-specific inhibitor plerixafor as a potential therapeutic agent, and miR-9 as a possible predictive biomarker of treatment response in HNSCC.
Topics: Antineoplastic Agents; Benzylamines; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cyclams; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; Heterocyclic Compounds; Humans; MicroRNAs; Neoplasm Invasiveness; Prognosis; Receptors, CXCR4; Treatment Outcome
PubMed: 29959873
DOI: 10.1002/1878-0261.12352 -
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 -
European Journal of Clinical... Nov 2018Chemokines play a critical role in orchestrating the distribution and trafficking of neutrophils in homeostasis and disease. (Review)
Review
BACKGROUND
Chemokines play a critical role in orchestrating the distribution and trafficking of neutrophils in homeostasis and disease.
RESULTS
The CXCR4/CXCL12 chemokine axis has been identified as a central regulator of these processes.
CONCLUSION
In this review, we focus on the role of CXCR4/CXCL12 chemokine axis in regulating neutrophil release from the bone marrow and the trafficking of senescent neutrophils back to the bone marrow for clearance under homeostasis and disease. We also discuss the role of CXCR4 in fine-tuning neutrophil responses in the context of inflammation.
Topics: Animals; Benzylamines; Bone Marrow; Cell Survival; Chemokine CXCL12; Cyclams; HMGB1 Protein; Hematologic Agents; Heterocyclic Compounds; Homeostasis; Humans; Imidazoles; Immunologic Deficiency Syndromes; Inflammation; Mice; Mutation; Neutrophils; Peptide Fragments; Primary Immunodeficiency Diseases; Receptors, CXCR4; Serum Albumin; Spleen; Warts
PubMed: 29734477
DOI: 10.1111/eci.12949 -
Blood Sep 2009Plerixafor (AMD3100) and granulocyte colony-stimulating factor (G-CSF) mobilize peripheral blood stem cells by different mechanisms. A rhesus macaque model was used to...
Plerixafor (AMD3100) and granulocyte colony-stimulating factor (G-CSF) mobilize peripheral blood stem cells by different mechanisms. A rhesus macaque model was used to compare plerixafor and G-CSF-mobilized CD34(+) cells. Three peripheral blood stem cell concentrates were collected from 3 macaques treated with G-CSF, plerixafor, or plerixafor plus G-CSF. CD34(+) cells were isolated by immunoselection and were analyzed by global gene and microRNA (miR) expression microarrays. Unsupervised hierarchical clustering of the gene expression data separated the CD34(+) cells into 3 groups based on mobilization regimen. Plerixafor-mobilized cells were enriched for B cells, T cells, and mast cell genes, and G-CSF-mobilized cells were enriched for neutrophils and mononuclear phagocyte genes. Genes up-regulated in plerixafor plus G-CSF-mobilized CD34(+) cells included many that were not up-regulated by either agent alone. Two hematopoietic progenitor cell miR, miR-10 and miR-126, and a dendritic cell miR, miR-155, were up-regulated in G-CSF-mobilized CD34(+) cells. A pre-B-cell acute lymphocytic leukemia miR, miR-143-3p, and a T-cell miR, miR-143-5p, were up-regulated in plerixafor plus G-CSF-mobilized cells. The composition of CD34(+) cells is dependent on the mobilization protocol. Plerixafor-mobilized CD34(+) cells include more B-, T-, and mast cell precursors, whereas G-CSF-mobilized cells have more neutrophil and mononuclear phagocyte precursors.
Topics: Animals; Anti-HIV Agents; Antigens, CD34; Benzylamines; Biomarkers; Cyclams; Drug Combinations; Gene Expression Profiling; Gene Expression Regulation; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cells; Heterocyclic Compounds; Macaca mulatta; MicroRNAs; Oligonucleotide Array Sequence Analysis; RNA, Messenger
PubMed: 19602709
DOI: 10.1182/blood-2009-04-214403 -
Skin Therapy Letter Mar 2022Warts, Hypogammaglobulinemia, Infections and Myelokathexis (WHIM) is a primary immunodeficiency syndrome. Patients with WHIM syndrome are more susceptible to human... (Review)
Review
Warts, Hypogammaglobulinemia, Infections and Myelokathexis (WHIM) is a primary immunodeficiency syndrome. Patients with WHIM syndrome are more susceptible to human papillomavirus (HPV) infections and commonly present to a dermatologist with recalcitrant to treatment warts. Other cardinal features of WHIM syndrome include recurrent sinopulmonary bacterial infections, neutropenia/lymphopenia, low levels of immunoglobulins (IgG, IgA, IgM) and myelokathexis. Research demonstrated that truncating gain-of-function mutations of the C-X-C chemokine receptor type 4 gene (CXCR4) are responsible for this disease. Plerixafor, a specific small molecule antagonist of CXCR4, is currently used for peripheral blood hematopoietic stem cell (HSC) mobilization in stem cell transplant recipients. It has recently shown promise for the treatment of WHIM syndrome in phase I/II clinical trials. In this paper we review the emerging patient clinical data for this medication and highlight the role of CXCR4 in other important skin diseases including keratinocyte carcinomas, psoriasis and cutaneous T-cell lymphoma.
Topics: Agammaglobulinemia; Benzylamines; Cyclams; Fantasy; Hematopoietic Stem Cell Mobilization; Heterocyclic Compounds; Humans; Neutropenia; Papillomavirus Infections; Primary Immunodeficiency Diseases; Receptors, CXCR4; Syndrome; Warts
PubMed: 35385630
DOI: No ID Found -
Haematologica Feb 2013In Europe, the combination of plerixafor + granulocyte colony-stimulating factor is approved for the mobilization of hematopoietic stem cells for autologous... (Clinical Trial)
Clinical Trial
Plerixafor and granulocyte colony-stimulating factor for first-line steady-state autologous peripheral blood stem cell mobilization in lymphoma and multiple myeloma: results of the prospective PREDICT trial.
In Europe, the combination of plerixafor + granulocyte colony-stimulating factor is approved for the mobilization of hematopoietic stem cells for autologous transplantation in patients with lymphoma and myeloma whose cells mobilize poorly. The purpose of this study was to further assess the safety and efficacy of plerixafor + granulocyte colony-stimulating factor for front-line mobilization in European patients with lymphoma or myeloma. In this multicenter, open label, single-arm study, patients received granulocyte colony-stimulating factor (10 μg/kg/day) subcutaneously for 4 days; on the evening of day 4 they were given plerixafor (0.24 mg/kg) subcutaneously. Patients underwent apheresis on day 5 after a morning dose of granulocyte colony-stimulating factor. The primary study objective was to confirm the safety of mobilization with plerixafor. Secondary objectives included assessment of efficacy (apheresis yield, time to engraftment). The combination of plerixafor + granulocyte colony-stimulating factor was used to mobilize hematopoietic stem cells in 118 patients (90 with myeloma, 25 with non-Hodgkin's lymphoma, 3 with Hodgkin's disease). Treatment-emergent plerixafor-related adverse events were reported in 24 patients. Most adverse events occurred within 1 hour after injection, were grade 1 or 2 in severity and included gastrointestinal disorders or injection-site reactions. The minimum cell yield (≥ 2 × 10(6) CD34(+) cells/kg) was harvested in 98% of patients with myeloma and in 80% of those with non-Hodgkin's lymphoma in a median of one apheresis. The optimum cell dose (≥ 5 × 10(6) CD34(+) cells/kg for non-Hodgkin's lymphoma or ≥ 6 × 10(6) CD34(+) cells/kg for myeloma) was harvested in 89% of myeloma patients and 48% of non-Hodgkin's lymphoma patients. In this prospective, multicenter European study, mobilization with plerixafor + granulocyte colony-stimulating factor allowed the majority of patients with myeloma or non-Hodgkin's lymphoma to undergo transplantation with minimal toxicity, providing further data supporting the safety and efficacy of plerixafor + granulocyte colony-stimulating factor for front-line mobilization of hematopoietic stem cells in patients with non-Hodgkin's lymphoma or myeloma.
Topics: Adult; Aged; Benzylamines; Cyclams; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Heterocyclic Compounds; Humans; Lymphoma, Non-Hodgkin; Male; Middle Aged; Multiple Myeloma; Treatment Outcome
PubMed: 22983579
DOI: 10.3324/haematol.2012.071456 -
Antiviral Chemistry & Chemotherapy 2019AMD3100 (plerixafor, Mozobil®) was first identified as an anti-HIV agent specifically active against the T4-lymphotropic HIV strains, as it selectively blocked the... (Review)
Review
AMD3100 (plerixafor, Mozobil®) was first identified as an anti-HIV agent specifically active against the T4-lymphotropic HIV strains, as it selectively blocked the CXCR4 receptor. Through interference with the interaction of CXCR4 with its natural ligand, SDF-1 (also named CXCL12), it also mobilized the CD34stem cells from the bone marrow into the peripheral blood stream. In December 2008, AMD3100 was formally approved by the US FDA for autologous transplantation in patients with Non-Hodgkin's Lymphoma or multiple myeloma. It may be beneficially used in various other malignant diseases as well as hereditary immunological disorders such as WHIM syndrome, and physiopathological processes such as hepatopulmonary syndrome.
Topics: Animals; Anti-HIV Agents; Antineoplastic Agents; Benzylamines; Cyclams; Drug Approval; Drug Repositioning; HIV Infections; Hematopoietic Stem Cell Transplantation; Hepatopulmonary Syndrome; Heterocyclic Compounds; Humans; Immunologic Deficiency Syndromes; Mice; Primary Immunodeficiency Diseases; Receptors, CXCR4; Time Factors; United States; United States Food and Drug Administration; Warts
PubMed: 30776910
DOI: 10.1177/2040206619829382