Pegfilgrastim improves the outcomes of mobilization and engraftment in autologous hematopoietic stem cell transplantation for the treatment of multiple myeloma.

Autologous stem cell transplantation (ASCT) is the only curable therapy for multiple myeloma (MM), while its success primarily relies on mobilization to obtain sufficient hematopoietic stem/progenitor cells (HPC). Although the role of Pegfilgrastim (PEG), a novel PEGylated form of the recombinant G-CSF filgrastim (FIL), in mobilization has been demonstrated, it remains unclear whether this approach is cost-effective in MM treatment. Here, we performed a real-world analysis to evaluate the efficacy and cost of PEG for mobilization in a cohort of MM patients, of which 53% carried high-risk cytogenetic abnormalities. A total of 91 patients who received either a single dose of PEG (6 or 12 mg, n = 42) or multiple dosing of 10 µg/kg/day FIL (n = 49) after chemotherapy for HPC mobilization were included. The yield of MNCs and CD34+ cells per milliliter of blood collected via apheresis was significantly greater in the PEG group than that in the FIL group (P = 0.014 and P = 0.038). Mobilization with PEG yielded significantly higher median number of collected CD34+ cells than FIL (5.56 vs. 4.82 × 106/kg; P = 0.038). Moreover, the average time-to-recovery of leukocytes and platelets after transplantation was markedly shorter in the PEG group than that in the FIL group (leukocyte, 11.59 ± 1.98 vs 12.93 ± 2.83 days, P = 0.019; platelet, 12.86 ± 2.62 vs 14.80 ± 5.47, P = 0.085). However, the total cost of mobilization and apheresis using PEG or FIL was comparable (P = 0.486). Of note, mobilization with 12 mg PEG further shortened time-to-recovery of leukocytes (10.64 ± 0.51 vs. 12.04 ± 2.26 days, P = 0.05) and platelets (10.60 ± 2.89 vs. 13.33 ± 2.35 days, P = 0.031) compared with 6 mg PEG. Our results support a notion that PEG (especially 12 mg) combined with chemotherapy is a cost-effective and convenient regimen of mobilization, which might improve the outcome of ASCT in MM.

Cytokine-induced hematopoietic stem and progenitor cell mobilization: unraveling interactions between stem cells and their niche.

Peripheral blood hematopoietic stem and progenitor cells (HSPCs), mobilized by granulocyte colony-stimulating factor, are widely used as a source for both autologous and allogeneic stem cell transplantation. The use of mobilized HSPCs has several advantages over traditional bone marrow-derived HSPCs, including a less invasive harvesting process for the donor, higher HSPC yields, and faster hematopoietic reconstitution in the recipient. For years, the mechanisms by which cytokines and other agents mobilize HSPCs from the bone marrow were not fully understood. The field of stem cell mobilization research has advanced significantly over the past decade, with major breakthroughs in the elucidation of the complex mechanisms that underlie stem cell mobilization. In this review, we provide an overview of the events that underlie HSPC mobilization and address the relevant cellular and molecular components of the bone marrow niche. Furthermore, current and future mobilizing agents will be discussed.

Hematopoietic Progenitor Cell Mobilization for Autologous Stem Cell Transplantation in Multiple Myeloma in Contemporary Era.

Successful stem cell mobilization and adequate harvesting of hematopoietic progenitor cells (HPCs) is necessary for patients with multiple myeloma (MM) undergoing high-dose chemotherapy and autologous stem cell transplantation (ASCT). Several advances have increased the efficiency and yield of HPC collection methods, and sufficient CD34+ cell collection can be expected for most patients with MM considered to be ASCT candidates. However, in some patients, HPCs will fail to mobilize and an adequate number of CD34+ cells will not be collected. In our review, we have discussed the various strategies available for mobilizing HPCs in patients with MM and the evolution of these strategies over time. We have also discussed the concept of mobilization failure, the factors predictive of poor mobilization, and the potential mobilization regimens for such patients.

Preemptive plerixafor injection added to pegfilgrastim after chemotherapy in non-Hodgkin lymphoma patients mobilizing poorly.

Filgrastim is usually combined with chemotherapy to mobilize hematopoietic progenitor cells in non-Hodgkin lymphoma (NHL) patients. Limited information is available on the efficacy of a preemptive plerixafor (PLER) injection in poor mobilizers after chemotherapy and pegfilgrastim. In this prospective study, 72 patients with NHL received chemotherapy plus pegfilgrastim, and 25 hard-to-mobilize patients received also PLER. The usefulness and efficacy of our previously developed algorithm for PLER use in pegfilgrastim-containing mobilization regimen were evaluated as well as the graft cellular composition, hematological recovery, and outcome after autologous stem cell transplantation (auto-SCT) according to the PLER use. A median 3.4-fold increase in blood CD34+ cell counts was achieved after the first PLER dose. The minimum collection target was achieved in the first mobilization attempt in 66/72 patients (92%) and 68 patients (94%) proceeded to auto-SCT. An algorithm for PLER use was fulfilled in 76% of the poor mobilizers. Absolute numbers of T-lymphocytes and NK cells were significantly higher in the PLER group, whereas the number of CD34+ cells collected was significantly lower. Early neutrophil engraftment was slower in the PLER group, otherwise hematological recovery was comparable within 12 months from auto-SCT. No difference was observed in survival according to the PLER use. Chemotherapy plus pegfilgrastim combined with preemptive PLER injection is an effective and convenient approach to minimize collection failures in NHL patients intended for auto-SCT. A significant effect of PLER on the graft cellular composition was observed, but no difference in outcome after auto-SCT was detected.

Tissue-engineered airway: a regenerative solution.

The use of synthetic degradable or permanent polymers and biomaterials has not yet helped to achieve successful clinical whole-airway replacement. A novel, clinically successful approach involves tissue engineering (TE) replacement using three-dimensional biologic scaffolds composed of allogeneic extracellular scaffolds derived from nonautologous sources and recellularized with autologous stem cells or differentiated cells. In this paper, we discuss this novel approach and review information that can lead to a better understanding of stem cell recruitment and/or mobilization and site-specific tissue protection, which can be pharmacologically boosted in humans.

[Hematopoietic stem cells mobilization: state of the art in 2011 and perspectives]. / Mobilisation des cellules souches hématopoïétiques: état de l'art en 2011 et perspectives.

High-dose chemotherapy with stem cells support has largely improved in terms of hematopoietic stem and progenitor cells harvest procedures as well as in those, which target or manipulate the cellular composition of autologous graft. Optimal preparative regimens and supportive care had lead to better use of autologous transplantation procedure. For other patients assigned to hematopoietic transplantation, availability of allogeneic donors appears to be an interesting alternative source of hematopoietic stem cells. Since three decades, hematopoietic growth factors development has allowed mobilization optimization and collection of peripheral hematopoietic stem cells leading to reduced days of hospitalization and less blood products requirements, being more cost-effective for patients in autologous transplantation settings and for stem cell collection facilities in allogeneic ones. New perspectives include, besides ex vivo manipulation of graft, development of mobilizing drugs in order to perform transplantation even in poor mobilizers patients. An important goal is achieved with the description of genetic polymorphisms related to optimal mobilization of stem cells. New approach using more promising and selective agents called chemokines, such as plerixafor the main leader among these agents are now available and appear complementary for alternative approach using cytokines alone (G-CSF, GM-CSF, SCF). The aim of this review is to assess the evolution of theses biotechnologies and their role in different steps of autologous transplantation and allogeneic stem cells collection.

Advances in mobilization for the optimization of autologous stem cell transplantation.

In autologous stem cell transplantation, mobilized peripheral blood has replaced the bone marrow as the preferred source of hematopoietic stem cells (HSCs). Because HSCs normally exist in the blood in very low numbers, the use of agents to "mobilize" HSCs from the marrow niche to the peripheral blood is essential for successful transplantation. Until recently, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor were the only approved agents by the US Food and Drug Administration for use as peripheral blood stem cell (PBSC)-mobilizing agents in the United States, but G-CSF has become the gold standard. Unfortunately, some patients fail to mobilize sufficient numbers of PBSCs for transplantation in response to G-CSF with or without chemotherapy. Recently, a new agent, plerixafor (AMD3100) added to G-CSF has been approved to enhance PBSC mobilization. This review will discuss the current methodologies to improve hematopoietic stem cell mobilization.

Contribution of stem cells to kidney repair.

A current explanation for development of chronic renal injury is the imbalance between injurious mechanism and regenerative repair. The possibility that stem cells contribute to the repair of glomerular and tubular damage is of great interest for basic and translational research. Endogenous bone marrow-derived stem cells have been implicated in the repair of renal tissue, although the lineage of stem cells recruited has not been determined. If endogenous bone marrow-derived stem cells repopulate injured nephrons directly or act indirectly over a paracrine/endocrine mechanism remains also controversial. Therapeutic administration of exogenous bone marrow derived stem cells in animal models of acute renal injury suggests that a stem cell-based therapy may improve the recovery of both glomerular and tubular compartments. Whereas the therapeutic benefit of sorted hematopoietic stem cells remains uncertain, several studies showed a beneficial effect of mesenchymal stem cell administration in models of acute tubular injury and of endothelial progenitors in acute glomerular injury. Recent studies demonstrate the presence of resident stem cells within the adult kidney. These cells are capable, when injected in animals with acute tubular injury, to localize to renal compartments and contribute to regeneration. This review summarizes the current literature on the physiological role of endogenous stem cells in renal regeneration and on the therapeutic potential of exogenous stem cell administration. Moreover, critical points that still need clarification, such as the homing mechanisms of stem cells to injured tissue, the secreted factors underlying the paracrine/endocrine mechanisms and the long-term behaviour of in vivo administered stem cells, are discussed.

Peripheral blood stem cell mobilization: new regimens, new cells, where do we stand.

PURPOSE OF REVIEW: Granulocyte colony-stimulating factor-mobilized peripheral blood stem cells are widely used to reconstitute hematopoiesis; however, preclinical and clinical studies show that improvements to this mobilization can be achieved. We discuss the development of new mobilizing regimens and evaluation of new findings on mobilized stem cell populations that may improve the utility and convenience of peripheral blood stem cell transplant. RECENT FINDINGS: Chemokines and their receptors regulate leukocyte trafficking, and altering chemokine signaling pathways mobilizes stem cells. In recent trials, combination use of the chemokine (C-X-C motif) receptor 4 antagonist AMD3100 and granulocyte colony-stimulating factor mobilized more CD34 cells in fewer days than granulocyte colony-stimulating factor alone and allowed more patients to proceed to autotransplant. In preclinical studies the chemokine GRObeta synergizes with granulocyte colony-stimulating factor and when used alone or with granulocyte colony-stimulating factor mobilizes more primitive hematopoietic stem cells with less apoptosis, higher integrin activation, lower CD26 expression and enhanced marrow homing compared with granulocyte colony-stimulating factor. Hematopoietic stem cells mobilized by GRObeta or AMD3100 demonstrate superior engraftment and contribution to chimerism in primary and secondary transplant studies in mice, and peripheral blood stem cells mobilized by AMD3100 and granulocyte colony-stimulating factor in patients demonstrate enhanced engraftment capabilities in immunodeficient mice. SUMMARY: Alternate regimens differentially mobilize stem cell populations with unique intrinsic properties with the potential to expand the utility of hematopoietic transplantation. Continued mechanistic evaluation will be critical to our understanding of mechanisms of mobilization and their use in regenerative medicine.

Safety and efficacy of allogeneic PBSC collection in normal pediatric donors: the pediatric blood and marrow transplant consortium experience (PBMTC) 1996-2003.

The use of peripheral blood stem cells (PBSC) for allogeneic transplants in adults has greatly increased. This trend is reflected in pediatrics, where healthy children increasingly are donating PBSC or donor lymphocyte infusion (DLI) via apheresis for use by ill siblings. There is a potential concern that the risks of PBSC collection may differ for pediatric donors. However, no large studies have assessed safety issues in this population. To address this need, we reviewed 218 (213 PBSC, five DLI) collections in 201 normal pediatric donors (8 months to 17 years, median 11.8 years) at 22 institutions in the Pediatric Blood and Marrow Transplant Consortium. Donors received a median of 4 days of growth factor, and mean collection yield was 9.1 x 10(6) CD34+ cells/kg recipient weight. Younger age, days of apheresis, and male gender predicted increased yield of CD34+ cells/kg donor weight. Growth factor-induced pain was mild and reported in less than 15% of patients. Most donors <20 kg (23/25, 92%) required PRBC priming of the apheresis machine. This experience with over 200 collections demonstrates that PBSC collection is safe in normal pediatric donors and desired CD34 cell yields are easily achieved. Younger children utilize more medical resources and children <20 kg usually require a single blood product exposure.

Clinical application of hematopoietic progenitor cell expansion: current status and future prospects.

In the past decade, we have witnessed significant advances in ex vivo hematopoietic stem cell culture expansion, progressing to the point where clinical trials are being designed and conducted. Preclinical milestone investigations provided data to enable expansion of portions of hematopoietic grafts in a clinical setting, indicating safety and feasibility of this approach. Data derived from current clinical trials indicate successful reconstitution of hematopoiesis after myeloablative chemoradiotherapy using infusion of ex vivo-expanded perfusion cultures. Future avenues of exploration will focus upon refining preclinical and clinical studies in which cocktails of available cytokines, novel molecules and sophisticated expansion systems will explore expansion of blood, marrow and umbilical cord blood cells.

[Mesenchymal stem cells. Potential use in cell and gene therapy of bone loss caused by aging and osteoporosis]. / Mesenkymale stamceller. Potentielle anvendelser i celle- og genterapi ved knogletab forårsaget af aldring og osteoporose.

Mesenchymal stem cells (MSC) originate from bone marrow and give rise to various cell types, including osteoblasts, chondrocytes, adipocytes, and myocytes. Lineage-specific differentiation is dependent on activation of specific transcription factors. MSCs play an important role in bone modelling and remodelling where they give rise to the osteoblasts necessary for bone formation. Human studies have shown that the number and differentiation potential of MSC are unchanged with age and osteoporosis. In recent years, there has been an increasing interest in the clinical use of MSCs. These have been used to augment healing of bone fractures. Some animal studies have shown that MSCs infused intravenously target bone and possibly participate in bone formation. These studies represent the beginning of a new era, where transplantation with autologous MSCs or genetically-modified MSCs expanded in vitro is a potential treatment strategy to augment bone formation in patients with diverse metabolic and genetic bone diseases, including osteoporosis.

Ex vivo expansion of hematopoietic stem and progenitor cells: are we there yet?

Ex vivo expansion of hematopoietic stem and progenitor cells is a very ambitious idea that would have major implications in the areas of stem cell transplantation and somatic gene therapy. However, successful ex vivo expansion has evaded and frustrated scientists for a number of years. The goal of ex vivo expansion is to induce cell division and proliferation of stem cells while maintaining their primary functional characteristic, namely, their ability to engraft and sustain long-term hematopoiesis. Only when a balance between these two requirements is reached can ex vivo expansion of stem cells be considered successful. Establishing such a balance has not been easy. However, many lessons have been learned along the way, and today we have a more profound understanding of the potential obstacles facing ex vivo expansion than we did only a few years ago. In this review, we discuss these obstacles and evaluate the current status of ex vivo expansion of stem and progenitor cells both from the perspective of basic stem cell biology and from the viewpoint of clinical utility of these cells in transplantation.

Peripheral Stem Cells in Bone Marrow Transplantation. Future prospects.

Mobilized peripheral blood cells are emerging to be the main haematopoietic progenitor cell sources in both autologous and allogeneic transplantation. The superior engraftment kinetics make high-dose therapy (HDT) safer and more cost-effective. Advances in mobilization protocols will enable an adequate, efficacious and predictable progenitor cell yield for most patients, and may even permit differential mobilization of normal and tumour cells. Peripheral blood stem cell transplantation is going to make an impact on tumour control by allowing dose escalation through multiple HDT and rescues, promoting various purging manoeuvres and facilitating immunomodulatory approaches to enhance graft-versus-tumour responses. Technological advances in ex vivo expansion and manipulation of haematopoietic progenitor cell grafts will add to our armamentarium of new therapeutic approaches and broaden our dimensions in the use of peripheral blood stem cell transplantation.