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Gu J, Zhu Y, Lin H, Huang Y, Zhang Y, Xing Q, Kang B, Zhang Z, Wang M, Zhou T, Mai Y, Chen Q, Li F, Hu X, Wang S, Peng J, Guo X, Long B, Wang J, Gao M, Shan Y, Cui Y, Pan G. Autophagy is essential for human myelopoiesis. Stem Cell Reports 2024; 19:196-210. [PMID: 38215759 PMCID: PMC10874853 DOI: 10.1016/j.stemcr.2023.12.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 12/11/2023] [Accepted: 12/12/2023] [Indexed: 01/14/2024] Open
Abstract
Emergency myelopoiesis (EM) is essential in immune defense against pathogens for rapid replenishing of mature myeloid cells. During the EM process, a rapid cell-cycle switch from the quiescent hematopoietic stem cells (HSCs) to highly proliferative myeloid progenitors (MPs) is critical. How the rapid proliferation of MPs during EM is regulated remains poorly understood. Here, we reveal that ATG7, a critical autophagy factor, is essential for the rapid proliferation of MPs during human myelopoiesis. Peripheral blood (PB)-mobilized hematopoietic stem/progenitor cells (HSPCs) with ATG7 knockdown or HSPCs derived from ATG7-/- human embryonic stem cells (hESCs) exhibit severe defect in proliferation during fate transition from HSPCs to MPs. Mechanistically, we show that ATG7 deficiency reduces p53 localization in lysosome for a potential autophagy-mediated degradation. Together, we reveal a previously unrecognized role of autophagy to regulate p53 for a rapid proliferation of MPs in human myelopoiesis.
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Affiliation(s)
- Jiaming Gu
- CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Hong Kong, Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Center for Cell Lineage and Development, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Yanling Zhu
- CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Hong Kong, Chinese Academy of Sciences, Guangzhou 510530, China; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Center for Cell Lineage and Development, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Huaisong Lin
- CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Hong Kong, Chinese Academy of Sciences, Guangzhou 510530, China; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Center for Cell Lineage and Development, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Yuhua Huang
- CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Hong Kong, Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Center for Cell Lineage and Development, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Yanqi Zhang
- CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Hong Kong, Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Center for Cell Lineage and Development, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Qi Xing
- CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Hong Kong, Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Center for Cell Lineage and Development, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Baoqiang Kang
- CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Hong Kong, Chinese Academy of Sciences, Guangzhou 510530, China; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Center for Cell Lineage and Development, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Zhishuai Zhang
- CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Hong Kong, Chinese Academy of Sciences, Guangzhou 510530, China; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Center for Cell Lineage and Development, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Mingquan Wang
- CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Hong Kong, Chinese Academy of Sciences, Guangzhou 510530, China; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Center for Cell Lineage and Development, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Tiancheng Zhou
- CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Hong Kong, Chinese Academy of Sciences, Guangzhou 510530, China; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Center for Cell Lineage and Development, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Yuchan Mai
- CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Hong Kong, Chinese Academy of Sciences, Guangzhou 510530, China; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Center for Cell Lineage and Development, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Qianyu Chen
- CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Hong Kong, Chinese Academy of Sciences, Guangzhou 510530, China; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Center for Cell Lineage and Development, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Fei Li
- CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Hong Kong, Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Center for Cell Lineage and Development, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Xing Hu
- CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Hong Kong, Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Center for Cell Lineage and Development, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Shuoting Wang
- Department of Hematology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China
| | - Jiaojiao Peng
- CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Hong Kong, Chinese Academy of Sciences, Guangzhou 510530, China; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Center for Cell Lineage and Development, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Xinrui Guo
- Shandong Medicinal Biotechnology Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250012, China
| | - Bing Long
- Department of Hematology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China
| | - Junwei Wang
- CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Hong Kong, Chinese Academy of Sciences, Guangzhou 510530, China; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Center for Cell Lineage and Development, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Minghui Gao
- CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Hong Kong, Chinese Academy of Sciences, Guangzhou 510530, China; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Center for Cell Lineage and Development, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Yongli Shan
- CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Hong Kong, Chinese Academy of Sciences, Guangzhou 510530, China; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Center for Cell Lineage and Development, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Yazhou Cui
- Shandong Medicinal Biotechnology Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250012, China
| | - Guangjin Pan
- CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Hong Kong, Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Center for Cell Lineage and Development, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Shandong Medicinal Biotechnology Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250012, China.
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Khanna A, Zamani M, Huang NF. Extracellular Matrix-Based Biomaterials for Cardiovascular Tissue Engineering. J Cardiovasc Dev Dis 2021; 8:137. [PMID: 34821690 PMCID: PMC8622600 DOI: 10.3390/jcdd8110137] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/10/2021] [Accepted: 10/19/2021] [Indexed: 12/12/2022] Open
Abstract
Regenerative medicine and tissue engineering strategies have made remarkable progress in remodeling, replacing, and regenerating damaged cardiovascular tissues. The design of three-dimensional (3D) scaffolds with appropriate biochemical and mechanical characteristics is critical for engineering tissue-engineered replacements. The extracellular matrix (ECM) is a dynamic scaffolding structure characterized by tissue-specific biochemical, biophysical, and mechanical properties that modulates cellular behavior and activates highly regulated signaling pathways. In light of technological advancements, biomaterial-based scaffolds have been developed that better mimic physiological ECM properties, provide signaling cues that modulate cellular behavior, and form functional tissues and organs. In this review, we summarize the in vitro, pre-clinical, and clinical research models that have been employed in the design of ECM-based biomaterials for cardiovascular regenerative medicine. We highlight the research advancements in the incorporation of ECM components into biomaterial-based scaffolds, the engineering of increasingly complex structures using biofabrication and spatial patterning techniques, the regulation of ECMs on vascular differentiation and function, and the translation of ECM-based scaffolds for vascular graft applications. Finally, we discuss the challenges, future perspectives, and directions in the design of next-generation ECM-based biomaterials for cardiovascular tissue engineering and clinical translation.
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Affiliation(s)
| | - Maedeh Zamani
- Department of Cardiothoracic Surgery, Stanford University, Stanford, CA 94305, USA;
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA 94305, USA
| | - Ngan F. Huang
- Department of Cardiothoracic Surgery, Stanford University, Stanford, CA 94305, USA;
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA 94305, USA
- Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA
- Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA
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Porfyriou E, Letsa S, Kosmas C. Hematopoietic stem cell mobilization strategies to support high-dose chemotherapy: A focus on relapsed/refractory germ cell tumors. World J Clin Oncol 2021; 12:746-766. [PMID: 34631440 PMCID: PMC8479351 DOI: 10.5306/wjco.v12.i9.746] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 06/19/2021] [Accepted: 07/30/2021] [Indexed: 02/06/2023] Open
Abstract
High-dose chemotherapy (HDCT) with autologous hematopoietic stem cell transplantation has been explored and has played an important role in the management of patients with high-risk germ cell tumors (GCTs) who failed to be cured by conventional chemotherapy. Hematopoietic stem cells (HSCs) collected from the peripheral blood, after appropriate pharmacologic mobilization, have largely replaced bone marrow as the principal source of HSCs in transplants. As it is currently common practice to perform tandem or multiple sequential cycles of HDCT, it is anticipated that collection of large numbers of HSCs from the peripheral blood is a prerequisite for the success of the procedure. Moreover, the CD34+ cell dose/kg of body weight infused after HDCT has proven to be a major determinant of hematopoietic engraftment, with patients who receive > 2 × 106 CD34+ cells/kg having consistent, rapid, and sustained hematopoietic recovery. However, many patients with relapsed/refractory GCTs have been exposed to multiple cycles of myelosuppressive chemotherapy, which compromises the efficacy of HSC mobilization with granulocyte colony-stimulating factor with or without chemotherapy. Therefore, alternative strategies that use novel agents in combination with traditional mobilizing regimens are required. Herein, after an overview of the mechanisms of HSCs mobilization, we review the existing literature regarding studies reporting various HSC mobilization approaches in patients with relapsed/refractory GCTs, and finally report newer experimental mobilization strategies employing novel agents that have been applied in other hematologic or solid malignancies.
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Affiliation(s)
- Eleni Porfyriou
- Department of Medical Oncology and Hematopoietic Cell Transplant Unit, “Metaxa” Cancer Hospital, Piraeus 18537, Greece
| | - Sylvia Letsa
- Department of Medical Oncology and Hematopoietic Cell Transplant Unit, “Metaxa” Cancer Hospital, Piraeus 18537, Greece
| | - Christos Kosmas
- Department of Medical Oncology and Hematopoietic Cell Transplant Unit, “Metaxa” Cancer Hospital, Piraeus 18537, Greece
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Intravenous delivery of granulocyte-macrophage colony stimulating factor impairs survival in lipopolysaccharide-induced sepsis. PLoS One 2019; 14:e0218602. [PMID: 31220157 PMCID: PMC6586330 DOI: 10.1371/journal.pone.0218602] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2018] [Accepted: 06/05/2019] [Indexed: 01/11/2023] Open
Abstract
Background Cell-based therapies with bone marrow-derived progenitor cells (BMDPC) lead to an improved clinical outcome in animal sepsis models. In the present study we evaluated the ability of granulocyte macrophage-colony stimulating factor (GM-CSF) to mobilize BMDPC in a lipopolysaccharide (LPS)-induced sepsis model and thereby its potential as a novel treatment strategy. Methods Male Wistar rats received LPS (25μg/kg/h for 4 days) intravenously and were subsequently treated with GM-CSF 12.5μg/kg (0h,24h,48h,72h). As control groups, rats were infused with sodium chloride or GM-CSF only. Clinical and laboratory parameters, proinflammatory plasma cytokines as well as BMDPC counts were analyzed. Cytokine release by isolated peripheral blood mononuclear cells from rat spleen upon incubation with LPS, GM-CSF and a combination of both were investigated in vitro. Results In vivo, rats receiving both LPS and GM-CSF, showed a reduced weight loss and increased mobilization of BMDPC. At the same time, this regime resulted in an increased release of proinflammatory cytokines (IL-6, IL-8) and a significantly increased mortality. In vitro, the combination of LPS and GM-CSF showed a significantly increased IL-6 release upon incubation compared to incubation with LPS or GM-CSF alone. Conclusions GM-CSF did not have a beneficial effect on the clinical course in our LPS-induced sepsis model. It synergistically promoted inflammation with LPS and probably thereby impaired survival.
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Wallis WD, Qazilbash MH. Peripheral blood stem cell mobilization in multiple myeloma: Growth factors or chemotherapy? World J Transplant 2017; 7:250-259. [PMID: 29104859 PMCID: PMC5661122 DOI: 10.5500/wjt.v7.i5.250] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Revised: 06/30/2017] [Accepted: 09/13/2017] [Indexed: 02/05/2023] Open
Abstract
High-dose therapy followed by autologous hematopoietic stem cell (HSC) transplant is considered standard of care for eligible patients with multiple myeloma. The optimal collection strategy should be effective in procuring sufficient HSC while maintaining a low toxicity profile. Currently available mobilization strategies include growth factors alone, growth factors in combination with chemotherapy, or growth factors in combination with chemokine receptor antagonists; however, the optimal strategy has yet to be elucidated. Herein, we review the risks and benefits of each approach.
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Affiliation(s)
- Whitney D Wallis
- the University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
| | - Muzaffar H Qazilbash
- the University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
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Duarte FB, Prado BDPA, Vieira GMM, Costa LJ. Mobilization of hematopoietic progenitor cells for autologous transportation: consensus recommendations. Rev Assoc Med Bras (1992) 2016; 62 Suppl 1:10-15. [PMID: 27982316 DOI: 10.1590/1806-9282.62.suppl1.10] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Selected patients with certain hematological malignancies and solid tumors have the potential to achieve long-term survival with autologous hematopoietic progenitor cell transplant. The collection of these cells in peripheral blood avoids multiple bone marrow aspirations, results in faster engraftment and allows treatment of patients with infection, fibrosis, or bone marrow hypocellularity. However, for the procedure to be successful, it is essential to mobilize a sufficient number of progenitor cells from the bone marrow into the blood circulation. Therefore, a group of Brazilian experts met in order to develop recommendations for mobilization strategies adapted to the reality of the Brazilian national health system, which could help minimize the risk of failure, reduce toxicity and improve the allocation of financial resources.
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Affiliation(s)
- Fernando Barroso Duarte
- Service of Hematology and Hematopoietic Cell Transplantation, Hospital Universitário Walter Cantídio, Universidade Federal do Ceará, Brazil
| | | | | | - Luciano J Costa
- Department of Bone Marrow Transplantation and Cell Therapy Program, Department of Medicine and UAB-CCC, Birmingham, AL, USA
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Goker H, Etgul S, Buyukasik Y. Optimizing mobilization strategies in difficult-to-mobilize patients: The role of plerixafor. Transfus Apher Sci 2015; 53:23-9. [PMID: 26099666 DOI: 10.1016/j.transci.2015.05.011] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Peripheral blood stem cell collection is currently the most widely used source for hematopoietic autologous transplantation. Several factors such as advanced age, previous chemotherapy, disease and marrow infiltration at the time of mobilization influence the efficacy of CD34(+) progenitor cell mobilization. Despite the safety and efficiency of the standard mobilization protocols (G-CSF ± chemotherapy), there is still a significant amount of mobilization failure rate (10-40%), which necessitate novel agents for effective mobilization. Plerixafor, is a novel agent, has been recently approved for mobilization of hematopoietic stem cells (HSCs). The combination of Plerixafor with G-CSF provides the collection of large numbers of stem cells in fewer apheresis sessions and can salvage those who fail with standard mobilization regimens. The development and optimization of practical algorithms for the use Plerixafor is crucial to make hematopoietic stem cell mobilization more efficient in a cost-effective way. This review is aimed at summarizing how to identify poor mobilizers, and define rational use of Plerixafor for planning mobilization in hard-to-mobilize patients.
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Affiliation(s)
- Hakan Goker
- Hematology Department, Hacettepe University School of Medicine, Ankara, Turkey.
| | - Sezgin Etgul
- Hematology Department, Hacettepe University School of Medicine, Ankara, Turkey
| | - Yahya Buyukasik
- Hematology Department, Hacettepe University School of Medicine, Ankara, Turkey
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Karakukcu M, Unal E. Stem cell mobilization and collection from pediatric patients and healthy children. Transfus Apher Sci 2015; 53:17-22. [PMID: 26116046 DOI: 10.1016/j.transci.2015.05.010] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Today, hematopoietic stem cell transplantation (HSCT) is a standard treatment for a variety of conditions in children, including certain malignancies, hemoglobinopathies, bone marrow failure syndromes, immunodeficiency and inborn metabolic disease. Two fundamentally different types of HSCT are categorized by the source of the stem cells. The first, autologous HSCT represents infusion of patient's own hematopoietic stem cells (HSCs) obtained from the patient; the second, allogeneic HSCT refers to the infusion of HSCs obtained from a donor via bone marrow harvest or apheresis. Bone marrow has been the typical source for HSCs for pediatric donors. Bone marrow harvest is a safe procedure mainly related to mild and transient side effects. Recently, a dramatically increased use of mobilized peripheral blood stem cells (PBSCs) in the autologous as well as allogeneic setting has been seen worldwide. There are limited data comparing mobilization regimens; also mobilization practices vary widely in children. The most commonly used approach includes granulocyte colony stimulating factor (G-CSF) at 10 mg/kg/day as a single daily dose for 4 days before the day of leukapheresis. G-CSF induced pain was less reported in children compared to adult donors. For the collection, there are several technical problems, derived from the size of the patient or donor, which must be considered before and during the apheresis. Vascular access, extracorporeal circuit volume, blood flow rates are the main limiting factors for PBSC collection in small children. Most children younger than 12 years require central vascular access for apheresis; line placement may require either general anesthesia or conscious sedation and many of the complications arise from the central venous catheter. In this review, we discuss that the ethical considerations and some principals regarding children serving as stem cell donors and the commonest sources of HSCs are presented in children, together with a discussion of how to collect and process these cells.
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Affiliation(s)
- Musa Karakukcu
- Department of Pediatric Hematology and Oncology, Faculty of Medicine, Erciyes Pediatric Stem Cell Transplantation Center, Erciyes University, Kayseri, Turkey.
| | - Ekrem Unal
- Department of Pediatric Hematology and Oncology, Faculty of Medicine, Erciyes Pediatric Stem Cell Transplantation Center, Erciyes University, Kayseri, Turkey
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Samaras P, Pfrommer S, Seifert B, Petrausch U, Mischo A, Schmidt A, Schanz U, Nair G, Bargetzi M, Taverna C, Stupp R, Stenner-Liewen F, Renner C. Efficacy of vinorelbine plus granulocyte colony-stimulation factor for CD34+ hematopoietic progenitor cell mobilization in patients with multiple myeloma. Biol Blood Marrow Transplant 2014; 21:74-80. [PMID: 25278456 DOI: 10.1016/j.bbmt.2014.09.020] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Accepted: 09/19/2014] [Indexed: 01/08/2023]
Abstract
We aimed to assess the efficacy of vinorelbine plus granulocyte colony-stimulating factor (G-CSF) for chemo-mobilization of CD34(+) hematopoietic progenitor cells (HPC) in patients with multiple myeloma and to identify adverse risk factors for successful mobilization. Vinorelbine 35 mg/m(2) was administered intravenously on day 1 in an outpatient setting. Filgrastim 5 μg/kg body weight (BW) was given twice daily subcutaneously from day 4 until the end of the collection procedure. Leukapheresis was scheduled to start on day 8 and be performed for a maximum of 3 consecutive days until at least 4 × 10(6) CD34(+) cells per kg BW were collected. Overall, 223 patients were mobilized and 221 (99%) patients proceeded to leukapheresis. Three (1.5%) patients required an unscheduled hospitalization after chemo-mobilization because of neutropenic fever and renal failure (n = 1), severe bone pain (n = 1), and abdominal pain with constipation (n = 1). In 211 (95%) patients, the leukaphereses were started as planned at day 8, whereas in 8 (3%) patients the procedure was postponed to day 9 and in 2 (1%) patients to day 10. In the great majority of patients (77%), the predefined amount of HPC could be collected with 1 leukapheresis. Forty-four (20%) patients needed a second leukapheresis, whereas only 6 (3%) patients required a third leukapheresis procedure. The median number of CD34(+) cells collected was 6.56 × 10(6) (range, .18 to 25.9 × 10(6)) per kg BW at the first day of leukapheresis and 7.65 × 10(6) (range, .18 to 25.9 × 10(6)) per kg BW in total. HPC collection was successful in 212 (95%) patients after a maximum of 3 leukaphereses. Patient age (P = .02) and prior exposition to lenalidomide (P < .001) were independent risk factors for a lower HPC amount collected in multiple regression analysis. Vinorelbine plus G-CSF enables a very reliable prediction of the timing of leukapheresis and results in successful HPC collection in 95% of the patients.
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Affiliation(s)
- Panagiotis Samaras
- Department of Oncology, University Hospital Zurich, Zurich, Switzerland.
| | - Sarah Pfrommer
- Department of Oncology, University Hospital Zurich, Zurich, Switzerland
| | - Burkhardt Seifert
- Biostatistics Unit, Institute of Social and Preventive Medicine, University of Zurich, Zurich, Switzerland
| | - Ulf Petrausch
- Department of Oncology, University Hospital Zurich, Zurich, Switzerland
| | - Axel Mischo
- Department of Oncology, University Hospital Zurich, Zurich, Switzerland
| | - Adrian Schmidt
- Medical Oncology and Hematology, Triemli City Hospital, Zurich, Switzerland
| | - Urs Schanz
- Department of Hematology, University Hospital Zurich, Zurich, Switzerland
| | - Gayathri Nair
- Department of Hematology, University Hospital Zurich, Zurich, Switzerland
| | - Mario Bargetzi
- Center of Oncology, Hematology and Transfusion Medicine, Cantonal Hospital Aarau, Aarau, Switzerland
| | - Christian Taverna
- Department of Oncology, University Hospital Zurich, Zurich, Switzerland
| | - Roger Stupp
- Department of Oncology, University Hospital Zurich, Zurich, Switzerland
| | | | - Christoph Renner
- Department of Oncology, University Hospital Zurich, Zurich, Switzerland
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Duong HK, Savani BN, Copelan E, Devine S, Costa LJ, Wingard JR, Shaughnessy P, Majhail N, Perales MA, Cutler CS, Bensinger W, Litzow MR, Mohty M, Champlin RE, Leather H, Giralt S, Carpenter PA. Peripheral blood progenitor cell mobilization for autologous and allogeneic hematopoietic cell transplantation: guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant 2014; 20:1262-73. [PMID: 24816581 DOI: 10.1016/j.bbmt.2014.05.003] [Citation(s) in RCA: 164] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2014] [Accepted: 05/01/2014] [Indexed: 02/03/2023]
Abstract
Peripheral blood progenitor cell mobilization practices vary significantly among institutions. Effective mobilization regimens include growth factor alone, chemotherapy and growth factor combined, and, more recently, incorporation of plerixafor with either approach. Many institutions have developed algorithms to improve stem cell mobilization success rates and cost-effectiveness. However, an optimal stem cell mobilization regimen has not been defined. Practical guidelines are needed to address important clinical questions, including which growth factor is optimal, what chemotherapy and dose is most effective, and when to initiate leukapheresis. We present recommendations, based on a comprehensive review of the literature, from the American Society of Blood and Marrow Transplantation.
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Affiliation(s)
- Hien K Duong
- Department of Blood and Marrow Transplant, Blood and Marrow Transplant Program, Cleveland Clinic Foundation, Cleveland, Ohio.
| | - Bipin N Savani
- Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Ed Copelan
- Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina
| | - Steven Devine
- Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio
| | - Luciano J Costa
- Division of Hematology and Oncology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - John R Wingard
- Division of Hematology/Oncology, University of Florida Health Cancer Center, Gainesville, Florida
| | - Paul Shaughnessy
- Department of Adult Bone Marrow Transplant, Texas Transplant Institute, San Antonio, Texas
| | - Navneet Majhail
- Department of Blood and Marrow Transplant, Blood and Marrow Transplant Program, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Miguel-Angel Perales
- Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, and Weill Cornell Medical College, New York, New York
| | - Corey S Cutler
- Department of Hematologic Oncology, Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - William Bensinger
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Mark R Litzow
- Division of Hematology, Division of Palliative Medicine, Mayo Clinic, Rochester, Minnesota
| | - Mohamad Mohty
- Department of Haematology, Saint Antoine Hospital, Paris, France
| | - Richard E Champlin
- Department of Stem Cell Transplantation, M.D. Anderson Cancer Center, Houston, Texas
| | - Helen Leather
- Division of Hematology/Oncology, University of Florida Health Cancer Center, Gainesville, Florida
| | - Sergio Giralt
- Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, and Weill Cornell Medical College, New York, New York
| | - Paul A Carpenter
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
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11
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Martino M, Laszlo D, Lanza F. Long-active granulocyte colony-stimulating factor for peripheral blood hematopoietic progenitor cell mobilization. Expert Opin Biol Ther 2014; 14:757-72. [DOI: 10.1517/14712598.2014.895809] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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12
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Samavedam UKSRL, Iwata H, Müller S, Schulze FS, Recke A, Schmidt E, Zillikens D, Ludwig RJ. GM-CSF Modulates Autoantibody Production and Skin Blistering in Experimental Epidermolysis Bullosa Acquisita. THE JOURNAL OF IMMUNOLOGY 2013; 192:559-71. [DOI: 10.4049/jimmunol.1301556] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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13
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Talhi S, Osmani S, Brahimi M, Yafour N, Bouhass R, Arabi A, Bekadja M. The use of granulocyte colony stimulating factoR (G-CSF) (filgrastim) alone in the mobilization of stem cell in the autologous stem cell transplantation. Transfus Apher Sci 2013; 49:97-9. [DOI: 10.1016/j.transci.2013.02.044] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2012] [Accepted: 02/13/2013] [Indexed: 11/16/2022]
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14
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Abstract
The use of mobilized peripheral blood stem cells (PBSCs) has largely replaced the use of bone marrow as a source of stem cells for both allogeneic and autologous stem cell transplantation. G-CSF with or without chemotherapy is the most commonly used regimen for stem cell mobilization. Some donors or patients, especially the heavily pretreated patients, fail to mobilize the targeted number of stem cells with this regimen. A better understanding of the mechanisms involved in hematopoietic stem cell (HSC) trafficking could lead to the development of newer mobilizing agents and therapeutic approaches. This review will cover the current methods for stem cell mobilization and recent developments in the understanding of the biology of stem cells and the bone marrow microenvironment.
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Affiliation(s)
- Ibraheem H Motabi
- Siteman Cancer Center, Washington University School of Medicine, 660 S Euclid Ave, St. Louis, MO 63110, USA.
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15
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Systematic Review of Randomized Controlled Trials of Hematopoietic Stem Cell Mobilization Strategies for Autologous Transplantation for Hematologic Malignancies. Biol Blood Marrow Transplant 2012; 18:1191-203. [DOI: 10.1016/j.bbmt.2012.01.008] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2011] [Accepted: 01/11/2012] [Indexed: 11/20/2022]
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16
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Attolico I, Pavone V, Ostuni A, Rossini B, Musso M, Crescimanno A, Martino M, Iacopino P, Milone G, Tedeschi P, Coluzzi S, Nuccorini R, Pascale S, Di Nardo E, Olivieri A. Plerixafor Added to Chemotherapy Plus G-CSF Is Safe and Allows Adequate PBSC Collection in Predicted Poor Mobilizer Patients with Multiple Myeloma or Lymphoma. Biol Blood Marrow Transplant 2012; 18:241-9. [DOI: 10.1016/j.bbmt.2011.07.014] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2010] [Accepted: 07/20/2011] [Indexed: 01/09/2023]
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17
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Ikuta T, Adekile AD, Gutsaeva DR, Parkerson JB, Yerigenahally SD, Clair B, Kutlar A, Odo N, Head CA. The proinflammatory cytokine GM-CSF downregulates fetal hemoglobin expression by attenuating the cAMP-dependent pathway in sickle cell disease. Blood Cells Mol Dis 2011; 47:235-42. [PMID: 21945571 PMCID: PMC3223356 DOI: 10.1016/j.bcmd.2011.08.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2011] [Revised: 08/10/2011] [Accepted: 08/20/2011] [Indexed: 02/02/2023]
Abstract
Although reduction in leukocyte counts following hydroxyurea therapy in sickle cell disease (SCD) predicts fetal hemoglobin (HbF) response, the underlying mechanism remains unknown. We previously reported that leukocyte counts are regulated by granulocyte-macrophage colony-stimulating factor (GM-CSF) in SCD patients. Here we examined the roles of GM-CSF in the regulation of HbF expression in SCD. Upon the analysis of retrospective data in 372 patients, HbF levels were inversely correlated with leukocyte counts and GM-CSF levels in SCD patients without hydroxyurea therapy, while HbF increments after hydroxyurea therapy correlated with a reduction in leukocyte counts, suggesting a negative effect of GM-CSF on HbF expression. Consistently, in vitro studies using primary erythroblasts showed that the addition of GM-CSF to erythroid cells decreased HbF expression. We next examined the intracellular signaling pathway through which GM-CSF reduced HbF expression. Treatment of erythroid cells with GM-CSF resulted in the reduction of intracellular cAMP levels and abrogated phosphorylation of cAMP response-element-binding-protein, suggesting attenuation of the cAMP-dependent pathway, while the phosphorylation levels of mitogen-activated protein kinases were not affected. This is compatible with our studies showing a role for the cAMP-dependent pathway in HbF expression. Together, these results demonstrate that GM-CSF plays a role in regulating both leukocyte count and HbF expression in SCD. Reduction in GM-CSF levels upon hydroxyurea therapy may be critical for efficient HbF induction. The results showing the involvement of GM-CSF in HbF expression may suggest possible mechanisms for hydroxyurea resistance in SCD.
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Affiliation(s)
- Tohru Ikuta
- Department of Anesthesiology and Perioperative Medicine, Medical College of Georgia, Georgia Health Sciences University, Augusta, USA.
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18
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Pierelli L, Perseghin P, Marchetti M, Accorsi P, Fanin R, Messina C, Olivieri A, Risso M, Salvaneschi L, Bosi A. Best practice for peripheral blood progenitor cell mobilization and collection in adults and children: results of a Società Italiana Di Emaferesi e Manipolazione Cellulare (SIDEM) and Gruppo Italiano Trapianto Midollo Osseo (GITMO) consensus process. Transfusion 2011; 52:893-905. [DOI: 10.1111/j.1537-2995.2011.03385.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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19
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Novel agents and approaches for stem cell mobilization in normal donors and patients. Bone Marrow Transplant 2011; 47:1154-63. [DOI: 10.1038/bmt.2011.170] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
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20
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Proposed definition of 'poor mobilizer' in lymphoma and multiple myeloma: an analytic hierarchy process by ad hoc working group Gruppo ItalianoTrapianto di Midollo Osseo. Bone Marrow Transplant 2011; 47:342-51. [PMID: 21625224 PMCID: PMC3296914 DOI: 10.1038/bmt.2011.82] [Citation(s) in RCA: 140] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Many lymphoma and myeloma patients fail to undergo ASCT owing to poor mobilization. Identification of poor mobilizers (PMs) would provide a tool for early intervention with new mobilization agents. The Gruppo italianoTrapianto di Midollo Osseo working group proposed a definition of PMs applicable to clinical trials and clinical practice. The analytic hierarchy process, a method for group decision making, was used in setting prioritized criteria. Lymphoma or myeloma patients were defined as ‘proven PM' when: (1) after adequate mobilization (G-CSF 10 μg/kg if used alone or ⩾5 μg/kg after chemotherapy) circulating CD34+ cell peak is <20/μL up to 6 days after mobilization with G-CSF or up to 20 days after chemotherapy and G-CSF or (2) they yielded <2.0 × 106 CD34+ cells per kg in ⩽3 apheresis. Patients were defined as predicted PMs if: (1) they failed a previous collection attempt (not otherwise specified); (2) they previously received extensive radiotherapy or full courses of therapy affecting SC mobilization; and (3) they met two of the following criteria: advanced disease (⩾2 lines of chemotherapy), refractory disease, extensive BM involvement or cellularity <30% at the time of mobilization; age ⩾65 years. This definition of proven and predicted PMs should be validated in clinical trials and common clinical practice.
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Vose JM, Ho AD, Coiffier B, Corradini P, Khouri I, Sureda A, Van Besien K, Dipersio J. Advances in mobilization for the optimization of autologous stem cell transplantation. Leuk Lymphoma 2011; 50:1412-21. [PMID: 19603345 DOI: 10.1080/10428190903096701] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
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.
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Affiliation(s)
- Julie M Vose
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198-7680, USA.
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22
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Rosenbeck LL, Srivastava S, Kiel PJ. Peripheral Blood Stem Cell Mobilization Tactics. Ann Pharmacother 2010; 44:107-16. [DOI: 10.1345/aph.1m289] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
OBJECTIVE To evaluate the methods and collection techniques currently used in stem cell mobilization for patients undergoing autologous transplantation. DATA SOURCES Literature search was performed through PubMed (1948-August 2009) and MEDLINE (1977-August 2009). Reference citations from publications identified were also reviewed. STUDY SELECTION AND DATA EXTRACTION All literature identified was reviewed for inclusion. Original research and retrospective cohorts, along with previously published systematic reviews of stem cell mobilization and growth factors, were evaluated. Abstract data on plerixafor were also reviewed. DATA SYNTHESIS Successful mobilization of an adequate number of progenitor cells can help ensure and improve time to neutrophil and platelet engraftment. A variety of methods have been studied to find the safest and most predictable mobilization of CD34+ progenitor cells, including use of single agents or the combinations of hematopoietic growth factors, chemotherapy, and a novel chemokine receptor 4 antagonist. Currently, granulocyte colony-stimulating factor (G-CSF) 10 Mg/kg daily started 4 days prior to apheresis remains the standard of care for initial mobilization therapy. In patients who fail to mobilize or who are at high risk for mobilization failure, cyclophosphamide in conjunction with G-CSF may be used. Plerixafor, a novel chemokine receptor antagonist, in combination with G-CSF has demonstrated superiority for achieving collection goals compared to G-CSF alone in 2 Phase 3 trials. CONCLUSIONS The optimal mobilization strategy is still unknown; however, colony-stimulating factors remain the most commonly used mobilization agents. Currently, chemotherapy or plerixafor in combination with G-CSF is a reasonable option in heavily pretreated and hard-to-mobilize patients with non-Hodgkin's lymphoma and multiple myeloma.
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Affiliation(s)
- Lindsay L Rosenbeck
- Lindsay L Rosenbeck PharmD, PGY-2 Hematology/Oncology Pharmacy Resident, Department of Pharmacy, Simon Cancer Center-Clarian Health, Indiana University, Indianapolis, IN
| | - Shivani Srivastava
- Shivani Srivastava MD, Assistant Professor of Medicine, Department of Medicine, Bone Marrow and Stem Cell Transplantation, School of Medicine, Indiana University
| | - Patrick J Kiel
- Patrick J Kiel PharmD BCPS, Clinical Pharmacy Specialist, Hematology/Stem Cell Transplant, Simon Cancer Center-Clarian Health, Indiana University
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Affiliation(s)
- Gary H Lyman
- Duke University and Duke Comprehensive Cancer Center, Durham, NC 27705, USA.
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Abstract
Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are well-recognized regulators of hematopoiesis and have an established role as growth factors in clinical practice. G-CSF and GM-CSF regulate myeloid cell production, differentiation and activation, and might also be important for driving inflammatory responses. Inappropriate engagement of this pathway could be a critical amplification mechanism when maladaptive immune responses predispose to autoimmunity and sterile tissue inflammation. We postulate that antagonism of G-CSF or GM-CSF could represent a novel therapeutic approach for a variety of autoimmune-mediated inflammatory diseases, including rheumatoid arthritis.
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25
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Cesselli D, Beltrami AP, Rigo S, Bergamin N, D'Aurizio F, Verardo R, Piazza S, Klaric E, Fanin R, Toffoletto B, Marzinotto S, Mariuzzi L, Finato N, Pandolfi M, Leri A, Schneider C, Beltrami CA, Anversa P. Multipotent progenitor cells are present in human peripheral blood. Circ Res 2009; 104:1225-34. [PMID: 19390058 DOI: 10.1161/circresaha.109.195859] [Citation(s) in RCA: 97] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
To determine whether the peripheral blood in humans contains a population of multipotent progenitor cells (MPCs), products of leukapheresis were obtained from healthy donor volunteers following the administration of granulocyte colony-stimulating factor. Small clusters of adherent proliferating cells were collected, and these cells continued to divide up to 40 population doublings without reaching replicative senescence and growth arrest. MPCs were positive for the transcription factors Nanog, Oct3/4, Sox2, c-Myc, and Klf4 and expressed several antigens characteristic of mesenchymal stem cells. However, they were negative for markers of hematopoietic stem/progenitor cells and bone marrow cell lineages. MPCs had a cloning efficiency of approximately 3%, and following their expansion, retained a highly immature phenotype. Under permissive culture conditions, MPCs differentiated into neurons, glial cells, hepatocytes, cardiomyocytes, endothelial cells, and osteoblasts. Moreover, the gene expression profile of MPCs partially overlapped with that of neural and embryonic stem cells, further demonstrating their primitive, uncommitted phenotype. Following subcutaneous transplantation in nonimmunosuppressed mice, MPCs migrated to distant organs and integrated structurally and functionally within the new tissue, acquiring the identity of resident parenchymal cells. In conclusion, undifferentiated cells with properties of embryonic stem cells can be isolated and expanded from human peripheral blood after granulocyte colony-stimulating factor administration. This cell pool may constitute a unique source of autologous cells with critical clinical import.
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Bensinger W, DiPersio JF, McCarty JM. Improving stem cell mobilization strategies: future directions. Bone Marrow Transplant 2009; 43:181-95. [DOI: 10.1038/bmt.2008.410] [Citation(s) in RCA: 169] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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Abstract
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.
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Affiliation(s)
- Louis M Pelus
- Department of Microbiology and Immunology, Walther Oncology Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
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Cashen AF, Nervi B, DiPersio J. AMD3100: CXCR4 antagonist and rapid stem cell-mobilizing agent. Future Oncol 2007; 3:19-27. [PMID: 17280498 DOI: 10.2217/14796694.3.1.19] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
As hematopoietic stem cells collected from peripheral blood are increasingly used for autologous and allogeneic stem cell transplantation, new approaches for the mobilization of stem cells are needed. These should have the goal of improving stem cell collection and reducing the duration and toxicity of the mobilization process. AMD3100, a specific inhibitor of CXCR4, one of the key molecules that tethers hematopoietic stem cells to the bone marrow microenvironment, is a promising new agent currently in clinical development for autologous and allogeneic stem cell mobilization. Early clinical trials have demonstrated that AMD3100 rapidly mobilizes stem cells to the peripheral blood, with minimal side effects. In Phase II trials, mobilization with the combination of AMD3100 and granulocyte colony-stimulating factor (G-CSF) results in the collection of more progenitor cells than G-CSF alone.
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Affiliation(s)
- Amanda F Cashen
- Washington University School of Medicine, Division of Oncology, 660 South Euclid Avenue, Campus Box 8007, St Louis, MO 63110, USA.
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Cashen AF, Lazarus HM, Devine SM. Mobilizing stem cells from normal donors: is it possible to improve upon G-CSF? Bone Marrow Transplant 2007; 39:577-88. [PMID: 17369869 DOI: 10.1038/sj.bmt.1705616] [Citation(s) in RCA: 89] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Currently, granulocyte colony stimulating factor (G-CSF) remains the standard mobilizing agent for peripheral blood stem cell (PBSC) donors, allowing the safe collection of adequate PBSCs from the vast majority of donors. However, G-CSF mobilization can be associated with some significant side effects and requires a multi-day dosing regimen. The other cytokine approved for stem cell mobilization, granulocyte-macrophage colony stimulating factor (GM-CSF), alters graft composition and may reduce the development of graft-versus-host disease, but a significant minority of donors fails to provide sufficient CD34+ cells with GM-CSF and some experience unacceptable toxicity. AMD3100 is a promising new mobilizing agent, which may have several advantages over G-CSF for donor mobilization. As it is a direct antagonist of the interaction between the chemokine stromal-derived factor-1 and its receptor CXCR4, AMD3100 mobilizes PBSCs within hours rather than days. It is also well tolerated, with no significant side effects reported in any of the clinical trials to date. Studies of autologous and allogeneic transplantation of AMD3100 mobilized grafts have demonstrated prompt and stable engraftment. Here, we review the current state of stem cell mobilization in normal donors and discuss novel strategies for donor stem cell mobilization.
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Affiliation(s)
- A F Cashen
- Department of Medicine, Washington University School of Medicine, St Louis, MO, USA
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Conran N, Saad STO, Costa FF, Ikuta T. Leukocyte numbers correlate with plasma levels of granulocyte-macrophage colony-stimulating factor in sickle cell disease. Ann Hematol 2007; 86:255-61. [PMID: 17205286 DOI: 10.1007/s00277-006-0246-6] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2006] [Accepted: 12/13/2006] [Indexed: 11/25/2022]
Abstract
Despite a clear role for leukocytes in modulating the pathophysiology of sickle cell disease (SCD), the mechanism by which leukocyte numbers are increased in this disorder remains unclear. Hypothesizing that the chronic inflammatory state, elicited by adhesive interactions involving various cell types, might underlie leukocytosis, we measured plasma levels of proinflammatory or myeloid cytokines that play a role in leukocytosis and examined their correlations with leukocyte numbers in patients with SCD. Our studies found that, although plasma levels of granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 3, and macrophage colony-stimulating factor are elevated in steady-state patients with SCD, only plasma GM-CSF levels are positively correlated with the numbers of total leukocytes, neutrophils, monocytes, and eosinophils, regardless of whether they received hydroxyurea. GM-CSF levels were significantly decreased in patients on hydroxyurea therapy. These data suggest a role of GM-CSF in leukocytosis of SCD. In contrast, plasma levels of granulocyte colony-stimulating factor, a major cytokine that induces leukocytosis due to bacterial infection, were lower than those of control subjects. These results indicate that elevated GM-CSF levels may contribute, at least in part, to high leukocyte numbers in SCD. As plasma GM-CSF levels were decreased in patients on hydroxyurea therapy, hydroxyurea may decrease leukocyte numbers by reducing circulating GM-CSF levels.
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Affiliation(s)
- Nicola Conran
- Hematology and Hemotherapy Center, University of Campinas, UNICAMP-SP, Campinas, Brazil
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31
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Quittet P, Ceballos P, Lopez E, Lu ZY, Latry P, Becht C, Legouffe E, Fegueux N, Exbrayat C, Pouessel D, Rouillé V, Daures JP, Klein B, Rossi JF. Low doses of GM-CSF (molgramostim) and G-CSF (filgrastim) after cyclophosphamide (4 g/m2) enhance the peripheral blood progenitor cell harvest: results of two randomized studies including 120 patients. Bone Marrow Transplant 2006; 38:275-84. [PMID: 16883311 PMCID: PMC2100150 DOI: 10.1038/sj.bmt.1705441] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The use of a combination of G-CSF and GM-CSF versus G-CSF alone, after cyclophosphamide (4 g/m2) was compared in two randomized phase III studies, including 120 patients. In study A, 60 patients received 5 x 2 microg/kg/day of G-CSF and GM-CSF compared to 5 mug/kg/day of G-CSF. In study B, 60 patients received 2.5 x 2 microg/kg/day G-CSF and GM-CSF compared to G-CSF alone (5 microg/kg/day). With the aim to collect at least 5 x 10(6)/kg CD34 cells in a maximum of three large volume leukapherises (LK), 123 LK were performed in study A, showing a significantly higher number of patients reaching 10 x 10(6)/kg CD34 cells (21/29 in G+GM-CSF arm vs 11/27 in G-CSF arm, P=0.00006). In study B, 109 LK were performed, with similar results (10/27 vs 15/26, P=0.003). In both the study, the total harvest of CD34 cells/kg was twofold higher in G-CSF plus GM-CSF group (18.3 x 10(6) in study A and 15.85 x 10(6) in study B) than in G-CSF group (9 x 10(6) in study A and 8.1 x 10(6) in study B), a significant difference only seen in multiple myeloma, with no significant difference in terms of mobilized myeloma cells between G-CSF and GM-CSF groups.
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Affiliation(s)
- Philippe Quittet
- Service d'hématologie et oncologie médicale
CHRU Montpellier Hôpital LapeyronieUniversité Montpellier I34295 Montpellier,FR
| | - Patrice Ceballos
- Service d'hématologie et oncologie médicale
CHRU Montpellier Hôpital LapeyronieUniversité Montpellier I34295 Montpellier,FR
| | - Ernesto Lopez
- Service d'hématologie et oncologie médicale
CHRU Montpellier Hôpital LapeyronieUniversité Montpellier I34295 Montpellier,FR
| | - Zhao-Yang Lu
- Unité de Thérapie Cellulaire
CHRU Montpellier Hôpital Saint-Eloi34295 Montpellier,FR
| | - Pascal Latry
- Service d'hématologie et oncologie médicale
CHRU Montpellier Hôpital LapeyronieUniversité Montpellier I34295 Montpellier,FR
| | - Catherine Becht
- Service d'hématologie et oncologie médicale
CHRU Montpellier Hôpital LapeyronieUniversité Montpellier I34295 Montpellier,FR
| | - Eric Legouffe
- Service d'hématologie et oncologie médicale
CHRU Montpellier Hôpital LapeyronieUniversité Montpellier I34295 Montpellier,FR
| | - Nathalie Fegueux
- Service d'hématologie et oncologie médicale
CHRU Montpellier Hôpital LapeyronieUniversité Montpellier I34295 Montpellier,FR
| | - Carole Exbrayat
- Service d'hématologie et oncologie médicale
CHRU Montpellier Hôpital LapeyronieUniversité Montpellier I34295 Montpellier,FR
| | - Damien Pouessel
- Service d'hématologie et oncologie médicale
CHRU Montpellier Hôpital LapeyronieUniversité Montpellier I34295 Montpellier,FR
| | - Valérie Rouillé
- Service d'hématologie et oncologie médicale
CHRU Montpellier Hôpital LapeyronieUniversité Montpellier I34295 Montpellier,FR
| | - Jean-Pierre Daures
- Laboratoire de biostatistique
Institut Universitaire de Recherche CliniqueUniversité Montpellier I34093 Montpellier cedex 5,FR
| | - Bernard Klein
- Unité de Thérapie Cellulaire
CHRU Montpellier Hôpital Saint-Eloi34295 Montpellier,FR
| | - Jean-François Rossi
- Service d'hématologie et oncologie médicale
CHRU Montpellier Hôpital LapeyronieUniversité Montpellier I34295 Montpellier,FR
- * Correspondence should be adressed to: Jean-François Rossi
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Kopf B, De Giorgi U, Vertogen B, Monti G, Molinari A, Turci D, Dazzi C, Leoni M, Tienghi A, Cariello A, Argnani M, Frassineti L, Scarpi E, Rosti G, Marangolo M. A randomized study comparing filgrastim versus lenograstim versus molgramostim plus chemotherapy for peripheral blood progenitor cell mobilization. Bone Marrow Transplant 2006; 38:407-12. [PMID: 16951690 DOI: 10.1038/sj.bmt.1705465] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
We conducted a prospective randomized clinical trial to assess the mobilizing efficacy of filgrastim, lenograstim and molgramostim following a disease-specific chemotherapy regimen. Mobilization consisted of high-dose cyclophosphamide in 45 cases (44%), and cisplatin/ifosfamide/etoposide or vinblastine in 22 (21%), followed by randomization to either filgrastim or lenograstim or molgramostim at 5 microg/kg/day. One hundred and three patients were randomized, and 82 (79%) performed apheresis. Forty-four (43%) patients were chemonaive, whereas 59 (57%) were pretreated. A median number of one apheresis per patient (range, 1-3) was performed. The median number of CD34+ cells obtained after mobilization was 8.4 x 10(6)/kg in the filgrastim arm versus 5.8 x 10(6)/kg in the lenograstim arm versus 4.0 x 10(6)/kg in the molgramostim arm (P=0.1). A statistically significant difference was observed for the median number of days of growth factor administration in favor of lenograstim (12 days) versus filgrastim (13 days) and molgramostim (14 days) (P<0.0001) and for the subgroup of chemonaive patients (12 days) versus pretreated patients (14 days) (P<0.001). In conclusion, all three growth factors were efficacious in mobilizing peripheral blood progenitor cells with no statistically significant difference between CD34+ cell yield and the different regimens, and the time to apheresis is likely confounded by the different mobilization regimens.
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Affiliation(s)
- B Kopf
- Department of Oncology and Hematology, Istituto Oncologico Romagnolo, Santa Maria delle Croci Hospital, Ravenna, Italy.
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Flomenberg N, DiPersio J, Calandra G. Role of CXCR4 chemokine receptor blockade using AMD3100 for mobilization of autologous hematopoietic progenitor cells. Acta Haematol 2005; 114:198-205. [PMID: 16269859 DOI: 10.1159/000088410] [Citation(s) in RCA: 57] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
G-CSF mobilization of hematopoietic progenitor cells (HPCs) is mediated through enzyme release from maturing myeloid cells, leading to digestion of adhesion molecules, trophic chemokines and their receptors, and the extracellular matrix. HPCs traffic to and are retained in the marrow through the trophic effects of the chemokine SDF-1alpha/CXCL12 binding to its receptor, CXCR4. AMD3100 reversibly inhibits SDF-1alpha/CXCR4 binding, and AMD3100 administration mobilizes CD34+ cells into the circulation. AMD3100 has been tested in several clinical trials which demonstrate that it improves the number of CD34+ cells mobilized including patients failing to mobilize with G-CSF alone. Engraftment of AMD3100-mobilized cells is prompt and durable. Toxicities are mild and infrequent. Lymphoma and myeloma cells do not appear to be mobilized. AMD3100 appears to be a promising agent for HPC mobilization.
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Devine SM, Brown RA, Mathews V, Trinkaus K, Khoury H, Adkins D, Vij R, Sempek D, Graubert T, Tomasson M, Goodnough LT, DiPersio JF. Reduced risk of acute GVHD following mobilization of HLA-identical sibling donors with GM-CSF alone. Bone Marrow Transplant 2005; 36:531-8. [PMID: 16025152 DOI: 10.1038/sj.bmt.1705091] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
We retrospectively reviewed the results of transplanting peripheral blood progenitor cell (PBPC) allografts from HLA-matched sibling donors mobilized using various hematopoietic cytokines. Patients had received allografts mobilized with Granulocyte colony-stimulating factor (G-CSF) (G, N = 65) alone, G plus Granulocyte-macrophage colony stimulating factor (GM-CSF) (G/GM, N = 70), or GM-CSF alone at 10 or 15 microg/kg/day (GM, N = 10 at 10 microg/kg/day and 21 at 15 microg/kg/day). The CD34+ and CD3+ cell content of grafts were significantly lower following GM alone compared to G alone (P < 0.001 and 0.04, respectively). Nonhematopoietic toxicity observed in donors precluded dose escalation of GM-CSF beyond 10 microg/kg/day. Hematopoietic recovery was similar among all three groups. Grades II-IV acute graft-versus-host disease (GVHD) was observed in only 13% of patients in the GM alone group compared to 49 and 69% in the G alone or G/GM groups, respectively (P < 0.001). In a multivariate analysis, receipt of PBPC mobilized with GM alone was associated with a lower risk of grades II-IV acute GVHD (hazard ratio 0.21; 95% CI 0.073, 0.58) compared to G alone or G/GM. There were no differences in relapse risk or overall survival among the groups. Donor PBPC grafts mobilized with GM-CSF alone result in prompt hematopoietic engraftment despite lower CD34+ cell doses and may reduce the risk of grades II-IV acute GVHD following HLA-matched PBPC transplantation.
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Affiliation(s)
- S M Devine
- Siteman Cancer Center and Department of Medicine, Division of Oncology, Section of Stem Cell Transplantation, Leukemia, and Stem Cell Biology, Washington University School of Medicine, St Louis, MO, USA.
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Komrokji RS, Lyman GH. The colony-stimulating factors: use to prevent and treat neutropenia and its complications. Expert Opin Biol Ther 2005; 4:1897-910. [PMID: 15571452 DOI: 10.1517/14712598.4.12.1897] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
The colony-stimulating factors (CSFs) represent the only biological response modifiers used in clinical practice to treat or prevent neutropenia. These pleiotropic cytokines are available in clinical practice as granulocyte CSF (G-CSF), granulocyte-macrophage CSF (GM-CSF) and pegylated G-CSF. Neutropenia and its complications, most importantly febrile neutropenia (FN), remain major and serious side effects of cancer chemotherapy. Several studies and meta-analyses have addressed the clinical applications of CSFs to treat or prevent neutropenia. Guidelines have been developed to foster the appropriate use of CSFs. This article reviews the nature and use of the CSFs, and summarises the critical studies and guidelines. A historical perspective briefly describes the discovery, synthesis and clinical use of CSFs. The major biological and pharmacological characteristics are highlighted. The clinical applications of the CSFs are reviewed, including primary FN prophylaxis, secondary FN prophylaxis, treatment of FN, support of dose-dense chemotherapy regimens, use in leukaemia and myelodysplastic syndromes, utility in stem cell transplantation, and use in elderly and paediatric patients. Finally, clinical efficacy data, as well as the economic impact of the CSFs, are discussed.
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Affiliation(s)
- Rami S Komrokji
- University of Rochester School of Medicine and Dentistry, Department of Medicine and the James P. Wilmot Cancer Center, Rochester, New York 14642, USA
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36
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Devine SM, Flomenberg N, Vesole DH, Liesveld J, Weisdorf D, Badel K, Calandra G, DiPersio JF. Rapid mobilization of CD34+ cells following administration of the CXCR4 antagonist AMD3100 to patients with multiple myeloma and non-Hodgkin's lymphoma. J Clin Oncol 2004; 22:1095-102. [PMID: 15020611 DOI: 10.1200/jco.2004.07.131] [Citation(s) in RCA: 320] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
PURPOSE Interactions between the chemokine receptor CXCR4 and its ligand stromal derived factor-1 regulate hematopoietic stem-cell trafficking. AMD3100 is a CXCR4 antagonist that induces rapid mobilization of CD34+ cells in healthy volunteers. We performed a phase I study assessing the safety and clinical effects of AMD3100 in patients with multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS Thirteen patients (MM, n=7; NHL, n=6) received AMD3100 at a dose of either 160 microg/kg (n=6) or 240 microg/kg (n=7). WBC and peripheral blood (PB) CD34+ cell counts were analyzed at 4 and 6 hours following injection. RESULTS AMD3100 caused a rapid and statistically significant increase in the total WBC and PB CD34+ counts at both 4 and 6 hours following a single injection. The absolute CD34+ cell count increased from a baseline of 2.6 +/- 0.7/microL (mean +/- SE) to 15.6 +/- 3.9/microL and 16.2 +/- 4.3/microL at 4 hours (P=.002) and 6 hours after injection (P =.003), respectively. The absolute CD34+ cell counts observed at 4 and 6 hours following AMD3100 were higher in the 240 microg/kg group (19.3 +/- 6.9/microL and 20.4 +/- 7.6/microL, respectively) compared with the 160 microg/kg group (11.3 +/- 2.7/microL and 11.3 +/- 2.5/microL, respectively). The drug was well tolerated and only grade 1 toxicities were encountered. CONCLUSION AMD3100 appears to be a safe and effective agent for the rapid mobilization of CD34+ cells in patients who have received prior chemotherapy. Further studies in combination with granulocyte colony-stimulating factor in patients with lymphoid malignancies are warranted.
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Affiliation(s)
- Steven M Devine
- Washington University School of Medicine, St Louis, MO 63110, USA.
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Liang DC. The role of colony-stimulating factors and granulocyte transfusion in treatment options for neutropenia in children with cancer. Paediatr Drugs 2004; 5:673-84. [PMID: 14510625 DOI: 10.2165/00148581-200305100-00003] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Children with cancer receiving anticancer therapy always experience neutropenia, and as a result often develop serious neutropenic infections that cause morbidity and/or mortality. Intensive chemotherapy with improved supportive care for neutropenia contribute to the recent advances in treatment outcome in children with cancer. Recombinant human granulocyte colony-stimulating factor (G-CSF) and recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) can shorten the duration and decrease the severity of neutropenia, and thus support intensive chemotherapy. Both G-CSF and GM-CSF stimulate proliferation and maturation of myeloid progenitor cells and are thus used to help mobilization of peripheral blood progenitor cells, and after stem-cell transplantation. The American Society of Clinical Oncology 2000 Guidelines recommended that colony-stimulating factors (CSFs) can be administered as a primary prophylaxis with a chemotherapy regimen if previous experiences with chemotherapy regimens have shown that the incidence of febrile neutropenia (neutropenic fever) is > or =40%. The routine use of CSFs for secondary prophylaxis or for patients with afebrile neutropenia is not recommended in order to avoid the overuse of CSFs. The use of a CSF may be considered in children with febrile neutropenia with a neutrophil count <100/microL, uncontrolled primary disease, pneumonia, hypotension, multiorgan dysfunction (sepsis syndrome), or invasive fungal infection. Although these guidelines are generally applicable to children with cancer, further studies on CSFs are certainly needed in pediatric oncology. The recent advances in granulocyte collection, using healthy volunteer donor stimulation with G-CSF and/or dexamethasone to yield large numbers of granulocytes has made granulocyte transfusion a more realistic option. Granulocyte transfusion has shown promising results in treating children with severe neutropenic infection; however, controlled trials are warranted to clarify the efficacy and cost-effectiveness of this procedure.
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Affiliation(s)
- Der-Cherng Liang
- Division of Hematology-Oncology, Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan.
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Gazitt Y. Homing and mobilization of hematopoietic stem cells and hematopoietic cancer cells are mirror image processes, utilizing similar signaling pathways and occurring concurrently: circulating cancer cells constitute an ideal target for concurrent treatment with chemotherapy and antilineage-specific antibodies. Leukemia 2004; 18:1-10. [PMID: 14574330 DOI: 10.1038/sj.leu.2403173] [Citation(s) in RCA: 80] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Adhesion molecules and stromal cell-derived factor-1 (SDF-1)/CXCR4 signaling play key role in homing and mobilization of hematopoietic progenitor (HPC) and hematopoietic cancer clonogenic cells (HCC). High expression of VLA-4 is required for homing of HPC and HCC, whereas downregulation of these molecules is required for successful mobilization of HPC and HCC. Upregulation and activation of the SDF-1/CXCR4 signaling is required for homing of HPC and HCC, whereas disruption of the SDF-1 signaling is required for mobilization of HPC and HCC. Hence, mobilizations of HPC and HCC occur concurrently. It is proposed that drug resistance evolves as a result of repeated cycles of chemotherapy. Following each cycle of chemotherapy, HCC lose adhesion molecules and SDF-1 signaling. Surviving cells, released from tumor sites, circulate until re-expression of adhesion molecules and CXCR4 occurs, then homing to stroma of distal tissues occurs. Cytokines secreted by cells in the new microenvironment induce proliferation and drug resistance of HCC. This process is amplified in each cycle of chemotherapy resulting in disease progression. A novel model for treatment is proposed in which circulating HCC are the target for clinical intervention, and concurrent treatment with chemotherapy and antilineage-specific antibodies will result in abrogation of the 'vicious cycle' of conventional anticancer therapy.
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Affiliation(s)
- Y Gazitt
- University of Texas Health Science Center, San Antonio, TX 78284, USA
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Sevilla J, González-Vicent M, Madero L, Díaz MA. Peripheral blood progenitor cell collection in low-weight children. JOURNAL OF HEMATOTHERAPY & STEM CELL RESEARCH 2002; 11:633-42. [PMID: 12201951 DOI: 10.1089/15258160260194776] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Peripheral blood progenitor cells (PBPC) are substituting bone marrow as a source of stem cells for either autologous or allogeneic hematopoietic transplantation. Several papers have been published on the experience of various groups in their mobilization and transplantation in children. Some technical problems have derived from the size of the patient or donor in the pediatric setting. Thereby, there is some concern regarding leukapheresis in very small children (weighing less than 15-20 kg). This paper summarizes our own data and that of other groups for the mobilization and collection of PBPC in the smallest children. Data from the literature show that mobilization with cytokines alone or in combination with chemotherapy is well tolerated by these patients. Pediatric donors may be used for allogeneic transplantation with no higher incidence of complications. PBPC collection even in the smallest children is a safe and efficient procedure when performed by experienced apheresis teams.
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Affiliation(s)
- Julián Sevilla
- Hospital Infantil Universitario Niño Jesús, Madrid, 28009 Spain.
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40
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Gazitt Y. Comparison between granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor in the mobilization of peripheral blood stem cells. Curr Opin Hematol 2002; 9:190-8. [PMID: 11953663 DOI: 10.1097/00062752-200205000-00003] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Peripheral blood stem cells (PBSC) have become the preferred source of stem cells for autologous transplantation because of the technical advantage and the shorter time to engraftment. Mobilization of CD34+ into the peripheral blood can be achieved by the administration of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), or both, either alone or in combination with chemotherapy. G-CSF and GM-CSF differ somewhat in the number and composition of PBSCs and effector cells mobilized to the peripheral blood. The purpose of this review is to give a recent update on the type and immunologic properties of CD34+ cells and CD34+ cell subsets mobilized by G-CSF or GM-CSF with emphasis on (1) relative efficacy of CD34+ cell mobilization; (2) relative toxicities of G-CSF and GM-CSF as mobilizing agents; (3) mobilization of dendritic cells and their subsets; (4) delineation of the role of adhesion molecules, CXC receptor 4, and stromal cell-derived factor-1 signaling pathway in the release of CD34+ cell to the peripheral blood after treatment with G-CSF or GM-CSF.
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Affiliation(s)
- Yair Gazitt
- Department of Medicine/Hematology, University of Texas Health Science Center, San Antonio, Texas 78284, USA.
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41
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Weaver CH, Buckner CD, Curtis LH, Bajwa K, Weinfurt KP, Wilson-Relyea BJ, Schulman KA. Economic evaluation of filgrastim, sargramostim, and sequential sargramostim and filgrastim after myelosuppressive chemotherapy. Bone Marrow Transplant 2002; 29:159-64. [PMID: 11850711 DOI: 10.1038/sj.bmt.1703341] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2001] [Accepted: 11/01/2001] [Indexed: 11/09/2022]
Abstract
Filgrastim alone and sequential sargramostim and filgrastim have been shown to be more effective than sargramostim alone in the mobilization of CD34(+) cells after myelosuppressive chemotherapy (MC). We sought to compare costs and resource use associated with these regimens. Data were collected prospectively alongside a multicenter, randomized trial of filgrastim, sargramostim, and sequential sargramostim and filgrastim. Direct medical costs were calculated for inpatient and outpatient visits and procedures, including administration of growth factors and MC. We followed 156 patients for 30 days or until initiation of high-dose chemotherapy. The main outcome measures were resource use and costs of inpatient and outpatient visits, platelet and red blood cell transfusions, antibiotic use, and apheresis procedures. Hospital admissions, red blood cell transfusions, and use of i.v. antibiotics were significantly more common in the sargramostim group than in the other treatment arms. In univariate and multivariable analyses, total costs were higher for patients receiving sargramostim alone than for patients in the other groups. Mean costs in multivariable analysis for the filgrastim and sequential sargramostim and filgrastim arms were not significantly different. Filgrastim alone and sequential sargramostim and filgrastim are less costly than sargramostim alone after MC, as well as therapeutically more beneficial.
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Affiliation(s)
- C H Weaver
- CancerConsultants.com, Inc, Ketchum, ID, USA
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42
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Fleming WH, Mulcahy JM, McKearn JP, Streeter PR. Progenipoietin-1: a multifunctional agonist of the granulocyte colony-stimulating factor receptor and fetal liver tyrosine kinase-3 is a potent mobilizer of hematopoietic stem cells. Exp Hematol 2001; 29:943-51. [PMID: 11495700 DOI: 10.1016/s0301-472x(01)00675-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
OBJECTIVE Progenipoietin-1 is an agonist of both the granulocyte colony-stimulating factor and fetal liver tyrosine kinase-3 receptors capable of inducing the proliferation of multiple hematopoietic cell lineages. The potential of progenipoietin-1 to mobilize transplantable hematopoietic stem cells into the peripheral blood was evaluated. METHODS Cohorts of donor mice were treated with either progenipoietin-1, fetal liver tyrosine kinase-3 ligand, granulocyte colony-stimulating factor, or a vehicle control. Hematopoietic progenitor/stem-cell activity in donor blood was assayed by radioprotection, multilineage reconstitution, secondary transplantation, and competitive repopulation. RESULTS Only 1 microL of peripheral blood from progenipoietin-1-treated donors was required to protect 80% of lethally irradiated mice, while in contrast 1 microL of peripheral blood from granulocyte colony-stimulating factor-treated donors failed to protect any recipients. The radioprotected recipients of progenipoietin-1-treated donor cells showed donor-derived (Ly5.2) multilineage hematopoietic reconstitution for up to 6 months. Serial transplantation studies using bone marrow from radioprotected, chimeric recipients demonstrated long-term donor-derived hematopoiesis, indicating the successful transplantation of multipotent hematopoietic stem cells. The engraftment potential of progenipoietin-1 donor-derived cells was directly compared with donors treated with granulocyte colony-stimulating factor or fetal liver tyrosine kinase-3 ligand alone or in combination. Both spleen colony-forming activity and competitive repopulating activity was highest in the blood from progenipoietin-1-treated donors. CONCLUSIONS These studies demonstrate that progenipoietin-1 is a potent mobilizer of transplantable hematopoietic stem cells and indicate that this dual-receptor agonist has greater biologic activity than its constituent molecules.
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Affiliation(s)
- W H Fleming
- BMT Program, Division of Hematology and Medical Oncology, Oregon Health Sciences University, Portland, OR 97201-3098, USA.
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43
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Gazitt Y, Shaughnessy P, Liu Q. Expression of adhesion molecules on CD34(+) cells in peripheral blood of non-hodgkin's lymphoma patients mobilized with different growth factors. Stem Cells 2001; 19:134-43. [PMID: 11239168 DOI: 10.1634/stemcells.19-2-134] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Adhesion molecules on CD34(+) cells were implicated in the process of peripheral blood stem cell (PBSC) mobilization and homing. We studied the mobilization of CD34(+)Thy1(+) cells, CD34(+) very late-acting antigen (VLA)4(+) cells, and CD34(+)L-selectin(+) cells in non-Hodgkin's lymphoma patients mobilized with cyclophosphamide plus G-CSF, GM-CSF, or GM-CSF followed by G-CSF. The mean percentage of CD34(+) cells in the bone marrow (BM) expressing Thy1 was 23.6% +/- 11% and 17.8% +/- 8% in the PB before mobilization, and was markedly decreased to 4.5% +/- 3.3% in the apheresis collections. Similarly, the mean percentage of CD34(+) cells expressing L-selectin was 35.8% +/- 4.3% in the BM, 21.6% +/- 4.1% in the PB before mobilization and was markedly decreased to 9.1% +/- 2.5% in the apheresis collections. Patients in the three arms of the study had a similar pattern of CD34(+)Thy1(+) and CD34(+)L-selectin(+) cell mobilization. Also, a similar pattern of coexpression of CD34(+)Thy1(+) and CD34(+)L-selectin(+) cells was observed when the patients were regrouped as "good mobilizers" (> or =2 x 10(6) CD34(+)CD45(dim) cells/kg, in four collections) and "poor mobilizers" (<0.4 x 10(6) CD34(+)CD45(dim) cells/kg, in two collections). The mean percentage of CD34(+) cells expressing VLA-4 in the BM and PB was relatively high (73.4% +/- 12% and 65.4% +/- 6.6%, respectively) and dropped considerably in the PBSC collections to 43.5% +/- 7.1% with a similar pattern observed for patients in arms A, B, and C. However, when the patients were regrouped as "good mobilizers" and "poor mobilizers," a higher percentage of CD34(+) cells expressing VLA-4 was observed in the PBSC of the pooled "good mobilizers" (50.5% +/- 9% versus 36.3% +/- 6.4%; p = 0.01). We conclude that release of CD34(+) cells to the PB involves a general downregulation of Thy1, L-selectin and VLA-4 on CD34(+) cells, irrespective of the growth factor used for mobilization. However, good mobilizers had a relatively higher percentage of CD34(+) cells expressing the VLA-4 antigen.
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Affiliation(s)
- Y Gazitt
- University of Texas Health Science Center and Wilford Hall Medical Center, San Antonio, Texas 78284, USA
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Goldman SC, Bracho F, Davenport V, Slack R, Areman E, Shen V, Lenarsky C, Weinthal J, Hughes R, Cairo MS. Feasibility study of IL-11 and granulocyte colony-stimulating factor after myelosuppressive chemotherapy to mobilize peripheral blood stem cells from heavily pretreated patients. J Pediatr Hematol Oncol 2001; 23:300-5. [PMID: 11464987 DOI: 10.1097/00043426-200106000-00013] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE Pediatric patients with solid tumors treated with prolonged dose-intensive chemoradiotherapy are poor mobilizers of peripheral blood stem cells (PBSC). We have conducted a pilot study to mobilize PBSC in eight pediatric patients with relapsed solid tumors using ifosfamide, carboplatin, and etoposide (ICE) followed-up by IL-11 plus granulocyte colony-stimulating factor (G-CSF). PATIENTS AND METHODS Patients received ifosfamide 1.8 g/m2 per day for 5 days, carboplatin 400 mg/m2 per day for 2 days, and etoposide 100 mg/m2 per day for 5 days. After completion of ICE chemotherapy, patients received daily subcutaneous injections of G-CSF (5 microg/kg per day) and IL-11 (50-100 microg/kg per day) until peripheral stem cell apheresis. RESULTS The median age was 11 years. Diagnosis included three relapsed Hodgkin disease, three relapsed central nervous system tumors, one relapsed Wilms tumor, and one relapsed rhabdomyosarcoma. The median number of apheresis procedures required to obtain 5 x 10(6) CD34+ cells/kg was one. The mean +/- standard error of mean (SEM) total CD34+ cells collected was 14.0+/-2.7 x 10(6)/kg. The mean +/- SEM total CD34+/CD41+ cells collected was 4.6+/-1.9 x 10(6)/kg. Seven of the eight patients have subsequently undergone myeloablative chemotherapy with autologous PBSC transplantation and have reconstituted hematopoiesis with a median time to neutrophil recovery of 10 days and platelet recovery of 15.5 days. CONCLUSIONS We conclude that the regimen of ICE/IL-11 plus G-CSF is successful in mobilizing large numbers of CD34+ PBSC cells with a limited number (one) of apheresis collections in patients that have previously been heavily pretreated with chemotherapy/radiotherapy.
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Affiliation(s)
- S C Goldman
- North Texas Hospital for Children, Dallas, USA
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Gazitt Y, Liu Q. Plasma levels of SDF-1 and expression of SDF-1 receptor on CD34+ cells in mobilized peripheral blood of non-Hodgkin's lymphoma patients. Stem Cells 2001; 19:37-45. [PMID: 11209089 DOI: 10.1634/stemcells.19-1-37] [Citation(s) in RCA: 60] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
CXCR4 is the receptor for the chemokine stromal derived factor-1 (SDF-1), is expressed on CD34+ cells, and has been implicated in the process of CD34+ cell migration and homing. We studied the mobilization of CD34/CXCR4 cells and the plasma levels of SDF-1 and flt3-ligand (flt3-L) in 36 non-Hodgkin's lymphoma patients receiving cyclophosphamide (Cy) plus G-CSF (arm A), Cy plus GM-CSF (arm B), or Cy plus GM-CSF followed by G-CSF (arm C) for peripheral blood stem cell (PBSC) mobilization and autotransplantation. We observed lower plasma levels of SDF-1 in PBSCs compared to premobilization bone marrow samples. The mean plasma SDF-1 levels were similar in PBSC collections in the three arms of the study. In contrast, SDF-1 levels in the apheresis collections of the "good mobilizers" (patients who collected a minimum of 2 x 10(6) CD34+ cells/kg in one to four PBSC collections) were significantly lower than the apheresis collections of the "poor mobilizers" (> or = 0.4 x 10(6) CD34+ cells/kg in the first two PBSC collections; 288 +/- 82 pg/ml versus 583 +/- 217 pg/ml; p = 0.0009). The mean percentage of CD34+ cells expressing CXCR4 in the apheresis collections was decreased in the PBSC collections compared with premobilization values from 28% to 19.4%. Furthermore, the percentage of CD34+ cells expressing CXCR4 in the good mobilizers was significantly lower compared with the poor mobilizers (14.7 +/- 2.1% versus 33.6 +/- 2.1%; p = 0.002). The good mobilizers had also significantly lower levels of flt3-L compared with the poor mobilizers (34 +/- 4 pg/ml versus 106 +/- 11 pg/ml; p = 0.006), Finally, the levels of flt3-L strongly correlated with SDF-1 levels (r = 0.8; p < 0.0001). We conclude: A) low plasma levels of SDF-1 and low expression of CXCR4 characterize patients with good mobilization outcome, and B) the levels of SDF-1 correlate with flt3-L, suggesting an association of these cytokines in mobilization of CD34+ cells.
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Affiliation(s)
- Y Gazitt
- Department of Medicine/Hematology, University of Texas Health Science Center, San Antonio, Texas 78284, USA.
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Weaver CH, Schulman KA, Buckner CD. Mobilization of peripheral blood stem cells following myelosuppressive chemotherapy: a randomized comparison of filgrastim, sargramostim, or sequential sargramostim and filgrastim. Bone Marrow Transplant 2001; 27 Suppl 2:S23-9. [PMID: 11436117 DOI: 10.1038/sj.bmt.1702865] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Myelosuppressive chemotherapy is frequently used for mobilization of autologous CD34(+) progenitor cells into the peripheral blood for subsequent collection and support of high-dose chemotherapy. The administration of myelosuppressive chemotherapy is typically followed by a myeloid growth factor and is associated with variable CD34 cell yields and morbidity. The two most commonly used myeloid growth factors for facilitation of CD34 cell harvests are granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). We performed a randomized phase III clinical trial comparing G-CSF, GM-CSF, and sequential administration of GM-CSF and G-CSF following administration of myelosuppressive chemotherapy. We evaluated CD34 yields, morbidity, and cost-effectiveness of the three cytokine schedules. One hundred and fifty-six patients with multiple myeloma, breast cancer, or lymphoma received cyclophosphamide with either paclitaxel or etoposide and were randomized to receive G-CSF 6 microg/kg/day s.c., GM-CSF 250 microg/m(2)/day s.c., or GM-CSF for 6 days followed by G-CSF until completion of the stem cell harvest. Compared with patients who received GM-CSF, patients who received G-CSF had faster recovery of absolute neutrophil count to 0.5 x 10(9) per liter (median of 11 vs14 days, P = 0.0001) with fewer patients requiring red blood cell transfusions (P= 0.008); fewer patients with fever (18% vs 52%, P = 0.001); fewer hospital admissions (20% vs 42%, P = 0.13); and less intravenous antibiotic therapy (24% vs 59%, P = 0.001). Patients who received G-CSF also yielded more CD34 cells (median 7.1 vs 2.0 x 10(6) kg per apheresis, P = 0.0001) and a higher percentage achieved 2.5 x 10(6) CD34 cells per kilogram (94% vs 78%, P = 0.21) and 5 x 10(6) CD34 cells per kilogram (88% vs 53%, P = 0.01) or more CD34 cells per kilogram with fewer aphereses (median 2 vs 3, P = 0.002) and fewer days of growth factor treatment (median 12 vs 14, P = 0.0001). There were no significant differences in outcomes between groups receiving G-CSF alone and the sequential regimen. After high-dose chemotherapy, patients who had peripheral blood stem cells mobilized with G-CSF or the sequential regimen received higher numbers of CD34 cells and had faster platelet recovery with fewer patients requiring platelet transfusions than patients receiving peripheral blood stem cells mobilized by GM-CSF. In summary, G-CSF alone is superior to GM-CSF alone for the mobilization of CD34(+) cells and reduction of toxicities following myelosuppressive chemotherapy. An economic analysis evaluating the cost-effectiveness of these three effective schedules is ongoing at the time of this writing.
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Affiliation(s)
- C H Weaver
- CancerConsultants.com Inc., Ketchum, ID, USA
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Perillo A, Pierelli L, Scambia G, Serafini R, Paladini U, Salerno MG, Bonanno G, Fattorossi A, Leone G, Mancuso S, Menichella G. Peripheral blood progenitor cell collection after epirubicin, paclitaxel, and cisplatin combination chemotherapy using EPO-based cytokine regimens: a randomized comparison of G-CSF and sequential GM-/G-CSF. Transfusion 2001; 41:674-80. [PMID: 11346705 DOI: 10.1046/j.1537-2995.2001.41050674.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND The peripheral blood progenitor cell (PBPC) mobilization capacity of EPO in association with either G-CSF or sequential GM-CSF/G-CSF was compared in a randomized fashion after epirubicin, paclitaxel, and cisplatin (ETP) chemotherapy. STUDY DESIGN AND METHODS Forty patients with stage IIIB, IIIC, or IV ovarian carcinoma were enrolled in this randomized comparison of mobilizing capacity and myelopoietic effects of G-CSF + EPO and GM-/G-CSF + EPO following the first ETP chemotherapy treatment. After ETP chemotherapy (Day 1), 20 patients received G-CSF 5 microg per kg per day from Day 2 to Day 13 and 20 patients received GM-CSF 5 microg per kg per day from Day 2 to Day 6 followed by G-CSF 5 microg per kg per day from Day 7 to Day 13. EPO (150 IU per kg) was given every other day from Day 2 to Day 13 to all patients in both arms of the study. Apheresis (two blood volumes) was performed during hematologic recovery. RESULTS The magnitude of CD34+ cell mobilization and the abrogation of patients' myelosuppression were comparable in both study arms; however, GM-/G-CSF + EPO patients had significantly higher CD34+ yields because of a higher CD34+ cell collection efficiency (57.5% for GM-/G-CSF + EPO and 46.3% for G-CSF + EPO patients; p = 0.0009). Identical doses of PBPCs mobilized by GM-/G-CSF + EPO and G-CSF + EPO drove comparable hematopoietic recovery after reinfusion in patients treated with identical high-dose chemotherapy. CONCLUSION The sequential administration of GM-CSF and G-CSF in combination with EPO is feasible and improves the PBPC collection efficiency after platinum-based intensive polychemotherapy, associating high PBPC mobilization to high collection efficiency during apheresis.
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Affiliation(s)
- A Perillo
- Istituto di Ginecologia e Ostetricia, Cattedra di Ematologia, Servizio Trasfusionale, Università Cattolica del Sacro Cuore, Rome, Italy.
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Gazitt Y. Recent Developments in the Regulation of Peripheral Blood Stem Cell Mobilization and Engraftment by Cytokines, Chemokines, and Adhesion Molecules. ACTA ACUST UNITED AC 2001; 10:229-36. [PMID: 11359670 DOI: 10.1089/15258160151134908] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Peripheral blood stem cells (PBSC) have become the preferred source of stem cells for autologous transplantation because of the technical advantage and the shorter time to engraftment. Administration of hematopoietic growth factors such as granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) results in mobilization of PBSCs into the peripheral blood. G-CSF and GM-CSF differ somewhat in the number and composition of CD34(+) cells and effector cells mobilized to the peripheral blood; however, the molecular mechanism underlying the release and engraftment of CD34(+) cells by these growth factors is poorly understood. This review provides a recent update on the involvement of hematopoietic growth factors, chemokines, adhesion molecules, and chemokine receptors in the regulation of stem cell release and engraftment. The involvement of very late antigen-4 (VLA-4), VLA-5, leukocyte function associated-1 molecule (LFA-1), and L-selectin and their receptors CXCR4 and its ligand SDF-1 will be discussed, and cross talk between these factors will also be reviewed in the context of stem cell release and engraftment. Finally, PBSC mobilization by chemokines will be reviewed in relation to hematopoietic growth factors.
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Affiliation(s)
- Y Gazitt
- Department of Medicine/Hematology, University of Texas, Health Science Center, San Antonio, TX 78284, USA.
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Gazitt Y. Immunologic profiles of effector cells and peripheral blood stem cells mobilized with different hematopoietic growth factors. Stem Cells 2001; 18:390-8. [PMID: 11072026 DOI: 10.1634/stemcells.18-6-390] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
BACKGROUND Peripheral blood stem cells (PBSC) have become the preferred source of stem cells for autologous transplantation because of the technical advantage and the shorter time to engraftment. Mobilization of CD34(+) cells into the peripheral blood can be achieved by the administration of G-CSF or GM-CSF, or both, alone or in combination with chemotherapy. G-CSF and GM-CSF differ somewhat in the number and composition of CD34(+) cells and effector cells mobilized to the peripheral blood. However, the molecular mechanism underlying the release and engraftment of CD34(+) cells is poorly understood. PURPOSE The purpose of this review is to give a recent update on the type and immunological properties of effector cells and CD34(+) cells mobilized by the different growth factors with emphasis on A) mobilization of T cells, natural killer cells, and dendritic cells; B) coexpression of adhesion molecules such as VLA-4 and L-selectin in mobilized PBSC collection, and C) coexpression of CXCR4-the receptor for the stromal-derived differentiation factor 1-with latest information shedding light on the molecular mechanism underlying the release and subsequent engraftment of CD34(+) cells. CONCLUSIONS A) The reported suppression of T cell and NK cell functions in PBSC apheresis collections in patients primed with G-CSF or GM-CSF is controversial and may merely reflect low effector cell activity before mobilization. B) A decrease in the expression of adhesion molecules such as VLA-4 and L-selectin is a necessary requirement for the release of CD34(+) cells to the peripheral blood. C) A decrease in the expression of CXCR4 is a necessary requirement for the release of CD34(+) cells to the peripheral blood and correlates with mobilization success.
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Affiliation(s)
- Y Gazitt
- Department of Medicine/Hematology, University of Texas, Health Science Center, San Antonio, Texas 78284, USA
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Gazitt Y, Shaughnessy P, Devore P. Mobilization of dendritic cells and NK cells in non-Hodgkin's lymphoma patients mobilized with different growth factors. JOURNAL OF HEMATOTHERAPY & STEM CELL RESEARCH 2001; 10:177-86. [PMID: 11276371 DOI: 10.1089/152581601750098471] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Conflicting results have been reported regarding the effect of various growth factors on the mobilization of natural killer (NK) cells and dendritic cells in patients undergoing stem cell mobilization for autotransplantation. We compared the extent of mobilization of NK cells and dendritic cells in non-Hodgkin's (NHL) patients undergoing mobilization with granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage (GM)-CSF, or GM-CSF followed by G-CSF. Overall, 35 patients were studied. NK cells and dendritic were quantitated by flow cytometry. NK cells were defined as the sum of CD56(+) cells and CD56/CD16(+) cells. Dendritic cells were defined as the sum of CD80(+) and CD80(+)/CD14(+) cells. NK activity was determined by by microcytotoxicity assay. NK activity correlated well with the total amount of CD56(+) cells mobilized to the peripheral blood. Patients in the three arms of the study mobilized similar amounts of NK cells and NK activity, and patients who lacked NK activity in the peripheral blood, before mobilization, lacked NK activity in their apheresis collections. In contrast to NK cell mobilization, mobilization of dendritic cells/kg was three- to five-fold higher in patients mobilized with GM-CSF-containing regimens compared to patients mobilized with G-CSF alone. We conclude that GM-CSF-containing mobilization regimens are superior for dendritic cell mobilization but similar in the mobilization of NK cells. Therefore, we recommend using GM-CSF-containing regimens for patients undergoing ex vivo or in vivo manipulation of dendritic cells.
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Affiliation(s)
- Y Gazitt
- University of Texas, Health Science Center, San Antonio, TX 78286, USA
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