425 results on '"Bone Marrow Purging methods"'
Search Results
2. Effects of CD3McAb and rhIL-2 activated bone marrow on the killing and purging of leukemia cells.
- Author
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Wei XC, Yang DD, Han XR, Zhao YA, Li YC, Zhang LJ, and Wang JJ
- Subjects
- Adolescent, Adult, Antibodies, Monoclonal immunology, Bone Marrow Cells metabolism, Bone Marrow Cells pathology, Bone Marrow Transplantation, CD3 Complex immunology, CD3 Complex metabolism, Cell Line, Tumor, Cell Survival drug effects, Colony-Forming Units Assay, Female, Granulocyte-Macrophage Progenitor Cells, HL-60 Cells, Humans, Immunophenotyping, K562 Cells, Leukemia metabolism, Leukemia pathology, Leukemia therapy, Male, Middle Aged, Phenotype, Young Adult, Antibodies, Monoclonal pharmacology, Bone Marrow Cells drug effects, Bone Marrow Purging methods, Interleukin-2 pharmacology
- Abstract
We investigated the roles of CD3McAb and rhIL-2 activated bone marrow in the killing and purging of leukemia cells. Cytotoxicity of activated bone marrow was detected with MTT assay. CFU-GM level in activated bone marrow and the destruction of leukemia cells were measured using the semi-solid cell culture. Immune activation markers in activated bone marrow were detected by indirect immunofluorescence assay. Bone marrow activated by CD3McAb and rhIL-2 displayed significantly upregulated the killing and purging abilities on the leukemia cell line K562 and HL-60. Such effects were superior to that of bone marrow activated by rhIL-2 or CD3McAb alone (P < 0.05, P < 0.01). Activation by rhIL-2 and (or) CD3McAb exerted no obvious influence on CFU-GM level in bone marrow. Compared with bone marrow activated by rhIL-2 or CD3McAb alone, the synergistic effect of both CD3McAb+ and hIL-2 caused significant increase of CD3(+), CD8(+), CD19(+), CD25(+), CD38(+), and CD56(+) levels. Our study indicates that CD3McAb enhanced the killing and purging effects of rhIL-2 activated bone marrow on leukemia cells.
- Published
- 2015
- Full Text
- View/download PDF
3. Influence of ex vivo purging with CliniMACS CD34(+) selection on outcome after autologous stem cell transplantation in non-Hodgkin lymphoma.
- Author
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Yahng SA, Yoon JH, Shin SH, Lee SE, Cho BS, Eom KS, Kim YJ, Lee S, Kim HJ, Min CK, Kim DW, Lee JW, Min WS, Park CW, Kim Y, and Cho SG
- Subjects
- Adolescent, Adult, Aged, Antigens, CD34 metabolism, Disease-Free Survival, Female, Humans, Male, Middle Aged, Retrospective Studies, Transplantation, Homologous, Treatment Outcome, Young Adult, Antigens, CD34 immunology, Bone Marrow Purging methods, Hematopoietic Stem Cell Transplantation methods, Lymphoma, Non-Hodgkin surgery, Transplantation Conditioning methods
- Abstract
The major limitation of autologous stem cell transplantation (auto-SCT) in non-Hodgkin lymphoma (NHL) is relapse. Although autologous graft contamination may be a potential cause, prior purging of the autograft remains controversial. Therefore, we retrospectively analysed 56 consecutive patients with NHL receiving auto-SCT at complete (n = 41) or partial remission (n = 15). Among them, 24 patients underwent autograft manipulation with positive selection of CD34(+) cells using a CliniMACS device (purged group). Twenty-five patients had received ≥2 previous chemotherapy regimens before auto-SCT. After a median follow-up of 41·4 months, transplant-related mortality was observed only in unpurged group (n = 2; 3·6%). The 3-year overall survival (91·7% vs. 56·1%, P = 0·009) and progression-free survival (78·7% vs. 53·1%, P = 0·034) favoured CD34(+) purification. While neutrophil recovery was similar, platelet recovery was delayed in the purged group. Cytomegalovirus reactivation was predominantly observed in the purged group, although no other clinically unmanageable infectious complications occurred. Although this study has the inevitable limitations of heterogeneity in previous treatment and NHL subtypes, and a small number of patients analysed, the high survival rate in the purged group may suggest the need for prospective randomized trials to determine the role of CD34(+) purification in auto-SCT for NHL., (© 2013 John Wiley & Sons Ltd.)
- Published
- 2014
- Full Text
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4. Reovirus as a successful ex vivo purging modality for multiple myeloma.
- Author
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Thirukkumaran CM, Shi ZQ, Luider J, Kopciuk K, Bahlis N, Neri P, Pho M, Stewart D, Mansoor A, and Morris DG
- Subjects
- Animals, Blood Component Removal, Cell Line, Cell Line, Tumor, Flow Cytometry, Green Fluorescent Proteins chemistry, Humans, Male, Mice, Mice, Inbred NOD, Mice, SCID, Recurrence, Reverse Transcriptase Polymerase Chain Reaction, Treatment Outcome, Bone Marrow Purging methods, Multiple Myeloma therapy, Oncolytic Virotherapy, Reoviridae
- Abstract
Autologous stem cell rescue (ASCT) following high-dose myeloablative chemotherapy is considered to be a therapeutic option for many multiple myeloma (MM) patients; however relapse post ASCT presents a major challenge. The oncolytic potential of reovirus has been previously demonstrated and is currently undergoing phase I monotherapy clinical trials for MM and phase II/III clinical trials for solid tumors. Here we tested the hypothesis that reovirus can successfully purge MM in a murine model that partially recapitulates human MM. RPMI 8226, MM1S, H929 and U266 human myeloma cell lines were exposed to reovirus and oncolysis was assessed. Apheresis product admixed with MM cells was purged with live reovirus (LV) or dead virus (DV) and purging efficacy was monitored via flow cytometry, reverse transcribed-PCR (RT-PCR) and disease relapse in non obese diabetic/severe combined immune deficient (NOD/SCID) mice. Significant LV purging was seen with MM1S, H929 and U266 and the complete ex vivo purging achieved with RPMI 8226 was confirmed by flow cytometry, RT-PCR and absence of disease relapse in vivo. Mice that received LV-purged autografts exhibited 100% survival in comparison to mice that received DV-purged controls. Reovirus's unique ability to kill MM while sparing hematopoietic stem cells places it as an attractive purging agent for MM during ASCT.
- Published
- 2014
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5. Rituximab maintenance or retreatment after autologous transplantation for relapsed follicular lymphoma?
- Author
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Fozza C
- Subjects
- Female, Humans, Male, Antibodies, Monoclonal, Murine-Derived therapeutic use, Antineoplastic Agents therapeutic use, Bone Marrow Purging methods, Lymphoma, Follicular therapy, Stem Cell Transplantation methods
- Published
- 2013
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6. Reply to C. Fozza.
- Author
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Pettengell R, Schmitz N, Dreger P, and Goldstone A
- Subjects
- Female, Humans, Male, Antibodies, Monoclonal, Murine-Derived therapeutic use, Antineoplastic Agents therapeutic use, Bone Marrow Purging methods, Lymphoma, Follicular therapy, Stem Cell Transplantation methods
- Published
- 2013
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7. Rituximab purging and/or maintenance in patients undergoing autologous transplantation for relapsed follicular lymphoma: a prospective randomized trial from the lymphoma working party of the European group for blood and marrow transplantation.
- Author
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Pettengell R, Schmitz N, Gisselbrecht C, Smith G, Patton WN, Metzner B, Caballero D, Tilly H, Walewski JA, Bence-Bruckler I, To B, Geisler CH, Schots R, Kimby E, Taverna CJ, Kozák T, Dreger P, Uddin R, Ruiz de Elvira C, and Goldstone AH
- Subjects
- Adult, Aged, Combined Modality Therapy, Female, Humans, Lymphoma, Follicular drug therapy, Lymphoma, Follicular pathology, Lymphoma, Follicular surgery, Male, Middle Aged, Prospective Studies, Recurrence, Rituximab, Salvage Therapy, Transplantation, Autologous, Antibodies, Monoclonal, Murine-Derived therapeutic use, Antineoplastic Agents therapeutic use, Bone Marrow Purging methods, Lymphoma, Follicular therapy, Stem Cell Transplantation methods
- Abstract
Purpose: The objective of this randomized trial was to assess the efficacy and safety of rituximab as in vivo purging before transplantation and as maintenance treatment immediately after high-dose chemotherapy and autologous stem-cell transplantation (HDC-ASCT) in patients with relapsed follicular lymphoma (FL)., Patients and Methods: Patients with relapsed FL who achieved either complete or very good partial remission with salvage chemotherapy were randomly assigned using a factorial design to rituximab purging (P+; 375 mg/m(2) once per week for 4 weeks) or observation (NP) before HDC-ASCT and to maintenance rituximab (M+; 375 mg/m(2) once every 2 months for four infusions) or observation (NM)., Results: From October 1999 to April 2006, 280 patients were enrolled. The median age was 51 years (range, 26 to 70 years), and baseline characteristics were well balanced between groups. On average, patients were 44 months (range, 3 to 464 months) from diagnosis, with 79% having received two lines and 15% three lines of prior therapy. Median follow-up was 8.3 years. In contrast to purging, 10-year progression-free survival (PFS) was 48% for P+ and 42% for NP groups (hazard ratio [HR], 0.80; 95% CI, 0.58 to 1.11; P = .18); maintenance had a significant effect on PFS (10-year PFS, 54% for M+ and 37% for NM; HR, 0.66; 95% CI, 0.47 to 0.91; P = .012). Overall survival (OS) was not improved by either rituximab purging or maintenance., Conclusion: Rituximab maintenance after HDC-ASCT is safe and significantly prolongs PFS but not OS in patients undergoing transplantation for relapsed FL. Pretransplantation rituximab in vivo purging, even in rituximab-naive patients, failed to improve PFS or OS.
- Published
- 2013
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8. What is the role of stem-cell transplantation for follicular non-hodgkin lymphoma in the rituximab era?
- Author
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Schouten HC
- Subjects
- Female, Humans, Male, Rituximab, Antibodies, Monoclonal, Murine-Derived therapeutic use, Antineoplastic Agents therapeutic use, Bone Marrow Purging methods, Lymphoma, Follicular therapy, Stem Cell Transplantation methods
- Published
- 2013
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9. [Leukemia SH-1 cells purged by ZnPcH(1)-based photodynamic therapy].
- Author
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Lin XL, Huang HF, and Chen WZ
- Subjects
- Apoptosis drug effects, Bone Marrow Purging methods, Cell Death drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Humans, Indoles therapeutic use, Isoindoles, Leukemia, Monocytic, Acute drug therapy, Organometallic Compounds therapeutic use, Photosensitizing Agents therapeutic use, Zinc Compounds, Indoles pharmacology, Leukemia, Monocytic, Acute pathology, Organometallic Compounds pharmacology, Photochemotherapy, Photosensitizing Agents pharmacology
- Abstract
The objective of this study was to investigate the effect of a novel Zinc phthalocyanine (ZnPcH(1)) based photodynamic therapy (PDT) on acute monocytic leukemia cell lines SHI-1 and its mechanism, so as to provide theory basis for bone marrow purging in vitro for patients with leukemia. The killing effect of ZnPcH(1)-PDT on SHI-1 cells were assessed by MTT method; the SHI-1 cell death patterns were analyzed by AO/EB fluorescence staining, TdT-mediated dUTP nick end labeling (TUNEL), DNA ploidy analysis, and Annexin V-FITC/PI double staining.Cell mixture was established by integrating SHI-1 cells with normal bone marrow MNC (by 1:100-1:10 000). Purging effect of ZnPcH(1)-PDT against SHI-1 mixed into normal MNC was assessed by analyzing the expression of fusion gene MLL/AF6 mRNA using nested RT-PCR. The results showed that ZnPcH(1)-PDT could effectively inhibit SHI-1 cell proliferation in dose-dependent manner, and ZnPcH(1)-PDT could induce cell apoptosis in time-dependent manner. 0.5 µmol/L ZnPcH(1)-PDT could completely photoinactivated kill SHI-1 cells in the simulated remission bone marrow. It concluded that ZnPcH(1)-PDT may be a effective and convenient promising purging technique for leukemia.
- Published
- 2012
10. Hexaminolevulinate-mediated photodynamic purging of marrow grafts with murine breast carcinoma.
- Author
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Čunderlíková B, Vasovič V, Sieber F, Furre T, Borgen E, Nesland JM, and Peng Q
- Subjects
- Aminolevulinic Acid pharmacokinetics, Aminolevulinic Acid pharmacology, Animals, Bone Marrow drug effects, Bone Marrow pathology, Cell Line, Tumor, Female, Hematopoietic Stem Cell Transplantation methods, Lung Neoplasms prevention & control, Lung Neoplasms secondary, Mice, Mice, Inbred BALB C, Photosensitizing Agents pharmacokinetics, Protoporphyrins pharmacokinetics, Protoporphyrins pharmacology, Tumor Cells, Cultured, Aminolevulinic Acid analogs & derivatives, Bone Marrow Purging methods, Mammary Neoplasms, Experimental drug therapy, Mammary Neoplasms, Experimental pathology, Photochemotherapy methods, Photosensitizing Agents pharmacology
- Abstract
Photodynamic therapy (PDT) with porphyrin precursors is an established therapy for certain tumors. This study aimed to explore the use of hexaminolevulinate (HAL), a porphyrin precursor, for photodynamic purging of BM grafts contaminated with cells of the 4T1 breast carcinoma cell line. The optimal PDT dose was not effective in eradicating 4T1 cells when the tumor cells were mixed with murine marrow cells in vitro. However, the number of pulmonary metastases was reduced, and the survival of experimental animals was prolonged substantially when they were subjected to TBI followed by transplantation of syngeneic BM containing metastasized 4T1 cells that had been treated ex vivo by HAL-PDT. Despite the failure of in vitro experiments, HAL-based photodynamic purging could be a useful modality for treating animals bearing an experimental breast carcinoma.
- Published
- 2011
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11. In-vivo purging of the circulating clonal T-cells with Alemtuzumab prior to autologous peripheral blood hematopoietic cell mobilization and transplantation.
- Author
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Shustov A, Cherian S, Shaw A, Lupinacci TA, Maloney D, Holmberg L, and Gopal AK
- Subjects
- Aged, Alemtuzumab, Antibodies, Monoclonal, Humanized, Drug Evaluation methods, Feasibility Studies, Female, Hematopoietic Stem Cell Mobilization methods, Humans, Antibodies, Monoclonal therapeutic use, Antibodies, Neoplasm therapeutic use, Antineoplastic Agents therapeutic use, Bone Marrow Purging methods, Lymphoma, T-Cell, Peripheral therapy, Peripheral Blood Stem Cell Transplantation methods
- Published
- 2011
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- View/download PDF
12. Ex vivo graft purging and expansion of autologous blood progenitor cell products from patients with multiple myeloma.
- Author
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Yang H, Robinson SN, Nieto Y, Jones RJ, Gocke CD, Lu J, Giralt SA, Jones RB, Decker WK, Xing D, Steiner D, Champlin RE, McMannis JD, Ng J, Thomas MW, Shah N, Andersson BS, Parmar S, and Shpall EJ
- Subjects
- Antibodies, Monoclonal, Murine-Derived administration & dosage, Antigens, CD34 biosynthesis, Antineoplastic Combined Chemotherapy Protocols pharmacology, Boronic Acids administration & dosage, Bortezomib, Cell Line, Tumor, Cell Separation methods, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells immunology, Humans, Magnetics, Multiple Myeloma drug therapy, Multiple Myeloma pathology, Pyrazines administration & dosage, Rituximab, Transplantation, Autologous, Antibodies, Monoclonal, Murine-Derived pharmacology, Bone Marrow Purging methods, Boronic Acids pharmacology, Hematopoietic Stem Cells drug effects, Multiple Myeloma surgery, Peripheral Blood Stem Cell Transplantation methods, Pyrazines pharmacology
- Abstract
Autologous peripheral blood progenitor cell (PBPC) transplantation is the treatment of choice for selected myeloma patients. However, tumor cells contaminating the apheresis product are a potential source of relapse. Here we report a sequential purging strategy targeting mature and immature clonogenic myeloma cell populations in the autograft. Thawed PBPC products of myeloma patients were treated with rituximab to kill CD138(-)20(+) B cells (highly clonogenic immature cells), and bortezomib to target CD138(+) cells (normal and differentiated myeloma plasma cells), followed by coculture with allogeneic mesenchymal stem cells (MSC) from normal donors. After 7 days of coculture, nonadherent cells were removed and cultured in the absence of MSC for an additional 7 days. Then, efficacy of purging (removal of CD138(-)20(+) and CD138(+) cells) was assessed by flow cytometry and PCR. We used our ex vivo purging strategy to treat frozen aphereses from 16 patients. CD138(+) and CD138(-)20(+)(19(+)) cells present in the initial products were depleted more than 3 and 4 logs, respectively based on 10(6) flow-acquisition events, and to levels below the limit of detection by PCR. In contrast, total nucleated cell (TNC), CD34(+) cell, and colony-forming cell numbers were increased by approximately 12 to 20, 8-, and 23-fold, respectively. Overall, ex vivo treatment of apheresis products with rituximab, bortezomib, and coculture with normal donor MSC depleted mature and immature myeloma cells from clinical aphereses while expanding the normal hematopoietic progenitor cell compartment., (©2011 AACR.)
- Published
- 2011
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13. High dose chemotherapy with autologous stem cell support for patients with histologically transformed B-cell non-Hodgkin lymphomas. A Norwegian multi centre phase II study.
- Author
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Eide MB, Lauritzsen GF, Kvalheim G, Kolstad A, Fagerli UM, Maisenhölder M, Østenstad B, Fluge Ø, Delabie J, Aarset H, Liestøl K, and Holte H
- Subjects
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Bone Marrow Purging methods, Disease Progression, Drug Administration Schedule, Epidemiologic Methods, Female, Humans, Lymphoma, Follicular pathology, Lymphoma, Large B-Cell, Diffuse pathology, Male, Middle Aged, Recurrence, Salvage Therapy methods, Tissue and Organ Harvesting methods, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Hematopoietic Stem Cell Transplantation methods, Lymphoma, Large B-Cell, Diffuse drug therapy
- Abstract
We present a prospective phase II study of patients with relapse after chemotherapy showing transformation of follicular lymphoma to diffuse large B-cell lymphoma, performed before rituximab was included in standard treatment. Patients in complete (CR) or partial remission (PR) after salvage chemotherapy were eligible for high-dose chemotherapy with autologous stem cell support (HDT). Forty-seven patients from five Norwegian centres were included, of whom 30 (63%) received HDT. Eighteen (60%) achieved CR, seven (23%) PR and five (10%) had progressive disease following HDT. Median follow-up for the surviving patients was 75 months; median progression-free (PFS) and overall survival (OS) were 26 and 47 months, respectively. Median OS for all patients was 43 months, compared to only 10 months for patients not eligible for HDT. Patients receiving CD34(+) enriched/B-cell depleted grafts had inferior PFS and a trend for inferior OS compared to patients receiving non-purged grafts (Log Rank 0·025 and 0·151, respectively). In conclusion, two thirds of patients with transformation of follicular lymphoma were eligible for HDT. The majority of patients achieved CR and a considerable number had prolonged OS. The use of in vitro purged grafts did not result in a survival benefit compared to that of non-purged grafts., (© 2011 Blackwell Publishing Ltd.)
- Published
- 2011
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14. Cardiovascular changes after PMMA vertebroplasty in sheep: the effect of bone marrow removal using pulsed jet-lavage.
- Author
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Benneker LM, Krebs J, Boner V, Boger A, Hoerstrup S, Heini PF, and Gisep A
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- Animals, Embolism, Fat prevention & control, Female, Injections, Models, Animal, Pulmonary Embolism prevention & control, Sheep, Therapeutic Irrigation, Blood Pressure physiology, Bone Cements, Bone Marrow Purging methods, Cardiac Output physiology, Polymethyl Methacrylate administration & dosage, Vertebroplasty methods
- Abstract
Clinically, the displacement of intravertebral fat into the circulation during vertebroplasty is reported to lead to problems in elderly patients and can represent a serious complication, especially when multiple levels have to be treated. An in vitro study has shown the feasibility of removing intravertebral fat by pulsed jet-lavage prior to vertebroplasty, potentially reducing the embolization of bone marrow fat from the vertebral bodies and alleviating the cardiovascular changes elicited by pulmonary fat embolism. In this in vivo study, percutaneous vertebroplasty using polymethylmethacrylate (PMMA) was performed in three lumbar vertebrae of 11 sheep. In six sheep (lavage group), pulsed jet-lavage was performed prior to injection of PMMA compared to the control group of five sheep receiving only PMMA vertebroplasty. Invasive recording of blood pressures was performed continuously until 60 min after the last injection. Cardiac output and arterial blood gas parameters were measured at selected time points. Post mortem, the injected cement volume was measured using CT and lung biopsies were processed for assessment of intravascular fat. Pulsed jet-lavage was feasible in the in vivo setting. In the control group, the injection of PMMA resulted in pulmonary fat embolism and a sudden and significant increase in mean pulmonary arterial pressure. Pulsed jet-lavage prevented any cardiovascular changes and significantly reduced the severity of bone marrow fat embolization. Even though significantly more cement had been injected into the lavaged vertebral bodies, significantly fewer intravascular fat emboli were identified in the lung tissue. Pulsed jet-lavage prevented the cardiovascular complications after PMMA vertebroplasty in sheep and alleviated the severity of pulmonary fat embolism.
- Published
- 2010
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15. Hexaminolevulinate-mediated photodynamic purging of leukemia cells from BM.
- Author
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Čunderlíková B, Vasovič V, Sieber F, Furre T, Nesland JM, and Peng Q
- Subjects
- Aminolevulinic Acid pharmacology, Animals, Bone Marrow Cells chemistry, Cell Line, Tumor, Cell Survival drug effects, Female, Gamma Rays, Granulocytes chemistry, Granulocytes drug effects, Leukemia L1210 mortality, Mice, Mice, Inbred DBA, Osmolar Concentration, Photochemotherapy, Protoporphyrins analysis, Survival Analysis, Tumor Stem Cell Assay, Whole-Body Irradiation mortality, Aminolevulinic Acid analogs & derivatives, Bone Marrow Cells drug effects, Bone Marrow Purging methods, Bone Marrow Transplantation, Leukemia L1210 therapy, Photosensitizing Agents pharmacology
- Abstract
Photodynamic therapy (PDT) with porphyrin precursors has been established for tumor treatment. This study aimed at examining applicability of hexaminolevulinate (HAL) for photodynamic purging of leukemic cells from BM grafts and evaluating the clinical relevance of in vitro models. The PDT dose resulting in no colony formation by leukemic cells in vitro, in pure form or in a mixture with BM cells, was insufficient for complete killing of the leukemic cells ex vivo and for the treatment of the leukemia-bearing animals in vivo. The efficacy of HAL-PDT in cell lines in vitro should be verified in clinically relevant in vivo models.
- Published
- 2010
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16. Incidence and reasons for late failure after allogeneic haematopoietic cell transplantation following BuCy2 in acute myeloid leukaemia.
- Author
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Pant S, Hamadani M, Dodds AJ, Szer J, Crilley PA, Stevenson D, Phillips G, Elder P, Nivison-Smith I, Avalos BR, Penza S, Topolsky D, Sobecks R, Kalaycio M, Bolwell BJ, and Copelan EA
- Subjects
- Adolescent, Adult, Bone Marrow Purging methods, Busulfan therapeutic use, Cyclophosphamide therapeutic use, Epidemiologic Methods, Female, Humans, Leukemia, Myeloid, Acute drug therapy, Male, Middle Aged, Prognosis, Treatment Failure, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute therapy
- Abstract
The long-term follow-up is presented for 317 patients with acute myeloid leukaemia who underwent human leucocyte antigen-identical sibling marrow transplants between 1984 and 1995 following preparation with busulfan 16 mg/kg and cyclophosphamide 120 mg/kg. Among the 142 (45%) who were alive and leukaemia-free 3 years following transplantation, the leukaemia-free survival at 15 years was 72.8%. The cumulative incidence of late (>3 years beyond transplant) non-relapse mortality at 15 years was 12.9% and of late relapse was 16.5%. None of the variables considered (including age, disease stage, and graft-versus-host disease) were predictive of late failure.
- Published
- 2010
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17. Fibrinolysis-independent role of plasmin and its activators in the haematopoietic recovery after myeloablation.
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Tjwa M, Moura R, Moons L, Plaisance S, De Mol M, Jansen S, Dewerchin M, Verfaillie C, and Carmeliet P
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- Animals, Extracellular Matrix drug effects, Extracellular Matrix metabolism, Fibrinogen metabolism, Fluorouracil pharmacology, Mice, Mice, Inbred C57BL, Plasminogen deficiency, Plasminogen metabolism, Bone Marrow Purging methods, Fibrinolysin metabolism, Fibrinolysis drug effects, Hematopoiesis drug effects, Tissue Plasminogen Activator metabolism, Urokinase-Type Plasminogen Activator metabolism
- Abstract
Proteinases have been implicated in the mobilization of haematopoietic progenitor cells (HPCs) from the bone marrow (BM). Here, we report the involvement of the plasminogen (Plg) system in the haematopoietic recovery following chemotherapy. By using gene-deficient mice, we found that plasmin and its activators tPA and uPA play a role in the haematopoietic recovery upon delivery of the cytotoxic agent 5-fluoro-uracil (5-FU). The impaired haematopoietic recovery of Plg-deficient (Plg(-/-)) mice after 5-FU was not rescued by depletion of fibrinogen, indicating that it was not due to defective fibrinolysis. Instead, loss of Plg impaired breakdown of fibronectin, VCAM-1 and laminin-BM matrix proteins involved in adhesion of HPCs to their BM microenvironment and in transendothelial migration of HPCs. These findings provide novel insights in how plasmin regulates haematopoietic recovery upon cytotoxic myeloablation.
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- 2009
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18. [Stem cell therapy in multiple sclerosis: a clinical update].
- Author
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Schippling S and Martin R
- Subjects
- Animals, Antilymphocyte Serum adverse effects, Antilymphocyte Serum therapeutic use, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bone Marrow Purging methods, Bone Marrow Transplantation methods, Carmustine administration & dosage, Carmustine adverse effects, Central Nervous System immunology, Central Nervous System pathology, Clinical Trials, Phase II as Topic, Controlled Clinical Trials as Topic, Cytarabine administration & dosage, Cytarabine adverse effects, Humans, Immunosuppressive Agents adverse effects, Immunosuppressive Agents therapeutic use, Magnetic Resonance Imaging, Melphalan administration & dosage, Melphalan adverse effects, Mitoxantrone adverse effects, Mitoxantrone therapeutic use, Multicenter Studies as Topic, Multiple Sclerosis immunology, Multiple Sclerosis mortality, Podophyllotoxin administration & dosage, Podophyllotoxin adverse effects, Risk Assessment, Survival Rate, Treatment Outcome, Hematopoietic Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation mortality, Multiple Sclerosis therapy
- Abstract
Promising results in an animal model of multiple sclerosis (MS; experimental autoimmune encephalomyelitis, EAE) have shown that immunosuppression followed by allogeneic bone marrow transplantation has the potential to significantly ameliorate the spontaneous course of the disease. Since 1995, emerging data on autologous hematopoietic stem cell transplantation (AHSCT) has supported a benefit also in patients with multiple sclerosis. To date, results on approximately 500 cases have been consecutively reported by the European Group for Blood and Marrow Transplantation (EBMT). These reports have not only proved a favourable outcome for many patients but also provided the rationale for the currently ongoing controlled trials on AHSCT in MS. At present, results from the ASTIMS study in particular, a multicenter active-controlled phase II study, are awaited. However, a number of critical issues remain unresolved. Furthermore, with upcoming new treatment compounds that to some extent act via lymphoablative properties, it remains essential to better select those patients who might profit most from stem cell therapy based on a justifiable benefit-to-risk ratio. Although transplant related mortality has dropped to 1%, mortality combined with concerns about long-term safety remain critical issues in a primarily non-life-threatening disease like MS.
- Published
- 2009
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19. Immunochemotherapy with in vivo purging and autotransplant induces long clinical and molecular remission in advanced relapsed and refractory follicular lymphoma.
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Arcaini L, Montanari F, Alessandrino EP, Tucci A, Brusamolino E, Gargantini L, Cairoli R, Bernasconi P, Passamonti F, Bonfichi M, Zoli V, Bottelli C, Calatroni S, Troletti D, Merli M, Pascutto C, Majolino I, Rossi G, Morra E, and Lazzarino M
- Subjects
- Adult, Anthracyclines administration & dosage, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal, Murine-Derived, Antigens, CD20 metabolism, Antigens, CD34 analysis, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Bleomycin administration & dosage, Combined Modality Therapy, Cyclophosphamide administration & dosage, Cytarabine administration & dosage, Disease Progression, Disease-Free Survival, Doxorubicin administration & dosage, Drug Administration Schedule, Etoposide administration & dosage, Female, Follow-Up Studies, Genes, bcl-2, Granulocyte Colony-Stimulating Factor administration & dosage, Hematopoietic Stem Cell Mobilization, Humans, Immunologic Factors administration & dosage, Immunosuppressive Agents administration & dosage, Kaplan-Meier Estimate, Lymphoma, Follicular drug therapy, Lymphoma, Follicular pathology, Male, Middle Aged, Multivariate Analysis, Recurrence, Remission Induction, Rituximab, Time Factors, Transplantation, Autologous, Treatment Outcome, Vincristine administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bone Marrow Purging methods, Lymphoma, Follicular therapy, Peripheral Blood Stem Cell Transplantation
- Abstract
Background: To evaluate the clinical outcome of patients with relapsed or refractory follicular lymphoma treated with immunochemotherapy, in vivo purging and high-dose therapy with autotransplant., Patients and Methods: Sixty-four patients were enrolled in the trial. Primary end point was progression-free survival (PFS). Secondary end points were the in vivo purging effect on stem-cell harvest and the impact of molecular response on the outcome., Results: At enrollment, 59% of patients were PCR+ for bcl-2 rearrangement in bone marrow (PCR-informative). After the immunochemotherapy, before mobilization, 97% obtained complete response or partial response and 87% of patients informative for bcl-2 were molecularly negative. Sixty-one patients proceeded to in vivo purging and peripheral blood stem cell (PBSC) mobilization with rituximab and high-dose AraC. The median number of CD34+ cells collected was 16.6 x 10(6)/kg. Of 33 PCR-informative patients, the harvests resulted in PCR- in all. Fifty-eight patients received high-dose therapy and autotransplant of in vivo purged PBSC. After a median follow-up of 3.5 years, 41 patients are in complete remission. Five-year PFS is 59%., Conclusion: This study demonstrates that patients with advanced relapsed or refractory follicular lymphoma treated with immunochemotherapy, in vivo purging and autotransplant may obtain long-lasting PFS. In bcl-2-positive patients, in vivo purging allows the harvest of lymphoma-free PBSC. Absence of the bcl-2 rearrangement after autotransplant is associated with persistent clinical remission.
- Published
- 2008
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20. Favourable long-term outcome after matched sibling transplantation for Fanconi-anemia (FA) and in vivo T-cell depletion.
- Author
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Huck K, Hanenberg H, Nürnberger W, Dilloo D, Burdach S, Göbel U, and Laws HJ
- Subjects
- Child, Child, Preschool, Combined Modality Therapy, Cyclophosphamide therapeutic use, Disease-Free Survival, Fanconi Anemia immunology, Fanconi Anemia mortality, Female, Follow-Up Studies, Graft vs Host Disease immunology, Humans, Immunosuppressive Agents therapeutic use, Lymphatic Irradiation methods, Male, Transplantation, Isogeneic, Bone Marrow Purging methods, Fanconi Anemia therapy, Graft vs Host Disease prevention & control, Hematopoietic Stem Cell Transplantation methods, Lymphocyte Depletion methods, T-Lymphocytes immunology
- Abstract
Hematopoietic stem cell transplantation is the only permanent treatment for the hematological manifestations in Fanconi anemia (FA). As FA patients have a dramatically increased intrinsic propensity to develop malignancies later in life and the genotoxic stress afflicted during conditioning advances the manifestation age especially of squamous cell carcinomas, choosing an optimally suited treatment regimen appears critical for long-term, tumor-free survival after stem cell transplantation. Here, we report our experiences in 6 consecutive FA patients transplanted with HLA-matched sibling donors where we combined an established pre-transplantation treatment consisting of thoraco-abdominal irradiation (TAI), cyclophosphamide (CYC) and cyclosporine A graft-versus-host prophylaxis with antibody-mediated IN VIVO T-cell depletion strategies after infusion of the graft. This approach has ensured sustained engraftment with long-term survival and an excellent post transplant performance status without any evidence of secondary malignancies in all six patients after a median follow-up of more than 10 years.
- Published
- 2008
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- View/download PDF
21. Mobilization of Ph chromosome-negative peripheral blood stem cells in a child with chronic myeloid leukemia after imatinib-induced complete molecular remission.
- Author
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Woods-Swafford W, Vnencak-Jones CL, Loken MR, Manes B, and Frangoul H
- Subjects
- Benzamides, Biomarkers, Tumor blood, Child, Filgrastim, Forecasting, Fusion Proteins, bcr-abl blood, Granulocyte Colony-Stimulating Factor pharmacology, Hematopoietic Stem Cells enzymology, Humans, Imatinib Mesylate, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myeloid, Chronic-Phase drug therapy, Male, Peripheral Blood Stem Cell Transplantation, Recombinant Proteins, Remission Induction, Antineoplastic Agents therapeutic use, Bone Marrow Purging methods, Hematopoietic Stem Cell Mobilization, Leukemia, Myelogenous, Chronic, BCR-ABL Positive blood, Leukemia, Myeloid, Chronic-Phase blood, Piperazines therapeutic use, Protein Kinase Inhibitors therapeutic use, Pyrimidines therapeutic use
- Abstract
Chronic myelogenous leukemia (CML) is rare in the pediatric population. Allogeneic stem cell transplant remains the only curative therapy; however, identifying a fully matched donor is not always possible. Imatinib mesylate has been shown to induce hematologic and cytogenetic response in adults and children with CML. We describe a child who achieved molecular remission with imatinib mesylate. BCR-ABL negative peripheral blood stem cells (PBSC) were successfully collected after mobilization with filgrastim., ((c) 2007 Wiley-Liss, Inc.)
- Published
- 2008
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- View/download PDF
22. Positive selection for CD90 as a purging option in acute myeloid leukemia stem cell transplants.
- Author
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Feller N, Kelder A, Westra G, Ossenkoppele GJ, and Schuurhuis GJ
- Subjects
- Antigens, CD34 immunology, Antigens, CD34 metabolism, Biomarkers, Tumor immunology, Female, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells immunology, Hematopoietic Stem Cells metabolism, Humans, Immunophenotyping, Leukemia, Myeloid, Acute immunology, Male, Middle Aged, Bone Marrow Purging methods, Flow Cytometry, Leukemia, Myeloid, Acute therapy, Peripheral Blood Stem Cell Transplantation methods, Thy-1 Antigens immunology
- Abstract
Background: Several studies showed the benefit of purging of acute myeloid leukemia (AML) stem cell transplants. We reported previously that purging by positive selection of CD34+ and CD133+ cells resulted in a 3-4 log tumor cell reduction (TCR) in CD34- and/or CD133- AML, but has been shown to be potentially applicable in only about 50% of cases. Similar to CD34 and CD133, CD90 marks the hematopoietic CD34 positive stem cells capable of full hematopoietic recovery after myeloablative chemotherapy, and therefore, in the present study, we explored whether a similar purging approach is possible using CD90., Methods: CD90 expression was established by flowcytometry in diagnosis AML on the clonogenic AML CD34+ blast population by flow cytometry. Positivity was defined as >3% CD90 (CD34+) expression on blasts. For the calculation of the efficacy of TCR by positive selection, AML blasts were recognized by either prelabeling diagnosis blasts with CD45-FITC in spiking model experiments or using expression of leukemia associated marker combinations both in spiking experiments and in real transplants., Results: In 119 patients with AML and myelodysplastic syndrome, we found coexpression of CD34 and CD90 (>3%) in 42 cases (35%). In AML patients 60 years or younger, representing the patients who are eligible for transplantation, only 23% (16/69) of the patients showed CD90 expression. Positive selection for CD90 in transplants containing CD90 negative AML resulted in a 2.8-4 log TCR in the models used., Conclusions: Purging by positive selection using CD90 can potentially be applied effectively in the majority of AML patients 60 years or younger., ((c) 2007 Clinical Cytometry Society)
- Published
- 2008
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23. Flow electroporation with pulsed electric fields for purging tumor cells.
- Author
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Craiu A and Scadden D
- Subjects
- Bone Marrow Purging instrumentation, Bone Marrow Purging methods, Cell Separation instrumentation, Electrochemotherapy instrumentation, Hematopoietic Stem Cell Transplantation, Humans, Lymphoma pathology, Lymphoma therapy, Multiple Myeloma pathology, Multiple Myeloma therapy, Neoplasms pathology, Cell Separation methods, Electrochemotherapy methods, Neoplasms therapy
- Abstract
Electroporation has been used in biological laboratories for many years to transiently porate cell membranes and permit plasmid or protein transfection. It has been shown that the application of pulsed electric fields (PEFs) of defined strength will kill off larger cells and select for viable small cells, in samples containing heterogeneous cells. This permits the selective killing of several blood and bone marrow-resident tumor cells. PEF technology is being applied to tumor purging of progenitor-cell transfusions, in support of high-dose chemotherapy, for the treatment of cancers such as lymphoma and multiple myeloma. Autologous stem-cell transplantation, in the setting of hematologic malignancies such as lymphoma, improves disease-free survival if the graft has undergone tumor purging. Progenitor cells are preserved or enriched. To overcome issues of electrical resistance, purging fidelity, and large sample volume, a flowing chamber PEF apparatus was designed and constructed for large-scale purging of clinical quantities of progenitor-cell transfusions. The specifics of this technique are described here. Treatment of greater than 10(9) cells is achieved in 30 min, under optimized flow conditions designed to overcome surface area or resistance issues and to optimize exposure of cells to electric fields. Efficient, large volume tumor purging of greater than 3 logs, for mixtures of tumor cells and mononuclear cells, is routinely achieved under defined conditions.
- Published
- 2008
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24. Long-term survival after autologous bone marrow transplantation for follicular lymphoma in first remission.
- Author
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Brown JR, Feng Y, Gribben JG, Neuberg D, Fisher DC, Mauch P, Nadler LM, and Freedman AS
- Subjects
- Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bone Marrow Purging methods, Bone Marrow Transplantation mortality, Cyclophosphamide therapeutic use, Doxorubicin therapeutic use, Female, Follow-Up Studies, Humans, Lymphoma, Follicular mortality, Male, Middle Aged, Prednisone therapeutic use, Prognosis, Remission Induction methods, Survival Rate, Transplantation Conditioning methods, Transplantation, Autologous, Vincristine therapeutic use, Bone Marrow Transplantation methods, Lymphoma, Follicular therapy
- Abstract
The role of autologous stem cell transplantation (ASCT) in the treatment of follicular lymphoma is still being defined in the era of antibody therapy. Here we report the long-term 12-year clinical outcomes of patients treated with autologous bone marrow transplantation (ABMT) for follicular non-Hodgkin's lymphoma (NHL) in first remission. Between 1988 and 1993, advanced-stage follicular NHL patients in need of initial therapy were enrolled in 2 consecutive prospective treatment trials of either standard-dose CHOP induction (83 patients) or high-dose CHOP plus granulocyte-colony stimulating factor (G-CSF) (20 patients). Patients who achieved an adequate remission with induction therapy underwent conditioning with cyclophosphamide and total body irradiation (TBI) followed by ABMT in first remission using bone marrow (BM) purged in vitro with anti-B cell monoclonal antibodies and rabbit complement (96 patients). At 12-year follow-up, 61% of the patients are alive and 43% remain in continuing complete remission. The only predictors of decreased progression-free survival proved to be histologic BM involvement at time of harvest (hazard ratio [HR] 2.27, 95% confidence interval [CI] 1.3-3.9, P<.004) and PCR detectable disease in the BM product after purging (HR 4.18, 95% CI 1.99-8.8, P=.0002). No significant predictors of overall survival were identified. These results at 12-year follow-up suggest that a subset of follicular lymphoma patients can experience prolonged survival with ABMT in first remission.
- Published
- 2007
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25. Relapse risk after autologous transplantation in patients with newly diagnosed myeloma is not related with infused tumor cell load and the outcome is not improved by CD34+ cell selection: long term follow-up of an EBMT phase III randomized study.
- Author
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Bourhis JH, Bouko Y, Koscielny S, Bakkus M, Greinix H, Derigs G, Salles G, Feremans W, Apperley J, Samson D, Björkstrand B, Niederwieser D, Gahrton G, Pico JL, and Goldschmidt H
- Subjects
- Adolescent, Adult, Aged, Antigens, CD34 analysis, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Dexamethasone administration & dosage, Disease-Free Survival, Doxorubicin administration & dosage, Female, Follow-Up Studies, Humans, Male, Middle Aged, Multiple Myeloma drug therapy, Multiple Myeloma mortality, Postoperative Complications epidemiology, Prognosis, Recurrence, Risk, Survival Analysis, Survival Rate, Transplantation Conditioning methods, Transplantation, Autologous statistics & numerical data, Treatment Outcome, Vincristine administration & dosage, Bone Marrow Purging methods, Multiple Myeloma surgery, Peripheral Blood Stem Cell Transplantation mortality, Peripheral Blood Stem Cell Transplantation statistics & numerical data
- Abstract
Background and Objectives: This European Group for Blood and Marrow Transplantation (EBMT) multicentre randomized phase III study was designed to assess the safety and efficacy of CD34+ selection in newly diagnosed myeloma patients undergoing autologous transplantation., Design and Methods: One hundred and eleven patients responsive to initial chemotherapy were randomized to receive CD34+ selected (arm A) or unselected PBPC (arm B) after conditioning with high-dose melphalan and TBI. ASO-PCR was used to assess purging efficacy and reinfused tumor load. Tumor load could be assessed in 59 patients., Results: CD34+ selection gave a median tumor cell depletion of 2.2 logs (0.77-5.96). No tumor cells were detected in products infused in 17/26 (A) and 5/33 (B) patients. The five year overall survival (OS), event free survival (EFS) and relapse rate (RR) were 51%, 20% and 80% in arm A and 45%, 18% and 80% in arm B respectively with no significant difference between the two groups. Thirteen patients in arm A and 2 in arm B experienced episodes of serious early infection (p=0.02). There were 3 early transplant related deaths in A but none in B., Interpretation and Conclusions: Despite significant tumor cell reduction, CD34+ selection does not reduce RR and increases the risk of severe post-transplant infections. There was also no difference in RR between patients in either arm who received grafts with detectable tumor cells and those receiving grafts with no detectable tumor cells, suggesting that reinfused tumor cells may not be the main cause of relapse after autologous transplant in myeloma.
- Published
- 2007
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26. Oncolytic Coxsackievirus A21 as a novel therapy for multiple myeloma.
- Author
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Au GG, Lincz LF, Enno A, and Shafren DR
- Subjects
- Bone Marrow Cells pathology, Bone Marrow Purging methods, CD55 Antigens metabolism, Cell Death, Coculture Techniques, Colony-Forming Units Assay, Humans, Intercellular Adhesion Molecule-1 metabolism, Leukocytes, Mononuclear pathology, Leukocytes, Mononuclear virology, Multiple Myeloma metabolism, Neoplasm Proteins metabolism, Tumor Cells, Cultured, Virus Replication, Enterovirus physiology, Multiple Myeloma pathology, Oncolytic Virotherapy methods
- Abstract
Oncolytic viruses are attractive biological agents for the control of human malignancy. This study assessed the capacity of Coxsackievirus A21 (CVA21) to target and destroy multiple myeloma (MM) and precursor aberrant plasma cells in vitro using established MM cell lines and 15 patient bone marrow (BM) biopsies [n = 10 MM and five monoclonal gammopathy of undetermined significance (MGUS)]. Cell surface analysis revealed that all tumour cells lines expressed high levels of intercellular adhesion molecule-1 (ICAM-1) and decay-accelerating factor (DAF), the receptor molecules to which CVA21 can bind, leading to subsequent cell-entry and infection. MM cell lines were remarkably susceptible to CVA21 lytic infection, producing 100-1000-fold increases in viral progeny within 24 h. In contrast, normal peripheral blood cells were refractile to CVA21 infection. Furthermore, challenge of patient BM biopsies with CVA21 for 48 h resulted in specific purging of up to 98.7% of CD138+ plasma cells, with no significant decrease in progenitor cell function. Data generated in this study suggests that CVA21 virotherapy may have potential applications as a systemic anti-tumour agent for MM, or in the ex vivo purging of malignant plasma cells prior to autologous stem cell transplantation.
- Published
- 2007
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27. The role of rituximab in autologous and allogeneic hematopoietic stem cell transplantation for non-Hodgkin's lymphoma.
- Author
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Naparstek E
- Subjects
- Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal, Murine-Derived, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Clinical Trials as Topic, Combined Modality Therapy, Epstein-Barr Virus Infections drug therapy, Epstein-Barr Virus Infections prevention & control, Graft vs Host Disease drug therapy, Humans, Immunologic Factors administration & dosage, Lymphoma, Non-Hodgkin drug therapy, Lymphoma, Non-Hodgkin immunology, Lymphoproliferative Disorders drug therapy, Lymphoproliferative Disorders prevention & control, Lymphoproliferative Disorders virology, Multicenter Studies as Topic, Rituximab, Salvage Therapy, Transplantation, Autologous, Transplantation, Homologous, Antibodies, Monoclonal therapeutic use, Bone Marrow Purging methods, Hematopoietic Stem Cell Transplantation, Immunologic Factors therapeutic use, Lymphoma, Non-Hodgkin surgery, Transplantation Conditioning methods
- Abstract
The addition of rituximab to chemotherapy has substantially changed the treatment strategies for patients with B-cell lymphomas. Rituximab, combined with standard chemotherapy regimens, shows consistently improved results compared with chemotherapy alone and has been extensively employed in both newly diagnosed and relapsed patients with B-cell lymphoma. Because of its low toxicity profile and its potent antilymphoma activity mediated through direct apoptotic and indirect effector mechanisms, rituximab also has been actively incorporated into stem cell transplantation (SCT) protocols to attain a state of minimal disease, provide a safe and effective method for in vivo purging prior to autologous SCT, and promote graft-versus-lymphoma effects in allogeneic SCT. This review compiles the still immature but rapidly growing data on this combined modality.
- Published
- 2006
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28. Peripheral blood stem cell tumor cell contamination and survival of neuroblastoma patients.
- Author
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Corrias MV, Haupt R, Carlini B, Parodi S, Rivabella L, Garaventa A, Pistoia V, and Dallorso S
- Subjects
- Bone Marrow Purging methods, Cell Separation methods, Child, Preschool, Disease-Free Survival, Female, Humans, Male, N-Acetylgalactosaminyltransferases metabolism, Neuroblastoma enzymology, Neuroblastoma therapy, Polymerase Chain Reaction methods, RNA, Neoplasm genetics, RNA, Neoplasm metabolism, Survival Rate, Transplantation, Autologous, Tyrosine 3-Monooxygenase metabolism, Hematopoietic Stem Cells pathology, N-Acetylgalactosaminyltransferases genetics, Neoplastic Cells, Circulating pathology, Neuroblastoma mortality, Tyrosine 3-Monooxygenase genetics
- Abstract
Purpose: Contribution of peripheral blood stem cell (PBSC) contaminating tumor cells to subsequent relapse and overall survival of neuroblastoma patients remains controversial., Experimental Design: Neuroblastoma cell contamination of 27 PBSC harvests from stage IV neuroblastoma patients was assessed by quantitative RT-PCR for both tyrosine hydroxylase (TH) and GD2 synthase (GD2-s). The effect of PBSC contamination on survival was then analyzed., Results: Seven PBSC tested negative for both markers; 19 were positive for GD2-s, 6 for TH, with 5 positive for both. Survival of the 20 patients with positive PBSC did not differ from that of the patients with negative PBSC (log-rank test, P = 0.134 and 0.218 for event-free survival and overall survival, respectively). By considering the TH and GD2-s results independently, a borderline (P = 0.053) negative effect on event-free survival was observed in patients reinfused with GD2-s-positive PBSC. When the status at transplant was taken into account, only the event-free survival of the patients rescued when in complete remission with GD2-s-negative PBSC was better, although not significantly, than that of patients infused with GD2-s-positive PBSC., Conclusions: Our results obtained in a small cohort of homogeneously treated stage IV patients suggest that patient survival is not affected by PBSC contamination with the exception of a borderline negative effect on event-free survival in patients rescued when in complete remission.
- Published
- 2006
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29. The evolving role of autologous and allogeneic stem cell transplantation in follicular lymphoma.
- Author
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Van Besien K
- Subjects
- Bone Marrow Purging methods, Humans, Randomized Controlled Trials as Topic, Transplantation Conditioning, Transplantation, Autologous, Transplantation, Homologous, Hematopoietic Stem Cell Transplantation methods, Lymphoma, Follicular therapy
- Abstract
Treatment options for follicular lymphoma have expanded dramatically. The most important relate to the introduction of monoclonal antibodies and the completion of important studies regarding autologous and allogeneic transplantation. The EBMTR-sponsored "CUP Trial" (conventional Chemotherapy, Unpurged autograft, Purged autograft), demonstrated that for patients under age 60 years with recurrent chemotherapy-sensitive disease, autologous stem cell transplantation (ASCT) provides a survival benefit over conventional therapy. Three randomized studies demonstrated that consolidation with autologous transplantation in first remission leads to improvement in progression free survival and perhaps in overall survival, but possibly with an increased risk for secondary MDS. Novel approaches involve the incorporation of rituximab as an in-vivo purging agent or as post-transplant therapy, and the use of radiolabelled monoclonals in the conditioning regimens. Allogeneic stem cell transplantation (alloSCT) has become a more effective option but continues to have a high TRM. Reduced-intensity alloSCT procedures now are being performed at an increasing rate and may have advantages in particular situations. A CIBMTR analysis unfortunately did not show a major advantage in terms of TRM or EFS to non-myeloablative transplantation. Performance status and disease sensitivity remain the major predictors of outcome for allogeneic transplantation.
- Published
- 2006
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30. Successful treatment of a patient with POEMS syndrome by tandem high-dose chemotherapy with autologous CD34+ purged stem cell rescue.
- Author
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Kojima H, Katsuoka Y, Katsura Y, Suzuki S, Suzukawa K, Hasegawa Y, and Nagasawa T
- Subjects
- Adult, Bone Marrow Purging methods, Dexamethasone administration & dosage, Doxorubicin administration & dosage, Etoposide administration & dosage, Granulocyte Colony-Stimulating Factor administration & dosage, Humans, Male, Melphalan administration & dosage, POEMS Syndrome blood, POEMS Syndrome pathology, Remission Induction, Transplantation, Autologous, Antigens, CD34, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Hematopoietic Stem Cell Mobilization, POEMS Syndrome therapy, Stem Cell Transplantation
- Abstract
A 36-year-old man was admitted because of numbness and muscle weakness in the lower extremities. He had gait disturbance, malaise, and body weight loss. Based on the existence of monoclonal gammopathy, the proliferation of abnormal plasma cells in the bone marrow, the presence of sclerotic bone lesion, polycythemia, mild splenomegaly, and an elevated level of serum vascular endothelial growth factor (VEGF) (14,900 pg/mL; normal, 62-707), he was diagnosed as having peripheral neuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome. Following 2 courses of conventional chemotherapy with doxorubicin and dexamethasone, peripheral blood stem cells were mobilized by high-dose etoposide (500 mg/m(2) x 3 days) and granulocyte colony-stimulating factor. After purging by CD34+ selection using the CliniMACS device, the selected cells (12.4 x 10(6)/kg) were cryopreserved. He was then treated with tandem high-dose chemotherapy (HDC) (melphalan 100 mg/m(2) x 2 days) with autologous stem cell rescue. After the first course of HDC, the serum level of VEGF normalized and the minimal residual disease in the bone marrow was reduced below the detection limit of CDR3 analysis by polymerase chain reaction. The patient has been in remission for more than 20 months. He has gradually recovered from the neurological symptoms and now has no impairments of daily living. Our experience suggests that autologous purged stem cell transplantation should be considered as the treatment of choice for POEMS syndrome.
- Published
- 2006
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- View/download PDF
31. A novel triple purge strategy for eliminating chronic myelogenous leukemia (CML) cells from autografts.
- Author
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Yang H, Eaves C, de Lima M, Lee MS, Champlin RE, McMannis JD, Robinson SN, Niu T, Decker WK, Xing D, Ng J, Li S, Yao X, Eaves AC, Jones R, Andersson BS, and Shpall EJ
- Subjects
- Antigens, CD blood, Antigens, CD34 blood, Antineoplastic Agents therapeutic use, Benzamides, Cell Survival, Cyclophosphamide analogs & derivatives, Cyclophosphamide therapeutic use, Flow Cytometry, Humans, Imatinib Mesylate, K562 Cells, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Neoplastic Cells, Circulating pathology, Piperazines therapeutic use, Pyrimidines therapeutic use, Bone Marrow Purging methods, Cell Separation methods, Leukemia, Myelogenous, Chronic, BCR-ABL Positive therapy, Stem Cell Transplantation methods, Transplantation, Autologous methods
- Abstract
Imatinib-refractory chronic myelogenous leukemia (CML) patients can experience long-term disease-free survival with myeloablative therapy and allogeneic hematopoietic cell transplantation; however, associated complications carry a significant risk of mortality. Transplantation of autologous hematopoietic cells has a reduced risk of complications, but residual tumor cells in the autograft may contribute to relapse. Development of methods for purging tumor cells that do not compromise the engraftment potential of the normal hematopoietic cells in the autograft has been a long-standing goal. Since primitive CML cells differentiate more rapidly in vitro than their normal counterparts and are also preferentially killed by mafosfamide and imatinib, we examined the purging effectiveness on CD34(+) CML cells using a strategy that combines a brief exposure to imatinib (0.5-1.0 microM for 72 h) and then mafosfamide (30-90 microg/ml for 30 min) followed by 2 weeks in culture with cytokines (100 ng/ml each of stem cell factor, granulocyte colony-stimulating factor and thrombopoietin). Treatment with 1.0 microM imatinib, 60 microg/ml mafosfamide and 14 days of culture with cytokines eliminated BCR-ABL(+) cells from chronic phase CML patient aphereses, while preserving normal progenitors. This novel purging strategy may offer a new approach to improving the effectiveness of autologous transplantation in imatinib-refractory CML patients.
- Published
- 2006
- Full Text
- View/download PDF
32. Purging of murine erythroblastic leukemia by ZnPcS2P2-based-photodynamic therapy.
- Author
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Huang HF, Chen YZ, Wu Y, and Chen P
- Subjects
- Animals, Bone Marrow Purging methods, Cell Line, Tumor, Female, Mice, Mice, Inbred BALB C, Neoplasms, Experimental therapy, Transplantation, Autologous, Hematopoietic Stem Cell Transplantation, Indoles pharmacology, Leukemia, Myeloid therapy, Organometallic Compounds pharmacology, Photochemotherapy methods, Photosensitizing Agents pharmacology
- Abstract
A key point for successful transplantation of autologous hematopoietic stem cells in the treatment of leukemia is the purging technique, of which photodynamic therapy (PDT) proved effective and promising. The aim of this study was to evaluate the purging effect of a novel amphipathic photosensitizer, di-sulfo-di-phthalimidomethyl phthalolcyanine zinc (ZnPcS2P2)-based PDT (ZnPcS2P2-PDT) on murine erythroblastic leukemic EL9611 cells. Bone marrow cells (BMC), harvested from normal BALB/c mice, were contaminated with variable EL9611 cells. Cell suspensions were incubated with 4 microg/ml ZnPcS2P2 for 5 h and then exposed to 2.1 J/cm2 irradiation by a semiconductor laser 670 nm. Lethally irradiated recipient BALB/c mice (7 Gy) received syngeneic bone marrow transplantation with purged or nonpurged cell mixtures of 10(7) BMC contaminated with variable numbers (10(2)-10(5)) of EL9611 cells. All of the irradiated controls died due to sepsis. All of the mice injected with nonpurged cell mixtures developed leukemia and died, whereas the mice transplanted with ZnPcS2P2-PDT-treated mixtures had a longer survival time, and the fewer leukemic cells there were in the cell mixtures, the higher the leukemia-free survival rate. We conclude that ZnPcS2P2-PDT could purge leukemic cells from bone marrow autografts but could retain sufficient progenitor cells for the hematopoietic activity.
- Published
- 2006
- Full Text
- View/download PDF
33. Randomised comparison of two B-cell purging protocols for patients with B-cell non-Hodgkin lymphoma: in vivo purging with rituximab versus ex vivo purging with CliniMACS CD34 cell enrichment device.
- Author
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van Heeckeren WJ, Vollweiler J, Fu P, Cooper BW, Meyerson H, Lazarus HM, Simic A, Laughlin MJ, Gerson SL, and Koç ON
- Subjects
- Adult, Aged, Antibodies, Monoclonal, Murine-Derived, Antigens, CD34 analysis, Feasibility Studies, Female, Hematopoietic Stem Cell Mobilization methods, Humans, Immunomagnetic Separation methods, Leukapheresis methods, Lymphoma, B-Cell drug therapy, Male, Middle Aged, Rituximab, Antibodies, Monoclonal therapeutic use, Antineoplastic Agents therapeutic use, Bone Marrow Purging methods, Lymphoma, B-Cell therapy, Peripheral Blood Stem Cell Transplantation methods
- Abstract
We investigated the feasibility, safety and efficacy of two B-cell purging methods in patients with CD20+ non-Hodgkin lymphoma (NHL) receiving autologous stsem cell transplantation. Myeloid and immune recoveries between the methods were compared. Twenty-seven patients were randomised to either in vivo purging with rituximab or ex vivo purging by CD34+ cell selection. Both purging methods were efficient at eliminating B-cells in infusates. When compared with in vivo purging, ex vivo purging was associated with CD34+ cell loss and delayed median neutrophil (10 d vs. 11 d) and platelet (12.5 d vs. 17 d) count recoveries. Lymphocyte recovery was similar in both groups, but immunoglobulin recovery was delayed after in vivo purging. Late-infectious complications were few in both arms. At a median follow-up of 27 months, 2-year probabilities of event-free survival (EFS) rates were 81% for in vivo purging and 76% for ex vivo purging (P = 0.66). When compared with 53 unpurged patients, all 27 purged patients had improved 3-year probabilities of overall survival (89% vs. 70%, P = 0.014) and a trend for improved EFS (78% vs. 57%, P = 0.075). In conclusion, although both purging methods were feasible and safe, rituximab purging was superior as it did not impair CD34+ cell mobilisation and was associated with faster myeloid recovery. Further studies are needed to determine whether rituximab purging is more effective than the use of unpurged autografts.
- Published
- 2006
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- View/download PDF
34. In-vivo purging with the anti-CD20 antibody rituximab along with standard allogeneic peripheral blood stem cell transplantation (PBSCT) for relapsed childhood pre-B acute lymphoblastic leukaemia (ALL).
- Author
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Ansari SH, Irfan M, Farzana, Panjwani VK, and Shamsi TS
- Subjects
- Antibodies, Monoclonal, Murine-Derived, Child, Humans, Male, Recurrence, Rituximab, Antibodies, Monoclonal therapeutic use, Bone Marrow Purging methods, Burkitt Lymphoma therapy, Immunologic Factors therapeutic use, Peripheral Blood Stem Cell Transplantation
- Abstract
This case report describes the use of Rituximab for in vivo purging (by intravenous infusion) in a 12 years old boy with second remission of pre-B ALL. It was followed by conditioning therapy consisted of Busulphan and Cyclophosphamide. rh-G-CSF primed stem cells from an HLA identical sibling donor were infused. Standard graft versus host disease prophylaxis was given. He engrafted within two weeks. He did not develop acute graft versus host disease (aGvHD) but localized chronic GvHD developed. He had been on regular follow-up at CMH, Rawalpindi and is in complete remission 13 months post-PBSCT with no evidence of chronic GvHD at present.
- Published
- 2006
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- View/download PDF
35. Imatinib interim therapy between chemotherapeutic cycles and in vivo purging prior to autologous stem cell transplantation, followed by maintenance therapy is a feasible treatment strategy in Philadelphia chromosome-positive acute lymphoblastic leukemia.
- Author
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Shin HJ, Chung JS, and Cho GJ
- Subjects
- Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Benzamides, Female, Humans, Imatinib Mesylate, Neoplasm, Residual diagnosis, Neoplasm, Residual drug therapy, Transplantation, Autologous, Bone Marrow Purging methods, Hematopoietic Stem Cell Transplantation methods, Piperazines therapeutic use, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Pyrimidines therapeutic use
- Published
- 2005
- Full Text
- View/download PDF
36. Development of a gene therapy based bone marrow purging system for leukemias.
- Author
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Huang W, Tan W, Zhong Q, and Schwarzenberger P
- Subjects
- Antigens, CD34, Cell Survival, Gene Expression Profiling, Genes, Reporter, Genes, Transgenic, Suicide, Genetic Vectors, Humans, Neoplastic Cells, Circulating, Polylysine, Transfection, Tumor Cells, Cultured, Bone Marrow Purging methods, Genetic Therapy methods, Hematopoietic Stem Cells, Leukemia genetics, Leukemia therapy
- Abstract
Although viable gene therapy based methods have been reported for the selective removal or purging of contaminating epithelial derived cancer cells from stem cell grafts, similar strategies for the purging of leukemia cells have been significantly less efficient. Hematopoietic cells are difficult targets for transduction with currently available vectors. Polylysine based molecular conjugate vectors (MCV) were previously found to effectively transduce both normal and malignant hematopoietic cells. A panel of human leukemia cell lines as well as CD34+ selected primary human hematopoietic progenitor cells (HPC) were tested for differential gene expression utilizing different promoters. Reporter gene expression under the control of RSV and SV40 promoters showed a 6-log fold increase in leukemia cells when compared to primary HPC. Using a polylysine based recombinant molecular conglomerate vector (recMCV) encoding the HSV-tk suicide gene under control of RSV, we demonstrated effective and specific cell killing in all leukemia cell lines as well as in primary human leukemia cells derived from chemotherapy refractory patients, while HPC survived under the same conditions at approximately 20% viability. These proof of principle experiments demonstrate that gene therapy technology could be utilized to successfully purge leukemia cells from HPC.
- Published
- 2005
- Full Text
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37. Stem cell transplantation as consolidation therapy for children in first-remission AML: a single-center report.
- Author
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Berger M, Ferrero I, Vassallo E, Gastaldo L, Carraro F, Biasin E, Madon E, and Fagioli F
- Subjects
- Adolescent, Antineoplastic Agents administration & dosage, Bone Marrow Purging methods, Child, Child, Preschool, Cytarabine administration & dosage, Disease-Free Survival, Etoposide administration & dosage, Female, Humans, Idarubicin administration & dosage, Infant, Leukemia, Myeloid, Acute mortality, Male, Recurrence, Remission Induction, Retrospective Studies, Transplantation, Autologous, Transplantation, Homologous, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Leukemia, Myeloid, Acute therapy, Stem Cell Transplantation methods
- Abstract
A large number of patients affected by acute myeloid leukemia (AML) achieve complete remission following induction chemotherapy based on high-dose aracytin and anthracyclines. However, a postremission consolidation treatment appears to be essential to maintain the remission status. Sixteen patients with newly diagnosed AML received induction chemotherapy according to the AIEOP LAM 92P/Mod protocol. All patients were HLA-typed, and if no donor was identified within the family, patients underwent autologous stem cell transplantation (autoSCT) with mafosfamide-purged bone marrow. Patients with very high-risk AML (cytogenetics with t(9;22), hyperleukocytosis (540x10(9)/L), and AML-M7 with trilineage myelodysplasia) underwent unrelated donor transplantation. One patient relapsed before autoSCT. Eleven patients underwent autoSCT with purged bone marrow, 3 patients underwent unrelated donor transplantation (UD), and 1 patient underwent HLA-identical, matched familiar donor transplantation (MFD). All patients achieved complete remission following one course. No treatment-related deaths occurred during first-line treatment. The median interval between diagnosis and transplant was 175 days (129-277). Three patients relapsed following autoSCT; none relapsed after alloSCT. Taking stem cell transplantation as the starting point, overall survival was 93%, disease-free survival (according to the chosen treatment) was 80%, the relapse rate was 20%, and transplant-related mortality was 0%.
- Published
- 2005
- Full Text
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38. New definition proposed for stem cell transplants.
- Subjects
- Bone Marrow Purging methods, Humans, Stem Cell Transplantation methods, Transplantation Conditioning methods, Transplantation, Autologous, Transplantation, Homologous, Bone Marrow Purging classification, Stem Cell Transplantation classification, Terminology as Topic, Tissue Donors, Transplantation Conditioning classification
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- 2005
- Full Text
- View/download PDF
39. Immunologic purging of autologous peripheral blood stem cell products based on CD34 and CD133 expression can be effectively and safely applied in half of the acute myeloid leukemia patients.
- Author
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Feller N, van der Pol MA, Waaijman T, Weijers GW, Westra G, Ossenkoppele GJ, and Schuurhuis GJ
- Subjects
- AC133 Antigen, Acute Disease, Female, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells immunology, Humans, Leukemia, Myeloid immunology, Leukocyte Common Antigens immunology, Lewis X Antigen immunology, Male, Treatment Outcome, Antigens, CD immunology, Antigens, CD34 immunology, Bone Marrow Purging methods, Glycoproteins immunology, Leukemia, Myeloid therapy, Peptides immunology, Peripheral Blood Stem Cell Transplantation methods
- Abstract
Purpose: Several studies have shown survival benefit by autologous stem cell transplantation in acute myeloid leukemia (AML) after purging of grafts. This has, however, not been confirmed in randomized studies due to high toxicity of purging modalities for normal progenitor/stem cells. In this study, we investigated whether positive selection for CD34+ and/or CD133+ cells, which results in high recovery of normal progenitor/stem cells, is applicable for purging AML grafts., Experimental Design: Positive selections of normal stem cells using CD34 and/or CD133 can be done if one or both markers are absent or have dim expression and remain so during the course of the disease. Marker expressions in newly diagnosed AML were measured with flow cytometry using a cutoff value for positivity of 1%. Stability of marker expression was studied by pairwise comparison of material at diagnosis and relapse. Leukemia associated phenotype expression was used to measure the efficacy of tumor cell reduction., Results: In newly diagnosed AML (n = 165), we found no CD34 and/or CD133 expression in 32% of the cases and dim expression in 20% of the cases. No increase in the percentage of CD34+ cells (n = 44) and CD133+ cells (n = 29) was found in corresponding relapses. Positive selection using grafts contaminated with AML blasts, showing either no or dim expression of CD34 or CD133, resulted in a 3 to 4 log tumor cell reduction (n = 11) with median 50% recovery of normal stem cells., Conclusions: Purging by positive selection of CD34+ and/or CD133+ cells can safely, effectively, and reproducibly be applied in about 50% of AML cases.
- Published
- 2005
- Full Text
- View/download PDF
40. Biological purging of breast cancer cell lines using a replication-competent oncolytic virus in human stem cell autografts.
- Author
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Thirukkumaran CM, Luider JM, Stewart DA, Alain T, Russell JA, Auer IA, Forsyth P, and Morris DG
- Subjects
- Antigens, CD34 biosynthesis, Blood Component Removal, Cell Line, Tumor, DNA Fragmentation, Disease Progression, Disease-Free Survival, Flow Cytometry, Hematopoietic Stem Cells cytology, Humans, Immunohistochemistry, Immunoprecipitation, Leukocyte Common Antigens biosynthesis, Methionine chemistry, Time Factors, Transplantation, Autologous, Treatment Outcome, Bone Marrow Purging methods, Breast Neoplasms therapy, Stem Cell Transplantation methods, Viruses genetics
- Abstract
Autologous hematological stem cell transplantation (ASCT) is used for the treatment of many hematological and several solid cancers. ASCT, however, has proven disappointing as a therapeutic strategy for breast cancer. Our group and others have previously shown that breast cancer micrometastases found in patients' apheresis products (APs) predict shorter progression-free and overall survival. The implications of this finding are twofold: (i) contaminating tumor cells (CTCs) in AP reflect a higher systemic disease burden and/or (ii) reinfused CTCs contribute to relapse/progressive disease. To date, purging strategies have been disappointing. We have previously demonstrated the oncolytic properties of reovirus in in vitro, in vivo and ex vivo systems. In the present study, we tested the hypothesis that reovirus purges CTCs in a breast cancer cell line purging model. Reovirus-infected human breast cancer cell lines (HTB 133, HTB 132, SKBR3 and MCF7) exhibited cell death within days. Admixtures of AP with cells from breast tumor cell lines, which were then exposed to reovirus, showed complete purging of CTCs (assessed via flow cytometry/tumor cell outgrowth analysis) without deleterious effect on CD34+ cells. Our results provide preclinical support for the ex vivo use of reovirus as a purging modality for breast cancer during ASCT.
- Published
- 2005
- Full Text
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41. Flowing cells through pulsed electric fields efficiently purges stem cell preparations of contaminating myeloma cells while preserving stem cell function.
- Author
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Craiu A, Saito Y, Limon A, Eppich HM, Olson DP, Rodrigues N, Adams GB, Dombkowski D, Richardson P, Schlossman R, Choi PS, Grogins J, O'Connor PG, Cohen K, Attar EC, Freshman J, Rich R, Mangano JA, Gribben JG, Anderson KC, and Scadden DT
- Subjects
- Animals, Blood, Bone Marrow, Cell Size, Humans, Leukapheresis, Mice, Mice, Inbred NOD, Transplantation, Autologous methods, Bone Marrow Purging methods, Cell Separation methods, Electroporation, Hematopoietic Stem Cell Transplantation methods, Hematopoietic Stem Cells cytology, Multiple Myeloma pathology
- Abstract
Autologous stem cell transplantation, in the setting of hematologic malignancies such as lymphoma, improves disease-free survival if the graft has undergone tumor purging. Here we show that flowing hematopoietic cells through pulsed electric fields (PEFs) effectively purges myeloma cells without sacrificing functional stem cells. Electric fields can induce irreversible cell membrane pores in direct relation to cell diameter, an effect we exploit in a flowing system appropriate for clinical scale. Multiple myeloma (MM) cell lines admixed with human bone marrow (BM) or peripheral blood (PB) cells were passed through PEFs at 1.35 kV/cm to 1.4 kV/cm, resulting in 3- to 4-log tumor cell depletion by flow cytometry and 4.5- to 6-log depletion by tumor regrowth cultures. Samples from patients with MM gave similar results by cytometry. Stem cell engraftment into nonobese diabetic-severe combined immunodeficient (NOD/SCID)/beta2m-/- mice was unperturbed by PEFs. Flowing cells through PEFs is a promising technology for rapid tumor cell purging of clinical progenitor cell preparations.
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- 2005
- Full Text
- View/download PDF
42. Successful salvage with high-dose sequential chemotherapy coupled with in vivo purging and autologous stem cell transplantation in 2 patients with primary refractory mantle cell lymphoma presenting in the leukemic phase.
- Author
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Oyan B, Koc Y, and Kansu E
- Subjects
- Bone Marrow Purging methods, Hematopoietic Stem Cell Mobilization, Humans, Lymphoma, Mantle-Cell pathology, Male, Middle Aged, Neoplastic Cells, Circulating drug effects, Salvage Therapy methods, Transplantation, Autologous, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Hematopoietic Stem Cell Transplantation methods, Leukemia pathology, Lymphoma, Mantle-Cell therapy
- Abstract
We report the results of an aggressive salvage regimen in 2 patients with advanced-stage leukemic-phase mantle cell lymphoma who were refractory to previous conventional therapies. We combined multiple phases of a cytoreductive regimen including rituximab and sequential high-dose treatment with autologous stem cell transplantation (ASCT). The regimen consisted of a debulking phase with fludarabine, idarubicin, high-dose cytarabine, and high-dose methotrexate; a mobilization and in vivo purging phase with rituximab, cyclophosphamide, and granulocyte colony-stimulating factor; high-dose sequential chemotherapy with etoposide, mitoxantrone, and melphalan followed by ASCT; and, finally, posttransplantation consolidation with rituximab for treatment of minimal residual disease. With this regimen, these 2 refractory patients with multiple poor prognostic factors are in complete remission at 41 and 42 months following transplantation. Although the fact that these 2 patients are still in remission beyond 3 years after ASCT is encouraging, we need a longer follow-up to comment on their long-term survival.
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- 2005
- Full Text
- View/download PDF
43. Bone marrow-resident memory T cells survive pretransplant chemotherapy and contribute to early immune reconstitution of patients with acute myeloid leukemia given mafosfamide-purged autologous bone marrow transplantation.
- Author
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Casorati G, Locatelli F, Pagani S, Garavaglia C, Montini E, Lisini D, Turin I, Rossi F, Dellabona P, Maccario R, and Montagna D
- Subjects
- Adjuvants, Immunologic therapeutic use, Adolescent, Child, Female, Humans, Male, Transplantation, Autologous, Bone Marrow immunology, Bone Marrow Purging methods, Bone Marrow Transplantation methods, Cyclophosphamide analogs & derivatives, Cyclophosphamide therapeutic use, Immunologic Memory, T-Lymphocytes immunology
- Abstract
Objective: Studies of memory T cells transferred with the graft are relevant to better understand the early immune reconstitution of patients given autologous bone marrow transplantation (A-BMT). A critical question is whether memory T cells resident in bone marrow (BM) of patients with hematological malignancies are resistant to either pretransplant chemotherapy or ex vivo pharmacological purging., Patients and Methods: To address these issues, we evaluated the frequency of tetanus-toxoid (TT)-specific proliferating T-cell precursors (TT-PTCp) in BM and peripheral blood (PB) of eight patients with acute myeloid leukemia (AML) given A-BMT after in vitro purging of BM with mafosfamide. Patients were studied at the time of BM harvesting and five of them also after A-BMT., Results: The range of TT-PTCp frequencies found after A-BMT were comparable with those observed in PB and in BM at the time of harvesting and did not differ significantly from those of eight age-matched healthy subjects who donated BM for a human leukocyte antigen-identical sibling. TT-PTCp frequencies in BM, studied before and after ex vivo purging, appeared not to be affected by incubation with mafosfamide. We also compared the T-cell receptor (TCR)-Vbeta-repertoire usage of TT-specific T-cell lines (TT-TCL) in BM of patients at the time of harvesting and in their PB 2 months after transplantation. The same TCR-clonotypes were detected in TT-TCL at time of harvesting and after A-BMT., Conclusion: These data indicate that BM-resident memory T cells of patients with AML are resistant to both pretransplant chemotherapy and ex vivo pharmacological purging and may contribute to immune reconstitution after A-BMT.
- Published
- 2005
- Full Text
- View/download PDF
44. [Recent advances in the study of autologous hematopoietic stem cell purging].
- Author
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Wu SK, Lin C, and Song ST
- Subjects
- Adenoviridae genetics, Animals, Genes, p53, Hematopoietic Stem Cell Transplantation methods, Hematopoietic Stem Cells virology, Humans, Receptors, Virus genetics, Transplantation, Autologous methods, Bone Marrow Purging methods, Hematopoietic Stem Cells cytology
- Published
- 2005
45. Purging of peripheral blood stem cell transplants in AML: a predictive model based on minimal residual disease burden.
- Author
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Feller N, Jansen-van der Weide MC, van der Pol MA, Westra GA, Ossenkoppele GJ, and Schuurhuis GJ
- Subjects
- Acute Disease, Adolescent, Adult, Bone Marrow Purging adverse effects, Cryopreservation methods, Decision Making, Female, Fever, Humans, Male, Middle Aged, Models, Biological, Neoplasm, Residual diagnosis, Neoplasm, Residual therapy, Neoplastic Cells, Circulating drug effects, Phospholipid Ethers pharmacology, Predictive Value of Tests, Prognosis, Recurrence, Bone Marrow Purging methods, Leukemia, Myeloid pathology, Leukemia, Myeloid therapy, Neoplastic Cells, Circulating pathology, Peripheral Blood Stem Cell Transplantation methods
- Abstract
Objective: Minimal residual disease (MRD) present in peripheral blood stem cell (PBSC) products of AML patients may contribute to relapse. Our goal was to 1) predict leukemia recurrence based on the frequency of MRD present in PBSC products, 2) establish the efficacy of different purging procedures, and 3) integrate this into a model that enables to predict whether or not to purge., Methods: Minimal residual disease was measured with flow cytometry using leukemia-associated phenotypes as established at diagnosis. Toxicity of purging procedures was established using clonogenic assays. Purging procedures used were cryopreservation, hyperthermia, ether lipid ET-18-OCH3, and combinations., Results: Minimal residual disease in PBSC products correlated significantly with relapse-free survival (n=24, p=0.003). At a cut-off value of 0.05% MRD the relative risk of relapse was 4.6 times lower in the group with less than 0.05% MRD. As measured in 54 PBSC products, the MRD level was less than 0.05% in 17 of 54 cases, between 0.05% and 0.5% in 19 of 54 cases, and higher than 0.5% in 18 of 54 cases. Based on the MRD cut-off of 0.05%, the log tumor reduction needed to achieve this threshold is zero for the 17 of 54 cases in which MRD was below 0.05%, less than or equal to 1 log in 19 of 54 cases, and greater than 1-2 log in 18 of 54 cases. When applying purging with 25 mug/mL ET-18-OCH3 combined with cryopreservation at 10% DMSO and hyperthermia at 42 degrees C combined with cryopreservation at 10% or 4% DMSO, there was greater than or equal to 1 log depletion of AML blasts., Conclusion: This study establishes (1) a threshold level for MRD above which prognosis is worse, (2) that stem cell products from 69% of patients have higher than this "safe" MRD level, and (3) that ET-18-OCH3 and hyperthermia may be used to purge products in part of these patients.
- Published
- 2005
- Full Text
- View/download PDF
46. N-desmethyl clozapine as purging agent of leukemic cells in vitro.
- Author
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Ratna S and Sastry PS
- Subjects
- Humans, Tumor Cells, Cultured, Bone Marrow Purging methods, Clozapine analogs & derivatives, Clozapine metabolism, Leukemia pathology, Models, Biological
- Abstract
Attempts have been made to improve the results of autologous transplant in leukemia by purging strategies to deplete malignant cells. Clozapine is an atypical antipsychotic agent, which has been associated with hematopoietic toxicity. It has been shown that N-desmethyl clozapine a metabolite of clozapine is toxic to the hematological precursors. There is also evidence that this toxicity is confined to precursors and does not affect hematopoietic stem cells. The metabolite of clozapine (N-desmethyl clozapine) has been found to be more toxic than clozapine itself. This suggests that perhaps this metabolite can be used for purging of leukemic cells. Here it is being hypothesized that N-desmethyl clozapine could be used as an in vitro purging agent for leukemia patients. This might improve the therapeutic efficacy of autologous transplantation in leukemic patients.
- Published
- 2005
- Full Text
- View/download PDF
47. Activation of protein kinase A (PKA) by 8-Cl-cAMP as a novel approach for antileukaemic therapy.
- Author
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Weissinger EM, Oettrich K, Evans C, Genieser HG, Schwede F, Dangers M, Dammann E, Kolb HJ, Mischak H, Ganser A, and Kolch W
- Subjects
- DNA biosynthesis, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Transplantation, Autologous, Tumor Cells, Cultured, Tumor Stem Cell Assay, 8-Bromo Cyclic Adenosine Monophosphate analogs & derivatives, 8-Bromo Cyclic Adenosine Monophosphate pharmacology, Antineoplastic Agents pharmacology, Bone Marrow Cells physiology, Bone Marrow Purging methods, Bone Marrow Transplantation, Cyclic AMP-Dependent Protein Kinases pharmacology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy
- Abstract
Activation of PKA by cAMP agonists, such as 8-Cl-cAMP activation, selectively causes rapid apoptosis in v-abl transformed fibroblasts by inhibiting the Raf-1 kinase. Here we investigated whether 8-Cl-cAMP is useful for the treatment of chronic myelogenous leukaemia (CML), which is hallmarked by the expression of the p210(bcr/abl) oncogene. Autologous bone marrow transplantation is a feasible alternative for patients with no suitable donor, but hampered by the risk of relapse due to the persistence of leukaemia cells in the transplant. To study the effects of 8-Cl-cAMP on primary leukaemic cells, bone marrow cells (BMCs) from eight CML patients (one at diagnosis, three in chronic and four in accelerated phase) were treated. Ex vivo treatment of BMCs obtained in chronic phase of CML with 100 microM 8-Cl-cAMP for 24-48 h led to the selective purging of Philadelphia Chromosome (Ph1 chromosome) without toxic side effects on BMCs from healthy donors as measured by colony-forming unit (CFU) assays. BMCs from patients in accelerated phase showed selective, but incomplete elimination of Ph1 chromosome positive colony forming cells. The mechanism of 8-Cl-cAMP was investigated in FDCP-mix cells transformed by p210(bcr/abl), a cell culture model for CML. The results showed that 8-Cl-cAMP reduced DNA synthesis and viability independent of Raf inhibition as Raf inhibitors had no effect. MEK inhibitors interfered with DNA synthesis, but not with viability. In summary, our results indicate that 8-Cl-cAMP could be useful to purge malignant cells from the bone marrow of patients with CML and certain other forms of leukaemias.
- Published
- 2004
- Full Text
- View/download PDF
48. Ex-vivo purging of hematopoietic progenitor cells.
- Author
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de Lima M and Shpall EJ
- Subjects
- Antineoplastic Agents therapeutic use, Cell Separation methods, Cells, Cultured, Hematologic Neoplasms therapy, Hematopoietic Stem Cell Transplantation methods, Hematopoietic Stem Cell Transplantation standards, Humans, Immunotherapy methods, Bone Marrow Purging methods, Hematopoietic Stem Cells cytology
- Abstract
High-dose chemoradiation therapy with autologous hematopoietic progenitor cell support is effective treatment for patients with a variety of high-risk malignancies. In this setting, tumor cell contamination of the hematopoietic progenitor cell product is a frequently observed problem. The malignant cells in the autograft may be a source of relapse after transplant. Purging the hematopoietic cell grafts ex-vivo may eradicate malignant cells that may contaminate the autologous product. This chapter describes the major purging strategies that have been investigated clinically over the past decade. This investigation includes negative purging with pharmacologic agents and monoclonal antibodies, positive selection with immunoadsorption, immunomagnetic and flow cytometric sorting techniques, ex-vivo culture method, treatment with cytotoxic T cells, and virally mediated purging methods.
- Published
- 2004
49. Effect of DCEP mobilizing regimen in in vivo purging of PBSC harvests in multiple myeloma.
- Author
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Novella E, Madeo D, Albiero E, Roberti S, Castaman G, Elice F, and Rodeghiero F
- Subjects
- Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols pharmacology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cisplatin administration & dosage, Cisplatin pharmacology, Cyclophosphamide administration & dosage, Cyclophosphamide pharmacology, Cytarabine administration & dosage, Dexamethasone administration & dosage, Dexamethasone pharmacology, Doxorubicin administration & dosage, Etoposide administration & dosage, Etoposide pharmacology, Granulocyte Colony-Stimulating Factor pharmacology, Humans, Leukapheresis, Multiple Myeloma blood, Multiple Myeloma drug therapy, Transplantation, Autologous, Treatment Outcome, Vincristine administration & dosage, Bone Marrow Purging methods, Hematopoietic Stem Cell Mobilization methods, Multiple Myeloma therapy, Peripheral Blood Stem Cell Transplantation
- Published
- 2004
- Full Text
- View/download PDF
50. A model of in vivo purging with Rituximab and high-dose AraC in follicular and mantle cell lymphoma.
- Author
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Arcaini L, Orlandi E, Alessandrino EP, Iacona I, Brusamolino E, Bonfichi M, Bernasconi P, Calatroni S, Tenore A, Montanari F, Troletti D, Pascutto C, Regazzi M, and Lazzarino M
- Subjects
- Adult, Antibodies, Monoclonal pharmacokinetics, Antibodies, Monoclonal, Murine-Derived, Antigens, CD34 analysis, Antineoplastic Combined Chemotherapy Protocols therapeutic use, B-Lymphocytes drug effects, B-Lymphocytes immunology, Female, Humans, Immunophenotyping, Lymphoma, Follicular therapy, Lymphoma, Mantle-Cell therapy, Male, Middle Aged, Peripheral Blood Stem Cell Transplantation methods, Rituximab, Salvage Therapy methods, Transplantation, Autologous, Antibodies, Monoclonal therapeutic use, Bone Marrow Purging methods, Cytarabine therapeutic use, Hematopoietic Stem Cell Mobilization methods, Lymphoma, Follicular drug therapy, Lymphoma, Mantle-Cell drug therapy
- Abstract
We studied a model of in vivo purging with Rituximab and high-dose (HD) cytarabine in 14 patients with relapsed/refractory follicular lymphoma and two with refractory mantle cell lymphoma enrolled in a program of HD chemotherapy and autotransplant. After two courses of debulking immunochemotherapy with Rituximab, Vincristine and Cyclophosphamide, we used a combination of Rituximab, HD cytarabine and granulocyte colony-stimulating factor for peripheral blood stem cells (PBSC) mobilization. The median number of CD34+ cells collected was 14.69 x 10(6)/kg (range 5.74-73.2). Monitoring of peripheral CD19+ and CD20+ B cells prior to and throughout the purging period showed that a treatment with Rituximab, Vincristine and Cyclophosphamide results in a profound depletion of B cells in peripheral blood. B-cell depletion persists during mobilization with Rituximab and HD cytarabine allowing a collection of PBSC free of B cells (median CD19+ and CD20+ cells counts 0%). Of nine patients PCR positive for bcl-2 or bcl-1 in blood and marrow at the start of immunochemotherapy, all showed PCR-negative PBSC. In conclusion, in patients with indolent lymphoma, the concurrent administration of Rituximab and HD cytarabine is a safe and efficient method to obtain in vivo purged PBSC. Immunochemotherapy prior to mobilization produces B-cell depletion and seems to be a useful preparative step.
- Published
- 2004
- Full Text
- View/download PDF
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