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Roy B, Pekec T, Yuan L, Shivashankar GV. Implanting mechanically reprogrammed fibroblasts for aged tissue regeneration and wound healing. Aging Cell 2024; 23:e14032. [PMID: 38010905 PMCID: PMC10861198 DOI: 10.1111/acel.14032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Revised: 08/22/2023] [Accepted: 10/05/2023] [Indexed: 11/29/2023] Open
Abstract
Cell-based therapies are essential for tissue regeneration and wound healing during aging. Autologous transplantation of aging cells is ineffective due to their increased senescence and reduced tissue remodeling capabilities. Alternatively, implanting reprogrammed aged cells provides unique opportunities. In this paper, we demonstrate the implantation of partially reprogrammed aged human dermal fibroblasts into in vitro aged skin models for tissue regeneration and wound healing. The partially reprogrammed cells were obtained using our previously reported, highly efficient mechanical approach. Implanted cells showed enhanced expression of extracellular matrix proteins in the large area of aged tissue. In addition, the implanted cells at wound sites showed increased extracellular matrix protein synthesis and matrix alignment. Transcriptome analysis, combined with chromatin biomarkers, revealed these implanted cells upregulated tissue regeneration and wound healing pathways. Collectively our results provide a novel, nongenetic, partial reprogramming of aged cells for cell-based therapies in regenerative medicine.
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Affiliation(s)
- Bibhas Roy
- Division of Biology and ChemistryPaul Scherrer InstituteVilligenSwitzerland
| | - Tina Pekec
- Division of Biology and ChemistryPaul Scherrer InstituteVilligenSwitzerland
| | - Luezhen Yuan
- Division of Biology and ChemistryPaul Scherrer InstituteVilligenSwitzerland
- Department of Health Sciences and TechnologyETH ZurichZurichSwitzerland
| | - G. V. Shivashankar
- Division of Biology and ChemistryPaul Scherrer InstituteVilligenSwitzerland
- Department of Health Sciences and TechnologyETH ZurichZurichSwitzerland
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Abstract
Genetically engineered T cells are powerful new medicines, offering hope for curative responses in patients with cancer. Chimeric antigen receptor (CAR) T cells were recently approved by the US Food and Drug Administration and are poised to enter the practice of medicine for leukemia and lymphoma, demonstrating that engineered immune cells can serve as a powerful new class of cancer therapeutics. The emergence of synthetic biology approaches for cellular engineering provides a broadly expanded set of tools for programming immune cells for enhanced function. Advances in T cell engineering, genetic editing, the selection of optimal lymphocytes, and cell manufacturing have the potential to broaden T cell-based therapies and foster new applications beyond oncology, in infectious diseases, organ transplantation, and autoimmunity.
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Affiliation(s)
- Sonia Guedan
- Department of Hematology, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain;
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
| | - Marco Ruella
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
- Department of Medicine, Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Parker Institute for Cellular Immunotherapy at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Carl H June
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
- Department of Medicine, Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Parker Institute for Cellular Immunotherapy at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
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Epperla N, Fenske TS, Hari PN, Hamadani M. Recent advances in post autologous transplantation maintenance therapies in B-cell non-Hodgkin lymphomas. World J Transplant 2015; 5:81-88. [PMID: 26421260 PMCID: PMC4580930 DOI: 10.5500/wjt.v5.i3.81] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Revised: 05/27/2015] [Accepted: 06/19/2015] [Indexed: 02/05/2023] Open
Abstract
Lymphomas constitute the second most common indication for high dose therapy (HDT) followed by autologous hematopoietic cell transplantation (auto-HCT). The intent of administering HDT in these heterogeneous disorders varies from cure (e.g., in relapsed aggressive lymphomas) to disease control (e.g., most indolent lymphomas). Regardless of the underlying histology or remission status at transplantation, disease relapse remains the number one cause of post auto-HCT therapy failure and mortality. The last decade has seen a proliferation of clinical studies looking at prevention of post auto-HCT therapy failure with various maintenance strategies. The benefit of such therapies is in turn dependent on disease histology and timing of transplantation. In relapsed, chemosensitive diffuse large B-cell lymphoma (DLBCL), although post auto-HCT maintenance rituximab seems to be safe and feasible, it does not provide improved survival outcomes and is not recommended. The preliminary results with anti- programmed death -1 (PD-1) antibody therapy as post auto-HCT maintenance in DLBCL is promising but requires randomized validation. Similarly in follicular lymphoma, maintenance therapies including rituximab following auto-HCT should be considered investigational and offered only on a clinical trial. Rituximab maintenance results in improved progression-free survival but has not yet shown to improve overall survival in mantle cell lymphoma (MCL), but given the poor prognosis with post auto-HCT failure in MCL, maintenance rituximab can be considered on a case-by-case basis. Ongoing trials evaluating the efficacy of post auto-HCT maintenance with novel compounds (e.g., immunomodulators, PD-1 inhibitors, proteasome inhibitors and bruton’s tyrosine kinase inhibitors) will likely change the practice landscape in the near future for B cell non-Hodgkin lymphomas patients following HDT and auto-HCT.
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4
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Post-autologous transplant maintenance therapies in lymphoid malignancies: are we there yet? Bone Marrow Transplant 2015; 50:1393-404. [DOI: 10.1038/bmt.2015.184] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Revised: 06/30/2015] [Accepted: 07/06/2015] [Indexed: 12/16/2022]
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Arcaini L, Morello L, Tucci A, Rusconi C, Ladetto M, Rattotti S, Bonfichi M, Bottelli C, Gabutti C, Bernasconi P, Varettoni M, Gotti M, Troletti D, Guerrera ML, Fiaccadori V, Sciarra R, Ferretti VV, Alessandrino EP, Rossi G, Morra E. Autologous stem cell transplantation with in vivo purged progenitor cells shows long-term efficacy in relapsed/refractory follicular lymphoma. Am J Hematol 2015; 90:230-4. [PMID: 25502635 DOI: 10.1002/ajh.23919] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Revised: 11/24/2014] [Accepted: 12/08/2014] [Indexed: 11/06/2022]
Abstract
High-dose chemotherapy with autologous stem cell transplantation (ASCT) has been shown effective in the control of relapsed/refractory follicular lymphoma. We evaluate the long-term outcome of patients with relapsed or refractory follicular lymphoma treated with ASCT with in vivo purged progenitors cells. We report the long-term results of a prospective multicenter phase 2 trial on 124 relapsed/refractory follicular lymphoma patients treated with a program of anthracycline-based debulking chemotherapy, immunochemotherapy, mobilization of in vivo purged PBSC followed by ASCT. Median age was 52 years; 14% of patients had grade 3A histology. Debulking chemotherapy produced CR in 16% and PR in 71%, while 13% of patients progressed. After rituximab, cyclophosphamide, vincristine, prednisone (R-COP), CR was obtained in 60% and PR in 35%; 118 patients successfully mobilized PBSC and 117 proceeded to ASCT. The harvest in all the 32 molecularly informative patients was bcl-2 negative. TRM was 0%. The 5-year PFS was 54% and the 5-year OS was 83%. After a median f-up of 6.7 years (range 1.5-13.6), 54% are still in CR. These data show that prolonged PFS is achievable in relapsed/refractory patients with high dose autologous transplantation of in vivo purged progenitor cells.
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Affiliation(s)
- Luca Arcaini
- Department of Molecular Medicine; University of Pavia; Pavia Italy
- Department of Hematology and Oncology; Fondazione Istituto Di Ricovero E Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo; Pavia Italy
| | - Lucia Morello
- Department of Molecular Medicine; University of Pavia; Pavia Italy
| | | | - Chiara Rusconi
- Division of Hematology; Niguarda Ca'granda Hospital; Milano Italy
| | - Marco Ladetto
- Division of Hematology; Azienda Ospedaliera Santi Antonio e Biagio e Cesare Arrigo; Alessandria
| | - Sara Rattotti
- Department of Hematology and Oncology; Fondazione Istituto Di Ricovero E Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo; Pavia Italy
| | - Maurizio Bonfichi
- Department of Hematology and Oncology; Fondazione Istituto Di Ricovero E Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo; Pavia Italy
| | | | - Cristina Gabutti
- Division of Hematology; Niguarda Ca'granda Hospital; Milano Italy
| | - Paolo Bernasconi
- Department of Molecular Medicine; University of Pavia; Pavia Italy
- Department of Hematology and Oncology; Fondazione Istituto Di Ricovero E Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo; Pavia Italy
| | - Marzia Varettoni
- Department of Hematology and Oncology; Fondazione Istituto Di Ricovero E Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo; Pavia Italy
| | - Manuel Gotti
- Department of Hematology and Oncology; Fondazione Istituto Di Ricovero E Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo; Pavia Italy
| | - Daniela Troletti
- Department of Hematology and Oncology; Fondazione Istituto Di Ricovero E Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo; Pavia Italy
| | - Maria Luisa Guerrera
- Department of Hematology and Oncology; Fondazione Istituto Di Ricovero E Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo; Pavia Italy
| | | | - Roberta Sciarra
- Department of Molecular Medicine; University of Pavia; Pavia Italy
| | - Virginia Valeria Ferretti
- Department of Hematology and Oncology; Fondazione Istituto Di Ricovero E Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo; Pavia Italy
| | - Emilio Paolo Alessandrino
- Department of Hematology and Oncology; Fondazione Istituto Di Ricovero E Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo; Pavia Italy
| | | | - Enrica Morra
- Division of Hematology; Niguarda Ca'granda Hospital; Milano Italy
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High-dose chemotherapy followed by autologous and allogeneic hematopoietic stem cell transplantation in patients with follicular non-Hodgkin’s lymphoma in the rituximab era. TUMORI JOURNAL 2015; 101:2-7. [PMID: 25702654 DOI: 10.5301/tj.5000203] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/09/2014] [Indexed: 11/20/2022]
Abstract
High-dose chemotherapy in lymphomas, and mainly non-Hodgkin’s lymphomas, has been advancing since the 1970s. This therapeutic strategy is based on the supposed existence of a dose-response curve for cytotoxic agents. However, the available data are contradictory, so high-dose chemotherapy cannot be guaranteed as consolidation treatment for first-remission follicular lymphoma or diffuse large cell lymphoma. The objective of this paper is to review the current knowledge about high-dose chemotherapy followed by hematopoietic stem cell transplantation in follicular non-Hodgkin’s lymphoma. The published studies on follicular lymphoma after first remission, recurrent follicular lymphoma, and transformed follicular lymphoma were assessed together with the data available on diffuse large cell lymphoma. During analysis of the studies, difficulties were encountered in comparing studies due to the heterogeneous nature of the data. High-dose chemotherapy as consolidation treatment after first remission or in recurrent or refractory disease was also analyzed.
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Abstract
High-dose chemotherapy followed by transplantation of autologous hematopoietic progenitor cells has a proven track record of safety and efficacy in hematological malignancies and select solid tumors. The near-universal use of peripheral blood stem cells as source for autografts, routine growth factor support, and antimicrobial prophylaxis post transplantation has improved the safety of this procedure. However, the advent of highly active novel therapies in the last few years warrants reappraisal of the role of autologous transplantation in the therapeutic armamentarium of malignant disorder. This review summarizes the current role of autologous transplantation for hematological malignancies, discusses modern standards for patient selection, and highlights long-term care issues of transplant survivors from an internist's perspective. Role of tumor purging in autologous transplantation, novel transplant conditioning regimens, and post-transplant therapies to prevent disease relapse are reviewed.
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Affiliation(s)
- Mehdi Hamadani
- Division of Hematology & Oncology, Medical College of Wisconsin , Milwaukee, WI , USA
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Controversies and recent advances in hematopoietic cell transplantation for follicular non-hodgkin lymphoma. BONE MARROW RESEARCH 2012; 2012:897215. [PMID: 23097707 PMCID: PMC3477524 DOI: 10.1155/2012/897215] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/30/2012] [Revised: 09/19/2012] [Accepted: 09/19/2012] [Indexed: 11/17/2022]
Abstract
Commonly designated as an indolent non-Hodgkin lymphoma, follicular lymphoma (FL) presents with striking pathobiological and clinical heterogeneity. Initial management strategies for FL have evolved to involve combination chemoimmunotherapy and/or radio-immunoconjugates. Unfortunately even with the best available nontransplant treatment, which nowadays results in higher frequency of response, FL remains incurable. Although considered a feasible therapeutic option, the use of hematopoietic cell transplantation (HCT) remains controversial. The appropriate timing, graft source, and intensity of HCT conditioning regimens in FL are often matters of debate. Herein we review the available published data pertaining to the use of autologous or allogeneic HCT in patients with FL across different stages of the disease, discuss major recent advances in the field, and highlight avenues for future research. The current literature does not support a role of HCT for FL in first remission, but in the relapsed setting autologous HCT remains appropriate for patients with early chemosensitive relapses, while allogeneic transplantation remains the sole curative modality for this disease, in relatively younger patients without significant comorbidities.
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Reappraising the role of autologous transplantation for indolent B-cell lymphomas in the chemoimmunotherapy era: is it still relevant? Bone Marrow Transplant 2012; 48:1013-21. [PMID: 23000653 DOI: 10.1038/bmt.2012.182] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2012] [Accepted: 08/22/2012] [Indexed: 12/28/2022]
Abstract
The role of autologous hematopoietic cell transplantation (auto-HCT) in the management of indolent non-Hodgkin lymphomas (NHL) is shrouded in controversy. The outcomes of conventional therapies for many indolent lymphoma subtypes have dramatically improved over the last several years with the use of monoclonal antibodies, maintenance therapy programs and with the incorporation of radio-immunoconjugates. These significant advances in the armamentarium of lymphoma therapeutics warrant reappraisal of the current role of auto-HCT in the treatment algorithm of indolent NHL. Prospective randomized studies comparing contemporary chemoimmunotherapies against auto-HCT are lacking, leading to significant debate about the role and timing of auto-HCT for indolent NHL in the modern era. Although autografting for follicular lymphoma (FL) in first remission has been largely abandoned, it remains a useful modality for relapsed disease, especially for the subgroup of patients who are not candidates for allogeneic transplantation with a curative intent. Auto-HCT can provide durable disease control in chemosensitive transformed FL and mantle cell lymphoma (MCL) in first remission, with relatively low toxicity, and remains appropriate in chemoimmunotherapy era. Contemporary data are also reviewed to clarify the often underutilized role of autografting in relapsed MCL and other less frequent indolent NHL histologies. The biological basis of the increased risks of second malignancies with auto-HCT are reviewed to identify strategies designed to mitigate this risk by, for example, avoiding exposure to genotoxic agents, planning early stem cell collection/cryopreservation and minimizing the use of TBI with transplant conditioning, and so on. Genetic testing able to identify patients at high risk of therapy-related complications and novel post-transplant immune therapies with the potential of transforming autografting in indolent NHL from a remission-extending therapy to a curative modality are discussed to examine the possibly expanding role of auto-HCT for lymphoid malignancies in the coming years.
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10
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Pott C. Minimal residual disease detection in mantle cell lymphoma: technical aspects and clinical relevance. Semin Hematol 2012; 48:172-84. [PMID: 21782059 DOI: 10.1053/j.seminhematol.2011.05.002] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The prognostic impact of minimal residual disease (MRD) has been demonstrated for several hematologic malignancies. While in acute lymphoblastic leukemias MRD assessment by polymerase chain reaction (PCR)-based methods has been established as an important tool for clinical risk assessment and is part of clinical management, data demonstrating a prognostic value of MRD in mantle cell lymphoma (MCL) were sparse and results from randomized trials have been published only recently. In the present review technical aspects of different MRD detection methods are discussed, as well as the prognostic relevance of MRD in the context of clinical trials in patients with MCL. Furthermore, recommendations are given for workflow and useful implication of MRD in future clinical trials design.
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Affiliation(s)
- Christiane Pott
- Second Medical Department, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
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11
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Foster M, Gabriel DA, Shea T. Role of hematopoietic stem cell transplant in the management of follicular lymphoma. Oncologist 2009; 14:726-38. [PMID: 19561292 PMCID: PMC2948435 DOI: 10.1634/theoncologist.2009-0045] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Despite decades of published data regarding the application of autologous and allogeneic stem cell transplant in patients with follicular lymphoma, there remain no uniform indications for its use in this disease. Autologous transplant has been shown to lead to longer progression-free survival times in randomized trials when compared with postremission interferon-based chemoimmunotherapy. However, the development of rituximab and its use in frontline, salvage, and maintenance therapy complicates the decision to pursue autologous transplant, a modality developed prior to the advent of anti-CD20 monoclonal antibodies. Allogeneic transplant offers the advantages of lymphoma-free grafts and the immunologic graft-versus-lymphoma effect. These factors may confer the possibility of long-term remission, though historically they have been accompanied by high rates of upfront morbidity and mortality, especially in heavily pretreated patients with a poor performance status or chemotherapy-refractory disease. Advances in patient selection, human leukocyte antigen (HLA) matching, conditioning regimens, and supportive care have reduced transplant-related mortality and the incidence of graft-versus-host disease. Recently published data focus on the incorporation of rituximab and radioimmunoconjugates prior to, during, and following autologous transplant. Furthermore, reduced-intensity allogeneic stem cell transplantation has increasingly been used for relapsed follicular lymphoma patients with comorbidities or advanced age. Several recent reports suggest that reduced-intensity regimens may provide a high likelihood of long-term disease-free survival for patients up to 70 years of age with a good performance status, chemotherapy-sensitive disease, and HLA-matched sibling donors. Such patients with relapsed disease should be referred to a transplant center that can enroll them in one of the forthcoming clinical trials that aim to confirm these outcomes.
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Affiliation(s)
- Matthew Foster
- Division of Hematology/Oncology, Department of Medicine, University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina 27599-7305, USA.
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Schüler F, Dölken G. Detection and monitoring of minimal residual disease by quantitative real-time PCR. Clin Chim Acta 2005; 363:147-56. [PMID: 16154122 DOI: 10.1016/j.cccn.2005.05.045] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2005] [Accepted: 05/05/2005] [Indexed: 11/16/2022]
Abstract
BACKGROUND The detection of malignant cells by quantitative real-time PCR has become state of the art for diagnosis, monitoring response to treatment and detection of minimal residual disease (MRD) in patients with leukemia or lymphoma. In order to be used in high-throughput analyses technical details have to be standardized to improve reproducibility and comparability of quantitative results obtained in different laboratories. METHODS Molecular monitoring of disease activity during and after treatment based on the detection of malignant cells in circulation or bone marrow by quantitative real-time PCR will be helpful to develop individualized treatment strategies for every patient. CONCLUSIONS The effectiveness of any kind of innovative treatment with specific antibodies, cellular immunotherapy or molecules designed for specific targets of tumor cells can be controlled at a very high level of sensitivity and accuracy. Based on quantitative results indicative for success or treatment failure, therapeutic changes upon the detection of progressive disease at the molecular level can be made even before symptoms or signs of clinical relapse occur. Hopefully, this will lead to higher cure rates and improved long-term survival.
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MESH Headings
- Biomarkers, Tumor/analysis
- Blood Circulation
- Bone Marrow/pathology
- Humans
- Leukemia/diagnosis
- Leukemia/genetics
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
- Lymphoma/diagnosis
- Lymphoma/genetics
- Neoplasm, Residual/diagnosis
- Neoplasm, Residual/genetics
- Philadelphia Chromosome
- Polymerase Chain Reaction/methods
- Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis
- Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics
- Sensitivity and Specificity
- Tumor Cells, Cultured
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Affiliation(s)
- Frank Schüler
- Clinic for Internal Medicine C, Hematology/Oncology, Ernst-Moritz-Arndt-University Greifswald, Germany
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Jacobsen E, Freedman A. B-cell purging in autologous stem-cell transplantation for non-Hodgkin lymphoma. Lancet Oncol 2005; 5:711-7. [PMID: 15581541 DOI: 10.1016/s1470-2045(04)01646-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Autologous stem-cell transplantation is a common therapy for B-cell non-Hodgkin lymphoma. However, a concern with the procedure is the potential of malignant cells to reinfuse with the stem-cell graft. Thus attempts have been made to purge, or eliminate, malignant cells from the graft. The oldest, and most well studied, method for prevention of reinfusion is in vitro use of antibodies against B cells that bind or lyse malignant B cells and healthy cells, while leaving T cells and stem cells to be reinfused. In the past 5 years, investigators have used rituximab, an antibody against CD20, to purge malignant cells in vivo without any manipulation in vitro. Both conventional and new techniques have shown promise, but their exact role remains to be defined. We analysed data on the purging of B cells by use of antibodies in the setting of autologous transplantation, with emphasis on the emerging technique of in vivo purging.
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Affiliation(s)
- Eric Jacobsen
- Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA 02115, USA
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14
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Corradini P, Ladetto M, Zallio F, Astolfi M, Rizzo E, Sametti S, Cuttica A, Rosato R, Farina L, Boccadoro M, Benedetti F, Pileri A, Tarella C. Long-term follow-up of indolent lymphoma patients treated with high-dose sequential chemotherapy and autografting: evidence that durable molecular and clinical remission frequently can be attained only in follicular subtypes. J Clin Oncol 2004; 22:1460-8. [PMID: 15084619 DOI: 10.1200/jco.2004.10.054] [Citation(s) in RCA: 107] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
PURPOSE To evaluate the prognostic relevance of molecular monitoring of minimal residual disease in indolent lymphomas receiving high-dose sequential chemotherapy and autografting. PATIENTS, MATERIALS, AND METHODS A polymerase chain reaction- (PCR-)based strategy was used to evaluate the presence of residual tumor cells in a panel of 70 indolent lymphoma patients: 40 with follicular (FCL), 14 with small lymphocytic (SLL), and 16 with mantle-cell (MCL) lymphomas. They were treated either with first-line (n = 61) or second-line (n = 9) therapy with an intensified high-dose chemotherapy program followed by peripheral-blood progenitor cells autografting. The Bcl-1, Bcl-2, and immunoglobulin gene rearrangements were used as lymphoma-specific markers. Overall, a molecular marker was obtained from the diagnostic tissue in 60 of 70 patients (86%). Results The collection of PCR-negative cells and the achievement of posttransplantation molecular remission (MR) were common in patients with FCL subtype (54% and 70%, respectively), whereas they were not frequent among SLL and MCL (25% and 12.5%, respectively) patients. With a median molecular follow-up of 75 months, an 88% incidence of relapse was observed among patients never attaining MR. In contrast, relapse incidence was only 8% among patients attaining a durable MR (P <.005). At present, 26 patients (20 with FCL and six with non-FCL) are long-term survivors in absence of clinical and molecular disease. CONCLUSION Our results indicate that among indolent lymphomas, FCL and non-FCL subtypes show a significantly different behavior in terms of MR achievement, and MR after intensive chemotherapy and autografting is predictive for a prolonged disease-free survival, whereas persistent PCR positivity is associated with a high risk of relapse.
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Affiliation(s)
- Paolo Corradini
- U.O. Ematologia-Trapianto Midollo Osseo, Istituto Nazionale per lo Studio e la Cura dei Tumori, Via Venezian 1, 20133 Milan, Italy.
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Abstract
BACKGROUND Autologous stem cell transplantation (SCT) has become the treatment of choice for patients with relapsed chemo-sensitive intermediate grade lymphoma, but its role in the treatment of low-grade lymphomas and in selected patients in first remission remains controversial. METHODS A large number of clinical trials have evaluated the role autologous SCT in both low grade and intermediate grade non-Hodgkin's lymphomas (NHL). These studies have attempted to evaluate the role of high dose therapy with stem cell support in comparison to more conventional chemotherapy approaches. Studies have also focused on methods to assess whether contaminating tumor cells are contained with the stem cell collection and whether this has impact on outcome. With an increased number of patients now long term survivors, additional studies are focusing on long term complications and in particular the emergence of secondary malignancies. RESULTS Virtually all patients now receive peripheral blood stem cells rather than bone marrow as a source of stem cells. The role of purging of residual tumor cells remains controversial and no randomized trial has been published to date that could evaluate the clinical utility of cell manipulation to attempt to remove contaminating lymphoma cells. Secondary leukemia is emerging as a major source of long-term morbidity and mortality after autologous stem cell transplantation. CONCLUSION Autologous SCT is associated with improved outcome in patients with relapsed intermediate grade lymphoma and most likely prolongs disease free survival in patients with low grade NHL. Morbidity and mortality of the procedure is low and major efforts are being made to attempt to decrease the major causes of failure, which remain disease relapse and occurrence of secondary malignancies.
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Affiliation(s)
- J G Gribben
- Department of Adults Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
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16
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Derigs HG. In vitro and in vivo purging of B lymphoma cells from stem-cell products using anti-CD20 Abs. Cytotherapy 2003; 2:445-53. [PMID: 12044225 DOI: 10.1080/146532400539396] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
BACKGROUND Autologous stem-cell transplantation has proved curative therapy for relapsed NHL. However, recurrence of underlying disease remains the major cause of treatment failure in this setting. METHODS Development of effective MAb therapy directed against the B cell surface antigen CD20 has added a valuable tool of clearing contaminating lymphoma cells from stem-cell products by either in vitro or in vivo application. RESULTS Transplantation of successfully in vitro purged bone marrow using Mabs has been correlated with prolonged survival in large Phase-II study. So far, no randomized trial could demonstrate a therapeutic benefit for in vitro purging. The anti-CD20 Mab rituximab has been used for in vivo purging at the time of stem cell collection or peritransplantation. This method has been shown to be safe and feasible. In the majority of patients the combination of rituximab with anti-lymphoma chemotherapy meant the collected stem cell products were free of molecularly-detectable lymphoma cells. DISCUSSION The increasing ability to kill all lymphoma cells in vivo by regimens including myeloablative therapy renders contaminating lymphoma cells of the autologous stem cell product the main source for disease recurrence. Clearing of these cells remains a prerequisite for curative stem-cell transplantation. Establishment of safe and effective therapeutic schedules using Mabs will enhance the chance for collection of lymphoma-free hematopoietic stems cells.
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MESH Headings
- Antibodies, Monoclonal/immunology
- Antibodies, Monoclonal/therapeutic use
- Antibodies, Monoclonal, Murine-Derived
- Antigens, CD20/immunology
- Antineoplastic Agents/pharmacology
- Bone Marrow Purging/adverse effects
- Bone Marrow Purging/methods
- Cell Separation/methods
- Clinical Trials, Phase II as Topic
- Humans
- Lymphoma, B-Cell/drug therapy
- Lymphoma, B-Cell/immunology
- Lymphoma, B-Cell/pathology
- Lymphoma, B-Cell/therapy
- Neoplasm, Residual/prevention & control
- Rituximab
- Stem Cell Transplantation/methods
- Stem Cells/cytology
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Affiliation(s)
- H G Derigs
- Division of Hematology II, Department of Medicine, Johannes Gutenberg-University, Mainz, Germany
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17
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Rohatiner AZS. High-dose treatment with autologous haemopoietic progenitor cell support for large B-cell, follicular and mantle-cell lymphoma. Best Pract Res Clin Haematol 2002; 15:467-80. [PMID: 12468400 DOI: 10.1053/beha.2002.0221] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The purpose of this chapter is to review the available information on the use of high-dose treatment (HDT) in large B-cell, follicular and mantle-cell lymphoma. The last 10 years have seen a dramatic increase in the number of patients receiving high-dose treatment with autologous haemopoietic progenitor cell support for non-Hodgkin's lymphoma. In patients with recurrent large B-cell lymphoma, HDT is now accepted as the 'standard of care', provided responsiveness to conventional chemotherapy at the time of recurrence has been demonstrated. In contrast, the situation in newly diagnosed patients is far from clear. Several phase III studies have been conducted, comparing conventional chemotherapy with either: the same treatment followed by HDT or an abbreviated number of cycles of conventional therapy followed by HDT. The results hitherto have not conclusively shown an advantage for HDT. In mantle-cell and follicular lymphoma, HDT should still be regarded as experimental. Current studies are evaluating the use of anti-CD20, given either as part of the treatment prior to HDT or as maintenance therapy. In view of the propensity for both of these illnesses to involve the bone marrow, a number of studies have addressed the question of in vitro treatment of the stem cell product. The advent of PCR analysis has made it possible to evaluate the significance of 'molecular remission'. In follicular lymphoma, there is a correlation between freedom from recurrence and persistent PCR negativity for bcl-2 rearrangement-containing cells in follow-up bone marrow samples.
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MESH Headings
- Antineoplastic Combined Chemotherapy Protocols/administration & dosage
- Hematopoietic Stem Cell Transplantation/methods
- Hematopoietic Stem Cell Transplantation/mortality
- Humans
- Lymphoma, B-Cell/mortality
- Lymphoma, B-Cell/therapy
- Lymphoma, Follicular/mortality
- Lymphoma, Follicular/therapy
- Lymphoma, Large B-Cell, Diffuse/mortality
- Lymphoma, Large B-Cell, Diffuse/therapy
- Lymphoma, Mantle-Cell/mortality
- Lymphoma, Mantle-Cell/therapy
- Lymphoma, Non-Hodgkin/mortality
- Lymphoma, Non-Hodgkin/therapy
- Transplantation, Autologous
- Treatment Outcome
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Affiliation(s)
- Ama Z S Rohatiner
- Department of Medical Oncology, St Bartholomew's Hospital, 45 Little Britain, London EC1A 7BE, UK
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18
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Altès A, Sierra J, Esteve J, Martín-Henao G, Marín P, Sureda A, Briones J, Martino R, Villamor N, Colomer D, Carreras E, Garcia J, Brunet S, Montserrat E. CD34+-enriched-CD19+-depleted autologous peripheral blood stem cell transplantation for chronic lymphoproliferative disorders: high purging efficiency but increased risk of severe infections. Exp Hematol 2002; 30:824-30. [PMID: 12135682 DOI: 10.1016/s0301-472x(02)00828-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
OBJECTIVE The main objective of this work was to decrease the incidence of relapse after autologous stem cell transplantation with a "double purging" procedure. METHODS We used a "positive" (CD34) and "negative" (CD19) double selection method to improve the efficacy of "single purging" of hematopoietic harvests in poor-prognosis lymphoproliferative disorders. All patients included in the study had a positive molecular marker of their disease. Minimal residual disease (MRD) was studied by flow cytometry and PCR techniques during the purging procedure and after transplantation. RESULTS Twenty-six patients fulfilled entry criteria. Median age of patients was 50 years (range: 33-66); 17 were male and 9 female. Thirteen (50%) of the patients mobilized an adequate number of CD34+ cells (>or=3 x 10(6)/kg) to proceed with the double-selection protocol. Twelve of the 13 harvests became PCR negative after purging. Ten patients were grafted with the selected products and all but one engrafted without delay. After a median follow-up of 30 months, 2 of 10 patients suffered a molecular relapse at 7 and 19 months respectively. The earlier relapse was observed in the patient who received a MRD+ product. Only one patient experienced a clinical relapse. Three patients died due to obliterans bronchiolitis, pneumococcal sepsis, and septic shock of unknown origin, respectively, and three others presented life-threatening infections. CONCLUSION Therefore, CD34+/CD19+ positive/negative selection is an effective purging approach in patients with chronic lymphoproliferative disorders. This favorable effect is, however, counterbalanced by the high frequency of life-threatening infections.
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MESH Headings
- Adult
- Aged
- Antigens, CD19/analysis
- Antigens, CD34/analysis
- Bacterial Infections/etiology
- Bacterial Infections/prevention & control
- Blood Cells/chemistry
- Blood Cells/transplantation
- Bone Marrow Purging/methods
- Bronchiolitis Obliterans/etiology
- Disease Susceptibility
- Female
- Follow-Up Studies
- Graft Survival
- Hematopoietic Stem Cell Mobilization
- Hematopoietic Stem Cell Transplantation
- Hematopoietic Stem Cells/chemistry
- Hematopoietic Stem Cells/classification
- Humans
- Immunocompromised Host
- Immunomagnetic Separation
- Leukemia, Lymphocytic, Chronic, B-Cell/complications
- Leukemia, Lymphocytic, Chronic, B-Cell/pathology
- Leukemia, Lymphocytic, Chronic, B-Cell/therapy
- Lymphoma, Follicular/complications
- Lymphoma, Follicular/pathology
- Lymphoma, Follicular/therapy
- Lymphoma, Mantle-Cell/complications
- Lymphoma, Mantle-Cell/pathology
- Lymphoma, Mantle-Cell/therapy
- Male
- Middle Aged
- Neoplasm, Residual
- Prospective Studies
- Recurrence
- Risk
- Sepsis/etiology
- Shock, Septic/etiology
- Transplantation Conditioning
- Treatment Outcome
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Affiliation(s)
- Albert Altès
- Clinical Hematology Division, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain.
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19
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Abstract
Follicular lymphoma and mantle cell lymphoma are incurable with standard chemotherapy regimens. One approach to improve outcome in patients with these diseases is high-dose therapy and autologous stem cell transplantation. Rituximab, an anti-CD20 monoclonal antibody, is specific for the B-cell surface antigen and can be used in autologous stem cell transplantation to eliminate lymphoma cells before the harvest (in vivo purging) or to prevent regrowth of malignant cells following transplant (post-transplant therapy). Preliminary data from an ongoing multicenter study evaluating the safety and efficacy of rituximab as a post-transplant consolidation therapy in patients with follicular lymphoma and mantle cell lymphoma are presented. After high-dose therapy and autologous stem cell transplantation together with rituximab treatment, 92% of patients are in complete remission at the 18-month study follow-up, suggesting that rituximab is a valuable and potentially curative treatment for patients with follicular lymphoma and mantle cell lymphoma. Six months after treatment, all evaluable patients became polymerase chain reaction-negative for the bcl-1 and bcl-2 chromosomal rearrangements and remained so during follow-up, indicating that rituximab is able to eliminate minimal residual disease and bring about high rates of durable remissions in these patients.
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Affiliation(s)
- Wolfram Brugger
- Eberhard-Karls Universität, Hämatologie und Onkologie, Medizinische Klinik II, Tübingen, Germany
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20
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Straka C, Oduncu F, Drexler E, Mitterer M, Schnabel B, König A, Brack N, Nerl C, Emmerich B. The CD19+ B-cell counts at peripheral blood stem cell mobilization determine different levels of tumour contamination and autograft purgability in low-grade lymphoma. Br J Haematol 2002; 116:695-701. [PMID: 11849235 DOI: 10.1046/j.0007-1048.2001.03313.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The tumour load of peripheral blood stem cell (PBSC) harvests and the outcome of ex vivo immunomagnetic B-cell purging was investigated in 19 patients with low-grade lymphoma. To quantify the tumour load, we combined fluorescence-activated cell sorting measurement of CD19+ B-cells and determination of the B-cell light chain ratio (LCR) with consensus complementarity-determining region III-polymerase chain reaction (CDRIII-PCR) and gene scan analysis. The number of tumour cells was calculated using B-cell extracts from the PBSCs. Two different patterns were distinguished. In eight patients (42%) with CD19+ B cells >1% in the apheresis product, a high tumour load was found, characterized by a monoclonal LCR, positive PCR in seven out of eight cases, >5 x 10(7) extracted lymphoma cells in six out of seven PCR-assessable cases, and the presence of residual lymphoma after purging in six of seven cases. In 11 patients (58%) with <1% CD19+ B-cells in the product, a low tumour load was indicated by a polyclonal LCR, positive PCR in only 4 out of 11 cases, >5 x 10(7) extracted lymphoma cells in zero out of four PCR-assessable cases, and the presence of residual lymphoma after purging in zero out of four of these cases. The level of residual lymphoma following purging largely depended on the level of tumour contamination. CD19+ B-cells >50/microl in the peripheral blood at mobilization predicted a high tumour load in the apheresis product.
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Affiliation(s)
- Christian Straka
- Medizinische Klinik-Innenstadt, University of Munich, Munich, Germany.
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21
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Gianni AM, Cortelazzo S, Magni M, Martelli M. Rituximab: enhancing stem cell transplantation in mantle cell lymphoma. Bone Marrow Transplant 2002; 29 Suppl 1:S10-3. [PMID: 11840155 DOI: 10.1038/sj.bmt.1703296] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Mantle cell lymphoma (MCL) responds poorly to standard chemotherapy regimens used in non-Hodgkin's lymphoma. As a result, a combination of high-dose chemotherapy (HDT) with autologous stem cell transplantation (ASCT) is being investigated in patients with MCL. So far, however, there is no evidence for long-term remission -- believed, in part, to be due to contamination of the transfusion product with residual cancer cells. Many ex-vivo purging methods have been developed to remove tumour cells, but these are complicated, time-consuming and expensive. This study describes an in vivo purging method using rituximab to produce a tumour-free stem cell product for re-infusion following HDT. The regimen is split into a purging phase and a myeloablative phase, which together consist of four-step high-dose sequential chemotherapy (sHDT) and six infusions of rituximab immunotherapy. The sHDT comprises cyclophosphamide, cytosine arabinoside, melphalan and mitoxantrone plus melphalan. There are two separate stem cell harvests and three reinfusions. In a pilot study 28 patients with untreated MCL received standard chemotherapy followed by sHDT with rituximab in vivo purging. Preliminary results indicate that in PCR analyses of leukaphereses from 20 assessable patients, 100% lymphoma-negative harvests were achieved following in vivo purging. PCR analyses of the bone marrow following the four-step high-dose regimen with purging and transplantation showed that all patients achieved molecular remission. After a median follow-up of 22 months (range 10-42 months), two patients had died while 26 were alive and disease free. This method allows efficient in vivo purging in the context of an effective chemotherapy regimen and may have a role as first-line therapy in MCL patients who respond poorly to standard treatment.
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Affiliation(s)
- A M Gianni
- Instituto Nazionale Tumori, Milan, Italy
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22
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Corradini P, Tarella C, Olivieri A, Gianni AM, Voena C, Zallio F, Ladetto M, Falda M, Lucesole M, Dodero A, Ciceri F, Benedetti F, Rambaldi A, Sajeva MR, Tresoldi M, Pileri A, Bordignon C, Bregni M. Reduced-intensity conditioning followed by allografting of hematopoietic cells can produce clinical and molecular remissions in patients with poor-risk hematologic malignancies. Blood 2002; 99:75-82. [PMID: 11756155 DOI: 10.1182/blood.v99.1.75] [Citation(s) in RCA: 124] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
A reduced-intensity conditioning regimen was investigated in 45 patients with hematologic malignancies who were considered poor candidates for conventional myeloablative regimens. Median patient age was 49 years. Twenty-six patients previously failed autologous transplantation, and 18 patients had a refractory disease at the time of transplantation. In order to decrease nonrelapse mortality, and enhance the graft-versus-tumor effect, a program was designed in which a reduced conditioning with thiotepa, fludarabine, and cyclophosphamide was associated with programmed reinfusions of donor lymphocytes for patients without graft-versus-host disease (GVHD), not achieving clinical and molecular remission after transplantation. GVHD prophylaxis consisted of cyclosporine A and methotrexate. Seventeen patients received marrow cells and 28 received mobilized hematopoietic cells. All patients engrafted. The probability of grades II-IV and III-IV acute GVHD were 47% and 13%, respectively. The probability of nonrelapse mortality, progression-free survival, and overall survival were 13%, 57%, and 53%, respectively. Thirteen patients in complete remission had a polymerase chain reaction marker for minimal disease monitoring; 10 achieved molecular remission after transplantation. Nine patients received donor lymphocytes: one patient with mantle cell lymphoma had a minimal response, one patient with refractory anemia with excess of blasts in transformation achieved complete remission, and 7 patients did not respond. At a median follow-up of 385 days (range, 24 to 820 days), 25 patients (55%) were alive in complete remission. Although longer follow-up is needed to evaluate the long-term outcome, the study shows that this regimen is associated with a durable engraftment, has a low nonrelapse mortality rate, and can induce clinical and molecular remissions.
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Affiliation(s)
- Paolo Corradini
- Department of Hematology, Istituto Scientifico HS Raffaele, Milano, Italy.
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23
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Olavarria E, Child F, Woolford A, Whittaker SJ, Davis JG, McDonald C, Chilcott S, Spittle M, Grieve RJ, Stewart S, Apperley JF, Russell-Jones R. T-cell depletion and autologous stem cell transplantation in the management of tumour stage mycosis fungoides with peripheral blood involvement. Br J Haematol 2001; 114:624-31. [PMID: 11552988 DOI: 10.1046/j.1365-2141.2001.02919.x] [Citation(s) in RCA: 59] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Nine patients with tumour stage mycosis fungoides (MF) have been entered into a pilot study of T-cell depletion and autologous stem cell transplantation (SCT). Eight patients had detectable rearrangements of the T-cell receptor (TCR) gamma-gene demonstrated by polymerase chain reaction (PCR)/single-stranded conformation polymorphism (SSCP) in the peripheral blood. The median age was 47 years and the median duration of disease before SCT was 61 months; Peripheral blood progenitor cells were mobilized using high-dose etoposide (1.6 g/m2) and granulocyte colony-stimulating factor (G-CSF). The apheresis products underwent rigorous T-cell depletion with immunomagnetic methods. Double CD34-positive and CD4/CD8-negative selection achieved a median reduction of 3.89 log of T cells. All nine patients have been transplanted. Conditioning included carmustine (BCNU), etoposide and melphalan (BEM) in seven patients and total body irradiation plus etoposide or melphalan in two. Eight patients engrafted promptly and one patient died of septicaemia. All survivors entered complete remission. Seven patients have relapsed at a median of 7 months (2-14) post SCT. However, most patients have relapsed into a less aggressive stage, which has responded to conventional therapy. Four out of seven evaluable patients had detectable TCR rearrangements in the T-cell depleted graft. A T-cell clone was also detected in the peripheral blood before relapse in four cases. Autologous SCT is feasible, safe and can result in complete remission in a significant proportion of patients with tumour stage mycosis fungoides. Despite a short relapse-free survival, most patients achieved good disease control at the time of relapse.
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Affiliation(s)
- E Olavarria
- Department of Haematology, Hammersmith Hospital, ICSM, London, UK.
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24
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Ladetto M, Sametti S, Donovan JW, Ferrero D, Astolfi M, Mitterer M, Ricca I, Drandi D, Corradini P, Coser P, Pileri A, Gribben JG, Tarella C. A validated real-time quantitative PCR approach shows a correlation between tumor burden and successful ex vivo purging in follicular lymphoma patients. Exp Hematol 2001; 29:183-93. [PMID: 11166457 DOI: 10.1016/s0301-472x(00)00651-2] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
OBJECTIVE Purging procedures are increasingly used to provide stem cell collections devoid of contaminating tumor cells. In follicle center lymphoma (FCL), most approaches eradicate polymerase chain reaction (PCR);-detectable disease in only a fraction of harvests undergoing ex vivo manipulation. In this study we evaluated whether there is a relationship between tumor burden of stem cell harvests and successful clearance of PCR-detectable disease following ex vivo manipulation. MATERIALS AND METHODS To address this issue, we developed a real-time PCR approach for quantitative measurement of tumor contamination using the bcl-2 rearrangement. Real-time PCR was used to evaluate the relationship between tumor burden of stem-cell harvests and purging effectiveness in PCR(+) samples derived from 10 FCL patients. Ex vivo purging was performed using the MaxSep cell separator (Baxter Immunotherapy, Deerfield, IL, USA). RESULTS Our real-time PCR method proved effective, sensitive, accurate, and reproducible. Four collections were successfully cleared of minimal residual disease (MRD) whereas six remained PCR(+). Real-time PCR showed that the four collections successfully cleared of MRD had a prepurging tumor burden significantly lower than those remaining PCR(+) (p = 0.04). CONCLUSION This study provides the first evidence that evaluation of tumor burden in stem-cell harvests by real-time PCR can predict the effectiveness of therapeutic intervention in non-Hodgkin's lymphoma. Based on these findings, we foresee a more widespread use of this technique to evaluate the impact of different therapeutic approaches in FCL.
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Affiliation(s)
- M Ladetto
- Divisione Universitaria di Ematologia, Azienda Ospedaliera S. Giovanni Battista, Torino, Italy.
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25
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Abstract
Preliminary results of new therapies in the areas of cytotoxic agents and immunotherapy for advanced indolent lymphomas have been encouraging. Long-term follow-up on high-dose therapy suggests a potential role for this modality in this group of lymphomas. In aggressive lymphomas, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) continues to hold ground as first-line therapy when compared against other regimens. Several studies reinforce past findings that patients with chemosensitive relapse are better candidates for high-dose therapy. In relapsed or refractory disease, selected compounds appear to have activity as single agents and others have shown activity in combination therapy. Despite high treatment-related mortality rates, allogeneic transplantation in relapsed aggressive lymphoma warrants further investigation. Last, as patients are surviving longer, complications of therapy are having to be addressed.
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Affiliation(s)
- R J Hauke
- Section of Hematology/Oncology, University of Nebraska Medical Center, Omaha 68198-7680, USA.
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26
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Successful in vivo purging of CD34-containing peripheral blood harvests in mantle cell and indolent lymphoma: evidence for a role of both chemotherapy and rituximab infusion. Blood 2000. [DOI: 10.1182/blood.v96.3.864.015k26_864_869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Elimination of tumor cells (“purging”) from hematopoietic stem cell products is a major goal of bone marrow–supported high-dose cancer chemotherapy. We developed an in vivo purging method capable of providing tumor-free stem cell products from most patients with mantle cell or follicular lymphoma and bone marrow involvement. In a prospective study, 15 patients with CD20+ mantle cell or follicular lymphoma, bone marrow involvement, and polymerase chain reaction (PCR)–detectable molecular rearrangement received 2 cycles of intensive chemotherapy, each of which was followed by infusion of a growth factor and 2 doses of the anti-CD20 monoclonal antibody rituximab. The role of rituximab was established by comparison with 10 control patients prospectively treated with an identical chemotherapy regimen but no rituximab. The CD34+ cells harvested from the patients who received both chemotherapy and rituximab were PCR-negative in 93% of cases (versus 40% of controls;P = .007). Aside from providing PCR-negative harvests, the chemoimmunotherapy treatment produced complete clinical and molecular remission in all 14 evaluable patients, including all 6 with mantle cell lymphoma (versus 70% of controls). In vivo purging of hematopoietic progenitor cells can be successfully accomplished in most patients with CD20+ lymphoma, including mantle cell lymphoma. The results depended on the activity of both chemotherapy and rituximab infusion and provide the proof of principle that in vivo purging is feasible and possibly superior to currently available ex vivo techniques. The high short-term complete-response rate observed suggests the presence of a more-than-additive antilymphoma effect of the chemoimmunotherapy combination used.
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27
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Successful in vivo purging of CD34-containing peripheral blood harvests in mantle cell and indolent lymphoma: evidence for a role of both chemotherapy and rituximab infusion. Blood 2000. [DOI: 10.1182/blood.v96.3.864] [Citation(s) in RCA: 165] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
Elimination of tumor cells (“purging”) from hematopoietic stem cell products is a major goal of bone marrow–supported high-dose cancer chemotherapy. We developed an in vivo purging method capable of providing tumor-free stem cell products from most patients with mantle cell or follicular lymphoma and bone marrow involvement. In a prospective study, 15 patients with CD20+ mantle cell or follicular lymphoma, bone marrow involvement, and polymerase chain reaction (PCR)–detectable molecular rearrangement received 2 cycles of intensive chemotherapy, each of which was followed by infusion of a growth factor and 2 doses of the anti-CD20 monoclonal antibody rituximab. The role of rituximab was established by comparison with 10 control patients prospectively treated with an identical chemotherapy regimen but no rituximab. The CD34+ cells harvested from the patients who received both chemotherapy and rituximab were PCR-negative in 93% of cases (versus 40% of controls;P = .007). Aside from providing PCR-negative harvests, the chemoimmunotherapy treatment produced complete clinical and molecular remission in all 14 evaluable patients, including all 6 with mantle cell lymphoma (versus 70% of controls). In vivo purging of hematopoietic progenitor cells can be successfully accomplished in most patients with CD20+ lymphoma, including mantle cell lymphoma. The results depended on the activity of both chemotherapy and rituximab infusion and provide the proof of principle that in vivo purging is feasible and possibly superior to currently available ex vivo techniques. The high short-term complete-response rate observed suggests the presence of a more-than-additive antilymphoma effect of the chemoimmunotherapy combination used.
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28
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Tarella C, Caracciolo D, Corradini P, Zallio F, Ladetto M, Cuttica A, Rossi G, Novero D, Gavarotti P, Pileri A. Long-term follow-up of advanced-stage low-grade lymphoma patients treated upfront with high-dose sequential chemotherapy and autograft. Leukemia 2000; 14:740-7. [PMID: 10764164 DOI: 10.1038/sj.leu.2401737] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Long-term outcome, after first line intensified high-dose sequential (i-HDS) chemotherapy, was evaluated in 46 patients, aged < or =65 years, with advanced low-grade lymphoma. Seventeen patients had small lymphocytic lymphoma (SLL), 29 had follicular lymphoma (FL), 10 of them with histologic transformation. I-HDS included: (1) tumor debulking, by 2 APO+2 DHAP courses; (2) sequential administration of high-dose (hd) etoposide, methotrexate, and cyclophosphamide, followed by peripheral blood progenitor cell (PBPC) harvest; (3) hd-mitoxantrone + melphalan with PBPC autograft. Ten FL patients had their PBPC immunologically purged ex vivo. There were two treatment-related deaths; five FL patients had short-lasting response followed by disease progression, five SLL reached a stable PR; overall, 34 patients (74%) reached CR. At a median follow-up of 4.3 years, the estimated 9-year OS and EFS were 84% and 45%, respectively. No significant differences were observed in the OS among patients at low, intermediate or high IPI score, with an estimated OS projection of 95%, 78%, and 75%, respectively. FL had longer survival without evidence of residual disease (9-year EFS: 59%) as compared to SLL patients (8.8-year EFS: 17%); however, both groups had prolonged survival and no need of salvage treatment, as shown by the time to disease progression curve, projected to 66% and 62% for SLL and FL, respectively. The results indicate that hd-approach in low-grade lymphoma: (1) is associated with longer progression-free survival as compared to conventional therapies; (2) may imply higher tumor mass reduction in FL as compared to SLL patients; (3) offers long life expectancy, with potential survival benefits at least for patients at intermediate/high IPI score.
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MESH Headings
- Adult
- Antineoplastic Combined Chemotherapy Protocols/administration & dosage
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Cisplatin/administration & dosage
- Combined Modality Therapy
- Cyclophosphamide/administration & dosage
- Cytarabine/administration & dosage
- Dexamethasone/administration & dosage
- Disease Progression
- Disease-Free Survival
- Doxorubicin/administration & dosage
- Drug Administration Schedule
- Etoposide/administration & dosage
- Feasibility Studies
- Female
- Follow-Up Studies
- Hematopoietic Stem Cell Transplantation
- Humans
- Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy
- Leukemia, Lymphocytic, Chronic, B-Cell/mortality
- Leukemia, Lymphocytic, Chronic, B-Cell/therapy
- Lymphoma, Follicular/drug therapy
- Lymphoma, Follicular/mortality
- Lymphoma, Follicular/therapy
- Lymphoma, Non-Hodgkin/drug therapy
- Lymphoma, Non-Hodgkin/mortality
- Lymphoma, Non-Hodgkin/therapy
- Male
- Melphalan/administration & dosage
- Methotrexate/administration & dosage
- Middle Aged
- Mitoxantrone/administration & dosage
- Remission Induction
- Survival Analysis
- Treatment Outcome
- Vincristine/administration & dosage
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Affiliation(s)
- C Tarella
- Dipartimento di Medicina e Oncologia Sperimentale, Azienda Ospedaliera S Giovanni Battista di Torino, Italy
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