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Szczepiorkowski ZM. Indications for therapeutic apheresis in hematological disorders. Semin Hematol 2020; 57:57-64. [PMID: 32892844 DOI: 10.1053/j.seminhematol.2020.07.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The early apheresis devices were developed in 1930s, but therapeutic apheresis only became widely used decades later, when automated cell separators were introduced. Progress in technical development of these devices continues to this day. Initial use of therapeutic apheresis has not been evidence based. Documents such as the Guidelines by the American Society for Apheresis provided hematologist with better tools to assess the role of therapeutic apheresis in daily practice. This review focuses on the use of therapeutic apheresis in patients with hematological disorders. Four separate apheresis modalities most encountered by hematologists are discussed: therapeutic plasma exchange, therapeutic leukocytapheresis, red blood cell exchange, and extracorporeal photopheresis. Examples of indications are provided and discussed. The future of therapeutic apheresis and its role in different diseases is undergoing continuous re-evaluation as disease pathogenesis is better understood and new treatment options become available.
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Affiliation(s)
- Zbigniew M Szczepiorkowski
- Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA; Geisel School of Medicine at Dartmouth, Hanover, NH, USA; Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
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Kutane Lymphome. MEDIKAMENTÖSE TUMORTHERAPIE IN DER DERMATO-ONKOLOGIE 2019. [PMCID: PMC7121154 DOI: 10.1007/978-3-662-58012-7_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Kutane Lymphome (cutaneous lymphomas: CL) umfassen die Gruppe der kutanen T-Zell-Lymphome (cutaneous T-cell lymphomas: CTCL), kutanen B-Zell-Lymphome (cutaneous B-cell lymphomas: CBCL) und die sog. hämatodermischen Neoplasien (HN). CL gehören zur Gruppe der Non-Hodgkin-Lymphome (NHL) und stellen in der Subgruppe der extranodalen NHL die zweithäufigste Gruppe hinter den gastrointestinalen Lymphomen dar (Jaffe et al. 2009). Man unterscheidet zwischen primären und sekundären CL. Primäre CL haben ihren Ursprung in der Haut und bleiben in der Regel darauf auch längere Zeit beschränkt, während sekundäre CL kutane Manifestationen von primär nodalen oder extranodalen Lymphomen darstellen (Willemze 2005). Die primären CL unterscheiden sich hinsichtlich klinischem Verlauf, Therapieoptionen und Prognose erheblich von nodalen und extrakutanen Lymphomen. So zeigen z. B. die primär kutanen CD30+-T-Zell-Lymphome einen gutartigen Verlauf, wogegen die nodalen Varianten als aggressiv eingestuft werden. Da die CL zumeist weniger aggressiv sind, werden sie auch weniger aggressiv behandelt.
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3
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Vonderheid EC. Photopheresis: Current and Future Perspectives. J Cutan Med Surg 2016. [DOI: 10.1177/12034754030070s401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- Eric C. Vonderheid
- Department of Dermatology, Johns Hopkins Medical Institutes, Baltimore, MD, USA
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Hu SCS. Mycosis fungoides and Sézary syndrome: Role of chemokines and chemokine receptors. World J Dermatol 2015; 4:69-79. [DOI: 10.5314/wjd.v4.i2.69] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Revised: 03/16/2015] [Accepted: 04/09/2015] [Indexed: 02/06/2023] Open
Abstract
Mycosis fungoides is the most common form of cutaneous T-cell lymphoma (CTCL), and is characterized by a clonal expansion of malignant CD4+ T lymphocytes with skin-homing properties. Clinically and pathologically, mycosis fungoides can be categorized into patch, plaque and tumor stages. The clinical course of mycosis fungoides is usually chronic and indolent, but a proportion of patients may develop progressive disease with peripheral blood, lymph node and visceral organ involvement. Sézary syndrome is an aggressive leukemic form of CTCL characterized by a clonal population of malignant T cells in the peripheral blood. Various forms of skin-directed and systemic treatments are available for mycosis fungoides and Sézary syndrome. However, current treatments are generally not curative, and can only control the disease. Currently, the etiology and pathogenesis of mycosis fungoides and Sézary syndrome are not well defined. Proposed mechanisms include chronic antigenic stimulation by infectious agents, expression of specific adhesion molecules, altered cytokine production, mutations of oncogenes and tumor suppressor genes, and avoidance of apoptosis. In recent years, a number of chemokine receptors and their corresponding chemokine ligands have been found to contribute to the migration and survival of lymphoma cells in mycosis fungoides and Sézary syndrome, including CC chemokine receptor 4 (CCR4), CCR10, C-X-C chemokine receptor type 4 (CXCR4), CCR7, CCR3 and CXCR3. Since chemokines and chemokine receptors have been found to play important roles in the pathophysiology of mycosis fungoides and Sézary syndrome, they may be potentially useful targets for the development of new treatments for these diseases in the future.
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Kutane Lymphome. MEDIKAMENTÖSE TUMORTHERAPIE IN DER DERMATO-ONKOLOGIE 2014. [PMCID: PMC7122836 DOI: 10.1007/978-3-642-24837-5_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Kutane Lymphome (cutaneous lymphomas: CL) umfassen die Gruppe der kutanen T-Zell-Lymphome (cutaneous T-cell lymphomas: CTCL), kutanen B-Zell-Lymphome (cutaneous B-cell lymphomas: CBCL) und die sog. hämatodermischen Neoplasien (HN). CL gehören zur Gruppe der Non-Hodgkin-Lymphome (NHL) und stellen in der Subgruppe der extranodalen NHL die zweithäufigste Gruppe hinter den gastrointestinalen Lymphomen dar (Jaffe et al. 2009). Man unterscheidet zwischen primären und sekundären CL. Primäre CL
haben ihren Ursprung in der Haut und bleiben in der Regel darauf auch längere Zeit beschränkt, während sekundäre LymphomekutaneCL kutane Manifestationen von primär nodalen oder extranodalen Lymphomen darstellen (Willemze 2005). Die primären CL unterscheiden sich hinsichtlich klinischem Verlauf, Therapieoptionen und Prognose erheblich von nodalen und extrakutanen Lymphomen. So zeigen z. B. die primär kutanen CD30+ Lymphome einen gutartigen Verlauf, wogegen die nodalen Varianten als aggressiv eingestuft werden. Da die CL zumeist weniger aggressiv sind, werden sie weniger aggressiv behandelt.
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6
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Schlaak M, Pickenhain J, Theurich S, Skoetz N, von Bergwelt‐Baildon M, Kurschat P. Allogeneic stem cell transplantation versus conventional therapy for advanced primary cutaneous T-cell lymphoma. Cochrane Database Syst Rev 2013; 2013:CD008908. [PMID: 23986525 PMCID: PMC7156921 DOI: 10.1002/14651858.cd008908.pub3] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
BACKGROUND Primary cutaneous T-cell lymphomas (CTCL) belong to the group of non-Hodgkin lymphomas and usually run an indolent course. However, some patients progress to advanced tumour or leukaemic stages. To date, there is no cure for those cases. In the last few years, several publications reported durable responses in some patients following allogeneic stem cell transplantation (alloSCT). This is an update of a Cochrane review first published in 2011 and updated in 2013. OBJECTIVES To compare the efficacy and safety of conventional therapies with allogeneic stem cell transplantation in patients with advanced primary cutaneous T-cell lymphomas. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 1), MEDLINE (1950 to January 2013), Internet-databases of ongoing trials, conference proceedings of the American Society of Clinical Oncology (ASCO, 2009 to July 2013) and the American Society of Hematology (ASH, 2009 to July 2013). We also contacted members of the European Organisation for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Task Force to check for ongoing study activities. We handsearched citations from identified trials and relevant review articles. In addition, we handsearched randomised controlled trials from the European Group for Blood and Marrow Transplantation (EBMT) and International Conference on Cutaneous T-cell Lymphoma, ASCO and ASH up to July 2013. SELECTION CRITERIA Trials eligible for inclusion were genetically randomised controlled trials (RCTs) comparing alloSCT plus conditioning therapy (regardless of agents) with conventional therapy as treatment for advanced CTCL. DATA COLLECTION AND ANALYSIS Two review authors would have extracted data from eligible studies and assessed their quality. The primary outcome measure was overall survival; secondary outcomes were time to progression, response rate, treatment-related mortality, adverse events and quality of life. MAIN RESULTS We did not identify any randomised controlled trials from the updated search in January 2013. In 2011, we found 2077 citations but none were relevant genetically or non-genetically randomised controlled trials. All 41 studies that were thought to be potentially suitable were excluded after full text screening for being non-randomised, not including CTCL or being review articles. AUTHORS' CONCLUSIONS We planned to report evidence from genetically or non-genetically randomised controlled trials comparing conventional therapy and allogeneic stem cell transplantation. However, we did not identify any randomised controlled trials addressing this question. Nevertheless, prospective genetically randomised controlled trials need to be initiated to evaluate the precise role of alloSCT in advanced CTCL.
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Affiliation(s)
- Max Schlaak
- University Hospital of CologneDepartment of Dermatology and VenerologyKerpener Str. 62CologneGermany50924
| | - Juliane Pickenhain
- University Hospital of CologneDepartment of Dermatology and VenerologyKerpener Str. 62CologneGermany50924
| | - Sebastian Theurich
- University Hospital of CologneDepartment I of Internal Medicine, Stem Cell Transplantation ProgramKerpener Str. 62CologneGermany50924
| | - Nicole Skoetz
- University Hospital of CologneCochrane Haematological Malignancies Group, Department I of Internal MedicineKerpener Str. 62CologneGermany50924
| | - Michael von Bergwelt‐Baildon
- University Hospital of CologneDepartment I of Internal Medicine, Stem Cell Transplantation ProgramKerpener Str. 62CologneGermany50924
| | - Peter Kurschat
- University Hospital of CologneDepartment of Dermatology and VenerologyKerpener Str. 62CologneGermany50924
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8
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Abstract
The provision of therapeutic apheresis to children is a technically challenging procedure, requiring trained personnel and an understanding of the disease processes that leads to the need for apheresis. Most apheresis protocols are derived from studies in adult patients, even though most studies are of limited sample size. The focus of this review is to highlight the disease processes commonly treated with therapeutic apheresis in children, and to address the technical considerations pertinent to the provision of safe and effective apheresis in the pediatric setting.
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Affiliation(s)
- Stuart L Goldstein
- Department of Pediatrics, University of Cincinnati College of Medicine and the Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45206, USA.
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9
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Schlaak M, Pickenhain J, Theurich S, Skoetz N, von Bergwelt-Baildon M, Kurschat P. Allogeneic stem cell transplantation versus conventional therapy for advanced primary cutaneous T-cell lymphoma. Cochrane Database Syst Rev 2012; 1:CD008908. [PMID: 22258991 DOI: 10.1002/14651858.cd008908.pub2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Primary cutaneous T-cell lymphomas (CTCL) belong to the group of non-Hodgkin lymphomas and usually run an indolent course. However, some patients progress to advanced tumour or leukaemic stages. Up to now, no curative treatment has been established for those cases. In the last few years, several publications have reported durable responses in some patients following allogeneic stem cell transplantation (alloSCT). OBJECTIVES To compare the efficacy and safety of conventional therapies with allogeneic stem cell transplantation in patients with advanced primary cutaneous T-cell lymphomas. SEARCH METHODS The search strategy included the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1950 to May 2011), Internet-databases of ongoing trials (www.controlled-trials.com; www.clinicaltrials.gov), conference proceedings of the American Society of Clinical Oncology (ASCO, 2009 to present) and the American Society of Hematology (ASH, 2009 to present). We also contacted members of the European Organisation for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Task Force to check for ongoing study activities. We handsearched citations from identified trials and relevant review articles. In addition, randomised controlled trials from the European Group for Blood and Marrow Transplantation (EBMT) and International Conference on Cutaneous T-cell Lymphoma, ASCO and ASH up to 2010 were handsearched. SELECTION CRITERIA Genetically randomised controlled trials (RCT) comparing alloSCT plus conditioning therapy regardless of agents with conventional therapy as treatment for advanced CTCL were eligible to be included. DATA COLLECTION AND ANALYSIS From eligible studies data would have been extracted by two review authors and assessed for quality. Primary outcome measures were overall survival, secondary criteria were time to progression, response rate, treatment-related mortality, adverse events and quality of life. MAIN RESULTS We found 2077 citations but none were relevant genetically or non-genetically randomised controlled trials. All 41 studies that were thought to be potentially suitable were excluded after full text screening for being non-randomised, not including CTCL or being review articles. AUTHORS' CONCLUSIONS We planned to report evidence from genetically or non-genetically randomised controlled trials comparing conventional therapy and allogeneic stem cell transplantation. However, no randomised trials addressing this question were identified. Nevertheless, prospective genetically randomised controlled trials need to be initiated to evaluate the precise role of alloSCT in advanced CTCL.
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Affiliation(s)
- Max Schlaak
- Department ofDermatology andVenerology,UniversityHospital ofCologne,Cologne,Germany.
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10
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The role of extracorporeal photopheresis in the treatment of cutaneous T-cell lymphomas. Transfus Apher Sci 2011; 46:195-202. [PMID: 22067605 DOI: 10.1016/j.transci.2011.10.016] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2011] [Accepted: 10/13/2011] [Indexed: 11/20/2022]
Abstract
Extracorporeal photochemotherapy (ECP) is an effective treatment modality for patients with erythrodermic myocosis fungoides (MF) and Sezary syndrome (SS). During ECP, a fraction of peripheral blood mononuclear cells is collected, incubated ex-vivo with methoxypsoralen, UVA irradiated, and finally reinfused to the patient. Although the mechanism of action of ECP is not well established, clinical and laboratory observations support the hypothesis of a vaccination-like effect. ECP induces apoptosis of normal and neoplastic lymphocytes, while enhancing differentiation of monocytes towards immature dendritic cells (imDCs), followed by engulfment of apoptotic bodies. After reinfusion, imDCs undergo maturation and antigenic peptides from the neoplastic cells are expressed on the surface of DCs. Mature DCs travel to lymph nodes and activate cytotoxic T-cell clones with specificity against tumor antigens. Disease control is mediated through cytotoxic T-lymphocytes with tumor specificity. The efficacy and excellent safety profile of ECP has been shown in a large number of retrospective trials. Previous studies showed that monotherapy with ECP produces an overall response rate of approximately 60%, while clinical data support that ECP is much more effective when combined with other immune modulating agents such as interferons or retinoids, or when used as consolidation treatment after total skin electron beam irradiation. However, only a proportion of patients actually respond to ECP and parameters predictive of response need to be discovered. A patient with a high probability of response to ECP must fulfill all of the following criteria: (1) SS or erythrodermic MF, (2) presence of neoplastic cells in peripheral blood, and (3) early disease onset. Despite the fact that ECP has been established as a standard treatment modality, no prospective randomized study has been conducted so far, to the authors' knowledge. Considering the high cost of the procedure, the role of ECP in the treatment of SS/MF needs to be clarified via well designed multicenter prospective randomized trials.
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Pichardo DA, Querfeld C, Guitart J, Kuzel TM, Rosen ST. Cutaneous T-Cell Lymphoma: A Paradigm for Biological Therapies. Leuk Lymphoma 2009; 45:1755-65. [PMID: 15223633 DOI: 10.1080/10428190410001693560] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Mycosis Fungoides and Sézary Syndrome are the most common types of cutaneous T-cell lymphomas. There is no current standard of care for Mycosis Fungoides/Sézary Syndrome, with a general tendency to rely on topical interventions for early disease delaying systemic, more toxic therapy until the development of extensive symptoms. Knowledge of the biological characteristics of this disease has allowed for the development of rational interventions and a significant advance in its treatment. Retinoids are active in Mycosis Fungoides/Sézary Syndrome with the newer rexinoids being available in topical and systemic forms. Interferon alpha remains one of the most active therapeutic agents for Mycosis Fungoides/Sézary Syndrome, especially in combination with other agents such as PUVA. The monoclonal antibody alemtuzumab leads to responses in at least half of patients with advanced disease with its side effect profile consisting mainly of immunosupression and infusion reactions. The recombinant IL2-diphteria toxin denileukin diftitox (Ontak) is active in this disease and appears to have a beneficial effect in symptoms relief and quality of life. Extracorporeal photochemotherapy as an immunostimulating intervention seems to be very effective in a subset of patients, but its availability is limited to less than a hundred centers worldwide. Experimental and less studied interventions include autologous and allogeneic peripheral stem cell transplantation, Interleukin-12, the histone-deacetylator depsipeptide and the synthetic deoxynucleotide CpG7909. Cutaneous T-cell lymphoma has served as a paradigm for the development of biological agents. Further knowledge of the signaling pathways in Mycosis Fungoides/Sézary Syndrome will allow for the development of more effective treatment strategies.
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Affiliation(s)
- D A Pichardo
- Division of Hematology-Oncology, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine of Northwestern University, Chicago, IL 60611, USA.
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Abstract
Photopheresis, originally developed in dermatology, has become a treatment method accepted across various disciplines. A basic knowledge of photomedicine and photobiology is one of the cornerstones of dermatology. Even if photopheresis is used for indications that are not specifically dermatological, e.g. graft-versus-host disease or Crohn's disease, an experienced dermatologist trained in the use of photopheresis should therefore always be consulted.
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Abstract
Mycosis fungoides and Sézary syndrome are the most common of the cutaneous T-cell lymphomas, which are a heterogeneous group of neoplasms that affect the skin as a primary site. Although the aetiologies of mycosis fungoides and Sézary syndrome are unknown, important insights have been gained in the immunological and genetic perturbations that are associated with these diseases. Unlike some B-cell lymphomas, cutaneous T-cell lymphomas as a group are rarely if ever curable and hence need chronic-disease management. New approaches to treatments are being investigated and include biological and cytotoxic drugs, phototherapy, and monoclonal antibodies that are directed towards novel molecular targets. New molecular technologies such as complementary-DNA microarray have the potential to increase the accuracy of diagnosis and provide important prognostic information. Treatments can be combined to greatly improve clinical outcome without substantially increasing toxic effects in advanced disease that is otherwise difficult to treat. Although present treatment strategies are generally not curative, there is hope that experimental treatments, particularly immunotherapy, might eventually reverse or suppress the abnormalities of mycosis fungoides and Sézary syndrome to the point at which they become non-life-threatening, chronic diseases.
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Affiliation(s)
- Sam T Hwang
- Dermatology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, USA.
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Kuo PH, McClennan BL, Carlson K, Wilson LD, Edelson RL, Heald PW, Girardi M. FDG-PET/CT in the Evaluation of Cutaneous T-Cell Lymphoma. Mol Imaging Biol 2008; 10:74-81. [DOI: 10.1007/s11307-007-0127-y] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2007] [Revised: 10/31/2007] [Accepted: 11/02/2007] [Indexed: 02/06/2023]
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Miller JD, Kirkland EB, Domingo DS, Scull H, Jekutis B, Dallas M, Cooper KD, Baron ED. Review of extracorporeal photopheresis in early-stage (IA, IB, and IIA) cutaneous T-cell lymphoma. PHOTODERMATOLOGY PHOTOIMMUNOLOGY & PHOTOMEDICINE 2007; 23:163-71. [PMID: 17803594 DOI: 10.1111/j.1600-0781.2007.00300.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
BACKGROUND Extracorporeal photopheresis (ECP) has been used for nearly 20 years for the treatment of cutaneous T-cell lymphoma (CTCL). A substantial body of literature reports that this form of photoimmunotherapy improves or stabilizes the course of disease in a subset of patients across all stages. However, current clinical approach usually reserves ECP for patients who do not respond to other treatments or for patients with late-stage disease or Sézary syndrome (SS). METHODS A comprehensive Pubmed/Medline literature search was performed to identify studies reporting the use and efficacy of ECP in early stage (IA, IB, and IIA) CTCL. Information regarding prognostic factors and survival of early-stage patients treated with ECP was also obtained and summarized. RESULTS The heterogenous nature of the reports and lack of any prospective randomized trials made evaluation of response to treatment difficult. However, the current literature contains at least 124 early-stage patients treated with ECP or ECP plus adjuvant therapy from 1987-2007 in 16 different reports. Response rates of treatment for this patient population with ECP and ECP plus adjuvant therapy varied from 33-88%. CONCLUSIONS Given the very low side effect profile of ECP compared with other therapies and its demonstrated efficacy, this treatment modality is possibly beneficial for patients with earlier stages of CTCL. Randomized prospective studies are needed to establish the role of ECP in this disease subset.
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Affiliation(s)
- Janine D Miller
- Department of Dermatology, Case Western Reserve University, University Hospitals of Cleveland, Cleveland, OH 44106, USA.
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Gniadecki R, Assaf C, Bagot M, Dummer R, Duvic M, Knobler R, Ranki A, Schwandt P, Whittaker S. The optimal use of bexarotene in cutaneous T-cell lymphoma. Br J Dermatol 2007; 157:433-40. [PMID: 17553039 DOI: 10.1111/j.1365-2133.2007.07975.x] [Citation(s) in RCA: 113] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The management goal in cutaneous T-cell lymphomas (CTCLs) is to improve symptoms and induce remission. Early-stage disease is generally treated with skin-directed therapies. However, if these do not control the disease, systemic therapy becomes necessary. Bexarotene, a novel rexinoid, is an oral, noncytotoxic drug that has been approved in Europe for the treatment of refractory advanced-stage CTCL and in the U.S.A. for refractory CTCL. We provide guidance on the use of bexarotene in the management of CTCL, based on data from phase II/III clinical trials and the authors' clinical experience, and suggest how the potential of the drug can be maximized. The clinical trial results with bexarotene are reviewed, especially in comparison with interferon-alpha, which is the other commonly used noncytotoxic systemic therapy for CTCL. A treatment algorithm for bexarotene in refractory CTCL is suggested. As bexarotene may take time to achieve a maximum response, this algorithm recommends that therapy should be continued for a sufficient period to allow for a delayed onset of action. In addition, possible combination therapies with bexarotene are discussed. We conclude that bexarotene is effective in the management of CTCL, and has the advantage of oral administration. An on-going randomized clinical trial comparing psoralen plus ultraviolet A (PUVA) with PUVA plus bexarotene will provide valuable information about this combination regimen in early-stage disease, but further data are needed on the relative efficacies of other combination therapies with bexarotene in CTCL.
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Affiliation(s)
- R Gniadecki
- Department of Dermatology, University of Copenhagen, Bispebjerg Hospital, Bispebjerg bakke 23, DK-2400 Copenhagen, Denmark.
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17
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Shofner JD, Vasquez JG, Berger CL, Edelson RL. Improved generation of anti-tumor immunity by antigen dose limitation. JOURNAL OF IMMUNE BASED THERAPIES AND VACCINES 2007; 5:2. [PMID: 17291350 PMCID: PMC1800896 DOI: 10.1186/1476-8518-5-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/18/2006] [Accepted: 02/09/2007] [Indexed: 11/10/2022]
Abstract
Background The malignant cells of cutaneous T cell lymphoma (CTCL) display immunogenic peptides derived from the clonal T cell receptor (TCR) providing an attractive model for refinement of anti-tumor immunization methodology. To produce a clinically meaningful anti-tumor response, induction of cytotoxic anti-CTCL cells must be maximized while suppressive T regulatory cells (Treg) should be minimized. We have demonstrated that engulfment of apoptotic CTCL cells by dendritic cells (DC) can lead to either CD8 anti-CTCL responses or immunosuppressive Treg induction. Treg generation is favored when the number of apoptotic cells available for ingestion is high. Methods In this study, we sought to determine whether the balance between immunity and immunosuppression could be shifted towards a CD8 anti-CTCL response by lowering the ratio of apoptotic CTCL cells available for DC ingestion. CTCL cell apoptosis was produced by engagement of the TCR by anti-CD3 antibody affixed to magnetic beads. Results The physical perturbation inherent in passage through a separation column induced monocytes to differentiate into DC, demonstrated by increased expression of class II and CD86 and decreased expression of the monocyte marker CD14. The immature DC internalized and processed apoptotic CTCL cells and could potentially present the tumor-derived peptides in the context of MHC class I and II. As the number of apoptotic cells increased, there was a dose-dependent increase in the expression of Treg markers CTLA-4, CD25, and FoxP3, with a ratio of apoptotic cell/DC loading of > 10:1 corresponding to the greatest Treg induction. These inducible phenotypic Treg also functionally inhibited CD8-mediated perforin expression in vitro. At lower levels of apoptotic cell/DC loading of < 5:1, there was an expansion of the CD8 T cell compartment with increased perforin expression and increased CTCL cell death, indicating anti-tumor activity. Conclusion These findings demonstrate that the ratio of apoptotic cells supplied to DC is an important determinant of whether CD8 anti-tumor immunity or immunosuppression is generated.
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Affiliation(s)
- Joshua D Shofner
- Department of Dermatology, Yale University, 333 Cedar Street, New Haven, CT USA
| | - Juan G Vasquez
- Department of Dermatology, Yale University, 333 Cedar Street, New Haven, CT USA
| | - Carole L Berger
- Department of Dermatology, Yale University, 333 Cedar Street, New Haven, CT USA
| | - Richard L Edelson
- Department of Dermatology, Yale University, 333 Cedar Street, New Haven, CT USA
- Yale Comprehensive Cancer Center, Yale University, 333 Cedar Street, New Haven, CT USA
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Efficacy and tolerability of currently available therapies for the mycosis fungoides and Sezary syndrome variants of cutaneous T-cell lymphoma. Cancer Treat Rev 2007; 33:146-60. [PMID: 17275192 DOI: 10.1016/j.ctrv.2006.08.006] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2006] [Revised: 08/30/2006] [Accepted: 08/31/2006] [Indexed: 12/17/2022]
Abstract
Primary cutaneous T-cell lymphomas are a heterogenous group of non-Hodgkin lymphomas. The characteristic clinicopathologic and immunophenotypic features and prognoses of the various cutaneous lymphomas have been recently described by the World Health Organization and European Organization for Research and Treatment of Cancer. Cutaneous T-cell lymphoma variants include mycosis fungoides and Sezary syndrome, which are generally associated, respectively, with indolent and aggressive clinical courses and are the subject of this review. Currently utilized treatments for cutaneous T-cell lymphoma include skin-directed therapies (topical agents such as corticosteroids, mechlorethamine, carmustine, and retinoids, phototherapy, superficial radiotherapy, and total skin electron beam therapy), systemic therapies (photophoresis, retinoids, denileukin diftitox, interferons, and chemotherapy), and stem cell transplantation (autologous and allogeneic). This review will describe recent advances in our understanding of the biology (immunologic, cytogenetic, and genetic) of cutaneous T-cell lymphomas and discuss the efficacy and tolerability of the current therapeutic options for cutaneous T-cell lymphomas. Disease progression in over 20% of patients with early stages of disease and the current lack of a definitive treatment which produces durable responses in advanced stages of disease indicates a critical unmet need in CTCL. New insights into the molecular and immunologic changes associated with cutaneous T-cell lymphomas should ultimately lead to the identification of novel therapeutic targets and the development of improved therapeutic options for patients with these malignancies.
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Marshall SR. Technology insight: ECP for the treatment of GvHD--can we offer selective immune control without generalized immunosuppression? ACTA ACUST UNITED AC 2006; 3:302-14. [PMID: 16757968 DOI: 10.1038/ncponc0511] [Citation(s) in RCA: 85] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2005] [Accepted: 03/09/2006] [Indexed: 12/21/2022]
Abstract
Hematopoietic stem-cell transplantation remains an important curative therapy for many conditions and its use is increasing annually. Graft-versus-host disease (GvHD) is the major cause of mortality and suffering following allogeneic hematopoietic stem-cell transplantation. Conventional treatments are associated with multiple side effects and are often ineffective. New therapeutic approaches for the control of GvHD are desperately required. Extracorporeal photochemotherapy (ECP) was developed in the 1970s for the treatment of cutaneous T-cell lymphoma and was approved by the FDA as the first selective immunotherapy for a cancer. ECP has also proved an effective therapy for immune-related conditions, particularly GvHD, even in patients refractory to conventional therapies. The treatment involves the mechanical separation of circulating white cells, which are exposed to psoralen and UVA light and then returned to the patient. ECP is extremely well tolerated with minimal side effects and is not associated with the increased rates of infection or relapse of malignant disease typical of conventional immunosuppressive agents. Thus, ECP appears to offer selective immune modulation without generalized immunosuppression, but its mechanism of action remains poorly understood. This review discusses the development of ECP, its use in the treatment of GvHD, as well as current theories of its mechanism of action.
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Affiliation(s)
- Scott R Marshall
- Department of Haematological Sciences, School of Clinical and Laboratory Sciences, Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, UK.
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20
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Couriel DR, Hosing C, Saliba R, Shpall EJ, Anderlini P, Rhodes B, Smith V, Khouri I, Giralt S, de Lima M, Hsu Y, Ghosh S, Neumann J, Andersson B, Qazilbash M, Hymes S, Kim S, Champlin R, Donato M. Extracorporeal photochemotherapy for the treatment of steroid-resistant chronic GVHD. Blood 2006; 107:3074-80. [PMID: 16368882 DOI: 10.1182/blood-2005-09-3907] [Citation(s) in RCA: 198] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
Chronic graft-versus-host disease (GVHD) is a major limitation of successful allogeneic hematopoietic stem cell transplantation (HSCT). Extracorporeal photochemotherapy (ECP) has been tested extensively in small cohorts of patients with chronic GVHD. In this study, we retrospectively evaluated 71 patients with severe chronic GVHD treated with ECP. Response rate was 61% (n = 43), and 14 patients had complete responses (CRs). The best responses were observed in skin, liver, oral mucosa, and eye. Factors affecting outcomes were assessed in the less heavily pretreated subgroup (n = 63). Thrombocytopenia was associated with a lower response rate (P = .04), and there was a trend toward a higher response rate in de novo chronic GVHD. At 6 months, a total of 27 (69%) of 39 patients who were alive continued to have a sustained response (CR 4 [10%] of 39, and partial response [PR] 23 [59%] of 39). The cumulative incidence of steroid discontinuation at 1 year was 22%. The overall survival since initiation of therapy was 53% at 1 year. Response to ECP and platelet count at initiation of therapy were the strongest predictors of nonrelapse mortality (NRM) on univariate analysis. Objective responses were observed in a substantial number of patients with both skin and visceral chronic GVHD failing corticosteroids and other immunosuppression.
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MESH Headings
- Adolescent
- Adult
- Aged
- Anemia, Aplastic/complications
- Anemia, Aplastic/mortality
- Anemia, Aplastic/pathology
- Anemia, Aplastic/therapy
- Anemia, Sickle Cell/complications
- Anemia, Sickle Cell/mortality
- Anemia, Sickle Cell/pathology
- Anemia, Sickle Cell/therapy
- Breast Neoplasms/complications
- Breast Neoplasms/mortality
- Breast Neoplasms/pathology
- Breast Neoplasms/therapy
- Child
- Child, Preschool
- Chronic Disease
- Disease-Free Survival
- Drug Resistance/drug effects
- Eye/pathology
- Female
- Graft vs Host Disease/etiology
- Graft vs Host Disease/mortality
- Graft vs Host Disease/pathology
- Graft vs Host Disease/therapy
- Hematopoietic Stem Cell Transplantation/methods
- Hematopoietic Stem Cell Transplantation/mortality
- Humans
- Immunosuppression Therapy/adverse effects
- Immunosuppression Therapy/methods
- Immunosuppression Therapy/mortality
- Liver/pathology
- Lymphoproliferative Disorders/mortality
- Lymphoproliferative Disorders/pathology
- Male
- Middle Aged
- Mouth Mucosa/pathology
- Photopheresis/methods
- Photopheresis/mortality
- Retrospective Studies
- Skin/pathology
- Steroids/adverse effects
- Steroids/therapeutic use
- Thrombocytopenia/pathology
- Transplantation, Homologous
- Treatment Outcome
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Affiliation(s)
- Daniel R Couriel
- Department of Blood and Marrow Transplantation, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 423, Houston, TX 77030, USA.
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21
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Abstract
Cutaneous T-cell lymphomas are a heterogeneous group of rare lympho-proliferative disorders. In most cases, they are characterised by the accumulation of clonal CD4+ lymphocytes in the skin. Extracutaneous involvement is present in late stages only. Unfortunately, only few drugs are registered for these disfiguring diseases. Skin-directed therapies using topical formulations are the preferred first-line modalities for cutaneous lesions in early stages. In this field there are interesting developments using topical retinoids and gene therapy products, such as adeno-IFN-gamma. Systemic treatment uses biologicals, such as fusion molecules, monoclonal antibodies and immune response modifiers (IFNs, retinoids), and well-tolerated antiproliferative drugs, such as histone deacetylase inhibitors or liposomal doxorubicin.
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Affiliation(s)
- Reinhard Dummer
- Department of Dermatology, University Hospital of Zürich, Gloriastrasse 31, CH-8091 Zürich, Switzerland.
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22
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Karagiannis TC, Lobachevsky PN, Martin RF. DNA targeted UVA photosensitization: characterization of an extremely photopotent iodinated minor groove binding DNA ligand. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY 2006; 83:195-204. [PMID: 16488619 DOI: 10.1016/j.jphotobiol.2005.12.013] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/24/2005] [Revised: 12/15/2005] [Accepted: 12/15/2005] [Indexed: 11/29/2022]
Abstract
Previous studies have described UVA-induced DNA strand breakage at the binding sites of iodinated DNA minor groove binding bisbenzimidazoles. The DNA breakage, presumably mediated by the carbon-centred ligand radical produced by photodehalogenation, was also shown to be cytotoxic. The earlier studies included a comparison of three ligand isomers, designated ortho-, meta- and para-iodoHoechst, and the efficiency of photo-induction of strand breaks in plasmid DNA proved to be much higher for the ortho-isomer. We have now extended the comparison of the three isomers with respect to photo-induced cytotoxicity in K562 cells. Although the relationship between the extent of nuclear uptake and the concentration of the ligand in the medium was similar for the three isomers, assay of in situ dehalogenation in drug-treated cells indicated that the apparent cross-section for dehalogenation of the ortho-isomer was greater than 5-fold higher than that for the meta- and para-isomers. Also, analysis of clonogenic survival data showed that the dehalogenation event associated with ortho-iodoHoechst was a more efficient mediator of UVA-induced cytotoxicity in K562 cells than that for meta- or para-iodoHoechst. The number of dehalogenation events associated with 50% cell-kill for ortho-iodoHoechst (1.23+/-0.04 x 10(4)) was less than that for the para- (3.92+/-0.29 x 10(4)) and meta- (11.6+/-0.90 x 10(4)) isomers. Thus it is concluded that the photopotency of ortho-iodoHoechst, which is an important feature in the context of its potential use in clinical phototherapy, is due not only to more efficient UVA-mediated dehalogenation of the ligand, but also to greater cytotoxic potency per dehalogenation event.
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Affiliation(s)
- Tom C Karagiannis
- Trescowthick Research Laboratories, Peter MacCallum Cancer Centre, Molecular Radiation Biology Laboratory, Locked Bag No. 1, A'Beckett Street, Melbourne, Vic. 8086, Australia
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23
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Bladon J, Taylor PC. Lymphocytes treated by extracorporeal photopheresis can down-regulate cytokine production in untreated monocytes. PHOTODERMATOLOGY PHOTOIMMUNOLOGY & PHOTOMEDICINE 2005; 21:293-302. [PMID: 16313240 DOI: 10.1111/j.1600-0781.2005.00192.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Pro-inflammatory cytokines are actively involved in graft-versus host-disease (GvHD) aetiology. Treatment of GvHD, using extracorporeal photopheresis (ECP), has demonstrated clinical efficacy. ECP rapidly reduces the number of T cells that produce tumour necrosis factor alpha (TNFalpha), interferon gamma (IFNgamma) and interleukin (IL)2. ECP-treated cells are re-infused immediately after completion of treatment. This study attempted to determine the influence that ECP-treated cells would have on untreated cells following re-infusion. METHODS Heparinized samples were taken from 10 chronic GvHD patients, pre-ECP and immediately prior to re-infusion (post-ECP). Lymphocytes and monocytes were isolated using magnetic separation. The post-ECP lymphocytes were mixed with pre-ECP monocytes, while the post-ECP monocytes and pre-ECP lymphocytes were combined. After suitable stimulation, the T cells were tested for intracellular TNFalpha, IFNgamma and IL2, while the monocytes were evaluated for TNFalpha, IL1alpha, IL1beta, IL6 and IL8. RESULTS Although cytokine secretion is decreased in T cells exposed to ECP, pre-ECP T cells were unaffected by post-ECP monocytes. Post-ECP monocytes demonstrated a reduction in cytokine secretion. Furthermore, untreated monocytes down-regulated cytokine production following exposure to ECP-treated lymphocytes. CONCLUSION ECP has both a direct and indirect immunosuppressive action, both of which may be beneficial in the treatment of GvHD.
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Affiliation(s)
- John Bladon
- Department of Haematology, Rotherham General Hospital, South Yorkshire, UK.
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24
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McKenna KE, Whittaker S, Rhodes LE, Taylor P, Lloyd J, Ibbotson S, Russell-Jones R. Evidence-based practice of photopheresis 1987-2001: a report of a workshop of the British Photodermatology Group and the U.K. Skin Lymphoma Group. Br J Dermatol 2005; 154:7-20. [PMID: 16403088 DOI: 10.1111/j.1365-2133.2005.06857.x] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Photopheresis or extracorporeal photochemotherapy (ECP) is a novel immunomodulatory therapy which involves separation of the patient's leucocyte-rich plasma, followed by ex vivo administration of a photosensitizer and ultraviolet A radiation, before reinfusion. ECP has been used successfully for the treatment of cutaneous T-cell lymphoma (CTCL: Sézary syndrome), graft-versus-host disease (GVHD) and cardiac transplant rejection. ECP has a dose-sparing effect on concurrent immunosuppressive therapy. The procedure induces apoptosis of the irradiated lymphocytes, but the exact mechanism by which ECP exerts its therapeutic effect in these different conditions is uncertain. The treatment has very few adverse effects and in particular is not associated with an increased incidence of opportunistic infections. The evidence for the efficacy of ECP has been appraised by a combined British Photodermatology Group and U.K. Skin Lymphoma Group workshop on the basis of evidence published up to the end of 2001 and on the consensus of best practice. There is fair evidence for the use of ECP in erythrodermic CTCL and steroid-refractory GVHD, but randomized controlled studies are needed. There is good evidence supporting the use of ECP in preventing cardiac rejection following transplantation. Randomized controlled trials have also shown a therapeutic benefit in type 1 diabetes mellitus, but the inconvenience associated with the procedure outweighed the clinical benefit. There is fair evidence not to use ECP for the treatment of systemic sclerosis and multiple sclerosis, and good evidence not to use ECP for other forms of CTCL.
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Affiliation(s)
- K E McKenna
- Department of Dermatology, Belfast City Hospital, Belfast, UK.
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25
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Ivancic E, Knobler R, Quehenberger P, Hönigsmann H, Trautinger F. The course of anticoagulation after extracorporeal photochemotherapy. PHOTODERMATOLOGY PHOTOIMMUNOLOGY & PHOTOMEDICINE 2005; 21:150-1. [PMID: 15888132 DOI: 10.1111/j.1600-0781.2005.00127.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
During extracorporeal photochemotherapy (ECP) heparin is added to the extracorporeal circulation to avoid clotting. It has not been investigated whether and to what extend this procedure influences coagulation in patients after ECP. In this study activated partial thrombaplastin time (aPTT) and anti-factor Xa were monitored for up to 4 h after ECP in 10 patients. We found that anticoagulation followed the typical course of intravenously applied heparin: immediately after reinfusion anti-Xa was high (>1 IU/ml) and aPTT was prolonged to more than 180 s followed by a rapid decline and reaching normal values within 3-4 h in all patients. We conclude that anticoagulation and increased risk of bleeding after ECP is confined to a short period immediately following treatment. Physicians using ECP should be aware of the course of anticoagulation associated with this treatment.
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Affiliation(s)
- E Ivancic
- Department of Dermatology, Division of Special and Environmental Dermatology, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria.
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26
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Wollina U, Wurbs C, Schönlebe J. Papulose linfomatóide: relato de dois casos. An Bras Dermatol 2005. [DOI: 10.1590/s0365-05962005000200006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
A papulose linfomatóide (PL) constitui uma variante rara dos linfomas cutâneos de células T com a presença de amplo infiltrado intracutâneo de células T positivas para CD30. O exame histológico sugestivo de doença altamente maligna e agressiva opõe-se ao curso crônico-recidivante, muitas vezes auto-limitado, presente na maioria dos casos. São apresentados os relatos de dois pacientes. Uma mulher com 64 anos de idade e história de 10 anos de PL recebeu terapia Puva em creme, sendo a doença controlada. No segundo caso, uma mulher de 42 anos apresentava história de 18 anos de PL tratada com Puva e, posteriormente, com fotoquimioterapia extracorpórea (FEC). Durante a FEC, observou-se rápida disseminação metastática que não pôde ser controlada por poliquimioterapia. A paciente foi a óbito após um ano, em razão de metástase no sistema nervoso central.
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Affiliation(s)
- Uwe Wollina
- Ensino Acadêmico Dresden-Friedrichstadt, Alemanha
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27
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Beyeler M, Dummer R. [Standard and experimental therapy of cutaneous T-cell lymphoma]. Hautarzt 2003; 54:1177-84. [PMID: 14634747 DOI: 10.1007/s00105-003-0630-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Cutaneous T-cell lymphoma represent a heterogeneous group of diseases characterized by skin invasion of monoclonal T-lymphocytes. These cutaneous T-cell lymphomas are divided into 3 groups based on clinical, histological and immunohistological characteristics: Indolent with a survival time of over 10 years, aggressive with a survival time less than 10 years and provisional (EORTC classification). Standard treatments such as PUVA, total skin electron beam, methotrexate, polychemotherapy regimens, retinoids and photopheresis have been used for years. Bexarotene is a newly registered drug. To achieve better response rates, several new drugs are being evaluated in clinical trails, including imiquimod, denileukon-diftitox, liposomal doxorubicin, adeno-interferon-gamma and various combination approaches.
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MESH Headings
- Adrenal Cortex Hormones/administration & dosage
- Adrenal Cortex Hormones/therapeutic use
- Aminoquinolines/therapeutic use
- Antibiotics, Antineoplastic/administration & dosage
- Antibiotics, Antineoplastic/therapeutic use
- Anticarcinogenic Agents/administration & dosage
- Anticarcinogenic Agents/therapeutic use
- Antimetabolites, Antineoplastic/administration & dosage
- Antimetabolites, Antineoplastic/therapeutic use
- Antineoplastic Agents/administration & dosage
- Antineoplastic Agents/therapeutic use
- Antineoplastic Agents, Alkylating/administration & dosage
- Antineoplastic Agents, Alkylating/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Bexarotene
- Chlorambucil/administration & dosage
- Chlorambucil/therapeutic use
- Clinical Trials as Topic
- Cyclophosphamide/therapeutic use
- Doxorubicin/administration & dosage
- Doxorubicin/therapeutic use
- Humans
- Imiquimod
- Interferon alpha-2
- Interferon-alpha/administration & dosage
- Interferon-alpha/therapeutic use
- Lymphoma, T-Cell/classification
- Lymphoma, T-Cell/drug therapy
- Lymphoma, T-Cell/mortality
- Lymphoma, T-Cell/radiotherapy
- Lymphoma, T-Cell/therapy
- Methotrexate/administration & dosage
- Methotrexate/therapeutic use
- PUVA Therapy
- Photopheresis
- Prednisone/therapeutic use
- Radioisotope Teletherapy
- Radiotherapy Dosage
- Radiotherapy, High-Energy
- Recombinant Proteins
- Retinoids/administration & dosage
- Retinoids/therapeutic use
- Skin Neoplasms/classification
- Skin Neoplasms/drug therapy
- Skin Neoplasms/mortality
- Skin Neoplasms/radiotherapy
- Skin Neoplasms/therapy
- Tetrahydronaphthalenes/administration & dosage
- Tetrahydronaphthalenes/therapeutic use
- Vincristine/therapeutic use
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Affiliation(s)
- M Beyeler
- Dermatologische Klinik Universitätsspital Zürich, Zürich
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28
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Abstract
Extracorporeal photochemotherapy was originally conceived for the treatment of cutaneous T-cell lymphoma (CTCL) and as well as other T-cell mediated diseases. Evidence collected in the past 17 years has demonstrated that this treatment modality can have a very significant effect on the course of a subset of CTCL patients. The evidence available is positive but for a variety of reasons has been controversial within the medical community. A number of very well-designed multi-center trials which have been lacking since the first publication by Edelson et al. are being carried out so that hopefully a number of open questions will be resolved with greater clarity in the coming years. The fact remains that this innovative approach for the treatment of CTCL and T-cell mediated diseases has certainly opened new avenues of therapy and thought in photoimmunology and photomedicine. Clearly the very low side effect profile of this therapy has made it more attractive than the chemotherapeutic and immunosuppressive substances that are presently available or in experimental protocols. If and when the mechanisms of action are fully understood and appropriate studies investigating different treatment schedules and different combination therapies and modifications of its present form are performed the place of photopheresis in the therapeutics of CTCL as well as other T-cell mediated diseases and oncology will be better placed.
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Affiliation(s)
- R Knobler
- Division of Special and Environmental Dermatology, Department of Dermatology, Vienna Medical School, University of Vienna, Währinger Gürtel 18-20, Vienna A 1090, Austria.
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29
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Bladon J, Taylor PC. Treatment of cutaneous T cell lymphoma with extracorporeal photopheresis induces Fas-ligand expression on treated T cells, but does not suppress the expression of co-stimulatory molecules on monocytes. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY. B, BIOLOGY 2003; 69:129-38. [PMID: 12633985 DOI: 10.1016/s1011-1344(02)00414-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Following extracorporeal photopheresis (ECP), lymphocytes become apoptotic and upregulate class I MHC antigenic peptides. Conversely, ECP treated monocytes demonstrate activation markers and have an increased avidity for the phagocytosis of apoptotic T cells. Processing of apoptotic T cells by monocytes, following ECP, is thought to induce an immunomodulatory response, which targets untreated, but clonal T cells. Recently we detected apoptotic lymphocytes immediately post ECP. Although enhanced CD95 (Fas) expression has been observed 24 h post ECP, CD95 and Fas-ligand (Fas-L) expression have not been determined at this very early apoptotic stage. Exposure of monocytes to UV has previously suppressed expression of the co-stimulatory molecules required for the presentation of processed antigens to T cells. Our data demonstrate no increase in CD95 or Fas-L expression on T cells tested immediately following ECP. However, the number of T cells expressing Fas-L significantly increased 24 h post ECP (P<0.005). The expression of the co-stimulatory molecules, CD54, CD80 and CD86, remained unaltered on monocytes treated by ECP. Although the mechanism responsible for early induction of lymphocyte apoptosis remains unclear, the later apoptosis involves Fas-L expression. The maintenance of co-stimulatory molecules, on treated monocytes, indicates that they retain the ability to induce an immunomodulatory response.
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Affiliation(s)
- J Bladon
- Department of Haematology, Rotherham General Hospital, Rotherham, South Yorkshire S60 2UD, UK.
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30
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Heng AE, Sauvezie B, Genestier L, Demeocq F, Dosgilbert A, Deteix P. PUVA apoptotic response in activated and resting human lymphocytes. Transfus Apher Sci 2003; 28:43-50. [PMID: 12620268 DOI: 10.1016/s1473-0502(02)00099-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
In extracorporeal photopheresis (ECP) collected cells are treated by 8 methoxypsoralen and UVA (PUVA) which induced apoptosis. The mechanism of action of reinfused cell is unclear. A vaccination model postulates an efficient presentation of apoptotic alloreactive cells to the patient immune system. The efficiency may depend upon a predominance of apoptotic alloreactive cells after PUVA. Such selectivity could result from their activation. We studied apoptosis in resting and PHA-activated lymphocytes. Both were equally susceptible. Changes in early apoptosis were possibly missed. We evaluated the effect of preincubation before PUVA. During preincubation monocyte could affect lymphocytes susceptibility to apoptosis as an increase of number of apoptotic cells was observed after 72 hours in stimulated and resting cells. Our findings do not preclude a selectivity of other PUVA effects since expression of membrane marker also targets to PUVA is modified by activation.
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Affiliation(s)
- A E Heng
- Service de Néphrologie (Pr Deteix) Henri Dunant BP69 63003, CHU, Clermont-Ferrand Cedex, France.
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