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Management of cutaneous T-cell lymphoma: The future is here
Management of cutaneous T-cell lymphoma: The future is here
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n this issue of the Journal (pages 208-16), Yoo et al1 describe alterations in cytokine production by peripheral blood mononuclear leukocytes after successful treatment of 3 patients with leukemic cutaneous T-cell lymphoma (CTCL) with biologic response modifiers, specifically extracorporeal photopheresis and interferon alfa-2b. Advanced CTCL is associated with up-regulation of so-called helper T cell type 2 (TH2) cytokines (eg, interleukin [IL]-4, IL-5, and IL-10) and down-regulation of TH1 cytokines (including IL-2 and interferon gamma). Many of the immunologic abnormalities associated with advanced CTCL appear to be caused by this cytokine imbalance. Treatment induced a shift from TH2 to TH1 cytokine production and a restitution of natural killer cell function. These findings demonstrate the potential for in vivo reconstitution of immune function among patients with CTCL and suggest a bright future for the role of biologic response modifiers in the treatment of cutaneous lymphomas. Currently in early clinical trials are other promising agents such as IL-12 that may prove maximally effective in combination with additional cytokines such as interferon alfa-2b or IL-2. Beyond its implications for the future of CTCL therapy, the work by Yoo et al also provides evidence that the source of the excess TH2 cytokines is the CTCL tumor clone itself. By using polymerase chain reaction–based assays that detect tumor-specific T-cell receptor gene rearrangements,2 the authors were able to track the disappearance of the malignant clone in response to treatment. These molecular biologic assays are now available at many medical centers and allow clinicians to monitor the response of lymphomas to therapy and to detect early disease relapse with great sensitivity. Although not yet used widely as a treatment end point, these assays can be used to define disease remission with
a level of sensitivity that exceeds that of either clinical examination or routine histopathology. In fact, studies have shown that biopsy specimens of clinically normal skin from patients with CTCL can show a spectrum of findings, ranging from normal to nonspecific lymphoid infiltrates to putative subclinical CTCL.3 Furthermore, our own unpublished observations indicate that nonspecific lymphoid infiltrates remaining in the skin of patients with CTCL in apparent clinical remission can in fact contain residual tumor detectable with molecular biologic assays such as PCR/denaturing gradient gel electrophoresis. Cessation of treatment at this point has led to rapid relapse in some cases, which suggests that this low level of residual disease is clinically significant. It is apparent that we are entering an exciting phase in the history of CTCL management. Basic research in molecular biology and immunology is providing us with powerful new tools for detecting and treating this malignancy. Together, they promise to provide us with a “search and destroy” capability against CTCL that is unprecedented. Gary S. Wood, MD Madison, Wisconsin REFERENCES 1. Yoo EK, Lessin SR, Cassin M, Rook AH. Complete molecular remission during biologic response modifier therapy for Sezary syndrome is associated with enhanced helper T type 1 cytokine production and natural killer cell activity. J Am Acad Dermatol 2001;45:208-16. 2. Wood GS, Dummer R, Haeffner A, Crooks CF. Molecular biology techniques for the diagnosis of cutaneous T-cell lymphoma. Dermatol Clin 1994;12:231-41. 3. Bergman R, Cohen A, Harth Y, Shemer A, Ramon I, Lichtig C, et al. Histopathologic findings in the clinically uninvolved skin of patients with mycosis fungoides. Am J Dermatopathol 1995; 17:452-6.
From the Division of Dermatology, University of Wisconsin. Correspondence: Gary S. Wood, MD, Chairman, Division of Dermatology, University Station Clinics–Dermatology, 2880 University Ave, Madison, WI 53705-0902. J Am Acad Dermatol 2001;45:317. Copyright © 2001 by the American Academy of Dermatology, Inc. 0190-9622/2001/$35.00 + 0 16/1/117050 doi:10.1067/mjd.2001.117050
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n this issue of the Journal (pages 208-16), Yoo et al1 describe alterations in cytokine production by peripheral blood mononuclear leukocytes after successful treatment of 3 patients with leukemic cutaneous T-cell lymphoma (CTCL) with biologic response modifiers, specifically extracorporeal photopheresis and interferon alfa-2b. Advanced CTCL is associated with up-regulation of so-called helper T cell type 2 (TH2) cytokines (eg, interleukin [IL]-4, IL-5, and IL-10) and down-regulation of TH1 cytokines (including IL-2 and interferon gamma). Many of the immunologic abnormalities associated with advanced CTCL appear to be caused by this cytokine imbalance. Treatment induced a shift from TH2 to TH1 cytokine production and a restitution of natural killer cell function. These findings demonstrate the potential for in vivo reconstitution of immune function among patients with CTCL and suggest a bright future for the role of biologic response modifiers in the treatment of cutaneous lymphomas. Currently in early clinical trials are other promising agents such as IL-12 that may prove maximally effective in combination with additional cytokines such as interferon alfa-2b or IL-2. Beyond its implications for the future of CTCL therapy, the work by Yoo et al also provides evidence that the source of the excess TH2 cytokines is the CTCL tumor clone itself. By using polymerase chain reaction–based assays that detect tumor-specific T-cell receptor gene rearrangements,2 the authors were able to track the disappearance of the malignant clone in response to treatment. These molecular biologic assays are now available at many medical centers and allow clinicians to monitor the response of lymphomas to therapy and to detect early disease relapse with great sensitivity. Although not yet used widely as a treatment end point, these assays can be used to define disease remission with
a level of sensitivity that exceeds that of either clinical examination or routine histopathology. In fact, studies have shown that biopsy specimens of clinically normal skin from patients with CTCL can show a spectrum of findings, ranging from normal to nonspecific lymphoid infiltrates to putative subclinical CTCL.3 Furthermore, our own unpublished observations indicate that nonspecific lymphoid infiltrates remaining in the skin of patients with CTCL in apparent clinical remission can in fact contain residual tumor detectable with molecular biologic assays such as PCR/denaturing gradient gel electrophoresis. Cessation of treatment at this point has led to rapid relapse in some cases, which suggests that this low level of residual disease is clinically significant. It is apparent that we are entering an exciting phase in the history of CTCL management. Basic research in molecular biology and immunology is providing us with powerful new tools for detecting and treating this malignancy. Together, they promise to provide us with a “search and destroy” capability against CTCL that is unprecedented. Gary S. Wood, MD Madison, Wisconsin REFERENCES 1. Yoo EK, Lessin SR, Cassin M, Rook AH. Complete molecular remission during biologic response modifier therapy for Sezary syndrome is associated with enhanced helper T type 1 cytokine production and natural killer cell activity. J Am Acad Dermatol 2001;45:208-16. 2. Wood GS, Dummer R, Haeffner A, Crooks CF. Molecular biology techniques for the diagnosis of cutaneous T-cell lymphoma. Dermatol Clin 1994;12:231-41. 3. Bergman R, Cohen A, Harth Y, Shemer A, Ramon I, Lichtig C, et al. Histopathologic findings in the clinically uninvolved skin of patients with mycosis fungoides. Am J Dermatopathol 1995; 17:452-6.
From the Division of Dermatology, University of Wisconsin. Correspondence: Gary S. Wood, MD, Chairman, Division of Dermatology, University Station Clinics–Dermatology, 2880 University Ave, Madison, WI 53705-0902. J Am Acad Dermatol 2001;45:317. Copyright © 2001 by the American Academy of Dermatology, Inc. 0190-9622/2001/$35.00 + 0 16/1/117050 doi:10.1067/mjd.2001.117050
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