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Treatment of angioimmunoblastic T-cell lymphoma with cyclosporine
Annals of Oncology 8 601-603, 1997. O 1997 Kluwer Academic Publishers. Primed in the Netherlands
Short report Treatment of angioimmunoblastic T-cell lymphoma with cyclosporine R. Advani, R. Warnke, B. I. Sikic & S. Horning Department of Medicine, Oncology Division, Stanford University Medical Center, Stanford, CA, USA
Angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) or angioimmunoblastic like (AILD-like) T-cell lymphoma is a rare lymphoproliferative disorder which is frequently associated with acute constitutional symptoms of fever, night sweats and weight loss [1]. Patients may manifest generalized lymphadenopathy, hepatomegaly, a pruritic skin rash, polyclonal hypergammoglobulinemia and anemia. The latter is caused in many cases by Coomb's positive hemolysis [1]. The etiology and underlying pathophysiologic mechanisms of this disease remain uncertain. Evidence based on T-cell receptor gene rearrangements and non-random chromosome anomalies suggests that AILD is a clonal disease [2, 3]. In the Revised European-American Classification of lymphoid neoplasms, AILD has been classified as a peripheral T-cell neoplasm based on its immunophenotypic and genetic features [4]. Because AILD occurs rarely and has a variable clinical course, optimal management has not been established. Prednisone alone achieves a complete response rate of approximately 50% but relapse of disease generally follows [1]. Combination chemotherapy has also been associated with a similar complete response rate but only one-third were durable [1, 5]. Alternate, potentially immunomodulating therapies reported to have activity include alpha interferon [6] and cyclosporine [7]. In this case report, we describe the use of cyclosporine in a patient with angioimmunoblastic T-cell lymphoma and severe hemolytic anemia who failed to respond to prednisone. Because transfusion support was refused by the patient on religious principles, alternatives to myelosuppressive chemotherapy were offered. Case report The patient is a 47-year-old Caucasian female who was admitted to Stanford University Hospital (SUH) in February 1994. One month earlier the patient experienced the acute onset of fever, malaise, night sweats, generalized body rash and lymphadenopathy. She underwent an axillary lymph node biopsy at an outside
facility which was reported to be consistent with AILD. The patient elected alternative therapy with high-dose vitamins without response. Her condition deteriorated and by February 1994 she was noted to have a hemoglobin of 3.4 mg/dl, hematocrit of 9.6%, reticulocyte count 23% and a positive warm antibody direct Coomb's test. She was admitted to SUH with severe resting angina pectoris, fever and generalized lymphadenopathy. Negative tests included fluorescent antinuclear antibody, Veneral Disease Research Laboratory, monospot and human immunodeficiency virus antibody. A serum protein electrophoresis revealed a small gamma spike of 1.2 Gm. A computerized axial tomography scan of the chest showed bilateral axillary lymphadenopathy and the abdomen was negative. A bone marrow evaluation was not done. A lymph node biopsy was repeated which suggested the diagnosis of AILDlike T-cell lymphoma. In situ hybridization studies for Epstein-Barr virus (EBV), did not show increased numbers of EBV-labeled cells. A clonal population of T cells was identified by Southern blot analysis with a probe for the beta chain of the T-cell receptor. Therefore, the final diagnosis was angioimmunoblastic like T-cell lymphoma. Prednisone 100 mg/day was started, along with folate 1 mg/day orally. High-dose intravenous immunoglobulin (IgG), 1 g/kg x 2 days was employed to arrest the hemolytic anemia. Vincristine 2 mg i.v. was also administered. In spite of these measures, after two weeks, the patient's hematocrit remained 9.0% with a hemoglobin of 3.5 mg/dl. Because tranfusion support was refused by the patient, a Jehovah's Witness, myelosuppressive chemotherapy could not be offered. Likewise, the patient was considered a poor risk for splenectomy. Based on a literature search which indicated that cyclosporin A had been used successfully in two patients [7], therapy was begun with cyclosporine 300 mg p.o. BID six weeks after unsuccessful treatment with prednisone, vincristine and IgG had been initiated. One week later, the dose was increased to 400 mg p.o. BID as a cyclosporine level was 116 mg/ml. Within one week of starting cyclosporine her hematocrit rose to 15.4%
Downloaded from https://academic.oup.com/annonc/article-abstract/8/6/601/197913 by guest on 26 July 2019
Key words: AILD, angioimmunoblastic T-cell lymphoma, cyclosporine
602
Discussion The etiology and pathogenesis leading to the development of angioimmunoblastic like T-cell lymphoma are unclear. It is generally believed that angioimmunoblastic like T-cell lymphoma develops from a background of immune dysregulation because patients frequently present with a history of allergic reactions to various drugs or viral infection [1]. Increased polyclonal and rarely monoclonal serum proteins are thought to reflect an abnormal stimulation of lymphocytes [1]. Cytogenetic evaluation suggests that most cases are clonal and this is further confirmed by T-cell receptor (TCR) gene rearrangements in the majority of cases [2]. TCR genes are rearranged in 75% of cases and immunoglobulin heavy chains in 10% [4]. Tumor cells express T-cellassociated antigens and are usually CD4 positive. Trisomy 3 and/or 5 may occur [2]. EBV genomes are detected in many cases [8]. Various treatment modalities have been employed including steroids, cytotoxic chemotherapy and immunomodulators [1, 5, 6, 7]. Our patient did not respond to
90
120
150
Days Figure I. Correlation of hematocrit wilh therapeutic interventions over time. IgG - intravenous immunoglobulin; CsA - cyclosporine.
prednisone alone, and since she was unwilling to be tranfused due to religious beliefs, we felt that myelosuppressive agents carried an unusually high risk. A dramatic response to cyclosporine therapy occured with rapid rise in hematocrit from 9% to 30% in three weeks. It can be argued that this was a delayed steroid, vincristine or immunoglobulin effect, but we believe this is unlikely given the time course and rapidity of response. The immunosuppressive fungal metabolite cyclosporine was first used in clinical practice in the transplantation setting. One major advantage of cyclosporine over cytotoxic agents is its specific interference in T-cell expansion after antigen recognition. Thus it inhibits transplanted organ rejection without causing significant myelosuppression. Although incompletely characterized, the immunosuppression observed with cyclosporine is thought to be the result of an inhibition of transcription of cytokines, especially theT-helper growth factor interleukin-2 (IL-2) [9]. The mechanisms by which cyclosporine inhibits cytokine transcription and clonal T-cell expansion are unclear. Evidence suggests that the immunosuppressive properties of cyclosporine are mediated by the cytoplasmic protein cyclophilin [10] which results in inhibition of the protein phosphatase calcineurin. Calcineurin has recently been established as a key signalling enzyme in the T-cell signal transduction cascade and an important regulator of transcription factors such as NF-AT and OAP/Oct-1, which are involved in the expression of a number of important T-cell early genes [11]. It has been hypothesized that the complex of cyclosporine-cyclophilin interferes with the expression or activity of DNA binding proteins that are involved in the transcription of early T-cell activation genes [12], Therefore, in diseases in which abnormal T cells induce B-cell hyperactivity, cyclosporine is believed to block the production of IL-2, and the interaction between T and B cells. These effects may contribute to the control of proliferative events seen in AILD patients. Further support for this hypothesis comes from experience with other disorders with immune mediated components such as auto immune hemolytic anemia (AIHA) associated with chronic lymphocytic leukemia (CLL)
Downloaded from https://academic.oup.com/annonc/article-abstract/8/6/601/197913 by guest on 26 July 2019
and three weeks later was 25.2% (Figure 1). At that point the prednisone dose was reduced and she was maintained on oral prednisone 10 mg/5 mg alternating doses. Four weeks after cyclosporine was initiated, the cyclosporine dose was gradually tapered and the patient was maintained at 100 mg BID with an hematocrit above 30%. At this point she was asymptomatic with no palpable lymphadenopathy. Four months later, while she was on maintainence doses of prednisone and cyclosporine, the patient presented with high grade fever and a diffuse, generalized erythematous rash. Her hematocrit was 27.0%. A skin biopsy was consistent with angioimmunoblastic like T-cell lymphoma. Prednisone and cyclosporine were both re-initiated at higher doses (80 mg/day and 400 mg/day respectively). As she had a stable hematocrit at this presentation, oral cyclophosphamide was also started at 100 mg p.o. QD. Her symptoms were significantly better in one week. Cyclophosphamide was discontinued after nine months. The prednisone was tapered over nine weeks and maintained at 10 mg/5 mg alternating doses. Her CsA was tapered to 50 mg BID over nine months, then to 25 mg BID, and finally discontinued in January, 1996. She has been maintained on low-dose prednisone 5 mg/day along wih prophylaxis against Pneumocystis carini pneumonia with pentamidine inhalations for the past year. Currently the patient is asymptomatic with a stable hematocrit of 34.0%. In summary, this patient achieved a remission of angioimmunnoblastic like T-cell lymphoma for four months after cyclosporine therapy was initiated. Upon relapse she was retreated with cyclosporine, prednisone and cyclophosphamide and is now in remission for 2.5 years. Overall she has tolerated the treatment extremely well with no evidence of nephrotoxicity.
603 Table 1 Clinical features and response to cyclosponne in four patients with AILD or AlLD-likeT-cell lymphoma. Anemia
Prior treatments
Response to CsA
Reference no.
62/F
NA
CR
7
54/F 68/M
Mild None
CR CR
7 16
47/F
Severe
Prednisone, CVP, CVP + anthracycline, prednisone + ifosfamide, mitoxantrone, cytoxan, vindesine, interferon None Vincnstine, cytoxan, prednisone, doxorubicin, methotrexate, etoposide PTednisone, IgG, vincristine
CR
Tr This report
Age/Sex
Fever
Lymphadenopathy
Hepatosplenomegaly
6.
7. 8.
9.
10
11.
12. 13.
14.
15.
16.
References 1. Freter C, Cossman J. Angioimmunoblastic lymphadenopathy with dysproteinemia. Semin Oncol 1993; 20: 627-35. 2. Schlegelberger B, Feller A, Godde-Salz E et al. Stepwise development of chromosomal abnormalities in angioimmunoblastic lymphadenopathy. Cancer Genet Cytogenet 1990; 50: 15-29. 3. Weiss L, Stnckler J, Dorfman R et al. Clonal T-cell populations in angioimmunoblastic lymphadenopathy and angioimmunoblastic lymphadenopathy like lymphoma. Am J Path 1986; 122: 392-7. 4. Harris N, Jaffe ES, Stein H et al. A Revised European-American Classification of Lymphoid neoplasms: A proposal from the International Lymphoma Study Group. Blood 1994; 84: 1361-92. 5. Siegert W, Agthe A, Gnesser Het al. Treatment of angioimmuno-
blastic lymphadenopathy (AILD)-type - T-cell lymphoma using prednisone with or without the COPBLAM/IMVP-16 regimen Ann Intern Med 1992; 117: 364-7. Siegert W, Nerl C, Meuthen I et al . Recombinant human interferon-alpha in the treatment of angioimmunoblastic lymphadenopathy. Results in 12 patients. Leukemia 1991, 5: 892-5. Murayama T, Imoto S, Takahashi Tet al Successful treatment of AILD with cyclosponn A. Cancer 1992; 69: 2567-70. Weiss L, Jaffe E, Liu X et al. Detection and localization of Epstein-Barr viral genomes in angioimmunoblastic lymphadenopathy and angioimmunoblastic lymphadenopathy-like lymphomas. Blood 1992; 79: 1789-95. Kronke M, Leonard W, Depper J et al. Cyclosponn A inhibits T-cell growth factor gene expression at the level of m-RNA transcription. Proc Natl Acad Sci USA 1984; 81: 5214-8. Handschumacher R, Harding M, Rice J. Cyclophilin - a specific cytosolic binding protein for cyclosporin A. Science 1984; 224: 544-7. Li W, Handschumacher R. Specific interaction of the cyclophilin-cyclosporine complex with the beta sub-unit of calcineurin J Biol Chem 1993; 268. 14040-A Schreiber S, Crabtree G. The mechanism of action of cyclosporine and FK.506. Immunol Today 1992; 13: 136-42. Reuss-Borst M, Waller H, Muller C. Successful treatment of steroid resistant hemolysis in CLL with cyclosporin A. Am J Hematol 1994; 46- 375-6. Reid HIT, Mullaney M, Burrell L et al. Pure red cell aplasia after chemotherapy for Hodgkin's lymphoma' In vitro evidence for T-cell mediated suppression of erythropoiesis and response to sequential cyclosporine and erythropoetin. Am J Hematol 1994; 46: 48-53. Foss H, Anagnostopolilos I, Herbst H et al. Patterns of cytokine gene expression in peripheral-T-cell lymphoma of angioimmunoblastic lymphadenopathy type 1. Blood 1995, 85: 2862-9. Yamamura M, Honda M, Yamada Y et al. Increased levels of interleukin-6 (IL-6) in serum and spontaneous in vitro production of IL-6 by lymph node mononuclear cells of patients with AILD and clinical effectiveness of cyclosporin-A. Leukemia 1996; 9: 1504-8.
Received 11 February 1997; accepted 13 May 1997. Correspondence to • Sandra J. Horning, MD Division of Oncology Stanford University Medical Center 1000 Welch Road, Suite 202 Palo Alto, CA 94304-1808 USA
Downloaded from https://academic.oup.com/annonc/article-abstract/8/6/601/197913 by guest on 26 July 2019
and pure red blood cell aplasia associated with CLL or Hodgkin's disease, which have also been successfully treated with cyclosporine [13, 14]. The clinical features of our case and three other cases of AILD treated with cyclosporine are shown in Table 1. Recent studies indicate that angioimmunoblastic like T-cell lymphomas have elevated levels of cytokine transcripts , specifically tumor necrosis factor (TNF), lymphotoxin (LT) [15] and IL-6 [16], which may contribute to the well established histologic and clinical features of this disease. Cyclosporine has also been reported to decrease elevated IL-6 levels in a patient who was treated for refractory AILD [16]. By altering the immune circuit, cyclosporine seems to play a role in reversing the abnormal immune reactions which lead to AILD and immunoblastic T-cell lymphoma. Given our experience and that reported previously, further studies are warranted to establish the definitive role of cyclosporine in the management of AILD like and immunoblastic T-cell lymphomas, possibly as initial treatment alone, or in combination with prednisone or cytotoxic agents. There may also be a role for evaluating other newer immunosuppressive agents like FK 506 and Rapamycin which are structurally distinct from cyclosporines and have been shown to inhibit T-cell function with 10-100 times greater potency than cyclosporine [12].
Short report Treatment of angioimmunoblastic T-cell lymphoma with cyclosporine R. Advani, R. Warnke, B. I. Sikic & S. Horning Department of Medicine, Oncology Division, Stanford University Medical Center, Stanford, CA, USA
Angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) or angioimmunoblastic like (AILD-like) T-cell lymphoma is a rare lymphoproliferative disorder which is frequently associated with acute constitutional symptoms of fever, night sweats and weight loss [1]. Patients may manifest generalized lymphadenopathy, hepatomegaly, a pruritic skin rash, polyclonal hypergammoglobulinemia and anemia. The latter is caused in many cases by Coomb's positive hemolysis [1]. The etiology and underlying pathophysiologic mechanisms of this disease remain uncertain. Evidence based on T-cell receptor gene rearrangements and non-random chromosome anomalies suggests that AILD is a clonal disease [2, 3]. In the Revised European-American Classification of lymphoid neoplasms, AILD has been classified as a peripheral T-cell neoplasm based on its immunophenotypic and genetic features [4]. Because AILD occurs rarely and has a variable clinical course, optimal management has not been established. Prednisone alone achieves a complete response rate of approximately 50% but relapse of disease generally follows [1]. Combination chemotherapy has also been associated with a similar complete response rate but only one-third were durable [1, 5]. Alternate, potentially immunomodulating therapies reported to have activity include alpha interferon [6] and cyclosporine [7]. In this case report, we describe the use of cyclosporine in a patient with angioimmunoblastic T-cell lymphoma and severe hemolytic anemia who failed to respond to prednisone. Because transfusion support was refused by the patient on religious principles, alternatives to myelosuppressive chemotherapy were offered. Case report The patient is a 47-year-old Caucasian female who was admitted to Stanford University Hospital (SUH) in February 1994. One month earlier the patient experienced the acute onset of fever, malaise, night sweats, generalized body rash and lymphadenopathy. She underwent an axillary lymph node biopsy at an outside
facility which was reported to be consistent with AILD. The patient elected alternative therapy with high-dose vitamins without response. Her condition deteriorated and by February 1994 she was noted to have a hemoglobin of 3.4 mg/dl, hematocrit of 9.6%, reticulocyte count 23% and a positive warm antibody direct Coomb's test. She was admitted to SUH with severe resting angina pectoris, fever and generalized lymphadenopathy. Negative tests included fluorescent antinuclear antibody, Veneral Disease Research Laboratory, monospot and human immunodeficiency virus antibody. A serum protein electrophoresis revealed a small gamma spike of 1.2 Gm. A computerized axial tomography scan of the chest showed bilateral axillary lymphadenopathy and the abdomen was negative. A bone marrow evaluation was not done. A lymph node biopsy was repeated which suggested the diagnosis of AILDlike T-cell lymphoma. In situ hybridization studies for Epstein-Barr virus (EBV), did not show increased numbers of EBV-labeled cells. A clonal population of T cells was identified by Southern blot analysis with a probe for the beta chain of the T-cell receptor. Therefore, the final diagnosis was angioimmunoblastic like T-cell lymphoma. Prednisone 100 mg/day was started, along with folate 1 mg/day orally. High-dose intravenous immunoglobulin (IgG), 1 g/kg x 2 days was employed to arrest the hemolytic anemia. Vincristine 2 mg i.v. was also administered. In spite of these measures, after two weeks, the patient's hematocrit remained 9.0% with a hemoglobin of 3.5 mg/dl. Because tranfusion support was refused by the patient, a Jehovah's Witness, myelosuppressive chemotherapy could not be offered. Likewise, the patient was considered a poor risk for splenectomy. Based on a literature search which indicated that cyclosporin A had been used successfully in two patients [7], therapy was begun with cyclosporine 300 mg p.o. BID six weeks after unsuccessful treatment with prednisone, vincristine and IgG had been initiated. One week later, the dose was increased to 400 mg p.o. BID as a cyclosporine level was 116 mg/ml. Within one week of starting cyclosporine her hematocrit rose to 15.4%
Downloaded from https://academic.oup.com/annonc/article-abstract/8/6/601/197913 by guest on 26 July 2019
Key words: AILD, angioimmunoblastic T-cell lymphoma, cyclosporine
602
Discussion The etiology and pathogenesis leading to the development of angioimmunoblastic like T-cell lymphoma are unclear. It is generally believed that angioimmunoblastic like T-cell lymphoma develops from a background of immune dysregulation because patients frequently present with a history of allergic reactions to various drugs or viral infection [1]. Increased polyclonal and rarely monoclonal serum proteins are thought to reflect an abnormal stimulation of lymphocytes [1]. Cytogenetic evaluation suggests that most cases are clonal and this is further confirmed by T-cell receptor (TCR) gene rearrangements in the majority of cases [2]. TCR genes are rearranged in 75% of cases and immunoglobulin heavy chains in 10% [4]. Tumor cells express T-cellassociated antigens and are usually CD4 positive. Trisomy 3 and/or 5 may occur [2]. EBV genomes are detected in many cases [8]. Various treatment modalities have been employed including steroids, cytotoxic chemotherapy and immunomodulators [1, 5, 6, 7]. Our patient did not respond to
90
120
150
Days Figure I. Correlation of hematocrit wilh therapeutic interventions over time. IgG - intravenous immunoglobulin; CsA - cyclosporine.
prednisone alone, and since she was unwilling to be tranfused due to religious beliefs, we felt that myelosuppressive agents carried an unusually high risk. A dramatic response to cyclosporine therapy occured with rapid rise in hematocrit from 9% to 30% in three weeks. It can be argued that this was a delayed steroid, vincristine or immunoglobulin effect, but we believe this is unlikely given the time course and rapidity of response. The immunosuppressive fungal metabolite cyclosporine was first used in clinical practice in the transplantation setting. One major advantage of cyclosporine over cytotoxic agents is its specific interference in T-cell expansion after antigen recognition. Thus it inhibits transplanted organ rejection without causing significant myelosuppression. Although incompletely characterized, the immunosuppression observed with cyclosporine is thought to be the result of an inhibition of transcription of cytokines, especially theT-helper growth factor interleukin-2 (IL-2) [9]. The mechanisms by which cyclosporine inhibits cytokine transcription and clonal T-cell expansion are unclear. Evidence suggests that the immunosuppressive properties of cyclosporine are mediated by the cytoplasmic protein cyclophilin [10] which results in inhibition of the protein phosphatase calcineurin. Calcineurin has recently been established as a key signalling enzyme in the T-cell signal transduction cascade and an important regulator of transcription factors such as NF-AT and OAP/Oct-1, which are involved in the expression of a number of important T-cell early genes [11]. It has been hypothesized that the complex of cyclosporine-cyclophilin interferes with the expression or activity of DNA binding proteins that are involved in the transcription of early T-cell activation genes [12], Therefore, in diseases in which abnormal T cells induce B-cell hyperactivity, cyclosporine is believed to block the production of IL-2, and the interaction between T and B cells. These effects may contribute to the control of proliferative events seen in AILD patients. Further support for this hypothesis comes from experience with other disorders with immune mediated components such as auto immune hemolytic anemia (AIHA) associated with chronic lymphocytic leukemia (CLL)
Downloaded from https://academic.oup.com/annonc/article-abstract/8/6/601/197913 by guest on 26 July 2019
and three weeks later was 25.2% (Figure 1). At that point the prednisone dose was reduced and she was maintained on oral prednisone 10 mg/5 mg alternating doses. Four weeks after cyclosporine was initiated, the cyclosporine dose was gradually tapered and the patient was maintained at 100 mg BID with an hematocrit above 30%. At this point she was asymptomatic with no palpable lymphadenopathy. Four months later, while she was on maintainence doses of prednisone and cyclosporine, the patient presented with high grade fever and a diffuse, generalized erythematous rash. Her hematocrit was 27.0%. A skin biopsy was consistent with angioimmunoblastic like T-cell lymphoma. Prednisone and cyclosporine were both re-initiated at higher doses (80 mg/day and 400 mg/day respectively). As she had a stable hematocrit at this presentation, oral cyclophosphamide was also started at 100 mg p.o. QD. Her symptoms were significantly better in one week. Cyclophosphamide was discontinued after nine months. The prednisone was tapered over nine weeks and maintained at 10 mg/5 mg alternating doses. Her CsA was tapered to 50 mg BID over nine months, then to 25 mg BID, and finally discontinued in January, 1996. She has been maintained on low-dose prednisone 5 mg/day along wih prophylaxis against Pneumocystis carini pneumonia with pentamidine inhalations for the past year. Currently the patient is asymptomatic with a stable hematocrit of 34.0%. In summary, this patient achieved a remission of angioimmunnoblastic like T-cell lymphoma for four months after cyclosporine therapy was initiated. Upon relapse she was retreated with cyclosporine, prednisone and cyclophosphamide and is now in remission for 2.5 years. Overall she has tolerated the treatment extremely well with no evidence of nephrotoxicity.
603 Table 1 Clinical features and response to cyclosponne in four patients with AILD or AlLD-likeT-cell lymphoma. Anemia
Prior treatments
Response to CsA
Reference no.
62/F
NA
CR
7
54/F 68/M
Mild None
CR CR
7 16
47/F
Severe
Prednisone, CVP, CVP + anthracycline, prednisone + ifosfamide, mitoxantrone, cytoxan, vindesine, interferon None Vincnstine, cytoxan, prednisone, doxorubicin, methotrexate, etoposide PTednisone, IgG, vincristine
CR
Tr This report
Age/Sex
Fever
Lymphadenopathy
Hepatosplenomegaly
6.
7. 8.
9.
10
11.
12. 13.
14.
15.
16.
References 1. Freter C, Cossman J. Angioimmunoblastic lymphadenopathy with dysproteinemia. Semin Oncol 1993; 20: 627-35. 2. Schlegelberger B, Feller A, Godde-Salz E et al. Stepwise development of chromosomal abnormalities in angioimmunoblastic lymphadenopathy. Cancer Genet Cytogenet 1990; 50: 15-29. 3. Weiss L, Stnckler J, Dorfman R et al. Clonal T-cell populations in angioimmunoblastic lymphadenopathy and angioimmunoblastic lymphadenopathy like lymphoma. Am J Path 1986; 122: 392-7. 4. Harris N, Jaffe ES, Stein H et al. A Revised European-American Classification of Lymphoid neoplasms: A proposal from the International Lymphoma Study Group. Blood 1994; 84: 1361-92. 5. Siegert W, Agthe A, Gnesser Het al. Treatment of angioimmuno-
blastic lymphadenopathy (AILD)-type - T-cell lymphoma using prednisone with or without the COPBLAM/IMVP-16 regimen Ann Intern Med 1992; 117: 364-7. Siegert W, Nerl C, Meuthen I et al . Recombinant human interferon-alpha in the treatment of angioimmunoblastic lymphadenopathy. Results in 12 patients. Leukemia 1991, 5: 892-5. Murayama T, Imoto S, Takahashi Tet al Successful treatment of AILD with cyclosponn A. Cancer 1992; 69: 2567-70. Weiss L, Jaffe E, Liu X et al. Detection and localization of Epstein-Barr viral genomes in angioimmunoblastic lymphadenopathy and angioimmunoblastic lymphadenopathy-like lymphomas. Blood 1992; 79: 1789-95. Kronke M, Leonard W, Depper J et al. Cyclosponn A inhibits T-cell growth factor gene expression at the level of m-RNA transcription. Proc Natl Acad Sci USA 1984; 81: 5214-8. Handschumacher R, Harding M, Rice J. Cyclophilin - a specific cytosolic binding protein for cyclosporin A. Science 1984; 224: 544-7. Li W, Handschumacher R. Specific interaction of the cyclophilin-cyclosporine complex with the beta sub-unit of calcineurin J Biol Chem 1993; 268. 14040-A Schreiber S, Crabtree G. The mechanism of action of cyclosporine and FK.506. Immunol Today 1992; 13: 136-42. Reuss-Borst M, Waller H, Muller C. Successful treatment of steroid resistant hemolysis in CLL with cyclosporin A. Am J Hematol 1994; 46- 375-6. Reid HIT, Mullaney M, Burrell L et al. Pure red cell aplasia after chemotherapy for Hodgkin's lymphoma' In vitro evidence for T-cell mediated suppression of erythropoiesis and response to sequential cyclosporine and erythropoetin. Am J Hematol 1994; 46: 48-53. Foss H, Anagnostopolilos I, Herbst H et al. Patterns of cytokine gene expression in peripheral-T-cell lymphoma of angioimmunoblastic lymphadenopathy type 1. Blood 1995, 85: 2862-9. Yamamura M, Honda M, Yamada Y et al. Increased levels of interleukin-6 (IL-6) in serum and spontaneous in vitro production of IL-6 by lymph node mononuclear cells of patients with AILD and clinical effectiveness of cyclosporin-A. Leukemia 1996; 9: 1504-8.
Received 11 February 1997; accepted 13 May 1997. Correspondence to • Sandra J. Horning, MD Division of Oncology Stanford University Medical Center 1000 Welch Road, Suite 202 Palo Alto, CA 94304-1808 USA
Downloaded from https://academic.oup.com/annonc/article-abstract/8/6/601/197913 by guest on 26 July 2019
and pure red blood cell aplasia associated with CLL or Hodgkin's disease, which have also been successfully treated with cyclosporine [13, 14]. The clinical features of our case and three other cases of AILD treated with cyclosporine are shown in Table 1. Recent studies indicate that angioimmunoblastic like T-cell lymphomas have elevated levels of cytokine transcripts , specifically tumor necrosis factor (TNF), lymphotoxin (LT) [15] and IL-6 [16], which may contribute to the well established histologic and clinical features of this disease. Cyclosporine has also been reported to decrease elevated IL-6 levels in a patient who was treated for refractory AILD [16]. By altering the immune circuit, cyclosporine seems to play a role in reversing the abnormal immune reactions which lead to AILD and immunoblastic T-cell lymphoma. Given our experience and that reported previously, further studies are warranted to establish the definitive role of cyclosporine in the management of AILD like and immunoblastic T-cell lymphomas, possibly as initial treatment alone, or in combination with prednisone or cytotoxic agents. There may also be a role for evaluating other newer immunosuppressive agents like FK 506 and Rapamycin which are structurally distinct from cyclosporines and have been shown to inhibit T-cell function with 10-100 times greater potency than cyclosporine [12].