A novel chemotherapeutic regimen (interferon alfa, zidovudine, and etretinate) for adult T-cell lymphoma resulting in rapid tumor destruction
Authors: Edward F. Chan, Yvonne G. Dowdy, Benhur Lee, W.Gillies McKenna, Kevin R. Fox, Robert J. Levy, Mariusz A. Wasik, Alain H. Rook
Journal: Journal of the American Academy of Dermatology (1999)

We report a case of adult T-cell leukemia-lymphoma (ATLL), which was unresponsive to conventional systemic chemotherapy. Combination therapy with interferon alfa and zidovudine was initiated because recent evidence has suggested efficacy of such treatment in ATLL.1Hermine O Bouscary D Gessain A Turlure P Leblond V Franck N et al.Brief report: treatment of adult T-cell leukemia-lymphoma with zidovudine and interferon alfa.N Engl J Med. 1995; 332: 1749-1751Crossref PubMed Scopus (222) Google Scholar, 2Gill PS Harrington W Kaplan MH Ribeiro RC Bennett JM Leibman HA et al.Treatment of adult T-cell leukemia-lymphoma with a combination of interferon alfa and zidovudine.N Engl J Med. 1995; 332: 1744-1748Crossref PubMed Scopus (322) Google Scholar However, these drugs had only a limited effect on tumor growth. The subsequent addition to this regimen of a retinoid (etretinate, the trimethylmethoxyphenol analog of retinoic acid ethyl ester) was associated with rapid and marked regression of the patient’s cutaneous tumors. A 64-year-old African-American man initially presented with a subcutaneous nodule on his left forearm. Histologic examination revealed a diffuse infiltrate of medium-sized to large mononuclear cells with prominent nucleoli and slightly irregular nuclear outlines (Fig 1, A ). Immunohistochemical stains demonstrated tumor cells positive for the T-cell marker CD45R0 (UCHL1) and negative for the B-cell marker CD20 (L26), consistent with a lymphoma of T-cell origin (Fig 1, B ). At that time there was no evidence of peripheral blood, lymph node, or other internal organ involvement. The diagnosis of T-cell lymphoma was made and the patient was treated with 4 cycles of chemotherapy with cyclophosphamide, mitoxantrone, vincristine, and dexamethasone. Tumor nodules continued to develop on his trunk and extremities. Although local radiation therapy was effective in reducing the size of these tumors, new lesions continued to develop (Fig 2). Fig. 2Multiple tumor nodules on right arm.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Radiation therapy was discontinued, and new therapeutic options were considered. After referral of the patient to the University of Pennsylvania, flow cytometric analysis of the blood revealed that 40% of the T cells expressed CD25, and immunohistochemical studies performed on a biopsy specimen of a cutaneous tumor nodule also revealed that 60% of the dermal T cells expressed CD25. Serologic studies indicated that the patient had antibodies to HTLV-I by enzyme-linked immunosorbent assay and Western blotting. His white blood cell count remained normal. The concentration of sIL-2R in the patient’s serum was significantly increased (15,290 U/mL; normal value < 919 U/mL). The serum calcium level was normal and the lactate dehydrogenase level was mildly elevated (430 U/L; normal value, 94-250 U/L). Computed tomographic scans of the chest, abdomen, and pelvis revealed extensive enlargement of the mesenteric lymph nodes and focal thickening of small and large bowel walls suggestive of tumor involvement. The patient was sequentially treated with interferon alfa (5 × 106 U 5 times/wk) for 2 months, a combination of interferon alfa (5 × 106 U 5 times/wk) with zidovudine (600 mg/day) for 4 weeks, and monotherapy with 13-cis -retinoic acid or isotretinoin (1 mg/kg per day) for 4 weeks. His cutaneous disease continued to progress, and combination therapy was begun with interferon alfa (3-5 × 106 U 5 times/wk), zidovudine (600 mg/day), and etretinate (25 mg/day). During the next 2 weeks, rapid regression and involution of his cutaneous tumors occurred, leaving hyperpigmented, nonpalpable patches without evidence of necrosis. The serum soluble interleukin-2 receptor (sIL-2R) concentration showed a 2.3-fold decrease from 15,290 U/mL down to 6580 U/mL. However, at this time bowel wall perforation developed, which proved fatal despite surgical intervention. Two segments of resected colon were examined. The smaller segment contained a perforation, the larger segment contained localized areas of transmural thickening and mucosal hemorrhage with associated serosal edema. Microscopically, the colon demonstrated necrosis in areas containing outlines of the medium-sized to large cells consistent with involvement by a malignant neoplasm. Extensive fibrosis with chronic inflammatory cells infiltrating and extending focally into pericolic fat was also noted. In areas apparently not involved with lymphoma, inflammation, hemorrhage, and necrosis were minimal. Immunohistochemical analysis demonstrated that the membranes of the tumor “ghost” cells stained positively with the pan-leukocytic marker CD45 (LCA) and the T-cell markers CD45R0 and CD3 and were negative for the B-cell markers CD20 and MB2. These immunohistochemical findings confirmed the diagnosis of intestinal involvement by the T-cell lymphoma. In analysis of the skin and bowel, antibodies against the following markers were used: CD3 (Leu-4, Becton Dickinson), CD45R0 (UCHL1, Dako), CD45 (LCA, Dako), CD20 (L26, Dako), MB2 (Clonab), and CD25 (anti-tac, Becton Dickinson). Staining of the tissue sections was performed on buffered formalin with a standard three-step immunoperoxidase method.3Wasik MA Sackstein R Novick D Butmare JR Zhang Q Vonderheid EC et al.Cutaneous CD56+ large (T-) cell lymphoma associated with high serum concentration of IL-2.Hum Pathol. 1996; 27: 738-744Abstract Full Text PDF PubMed Scopus (22) Google Scholar The sIL-2R ELISA plates were obtained from T-Cell Diagnostics, Woburn, Mass. The assay was performed as recommended by the instruction manual and as previously described4Wasik MA Sioutos N Tuttle M Butmarc JR Kaplan W Kadin ME. Constitutive secretion of soluble IL-2 receptor by human T-cell lymphoma xenografted into immunodeficient SCID mice.Am J Pathol. 1994; 144: 1089-1097PubMed Google Scholar on serum samples stored at –70°C. The data are shown as a mean of duplicate samples (standard deviation < 10%). The mean normal value as determined in the study of 50 healthy subjects (see IL-2R test kit instruction manual) and confirmed by us5 was 573 U/mL (upper limit of normal 919 U/mL; mean + 2 standard deviations). Infection with HTLV-I is etiologically associated with the development of ATLL.6Poiesz BJ Ruscetti FW Gazdar AF Bunn PA Minna JD Gallo RC. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma.Proc Natl Acad Sci U S A. 1980; 77: 7415-7419Crossref PubMed Scopus (4001) Google Scholar All patients at our institution with T-cell lymphomas are routinely serologically screened for HTLV-I infection by ELISA and, if positive, by Western blotting to confirm the positive ELISA result. Endemic areas of HTLV-I infection include southern Japan, sub-Saharan Africa, the Caribbean basin, and the southeastern United States. The virus may be transmitted through breast-feeding, sexual contact, blood transfusion, and sharing of contaminated needles. In persons infected with HTLV-I, the lifetime risk of development of ATLL is 2% to 4%.7Tokudome S Tokunaga O Shimamoto Y Miyamoto Y Sumida L Kikuchi M et al.Incidence of adult T-cell leukemia/lymphoma among human T-lymphotropic virus type I carriers in Saga, Japan.Cancer Res. 1989; 49: 226-228PubMed Google Scholar Monoclonal integration of HTLV-I provirus has been found in the circulating malignant lymphocytes of ATLL.8Yoshida M Seiki M Yamaguchi K Takatsuki K. Monoclonal integration of human T-cell leukemia provirus in all primary tumors of adult T-cell leukemia suggests a causative role of human T-cell leukemia in the disease.Proc Natl Acad Sci U S A. 1984; 81: 2534-2537Crossref PubMed Scopus (745) Google Scholar This leukemic clone appears to emerge from a background of HTLV-I-initiated oligoclonal T-cell expansion.9Cavrios M Wain-Hobson S Gessain A Plumelle Y Wattel E. Adult T-cell leukemia/lymphoma on a background of clonally expanding human T-cell leukemia virus type-1-positive cells.Blood. 1996; 88: 4646-4650PubMed Google Scholar The clinical features of ATLL include skin involvement, hypercalcemia, lymphadenopathy, hepatosplenome-galy, and opportunistic infections. ATLL is classified into 4 clinical subtypes: smoldering, chronic, acute, and lymphoma. The acute subtype is characterized by a leukemic population of circulating T lymphocytes and tumor lesions; the lymphoma subtype is characterized by the lack of peripheral blood involvement (< 1% of abnormal circulating T lymphocytes), lymph node involvement, and variable extranodal involvement. Both these subtypes represent aggressive malignancies with poor prognosis. The median survival time is 6 months in the acute subtype and 10 months in the lymphoma subtype. Conventional combination chemotherapies have proven ineffective in prolonging survival.10Shimoyama M. Diagnostic criteria and classification of clinical subtypes of adult T-cell leukemia-lymphoma: a report from the Lymphoma Study Group (1984-87).Br J Hematol. 1991; 79: 428-437Crossref PubMed Scopus (1321) Google Scholar Because of the lack of effective therapy, there have been several attempts to develop new modalities for the treatment of ATLL. ATLL cells express on their surface a high concentration of the low-affinity IL-2 receptors (CD25),11Waldmann TA Greene WC Sarin PS Saxinger C Blayney DW Blattner WA et al.Functional and phenotypic comparison of human T cell leukemia/lymphoma virus positive adult T cell leukemia with human T cell leukemia/lymphoma virus negative Sezary leukemia, and their distinction using anti-Tac monoclonal antibody identifying human receptor for T cell growth factor.J Clin Invest. 1984; 73: 1711-1718Crossref PubMed Scopus (159) Google Scholar, 12Uchiyama T Hori T Tsudo M Wano Y Umadome H. Interleukin-2 receptor (Tac antigen) expressed on adult T-cell leukemia cells.J Clin Invest. 1985; 76: 446-453Crossref PubMed Scopus (186) Google Scholar and one approach has been to target these cells by the administration of anti-CD25 antibodies conjugated to yttrium-90. In a phase II trial involving 16 patients, a partial remission was noted in 9 patients and a complete remission was noted in 2 patients.13Waldmann TA White JD Carrasquillo JA. Radioimmunotherapy of interleukin-2Ra-expressing adult T-cell leukemia with Yttrium-90-labeled Anti-Tac.Blood. 1995; 86: 4063-4075PubMed Google Scholar An alternative approach was used in the treatment of a patient concomitantly infected with HIV-1 and HTLV-I, in which a significant response was noted to combination therapy with interferon alfa and zidovudine.14Shibata D Brynes RK Rabinowiz A hanson CA Slovak ML Spira TJ et al.Human T-cell lymphotropic virus type 1 (HTLV-1)-associated adult T-cell leukemia-lymphoma in a patient infected with human immunodeficiency virus type I (HIV-1).Ann Intern Med. 1989; 111: 871-875Crossref PubMed Scopus (53) Google Scholar This initial report led to two larger case studies in which a total of 24 patients with ATLL (21 with acute disease, 2 with lymphomatous disease, and 1 with smoldering disease) were treated with interferon alfa (9 million U/day) and zidovudine (1000 mg/day). Complete or partial responses were noted in 16 patients, in several of whom prior chemotherapy had failed.1Hermine O Bouscary D Gessain A Turlure P Leblond V Franck N et al.Brief report: treatment of adult T-cell leukemia-lymphoma with zidovudine and interferon alfa.N Engl J Med. 1995; 332: 1749-1751Crossref PubMed Scopus (222) Google Scholar, 2Gill PS Harrington W Kaplan MH Ribeiro RC Bennett JM Leibman HA et al.Treatment of adult T-cell leukemia-lymphoma with a combination of interferon alfa and zidovudine.N Engl J Med. 1995; 332: 1744-1748Crossref PubMed Scopus (322) Google Scholar In this report, a case is presented of a patient with the lymphoma form of ATLL in whom conventional chemotherapy failed. In addition, he did not respond to combination therapy with interferon alfa and zidovudine or monotherapy with isotretinoin. However, the addition of etretinate to interferon and zidovudine resulted in a rapid and marked regression of his skin nodules. The use of this novel systemic retinoid therapy in combination with interferon and zidovudine for the treatment of ATLL has not previously been reported. In vitro data suggest that the combination of retinoids and interferons have synergistic antiproliferative and differentiating effects in both hematologic and solid tumor models. 15 Studies in patients also support the conclusion that this combination may have a synergistic, antineoplastic effect particularly in cutaneous T-cell lymphoma.16Knobler RM Trautinger F Radaszkiewicz T. Treatment of cutaneous T-cell lymphoma with a combination of low-dose interferon alfa-2b and retinoids.J Am Acad Dermatol. 1991; 24: 247-251Abstract Full Text PDF PubMed Scopus (111) Google Scholar, 17Kessler JF Jones SE Levine N. Isotretinoin and cutaneous helper T-cell lymphoma (mycosis fungoides).Arch Dermatol. 1987; 123: 201-204Crossref PubMed Scopus (117) Google Scholar, 18Thomsen K Molin L Volden G. 13-cis retinoic acid effective in mycosis fungoides.Acta Derm Venereol (Stockh). 1984; 64: 563-566PubMed Google Scholar, 19Fox FE Cassin M Gottlieb S Fakharzadeh SS Kubin M Trinchieri G et al.Retinoids synergize with IL-2 to increase interferon gamma production by peripheral blood mononuclear cells via induction of IL-12.Ann N Y Acad Sci. 1996; 795: 337-340Crossref PubMed Scopus (2) Google Scholar Mechanisms of synergism may include the potentiation of antiangiogenic effects20Majewki S Szmurlo A Marczak S Jablonska S Bollag W. Synergistic effect of retinoids and interferon alpha on tumor-induced angiogenesis: anti-angiogenic effect on HPV-harboring tumor-cell lines.Intl J Cancer. 1994; 57: 81-85Crossref PubMed Scopus (135) Google Scholar and the induction of genes that have antiproliferative effects. Specifically, retinoids and interferon alfa in combination have been shown to transiently increase the expression of interferon regulatory factor–1,21Lancillotti F Giandomenico E Affabris G Fiorucci G Romeo G Rossi GB. Interferon alpha-2b and retinoic acid combined treatment affects proliferation and gene expression of human cervical carcinoma cells.Cancer Res. 1995; 55: 3158-3164PubMed Google Scholar a transcription factor that regulates interferon and interferon-inducible genes.22Harada H Fujita T Miyamoto M Kimura Y Maruyama M Furia A et al.Structurally similar but functionally distinct factors, IRF1 and IRF2, bind to the same regulatory elements of IFN and IFN-inducible genes.Cell. 1989; 58: 729-739Abstract Full Text PDF PubMed Scopus (807) Google Scholar There is evidence that interferon regulatory factor–1 may activate a group of genes with antiproliferative effects23Harada H Kitagawa M Tanaka N Yamamoto H Harada K Ishihara M et al.Antioncogenic and oncogenic potentials of interferon regulatory factors-1 and -2.Science. 1993; 259: 971-974Crossref PubMed Scopus (429) Google Scholar and may be involved in apoptosis.24Tanaka N Ishihara M Kitagawa M Harada H Kimura T Matsuyama T et al.Cellular commitment to oncogene-induced transformation or apoptosis is dependent on the transcription factor IRF1.Cell. 1994; 77: 829-839Abstract Full Text PDF PubMed Scopus (466) Google Scholar Recently, an inhibitory effect of retinoids alone on in vitro growth of ATLL cells has been reported.25Maeda Y Miyatake J Sono H Sumimoto Y Matsuda M Horiuchi F et al.New therapeutic effects of retinoid for adult T-cell leukemia.Blood. 1996; 88: 4726-4727PubMed Google Scholar The effect of zidovudine on ATLL is not likely to be due to its antiviral effects because viral replication is not required for proliferation of leukemic cells. Zidovudine more likely exerts its effects via termination of DNA replication.26Furman PA Fyfe JA St Clair MH Weinhold K Rideout JL Freeman GA et al.Phosphorylation of 3'-azido-3'-deoxythymidine and selective interaction of the 5'-triphosphate with human immunodeficiency virus reverse transcriptase.Proc Natl Acad Sci U S A. 1986; 83: 8333-8337Crossref PubMed Scopus (1245) Google Scholar This cytostatic effect may synergize with the effects of interferon alfa, which include the inhibition of protein synthesis and cell growth27Gendelman HE Baca LM Turpin J Kalter DC Hansen B Orenstein JM et al.Regulation of HIV replication in infected monocytes by IFN-alfa: mechanisms for viral restriction.J Immunol. 1990; 145: 2669-2676PubMed Google Scholar and the induction of expression of major histocompatibility complex antigens I and II.28Friedman RL Manley SP McMahon M Kerr IM Stark GR. Transcriptional and posttranscriptional regulation of interferon-induced gene expression in human cells.Cell. 1984; 38: 745-755Abstract Full Text PDF PubMed Scopus (475) Google Scholar, 29Morris A Tomkins PT Maudsley DJ Blackman M. Infection of cultured murine brain cells by Semliki Forest virus: effects of interferon-alpha beta on viral replication, viral antigen display, major histocompatibility complex antigen display and lysis by cytotoxic T lymphocytes.J Gen Virol. 1987; 68: 99-106Crossref PubMed Scopus (16) Google Scholar Thus interferon alfa can either have direct antiproliferative effects or enhance the immunologic recognition of leukemic cells. Regardless of the incompletely understood mechanism of action of these agents, combination therapy with interferon alfa, zidovudine, and etretinate appears to be an effective regimen in ATLL as demonstrated by a rapid involution of the patient’s cutaneous tumors and marked decrease in serum concentration of sIL-2R. It is noteworthy that in our patient tumor necrosis developed in his bowel that was localized to areas of previous tumor involvement; this led to perforation and fulminant peritonitis. This can be seen in aggressive combination chemotherapy. In conclusion, the rapid response of our patient’s cutaneous tumors to the novel regimen of interferon alfa, zidovudine, and etretinate warrants further investigation with clinical trials.