[Cancer Biology & Therapy 7:10, 1544-1546; October 2008]; ©2008 Landes Bioscience
Bedside-to-Bench Report
Successful treatment of relapsed lymphomatoid granulomatosis with bexarotene Sigrid E. Berg,1 Lisa H. Downs,1 Drew A. Torigian,2 Elise A. Chong,1 Donald E. Tsai,1 Mariusz A. Wasik3 and Stephen J. Schuster1,* 1Abramson Cancer Center; 2Department of Radiology; 3Department of Pathology and Laboratory Medicine; Hospital of the University of Pennsylvania; University of Pennsylvania; Philadelphia, Pennsylvania USA
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Abbreviations: CHOP, cyclophosphamide, adriamycin, vincristine, prednisone; EBV, epstein-barr virus; PTLD, post-transplant lymphoproliferative disorder
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Lymphomatoid granulomatosis is a rare lymphoproliferative disorder that affects the lungs but also may involve the skin, central nervous system, liver and kidney.1,2 The process represents an aberrant expansion of T-lymphocytes, mostly from the CD4+ T-cell subset, typically in association with expansion of Epstein-Barr virus (EBV)-infected B-cells.3-6 While patients with low-grade disease may experience complete remission without therapy in a minority of cases, most patients progress to an advanced-stage disease regardless of therapy, with a median survival of 14 months.2 Comparisons of observation alone, steroid therapy, cytotoxic chemotherapy and radiation therapy have demonstrated no benefit in any treatment group.2,7 Since the recognition of an EBV association, case reports of successful treatment with interferon-alpha and rituximab have been published, although these findings remain controversial.8-11 We present a patient with lymphomatoid granulomatosis that relapsed after six cycles of CHOP (cyclophosphamide, adriamycin, vincristine, prednisone) chemotherapy but subsequently has achieved a durable, two-year clinical remission in response to bexarotene therapy. *Correspondence to: Stephen J. Schuster; Abramson Cancer Center; University of Pennsylvania; 16 Penn Tower; 3400 Spruce Street; Philadelphia, Pennsylvania 19104 USA; Tel.: 215.614.1846; Fax: 215.662.4064; Email:
[email protected]. upenn.edu Submitted: 02/11/08; Revised: 02/28/08; Accepted: 08/21/08 Previously published online as a Cancer Biology & Therapy E-publication: http://www.landesbioscience.com/journals/cbt/article/6834 1544
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The patient is a previously healthy 39-year-old man who presented initially with painful paresthesias of his upper and lower extremities, followed soon thereafter by a painful, erythematous rash on his thighs. Despite administration of antihistamines and an epidural steroid injection, his symptoms continued to worsen. He then developed dyspnea on exertion, at which point a diagnosis of sarcoidosis was made based on an abnormal chest x-ray. High-dose intravenous steroids were administered without improvement. A skin biopsy performed at that time was nondiagnostic. Two months after initial presentation, the patient presented to a local hospital with worsening shortness of breath, fevers, night sweats and weight loss. CT scan of the chest revealed multiple pulmonary nodules with occasional cavitation. CT scan of the abdomen/pelvis, brain MRI and cervical-spine MRI were unremarkable. After a nondiagnostic transbronchial biopsy, a video-assisted thoracoscopic wedge biopsy was performed. The biopsied pulmonary lesions and a repeat skin biopsy were both consistent with grade 1 lymphomatoid granulomatosis. They both demonstrated an atypical, pleomorphic lymphohistiocytic infiltrate without any necrosis seen in the lung section and subtle, very focal angiocentric necrosis identified in the skin. Immunohistochemical stains of the pulmonary lesions revealed that the infiltrate was composed predominantly of CD4+ T-cells and CD68+ macrophages. Rare CD8+ T-cells, and scattered medium-sized and small CD20+, CD79a+, Pax5+ B-lymphocytes were also present. Immunohistochemical stains for latent membrane protein (LMP)-1 and EBV-encoded small RNA (EBER-1) by in-situ hybridization were negative. Immunoglobulin heavy chain and T-cell receptor gene rearrangement studies were also negative. Subsequent bone marrow biopsy revealed no abnormalities. Peripheral blood studies were notable for a positive serum EBV capsid IgG antibody titer (5.02 IU; positive if ≥1.00 IU) and a high CD4:CD8 T-cell ratio (3.7; normal range 0.9–3.4; absolute CD4 count 512 cells/mL, absolute CD8 count 140 cells/mL). A six assay PCR panel evaluating EBV DNA in both plasma and whole blood cells using primer sets
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Introduction
Case Report
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Lymphomatoid granulomatosis is a rare lymphoproliferative disorder involving the lungs, skin and other organs. Advanced-stage disease does not tend to respond well to cytotoxic chemotherapy and is associated with a poor prognosis. We present a case of successful treatment of relapsed lymphomatoid granulomatosis with bexarotene, a novel retinoid agent.
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Key words: lymphomatoid granulomatosis, lymphoproliferative disease, T-cell lymphoma, new drugs for lymphoma, bexarotene, retinoid, novel therapeutics
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Treatment of lymphomatoid granulomatosis with bexarotene
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Figure 1. Thirty-nine year-old man with history of lymphomatoid granulomatosis. (A and B) Axial noncontrast CT images through mid and lower chest demonstrate multiple bilateral subcentimeter soft tissue attenuation pulmonary nodules (arrows) in keeping with lymphomatoid granulomatosis. (C and D) Axial noncontrast CT images through chest performed five weeks later at same craniocaudal levels as above reveal interval decrease in size and attenuation of pulmonary nodules (arrows) following therapy. (E and F) Axial noncontrast CT images through chest performed five months after initiation of bexarotene therapy at same craniocaudal levels as above show further interval decrease in size and attenuation of pulmonary nodules (arrows).
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against EBER-1 (EBER), LMP-1 (LMP) and EBNA-1 (EBNA) was negative (ViraCor Laboratories, Lee’s Summit, Missouri). The patient initially received CHOP chemotherapy, with rapid improvement in his symptoms. Repeat chest CT after six cycles revealed a reduction in the number and size of his pulmonary lesions. Two months after completing CHOP, however, the patient developed recurrent painful paresthesias of his bilateral upper and lower extremities, dyspnea on exertion, and a solitary skin nodule. A CT scan at that time (Fig. 1A and B) demonstrated the presence of multiple (>20) bilateral, pulmonary lesions, averaging one cm in size, that were FDG-avid on a subsequent PET scan. Given anecdotal evidence for utility of bexarotene therapy in other T-cell lymphoproliferative disorders, therapy was initiated with bexarotene 225 mg by mouth twice daily.12 Three weeks after initiation of bexarotene, chest CT (Fig. 1C and D) demonstrated a reduction in the size and number of his pulmonary lesions. His dyspnea and skin lesions had resolved, although he still suffered from www.landesbioscience.com
painful bilateral lower extremity paresthesias. Five months after initiation of bexarotene, CT scan (Fig. 1E and F) demonstrated continued resolution of his pulmonary disease, with no areas of increased FDG uptake in the lung on concurrent PET scan. His painful paresthesias had also resolved by that time, and his CD4:CD8 T-cell ratio had normalized (1.9, normal range 0.9–3.4; absolute CD4 count 747 cells/uL, absolute CD8 count 396 cells/mL). Normalization of the CD4:CD8 ratio was related to a relatively greater increase in CD8 cells compared to CD4 cells. To date, nearly two years after initiation of bexarotene therapy, he remains asymptomatic. He has acquired hypertriglyceridemia as a side effect from the bexarotene and is being treated with Tricor. His thyroid function tests remain within normal limits.
Discussion This case illustrates, to the best of our knowledge, the first reported successful treatment of lymphomatoid granulomatosis with
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Treatment of lymphomatoid granulomatosis with bexarotene
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12. Tsai DE, Aqui NA, Vogl DT, Bloom RD, Schuster SJ, Nasta SD, Wasik MA. Successful treatment of T-cell post-transplant lymphoproliferative disorder with the retinoid analog bexarotene. Am J Transplant 2005; 5:2070-3. 13. Duvic M, Hymes K, Heald P, Breneman D, Martin AG, Myskowski P, Crowley C, Yocum RC, for Members of the Bexarotene Worldwide Study Group. Bexarotene is effective and safe for treatment of refractory advanced state cutaneous T cell lymphoma: multinational phase II–III trial results. J Clin Oncol 2001; 19:2456-71. 14. Boehm MF, Zhang L, Badea BA, White SK, Mais DE, Berger E, Suto CM, Goldman ME, Heyman RA. Synthesis and structure-activity relationships of novel retinoid X receptorselective retinoids. J Med Chem 1994; 37:2930-41.
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bexarotene. Bexarotene, approved for the treatment of refractory or relapsed cutaneous T-cell lymphoma, has also been demonstrated in a case report to be effective against relapsed T-cell post-transplant lymphoproliferative disorder (PTLD).12,13 While the exact mechanism of action remains unknown, bexarotene is known to selectively activate retinoid X receptors.14 The most common side effects include hypertriglyceridemia, hypothyroidism, rash, headache, leukopenia and anemia, but tend to be dose-related and reversible with discontinuation of the medication.13 Our patient relapsed after receiving CHOP chemotherapy. We opted to treat our patient with bexarotene given its favorable side effect profile, ease of administration and experience at our institution of positive responses in patients with chemotherapy-refractory T-cell lymphoproliferative disorders.12 Therapy with bexarotene was initiated at approximately 300 mg/ m2, the standard dose approved for cutaneous T-cell lymphoma. Once radiographic remission was obtained, the dose was reduced to approximately 150 mg/m2 in response to the patient’s hypertriglyceridemia. Clinical remission has been continuous for nearly two years on bexarotene therapy. We hypothesize that bexarotene may have qualitative effects on the cytotoxic activity of CD8 T-cells toward EBV-infected B-cell targets as well as a quantitative effect on CD8 T-cell number, as observed in this patient. Further studies using functional assays for cytotoxic T-cell activity against EBV targets are necessary to test this hypothesis, but are beyond the scope of this case report. Given our patient’s response to bexarotene, as well as its ease of administration and well-tolerated side effect profile, further studies are warranted to determine whether bexarotene may be a new agent for treatment of lymphomatoid granulomatosis. Acknowledgements
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The authors acknowledge Jim and Frannie Maguire for their enduring support of the Lymphoma Program at the University of Pennsylvania.
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References
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