Abstract
Enteropathy-associated T-cell lymphoma (EATL) is a rare non-Hodgkin lymphoma of T-cell origin. The recent 2008 World Health Organization classification of hematologic malignancies distinguishes between two types of EATL. The disease is associated with celiac disease, particularly with its late, adult onset. Currently, there are no standardized diagnostic or treatment protocols for EATL, mostly because of its rarity. Historically, the patients have been treated with anthracycline-based chemotherapy with or without surgery. The outcome of patients with EATL treated with these approaches is poor. The reported death rates in the biggest studies are approximately 80–84%, with median progression-free survival (PFS) of 3.4–6.0 months and overall survival of 7.1–10.0 months. The 5-year PFS ranged from 3.2% to 18% and OS from 19.7% to 20%. The results of a novel induction regimen with ifosfamide, etoposide, and epirubicin alternating with intermediate-dose methotrexate followed by autologous stem cell transplantation (ASCT) are more promising, with a 5-year PFS of 52% and OS of 60%. The alternative approach, with a more common induction with cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone followed by ASCT has also delivered promising results, with a 3-year PFS of 52% and OS of 47%. This review summarizes recently published data on epidemiology and clinical features, as well as standard and novel treatments including high-dose chemotherapy with ASCT and their outcome in EATL.
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Swerdlow SH, Campo E, Harris NL, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: IARC; 2008.
Gale J, Simmonds PD, Mead GM, Sweetenham JW, Wright DH. Enteropathy-type intestinal T-cell lymphoma: clinical features and treatment of 31 patients in a single center. J Clin Oncol. 2000;18:795–803.
Domizio P, Owen RA, Shepherd NA, Talbot IC, Norton AJ. Primary lymphoma of the small intestine. A clinicopathological study of 119 cases. Am J Surg Pathol. 1993;17:429–42.
Isaacson PG, Du MQ. Gastrointestinal lymphoma: where morphology meets molecular biology. J Pathol. 2005;205:255–74.
Catassi C, Fabiani E, Corrao G, et al. Risk of non-Hodgkin lymphoma in celiac disease. JAMA. 2002;287:1413.
Diamanti A, Colistro F, Calce A, et al. Clinical value of immunoglobulin A antitransglutaminase assay in the diagnosis of celiac disease. Pediatrics. 2006;118:e1696–700.
Green PH, Cellier C. Celiac disease. N Engl J Med. 2007;357:1731–43.
Cellier C, Delabesse E, Helmer C, et al. Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma. French coeliac disease study group. Lancet. 2000;356:203–8.
Isaacson PG. Malignant histiocytosis of the intestine. J Pathol. 1985;147(3):227–8.
Howdle PD, Jalal PK, Holmes GK, Houlston RS. Primary small-bowel malignancy in the UK and its association with coeliac disease. QJM. 2003;96:345–53.
Salmi TT, Collin P, Korponay-Szabo IR, et al. Endomysial antibody-negative coeliac disease: clinical characteristics and intestinal autoantibody deposits. Gut. 2006;55:1746–53.
Deleeuw RJ, Zettl A, Klinker E, et al. Whole-genome analysis and HLA genotyping of enteropathy-type T-cell lymphoma reveals 2 distinct lymphoma subtypes. Gastroenterology. 2007;132:1902–11.
Dube C, Rostom A, Sy R, et al. The prevalence of celiac disease in average-risk and at-risk Western European populations: a systematic review. Gastroenterology. 2005;128:S57–67.
Fasano A, Berti I, Gerarduzzi T, et al. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study. Arch Intern Med. 2003;163:286–92.
Verbeek WH, Van De Water JM, Al-Toma A, Oudejans JJ, Mulder CJ, Coupe VM. Incidence of enteropathy-associated T-cell lymphoma: a nation-wide study of a population-based registry in The Netherlands. Scand J Gastroenterol. 2008;43:1322–8.
Daum S, Cellier C, Mulder CJ. Refractory coeliac disease. Best Pract Res Clin Gastroenterol. 2005;19:413–24.
Al-Toma A, Verbeek WH, Hadithi M, von Blomberg BM, Mulder CJ. Survival in refractory coeliac disease and enteropathy-associated T-cell lymphoma: retrospective evaluation of single-centre experience. Gut. 2007;56:1373–8.
Chott A, Haedicke W, Mosberger I, et al. Most CD56+ intestinal lymphomas are CD8 + CD5-T-cell lymphomas of monomorphic small to medium size histology. Am J Pathol. 1998;153:1483–90.
Chott A, Vesely M, Simonitsch I, Mosberger I, Hanak H. Classification of intestinal T-cell neoplasms and their differential diagnosis. Am J Clin Pathol. 1999;111:S68–74.
Spencer J, Cerf-Bensussan N, Jarry A, et al. Enteropathy-associated T cell lymphoma (malignant histiocytosis of the intestine) is recognized by a monoclonal antibody (HML-1) that defines a membrane molecule on human mucosal lymphocytes. Am J Pathol. 1988;132:1–5.
Wright DH. Enteropathy associated T cell lymphoma. Cancer Surv. 1997;30:249–61.
Murray A, Cuevas EC, Jones DB, Wright DH. Study of the immunohistochemistry and T cell clonality of enteropathy-associated T cell lymphoma. Am J Pathol. 1995;146:509–19.
Howell WM, Leung ST, Jones DB, et al. HLA-DRB, -DQA, and -DQB polymorphism in celiac disease and enteropathy-associated T-cell lymphoma. Common features and additional risk factors for malignancy. Hum Immunol. 1995;43:29–37.
Zettl A, Ott G, Makulik A, et al. Chromosomal gains at 9q characterize enteropathy-type T-cell lymphoma. Am J Pathol. 2002;161:1635–45.
•• Sieniawski M, Angamuthu N, Boyd K, et al. Evaluation of enteropathy-associated T-cell lymphoma comparing standard therapies with a novel regimen including autologous stem cell transplantation. Blood. 2010;115:3664–3670. The Scotland and Newcastle Lymphoma Group (SNLG) performed a detailed, population-based evaluation of patients with EATL registered with the group between 1994 and 1998. Data obtained included patient demographics, details on baseline evaluations, treatment, and patient outcomes. They also presented the results of novel first-line treatment with ifosfamide, etoposide, and epirubicin with intermediate-dose methotrexate followed by ASCT.
• D’Amore F, Lauritzen G, Jantunen E, et al. Dose-dense induction followed by autologous stem cell transplant (ASCT) leads to sustained remissions in a large fraction of patients with previously untreated peripheral T-cell lymphomas (PTCLs) - overall and subtype specific results of a phase II study from the Nordic Lymphoma Group. 14th Congress of the EHA. 2009. This is an interim analysis of a big, multicenter, prospective study on dose-dense induction with CHOEP-14 followed by ASCT in patients with PTCL. Among the 160 patients included were 21 patients with EATL.
•• Delabie J, Holte H, Vose JM, et al. Enteropathy-associated T-cell lymphoma: clinical and histological findings from the International Peripheral T-Cell Lymphoma Project. Blood. 2011;118:148–155. The International T-cell Lymphoma Project (ITLP) studied a cohort of 62 EATL patients among 1,153 patients with PTCL from 22 centers worldwide, diagnosed between 1990 and 2002. Clinical correlation and survival analyses were performed.
Berman EL, Zauber NP, Rickert RR, Diss TC, Isaacson PG. Enteropathy-associated T cell lymphoma with brain involvement. J Clin Gastroenterol. 1998;26:337–41.
Tutt AN, Brada M, Sampson SA. Enteropathy associated T cell lymphoma presenting as an isolated CNS lymphoma three years after diagnosis of coeliac disease: T cell receptor polymerase chain reaction studies failed to show the original enteropathy to be a clonal disorder. Gut. 1997;40:801.
Daum S, Ullrich R, Heise W, et al. Intestinal non-Hodgkin’s lymphoma: a multicenter prospective clinical study from the German study group on intestinal non-Hodgkin’s Lymphoma. J Clin Oncol. 2003;21:2740–6.
Al-Toma A, Visser OJ, van Roessel HM, et al. Autologous hematopoietic stem cell transplantation in refractory celiac disease with aberrant T cells. Blood. 2007;109:2243–9.
O’Connor OA, Horwitz S, Hamlin P, et al. Phase II-I-II study of two different doses and schedules of pralatrexate, a high-affinity substrate for the reduced folate carrier, in patients with relapsed or refractory lymphoma reveals marked activity in T-cell malignancies. J Clin Oncol. 2009;27:4357–64.
Piekarz R, Wright J, Frye R, Allen SL, Craig M, Geskin L. Results of a phase 2 NCI multicentre study of romidepsin in patients with relapsed peripheral T-cell lymphoma (PTCL). Blood (ASH Annual Meeting Abstracts). 2008;112:1567.
Dueck GS, Chua N, Prasad A, Stewart D, White D, van der Jagt R. Activity of lenalidomide in a phase II trial for T-cell lymphoma: Report on the first 24 cases. J Clin Oncol (ASCO Meeting Abstracts). 2009;27:8524.
Furman RR, Gore L, Ravandi F, Hoelzer D. Forodesine IV (Bcx 1777) is clinically active in relapsed/refractory T-cell leukemia: Results of a phase II study (interim report). Blood (ASH Annual Meeting Abstracts). 2006;108:1851.
Zinzani PL, Magagnoli M, Bendandi M, et al. Therapy with gemcitabine in pretreated peripheral T-cell lymphoma patients. Ann Oncol. 1998;9:1351–3.
Sallah S, Wan JY, Nguyen NP. Treatment of refractory T-cell malignancies using gemcitabine. Br J Haematol. 2001;113:185–7.
• Reimer P, Rudiger T, Geissinger E, et al. Autologous stem-cell transplantation as first-line therapy in peripheral T-cell lymphomas: results of a prospective multicenter study. J Clin Oncol. 2009;27:106–113. This multicenter, prospective trial assessed the role of ASCT in consolidation in patients with PTCL in first remission after the standard treatment with CHOP.
Mounier N, Gisselbrecht C, Briere J, et al. All aggressive lymphoma subtypes do not share similar outcome after front-line autotransplantation: a matched-control analysis by the Groupe d’Etude des Lymphomes de l’Adulte (GELA). Ann Oncol. 2004;15:1790–7.
Okuda M, Nomura J, Tateno H, Kameoka J, Sasaki T. CD56 positive intestinal T-cell lymphoma: treatment with high dose chemotherapy and autologous peripheral blood stem cell transplantation. Intern Med. 2002;41:734–7.
Rongey C, Micallef I, Smyrk T, Murray J. Successful treatment of enteropathy-associated T cell lymphoma with autologous stem cell transplant. Dig Dis Sci. 2006;51:1082–6.
Al-Toma A, Verbeek WH, Visser OJ, et al. Disappointing outcome of autologous stem cell transplantation for enteropathy-associated T-cell lymphoma. Dig Liver Dis. 2007;39:634–41.
Nickelsen M, Ziepert M, Zeynalova S, et al. High-dose CHOP plus etoposide (MegaCHOEP) in T-cell lymphoma: a comparative analysis of patients treated within trials of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Ann Oncol. 2009;20:1977–84.
Goerres MS, Meijer JW, Wahab PJ, et al. Azathioprine and prednisone combination therapy in refractory coeliac disease. Aliment Pharmacol Ther. 2003;18:487–94.
Bernstein EF, Whitington PF. Successful treatment of atypical sprue in an infant with cyclosporine. Gastroenterology. 1988;95:199–204.
Wahab PJ, Crusius JB, Meijer JW, Uil JJ, Mulder CJ. Cyclosporin in the treatment of adults with refractory coeliac disease–an open pilot study. Aliment Pharmacol Ther. 2000;14:767–74.
Mulder CJ, Wahab PJ, Meijer JW, Metselaar E. A pilot study of recombinant human interleukin-10 in adults with refractory coeliac disease. Eur J Gastroenterol Hepatol. 2001;13:1183–8.
Al-Toma A, Goerres MS, Meijer JW, et al. Cladribine therapy in refractory celiac disease with aberrant T cells. Clin Gastroenterol Hepatol. 2006;4:1322–7. quiz 1300.
Mallant M, Hadithi M, Al-Toma AB, et al. Abdominal computed tomography in refractory coeliac disease and enteropathy associated T-cell lymphoma. World J Gastroenterol. 2007;13:1696–700.
Hadithi M, Mallant M, Oudejans J, van Waesberghe JH, Mulder CJ, Comans EF. 18 F-FDG PET versus CT for the detection of enteropathy-associated T-cell lymphoma in refractory celiac disease. J Nucl Med. 2006;47:1622–7.
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Sieniawski, M.K., Lennard, A.L. Enteropathy-Associated T-Cell Lymphoma: Epidemiology, Clinical Features, and Current Treatment Strategies. Curr Hematol Malig Rep 6, 231–240 (2011). https://doi.org/10.1007/s11899-011-0097-7
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DOI: https://doi.org/10.1007/s11899-011-0097-7