Sequential Evaluation of Outcome in Enteropathy Associated T Cell Lymphoma Comparing Standard Therapeutic Approaches – Surgery or CHOP-Like Chemotherapy with a New High Dose Ifosfamide/Methotrexate and Autologous Stem Cell Transplant Regimen: A Prospective Study of Scotland and Newcastle Lymphoma Group
Authors: Sieniawski Michal , Angamuthu Nithia , Boyd Kathryn , Chasty Richard , Davies John , Revell Paul , Proctor Stephen J , Lennard Anne L 
Published: April 2020

Abstract
Enteropathy associated T-cell lymphoma (EATL) is a rare disease with dismal prognosis. At present there are no standardised diagnostic or treatment protocols. The SNLG collected 5yrs of prospective data which uniquely enables us to describe the disease in a population-based setting. Additionally, we introduce results from a novel approach with aggressive chemotherapy (CT) and autologous stem cell transplantation (ASCT). From 1994 – 1998 all pts diagnosed with lymphoma in Scotland and the Northern region of England were prospectively registered. Pts with a diagnosis of EATL were evaluated for clinical features, treatment and outcome. The novel regimen was piloted from 1997 for new pts eligible for intensive treatment. This therapy delivers one cycle of CHOP, followed by 3 courses of IVE (ifosfamide, etoposide, epirubicin), alternating with intermediate dose methotrexate (MTX). Stem cells are harvested after IVE and complete remissions (CR) are consolidated with myeloablative ASCT. During the study period, 4542 pts were diagnosed with non-Hodgkin-lymphoma and of these 54 pts (1.2%) had features of EATL. In the population of 7.6 million, this equates to an overall incidence of 0.14/100,000 per yr. The median age at diagnosis was 57 yrs, 61% of pts were male. 40% of pts presented with Lugano clinical stage (CS) IIE (serosal penetration involving adjacent organs and tissues), 17% CS IV (disseminated extranodal involvement or supradiaphragmatic nodal involvement), 15% CS I (confined to GI-tract), 15% CS II1 (local abdominal involvement) and 12% CS II2 (distant abdominal involvement). Two pts had bone marrow involvement. Diagnosis of EATL was made at laparotomy in 91% of pts. Tumour was arising from the small bowel in 96% of pts; in one case involved the duodenum and in another the iliocaecal region. Pain was the most common presenting symptom (81%), followed by weight loss, visceral perforation, nausea/vomiting, bowel upset and subacute obstruction. Symptoms were present less than a month before diagnosis in 33% of pts and between 1–6 months in 55%. 92% of pts had co-existing coeliac disease (diagnosed prior to diagnosis of EATL in 35% of pts and co-incidently in 58%). 30 pts (56%) were treated with surgery and CT, 19 pts (35%) with surgery alone and 5 pts (9%) with CT alone. Of those pts treated with CT the majority (31/35) received CHOP-like regimens. There were no statistically significant differences between treatment groups with the exception of higher number of elderly pts treated with surgery alone. 44 pts died, mostly due to lymphoma or complications. For all pts, median progression free survival (PFS) was 3.4 months and overall survival (OS) 7 months. 5yr PFS and OS for pts treated with CHOP-like CT was 20% and 22%, respectively and no pts treated with surgery alone survived. 18 pts were subsequently treated with the new regimen. The median age was 52.5 yrs, 67% of pts were male, 39% presented with Lugano CS II1, 22% CS I, 22% CS IV, 11% CS IIE, 6% CS II2+E. The bone marrow was involved in one pt. Site of disease was small bowel in 83% of pts and two patients had involvement of stomach and duodenum and one of small bowel and colon. In all except one pt the diagnosis was made at laparotomy. 12 pts (67%) completed all planned treatment, 3 pts had progressing disease during treatment, two other did not received ASCT due to poor general condition and one pt declined further treatment. Most common severe toxicities were pancytopenia, infection, nausea/vomiting and obstruction/perforation. Treatment results were compared with historical control group treated with CHOP-like CT. There was no difference between the groups according to age, sex and features at presentation. Compared to pts treated with CHOP-like CT, those in the IVE/MTX group had improved CR at final evaluation (42% vs 72%), 5yr PFS (20% vs 56%; p=0.008) and 5yr OS (22% vs 67%; p=0.001). Additionally, in the IVE/MTX group fewer patients died than in the CHOP-like CT group (33% vs 81%; p=0.002). There were no treatment related deaths. In a population-based study of EATL we describe the natural history of the disease in the context of current treatments. We propose a new protocol with significantly improved outcome and acceptable toxicities. In conclusion, pts with EATL should be treated with systemic CT and where feasible an aggressive treatment like IVE/MTX – ASCT. We recommend patients should be entered into national studies such as (NCRI 1418) to evaluate this approach further.