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High frequency of fatal haemophagocytic lymphohistiocytosis syndrome in enteropathy-associated T cell lymphoma
Digestive and Liver Disease 44 (2012) 343–349
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Oncology
High frequency of fatal haemophagocytic lymphohistiocytosis syndrome in enteropathy-associated T cell lymphoma Aurelien Amiot a,∗ , Matthieu Allez b , Xavier Treton a , Claire Fieschi c , Lionel Galicier c , Francisca Joly a , Jean-Marc Gornet b , Eric Oksenhendler c , Marc Lémann b , Yoram Bouhnik a a
Pôle des Maladies de l’Appareil Digestif, Service de Gastroentérologie et d’Assistance Nutritive, Hôpital Beaujon, Clichy et Université Diderot, Paris VII, France Service d’Hépatogastroentérologie, Hôpital Saint Louis, Paris et Université Diderot, Paris VII, France c Service d’Immunologie Clinique, Hôpital Saint-Louis, Paris et Université Diderot, Paris VII, France b
a r t i c l e
i n f o
Article history: Received 23 January 2011 Accepted 13 October 2011 Available online 18 November 2011 Keywords: Coeliac disease EATL Haemophagocytic lymphohistiocytosis syndrome
a b s t r a c t Introduction: Enteropathy-associated T-cell lymphoma is a rare form of T-cell lymphoma associated with a poor prognosis and the relative ineffectiveness of standard chemotherapy. The occurrence of haemophagocytic lymphohistiocytosis has been reported only once with this entity. Patients and methods: A retrospective study of 15 patients with enteropathy-associated T-cell lymphoma (type 1 in 12), followed-up in our units, since 1985. Two patients died before starting chemotherapy. The remaining 13 patients were treated with standard chemotherapy (n = 7) and purine nucleotide analogues (n = 6). Results: Median follow-up was 8.7 (1–97) months. Surgery was required in 10 patients (66%) for intestinal complications (n = 7) or elective small bowel resection (n = 3). Survival probability was 40% and 20% at 1 and 5 years, respectively (Kaplan–Meier method). Survival was not significantly different between the two chemotherapy regimens. However, a slight decrease of febrile neutropenia was observed in the purine nucleotide analogues group (p = 0.06). Haemophagocytic lymphohistiocytosis occurred in 6/15 (40%) cases. In these six patients, haemophagocytic lymphohistiocytosis was always fatal within 3 months. Conclusion: Enteropathy-associated T-cell lymphoma is associated with a poor outcome, independently of the chemotherapy regimens administered and frequent occurrence of haemophagocytic lymphohistiocytosis. The latter complication should be considered for urgent rescue therapy. © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction Enteropathy-associated T-cell lymphoma (EATL) is a rare form of lymphoma which is associated with coeliac disease in almost 70% of cases [1] and has usually a poor prognosis with a 2- and 5-year survival of 30–40% and 10–20%, respectively [2–6]. Multimodal chemotherapy, mainly anthracycline-based regimen, has failed to improve survival in patients with EATL [2–5,7]. Purine nucleoside analogues (PNA) have shown interesting results in refractory coeliac disease and in 1 case of EATL, but need to be further investigated [8–10]. Haemophagocytic lymphohistiocytosis (HLH) is a clinicopathological entity characterised by the association of laboratory
and clinical features of increased proliferation and activation of benign macrophages with haemophagocytosis through the reticuloendothelial system [11,12]. Clinically, HLH presents with high fever, pancytopenia, hepatosplenomegaly, liver dysfunction, coagulopathy and hyperferritinemia. Impaired function of natural killer cells and cytotoxic T-cells is the characteristic hallmark of HLH [12]. HLH may be associated with various underlying disorders such as infections, autoimmune disease and primary, acquired immune deficiency syndrome or malignant lymphoma [12]. To the best of our knowledge, only one patient with an associated EATL has been reported so far in the literature [13]. In this retrospective study, we report a series of 15 EATL patients in which 6 experienced HLH with a rapid fatal outcome. 2. Patients and methods
∗ Corresponding author at: Service de Gastroentérologie et d’Assistance Nutritive, Hôpital Beaujon, France, AP-HP, 1, avenue du Général Leclerc, 92110, Clichy, France. Tel.: +33 1 40 87 57 84; fax: +33 1 40 87 45 74. E-mail addresses: [email protected], [email protected] (A. Amiot).
2.1. Patients Charts of adult patients with diagnosis of EATL that have been followed in our two institutions (Beaujon Hospital, Clichy
1590-8658/$36.00 © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2011.10.008
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and St-Louis Hospital, Paris) between January 1985 and March 2010 were reviewed. They were ascertained from our personal database or a standardized dataset of hospital inpatient diagnosis. Histopathological and immunohistochemical examination were systematically reviewed by one of our two pathologists (Pr Anne Lavergne-Slove, Pr Philippe Bertheau). Diagnosis of EATL was established according to the WHO classification [14]. EATL was classified according to 2008 WHO classification into either type 1 EATL characterised by frequent association with coeliac sprue and HLA-DQ2 haplotype, large-cell and/or pleiomorphic cytology and that may express CD30 and type 2 characterised by less frequent association with coeliac sprue and HLA-DQ2 haplotype and monomorphic cytology with frequent CD56 expression [15,16]. Exclusion criteria were refractory coeliac sprue without high grade component, Tcell intestinal lymphoma without enteropathy and extra-intestinal T-cell lymphoma with secondary intestinal invasion. Presence of underlying coeliac disease and/or refractory coeliac disease was systematically evaluated [17–21]. Clinical, laboratory and morphologic investigations, treatment and outcome were collected. Our primary objective was to report survival of EATL patients. Our secondary objective was to report and describe the occurrence of HLH and others EATL complications and to report survival of EATL patients considering the 2 chemotherapy regimens (PNA and standard chemotherapy). 2.1.1. Characteristics of EATL Characteristics of EATL included symptoms at diagnosis, endoscopic appearance and histopathological examination, presence of HLA-DQ2 haplotype. Endoscopic evaluation included upper gastrointestinal endoscopy or double balloon enteroscopy with small intestinal biopsies. Ulcerative jejunitis was defined as previously described [21]. Villous atrophy was assessed and graded as absent, partial, subtotal, or total. The percentage of intraepithelial cells (number of IELs per 100 epithelial cells) was established on well oriented serial sections by counting at least 500 epithelial cells [21]. Immunohistochemistry was performed on serial 3-m paraffin sections, using an automated immunohistochemical stainer according to the manufacturer’s guidelines (streptavidin-peroxidase protocol; BenchMark, Ventana, Tucson, AZ), using antibodies directed against CD3, CD4, CD5, CD8, CD30, CD56, TiA-1 and granzyme-B. In situ hybridisation for EBV was also performed. Molecular detection of clonal TCR␥ chain rearrangement was performed by multiplex PCR as described [18]. 2.1.2. Lymphoma severity Staging was established according to the Ann Arbor classification, on the basis of the patient history, physical examination, blood tests, thoracic and abdominal computed tomography (CT) scan, upper and lower endoscopies, and bone marrow biopsy. During follow-up, investigations were repeated according to the chemotherapy regimen , response to treatment and clinical status. Systemic symptoms related to lymphoma, so-called B symptoms, are defined as unexplained fever for approximately 8 days and/or intense nocturnal sweating. International prognostic index (IPI) and related factors were reported at baseline [22].
HLH was diagnosed according to the criteria defined by the HLH Study Group of the Histiocyte Society, recently revised: fever, splenomegaly, cytopenia affecting at least 2 cell lineages (haemoglobin < 9 g/dl, platelets < 100 × 109 /l, neutrophils < 1 × 109 /l), hypertriglyceridaemia and/or hypofibrinogenemia (fasting triglycerides > 3 mmol/l, fibrinogen < 1.5 g/l), ferritin > 500 g/l, sCD25 ≥ 2400 U/ml, decreased or absent NK-cell activity, haemophagocytosis in bone marrow, CSF or lymph nodes (5/8 criteria are required for a positive diagnosis) [12]. Fever, hepatosplenomegaly, peripheral lymphadenopathy and other organ involvement were reported. Laboratory findings including white cell, haemoglobin and platelet counts, plasma prothrombin time, aspartate aminotransferase, LDH activity, triglyceride and ferritin as well as treatment and outcome of HLH were also specifically reported. Other complications of EATL including chemotherapy-related adverse events and intestinal complications (perforation, bleeding and obstruction) were also reported. Febrile neutropenia was defined by fever and a neutrophil count <1 × 109 /l related to chemotherapy. 2.2.1. Modalities of treatment Three types of treatment were administered alone or in association: (a) surgical resection was performed in case of intestinal complications (perforation and/or obstruction) or in case of localized EATL. During surgical procedure, systematic lymph node resection, and liver biopsy were performed when feasible. Localization, local extension, hepatosplenic involvement, and modification of digestive circuit were also reported; (b) standard chemotherapy consisted in anthracycline-based regimen (CHVpP or ACVBP) or aracytin based regimen (DHAX), for patients without contraindication, every 2–3 weeks. (c) PNA regimen consisted in 2-CDA (10 mg/m2 from day 1 to 4, repeated every 6 months when necessary) or 2 deoxycoformycin (4 mg/m2 every 2 weeks for induction phase and tapered infusion for consolidation phase). In case of relapse, second line treatment was defined by various modalities. In patients with poor clinical condition, palliative treatment with or without corticosteroids was used. 2.2.2. Statistical analysis Survival time was calculated from the date of EATL diagnosis to death or to the end of the follow-up on March 2010. The cause of death was recorded. Survival probabilities have been calculated using the Kaplan–Meier method. Survival distributions taking into account concomitant variables were compared using the log rank test, with p values of 0.05 considered statistically significant. Qualitative categories of values were defined by dichotomy from median value in 2 distinct groups of equal size. Time to remission was calculated from the date of achievement of remission to the date of recurrence or the end of the follow-up. Quantitative variables were expressed as median with ranges or as mean ± standard deviation; hazard ratios were provided with 95% confidence intervals (CI). Characteristics of patients according to chemotherapy modality (PNA or standard chemotherapy) were compared by means using non-parametric Mann–Whitney tests. 3. Results
2.2. Outcomes
3.1. Study population characteristics
Survival, complete or partial remission, disease-free survival, and occurrence of complications were studied. Complete remission (CR) was defined as a return to normal by all documented tumour sites. Partial remission (PR) was defined as more than 50% decrease in disease bulk, evaluated with CT scan, persisting for at least 1 month.
Demographic and other baseline characteristics of the patients are shown in Table 1. The median follow-up was 8.7 (1–97) months after diagnosis of EATL. Eleven (73%) patients were previously diagnosed with coeliac disease. All patients, independently of the presence of a diagnosed coeliac disease, were assigned to gluten free diet, with a good compliance in 10 (63%) cases. Seven patients
A. Amiot et al. / Digestive and Liver Disease 44 (2012) 343–349 Table 1 Baseline characteristics of the patients with enteropathy-associated T-cell lymphoma (n = 15).
Table 2 Histopathological and molecular characteristics of enteropathy-associated T-cell lymphoma (n = 15).
Patients (n = 15) Sex, female (%) Age, year (median, range) Delay before diagnosis, month (median, range) Corticosteroid before diagnosis, n (%) Immunosuppressant before diagnosis, n (%) Body mass index, kg/m2 (mean ± SD) Serum albumin, g/l (mean ± SD) Nutritional Risk Index, % (mean ± SD) Parenteral nutrition support, n (%) Elevated serum lacate dehydrogenase, n (%) Ann Arbor staging ≥3, n (%) Performance status ≥2, n (%) B symptoms, n (%) Extranodal involvement, n (%) IPI scorea (mean ± SD)
6 (40) 55 (28–81) 17 (0.1–78) 7 (47) 4 (27) 19.8 ± 2.7 26.4 ± 7 68 ± 18 12 (73) 4 (27) 7 (47%) 9 (60) 9 (60) 5 (33) 1.2 ± 1.3
a The International prognostic index (IPI) is a composite score integrating features that reflect the growth and invasive potential of the tumour and the patient’s ability to tolerate chemotherapy. One point is assigned for each of the following risk factors: Age greater than 60 years, Ann Arbor stage III or IV, elevated serum lactate dehydrogenase, performance status ≥2 and more than one extranodal involvement.
were treated with steroids, including budesonide with PPI to optimise jejunal release of enteric coated budesonide in 4 cases. A previous history of refractory coeliac sprue was reported in 7 cases (type 2: n = 6 and type 1: n = 1). Four patients with type 2 refractory coeliac sprue received immunosuppressant therapy including cyclosporine (n = 1), methotrexate (n = 1), infliximab alone (n = 1) or associated with azathioprine (n = 1), before diagnosis of EATL. All patients had malnutrition (69.5% ± 18.5) and 12/15 had severe denutrition [23]. Parenteral nutrition was required in 12 out of 15 patients but did not succeed in improving nutritional status (73% ± 14, p = 0.54).
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Patients, n (%) HLA DQ2 phenotype Type of EATL Type 1 Type 2 Histology Cells size Cells morphology Immunohistochemistry CD3 CD4 CD5 CD8 CD20 CD30 CD56 TiA-1 Granzyme-B EBV (in situ hybridisation for EBV encoded small nuclear RNAs) Clonal TCR␥ chain rearrangement
12/12 (100%) 12/15 (80%) 3/15 (20%) Large 13/15 (87%) – small 2/15 (13%) Pleomorphic 3/15 (20%) – monomorphic 12/15 (80%) 15/15 (100%) 0/15 (0%) 3/14 (21%) 1/15 (7%) 0/15 (0%) 7/13 (54%) 2/14 (14%) 13/14 (93%) 11/11 (100%) 0/11 (0%) 14/14 (100%)
3.3. Lymphoma severity Performance status was measured with ECOG score and found stage 0 or 1 in 6 (40%) cases and stage higher than 2 in 9 cases (60%). B symptoms were noticed in 9 (60%) cases. Lactate dehydrogenase (LDH) was increased in four patients (27%). Extranodal involvement was noticed in 5 (33%) patients. LDH activity was increased in 4 (27%) patients and was always associated with Ann Arbor stage IV and with further haemophagocytosis in 3 of the 4 patients. According to Ann Arbor staging criteria, disease stage was stage I in 4 patients, stage II in 4 and stage IV in 7.
3.2. Characteristics of EATL 3.4. Survival The median duration between the first occurrence of symptoms and diagnosis of EATL was 13.2 (0–52) months. Symptoms at diagnosis were diarrhoea (93%), malabsorption (80%), weight loss (67%), abdominal pain (27%) and vomiting (7%). B symptoms (fever and sweating) were noticed in 9 cases (60%) and tumoural syndrome (haematodermia, peripheral adenopathy or hepatosplenomegaly) in 5 (33%) cases. Upper endoscopy showed macroscopic abnormalities in all cases, including disappearance of folds and mosaic pattern in 12 cases, nodular lymphoid hyperplasia in 4, and ulcerative duodenitis in 10. Small-bowel biopsies showed villous atrophy in all cases, including partial in 3 cases and severe in 12. Median numbers of IELs quantified in duodenal sections were 40 (30–70)/100 epithelial cells. According to immunohistochemical examination, the phenotype of IELs was normal in 9 cases and aberrant IELs that not expressing CD4 and CD8. The diagnosis of EATL was made at laparotomy in 5 cases. The remaining 11 patients were diagnosed from small-bowel biopsies in 9 cases, peripheral lymphadenopathy biopsy in one and liver biopsy in one. Endoscopical appearance showed ulcerative jejunitis and nodular hyperplasia in 3, ulcerated stenosis in 3 and deep jejunal ulceration in 2. Diffuse enteropathy was observed in 12 cases. Life-threatening complications occurred in 6 (40%) cases with acute intestinal obstruction (n = 4), peritonitis (n = 1) or intestinal bleeding (n = 1). Histopathological and molecular details are shown in Table 2. All but one patient exhibited clonality of the TCR␥ chain. EBV in situ hybridisation was negative in all of the 11 patients tested. EATL type 1 constituted 80% (12/15) and type 2 20% (3/15) of the cases.
Amongst the 15 patients examined, 13 died during follow-up. Thirteen of these patients could be treated and only 2 (15%) survived and fulfilled a 97- and 67-month period, respectively, without any sign of recurrence. The survival rates were 40%, 27% and 20% at 1, 3 and 5 years, respectively (Fig. 1). In univariate analysis, probability of survival was significantly lower in patients with IPI score >2 (p < 0.001), disseminated disease (Ann Arbor stage IV) >2 (p = 0.01) and high LDH activity (p = 0.04). In contrast, survival was improved in case of curative surgical procedure (p = 0.006) (Fig. 1). Survival was similar in patients with EATL type 1 compared to type 2. Survival was significantly decreased in EATL patients with HLH (median survival of 1.9 ± 0.7 (0.6–3) vs. 32.4 ± 20.1 (0.1–71.8) months, p = 0.001) (Fig. 1). 3.5. Haemophagocytosis lymphohistiocytosis HLH occurred in 6 cases with a median delay of 11.2 (8–21) days before diagnosis. At the time of HLH diagnosis, 2 patients were treated with 2-DCF, 1 with CHVpP and 3 did not received any treatment. Clinical manifestations and laboratory findings are illustrated in Table 3. High grade fever (>38 ◦ C) was observed in all cases. Hepatomegaly and peripheral lymphadenopathy were reported in 5 and 3 cases, respectively. Neuropsychiatric symptoms including coma, mood disorder, delirium and cognitive dysfunction were observed in 5 cases. All cases had anaemia and thrombocytopenia whereas leucopenia was observed in 4 cases. Liver dysfunction, high LDH activity, ferritin and triglyceridaemia were systematically reported. In 2 cases, HLH was triggered by an active
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Fig. 1. Kaplan–Meier curves of overall survival after diagnosis of enteropathy T-cell associated lymphoma: (a) by occurrence of haemophagocytosis (b) by IPI score (c) by curative surgery (d) by LDH activity (e) by Ann Arbor classification (HR: hazard ratio; CI: confidence interval; NS: not significant).
infection in 2 cases including a fungal infection (mucormycosis) in one patient (patient 4) previously treated with azathioprine and infliximab and a bacterial infection (Streptococcus catheter-related bloodstream infection) in the other (patient 3). Three out of 6 patients had refractory coeliac sprue before overt EATL, treated
with steroid (patient 1), cyclosporine (patient 2) and infliximab plus azathioprine (patient 4). All our patients with HLH presented an advanced stage according to Ann Arbor classification (stage IVBb in 83%) with extra-intestinal involvement (hepatosplenic and/or cutaneous). The median IPI score was 3 (2–5). All patients died
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Table 3 Clinical manifestations and laboratory data at the onset of haemophagocytic lymphohistiocytosis. Pt Age, sex Fever >7 days
Leukocytes (×109 /l)
Haemoglobin (g/dl)
Platelets (×109 /l)
LDH (U/l)
1 2 3 4 5 6
7.2 1.4 9.0 2.0 0.8 1.2
8.7 8.4 6.7 7.1 5.6 7.3
55 66 26 34 13 32
3586 1430 628 614 610 1258
41, F 52, F 60, M 68, F 64, M 50, M
8 30 21 10 14 8
Ferritin (ng/ml) 6550 >4000 >4000 9342 12430 2334
AST (U/l) 179 119 186 123 174 185
ALP (U/l) 1072 1235 375 350 339 326
Bilirubin (M) 23 276 283 64 123 98
Prothrombin time (%)
Triglyceridaemia (g/l)
58 70 46 80 71 80
10 30 10.3 9.2 8.1 15
LDH: lactate dehydrogenase; AST: aspartate aminotransferase; ALP: alkaline phosphatase.
within 3 months. The median survival time after HLH diagnosis was 11 (1–63) days. One patient treated with vinblastine had a temporary discontinuation in HLH but a rapid flare led to death despite rescue chemotherapy with a course of CHVpP. All the other cases died before any treatment could have been initiated or after the initiation of the best supportive care for multiple organ failure. 3.6. Other complications of EATL 3.6.1. Adverse events due to chemotherapy Amongst the 4 patients treated with vincristine, one developed an acute intestinal obstruction after the third course. Ten cases of febrile neutropenia were observed including 9 cases with standard chemotherapy and 1 case with PNA chemotherapy (p = 0.06). 3.6.2. Intestinal complications Ten (66%) patients experienced at least one intestinal complication for a total of 17 complications: acute intestinal obstruction (n = 9), free peritoneal perforation (n = 5) and intestinal bleeding (n = 3). Surgery was required in 13/17 cases. Curative resection (intestinal margin free of tumour and resection of adjacent lymph nodes) was performed in 3 patients. Two out of these three patients were still free of recurrence at the end of follow-up; the last patient had a diffuse recurrence after a 63.6-month period. Ten procedures were performed in emergency (77%) and three (23%) were scheduled. 3.7. Chemotherapy Two patients died of HLH before to receive any chemotherapy. Treatment characteristics are shown in Table 4. 3.7.1. Standard chemotherapy Standard chemotherapy was used in 10 (66%) patients. Seven patients received standard chemotherapy as first line treatment and 3 patients for rescue after PNA failure. Median survival time (at the time of the first line treatment) was 7.7 (CI95% [0.1; 27.7]) months with standard chemotherapy. In the first-line group, we observed a disease progression in 5 cases and a partial remission with an 11-month survival period free of events in one case. Chemotherapy was ineffective in the 3 patients treated after PNA failure. Standard chemotherapy consisted in CHOP or CHVpP chemotherapy in 6 cases, in ACVBP in 2 cases and in other protocols (VP16-aracytine, ESHAP, BAD, and MACOP-B) in 2 cases. Only one patient reached a complete remission after curative resection and 6 courses of CHVpP with no evidence of recurrence after a follow-up of 52 months. 3.7.2. Purine nucleotide analogues chemotherapy PNA chemotherapy with 2-DCF (n = 5) and 2-CDA (n = 2) was used in 7 (47%) cases. Six patients were treated with a first line chemotherapy with a median survival time of 10.8 (CI95 % [5.5; 16.1]) months. The 2 patients treated with 2-CDA experienced a rapid disease progression with a survival time of 1.7 and 5.4
Table 4 Treatment and relative outcome of our 15 patients with enteropathy T-cell associated lymphoma. Patients, n (%) Initial treatment Nonea Standard chemotherapy Purine nucleotide analogues Surgery None Palliative Curative First line treatment resultsb Non responsive Partial response Complete response Outcome Deadc Alive
2/15 (13%) 7/15 (47%) 6/15 (40%) 5/15 (33%) 7/15 (47%) 3/15 (20%) 7/13 (54%) 1/13 (8%) 5/13 (38%) 13/15 (87%) 2/15 (13%)
a
Two patients died before to receive any chemotherapy. Complete response was observed in two patients treated with curative surgery and standard chemotherapy, one with curative surgery and purine nucleotide analogues, one with palliative surgery and standard chemotherapy and one with purine nucleotide analogues alone. Partial response was observed in one patient treated with palliative surgery and purine nucleotide analogues. c Eight patients died despite first line chemotherapy; three patients died despite 2nd to 4th line rescue chemotherapy. b
months. On the 5 patients treated with 2-DCF, 2 experienced a CR, one a PR and 2 a disease progression. The mean overall and event free survival times were 17.9 and 22 months, respectively, after treatment with 2-DCF. The survival rate was similar in patients treated with PNA (33% at 2 years) as compared to patients treated with standard chemotherapy (43% at 2 years, p = 0.60). One patient was treated with 2-DCF after the failure of standard chemotherapy but no response was observed. 4. Discussion In the present series, we described the outcome and specific complications of 15 EATL patients. The prognosis was poor with a 5-year survival rate of 20% and a high rate of serious intestinal complications (acute obstruction, intestinal bleeding or perforation). We found a very high frequency of HLH, which occurred in 40% of the cases examined and was fatal in all the cases within 3 months. Despite a relatively small number of cases and methodological bias, the tolerance was better for PNA compared to standard chemotherapy but the efficacy was similar for both therapies. Recent studies have indicated that EATL could be classified into 2 distinct subtypes, based on morphological, molecular analysis and with respect to their frequency of association with coeliac sprue [15,16]. Type 1 EATL is characterised by frequent association with coeliac sprue, an HLA-DQ2 haplotype and large-cell and/or pleiomorphic cytology and that may express CD30. In contrast, type 2 is characterised by less frequent association with coeliac sprue, HLA-DQ2 haplotype and monomorphic cytology with frequent CD56 expression. Distinct molecular abnormalities have
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been found between type 1 and type 2 EATL, suggesting distinct lymphomagenic pathway [16]. In our series, it appears that some coeliac disease patients had type 2 EATL (patients 3 and 7) and that non-coeliac disease patient had type 1 EATL (patient 5). Such confusing findings have been previously reported [2]. Similarly, despite a relatively small number of cases, we did not found any difference between the two EATL subtypes [2]. It is conceivable that complementary immunohistochemical and molecular analysis could have permitted to re-classify patients into a right EATL subtype that fit with association with coeliac sprue [16]. It is also conceivable that current criteria for coeliac sprue in EATL patients lake of specificity [17–21]. Prognosis of EATL is usually poor. The 2- and 5-year survival rates are 30–40% and 10–20%, respectively [2–6]. Standard chemotherapy, mainly an anthracycline-based regimen, has shown a modest survival improvement, but a high complication rate and a rapid relapse have been previously reported [4]. In the present series, we evaluated PNA, which are very similar cytotoxic drugs, with proven efficacy in lymphoproliferative disorders [24–27]. In our study, the survival was not different between PNA and standard chemotherapy. Although retrospective study has inherent limitation, grouping two different subtypes of EATL limits firm conclusion and the number of patients included is relatively small, we thought that our results should be considered. Indeed, PNA was associated with less febrile neutropenia compared to standard chemotherapy. Therefore, new therapeutic modalities are needed to improve EATL survival. A novel chemotherapy regimen containing high dose methotrexate and IVE (Ifosfamide, vincristine and etoposide) with first-line autologous stem cell transplantation has recently been evaluated in two prospective series including 6 and 26 patients, respectively [28,29]. In both studies, complete remission was achieved in 5/6 and 17/26 patients, respectively [28,29]. In the more recent study, overall and progression-free survival were significantly improved compared to historical group treated with anthracycline-based regimen [28]. Haemophagocytosis is characterised by the pathological finding of activated macrophages engulfing erythrocytes, leukocytes, platelets, and their precursors [12]. HLH is a distinct clinicopathological entity with a clinical presentation related to macrophage proliferation and activation, and evidence of haemophagocytosis in bone marrow and other tissues [12]. In adults, acquired HLH is associated with various conditions including non-Hodgkin’s lymphoma [12]. Amongst these conditions, most cases of lymphomaassociated HLH are associated with T and NK lymphoma [30–33]. So far, only one patient with EATL has been reported with HLH in the literature [13]. In our series, HLH was reported in 6 (40%) EATL patients. All the patients with HLH presented an advanced stage according to Ann Arbor classification, with extra-intestinal involvement, high LDH level and IPI score. Therefore, the occurrence of HLH in EATL patients may have been underestimated and its detection should be systematically assessed, especially in patients with uncontrolled disease. When untreated, HLH is a highly fatal disease [34]. A comprehensive management is required to support organ failure, especially to manage infectious complications, correct coagulation disorders and restore fluid and electrolyte balance. Life-threatening hyperinflammation, caused by excessive levels of cytokines, can be treated with corticosteroids and/or intravenous immunoglobulins [12]. Etoposide, which is very effective in monocytic and histiocytic diseases, should be added to corticosteroids in case of severe HLH [35–38]. In severe HLH, the early administration of etoposide is primordial as the time to treat the patient is associated with the severity of the outcome [35]. In case of HLH secondary to lymphoproliferative diseases, treatment should target malignant lymphocytes using combined chemotherapy regimens. In our series, only one patient was treated with vinblastine with a
temporary discontinuation of HLH but a rapid flare was fatal, despite rescue chemotherapy with a course of CHVpP. All the other cases did not receive etoposide or chemotherapy. Two patients had active infections that delayed the initiation of specific therapy. Two patients died within 1 and 2 days, respectively, before any specific treatment could have been initiated. The last patient developed HLH after the failure of the first line chemotherapy (2-DCF) and was referred to the best supportive care. The median survival time was 11 (1–63) days and it did not permit to rule-out or exclude an active infection, especially in patients receiving immunosuppressive therapy or chemotherapy. However, we hope that an earlier treatment of HLH could have improved the survival of these patients. In conclusion, EATL remained a dramatically poor condition, associated with serious intestinal adverse events (acute obstruction and intestinal perforation) and a low survival. HLH is a frequent and rapidly fatal complication of EATL. Neither standard chemotherapy nor PNA are effective to improve its poor prognosis. Surgery could be effective only if curative procedure could be feasible. Conflict of interest statement None declared.
List of abbreviations 2-CDA, cladribine; 2-DCF, 2-deoxycoformycine; IPI, International prognostic index; LDH, lactate dehydrogenase; PEACE-BOM, prednisolone, doxorubicin, cyclophosphamide, and etoposide with prednisolone, bleomycin, vincristine, and methotrexate; MACOP B, methotrexate, doxorubicin, cyclophosphamide, vincristine, predonisolone, bleomycin; CHOEP, cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisolone; PNA, purine nucleotide analogues; EATL, enteropathy T-cell lymphoma; CHVpP, cyclophosphamide 750 mg/m2 , doxorubicin 50 mg/m2 , and etoposide 100 mg/m2 day 1, prednisolone 40 mg/m2 day 1–4; ACVBP, cyclophosphamide 1200 mg/m2 and doxorubicin 50 mg/m2 day 1, vindesine 2 mg/m2 and bleomycine 10 mg/m2 day 1 and 5, prednisolone 60 mg/m2 day 1–5; DHAX, dexamethasone 40 mg/m2 day 1–4, oxaliplatin 100 mg/m2 day 1, and aracytin 2 × 2 g/m2 day 2.
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Contents lists available at SciVerse ScienceDirect
Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Oncology
High frequency of fatal haemophagocytic lymphohistiocytosis syndrome in enteropathy-associated T cell lymphoma Aurelien Amiot a,∗ , Matthieu Allez b , Xavier Treton a , Claire Fieschi c , Lionel Galicier c , Francisca Joly a , Jean-Marc Gornet b , Eric Oksenhendler c , Marc Lémann b , Yoram Bouhnik a a
Pôle des Maladies de l’Appareil Digestif, Service de Gastroentérologie et d’Assistance Nutritive, Hôpital Beaujon, Clichy et Université Diderot, Paris VII, France Service d’Hépatogastroentérologie, Hôpital Saint Louis, Paris et Université Diderot, Paris VII, France c Service d’Immunologie Clinique, Hôpital Saint-Louis, Paris et Université Diderot, Paris VII, France b
a r t i c l e
i n f o
Article history: Received 23 January 2011 Accepted 13 October 2011 Available online 18 November 2011 Keywords: Coeliac disease EATL Haemophagocytic lymphohistiocytosis syndrome
a b s t r a c t Introduction: Enteropathy-associated T-cell lymphoma is a rare form of T-cell lymphoma associated with a poor prognosis and the relative ineffectiveness of standard chemotherapy. The occurrence of haemophagocytic lymphohistiocytosis has been reported only once with this entity. Patients and methods: A retrospective study of 15 patients with enteropathy-associated T-cell lymphoma (type 1 in 12), followed-up in our units, since 1985. Two patients died before starting chemotherapy. The remaining 13 patients were treated with standard chemotherapy (n = 7) and purine nucleotide analogues (n = 6). Results: Median follow-up was 8.7 (1–97) months. Surgery was required in 10 patients (66%) for intestinal complications (n = 7) or elective small bowel resection (n = 3). Survival probability was 40% and 20% at 1 and 5 years, respectively (Kaplan–Meier method). Survival was not significantly different between the two chemotherapy regimens. However, a slight decrease of febrile neutropenia was observed in the purine nucleotide analogues group (p = 0.06). Haemophagocytic lymphohistiocytosis occurred in 6/15 (40%) cases. In these six patients, haemophagocytic lymphohistiocytosis was always fatal within 3 months. Conclusion: Enteropathy-associated T-cell lymphoma is associated with a poor outcome, independently of the chemotherapy regimens administered and frequent occurrence of haemophagocytic lymphohistiocytosis. The latter complication should be considered for urgent rescue therapy. © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction Enteropathy-associated T-cell lymphoma (EATL) is a rare form of lymphoma which is associated with coeliac disease in almost 70% of cases [1] and has usually a poor prognosis with a 2- and 5-year survival of 30–40% and 10–20%, respectively [2–6]. Multimodal chemotherapy, mainly anthracycline-based regimen, has failed to improve survival in patients with EATL [2–5,7]. Purine nucleoside analogues (PNA) have shown interesting results in refractory coeliac disease and in 1 case of EATL, but need to be further investigated [8–10]. Haemophagocytic lymphohistiocytosis (HLH) is a clinicopathological entity characterised by the association of laboratory
and clinical features of increased proliferation and activation of benign macrophages with haemophagocytosis through the reticuloendothelial system [11,12]. Clinically, HLH presents with high fever, pancytopenia, hepatosplenomegaly, liver dysfunction, coagulopathy and hyperferritinemia. Impaired function of natural killer cells and cytotoxic T-cells is the characteristic hallmark of HLH [12]. HLH may be associated with various underlying disorders such as infections, autoimmune disease and primary, acquired immune deficiency syndrome or malignant lymphoma [12]. To the best of our knowledge, only one patient with an associated EATL has been reported so far in the literature [13]. In this retrospective study, we report a series of 15 EATL patients in which 6 experienced HLH with a rapid fatal outcome. 2. Patients and methods
∗ Corresponding author at: Service de Gastroentérologie et d’Assistance Nutritive, Hôpital Beaujon, France, AP-HP, 1, avenue du Général Leclerc, 92110, Clichy, France. Tel.: +33 1 40 87 57 84; fax: +33 1 40 87 45 74. E-mail addresses: [email protected], [email protected] (A. Amiot).
2.1. Patients Charts of adult patients with diagnosis of EATL that have been followed in our two institutions (Beaujon Hospital, Clichy
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and St-Louis Hospital, Paris) between January 1985 and March 2010 were reviewed. They were ascertained from our personal database or a standardized dataset of hospital inpatient diagnosis. Histopathological and immunohistochemical examination were systematically reviewed by one of our two pathologists (Pr Anne Lavergne-Slove, Pr Philippe Bertheau). Diagnosis of EATL was established according to the WHO classification [14]. EATL was classified according to 2008 WHO classification into either type 1 EATL characterised by frequent association with coeliac sprue and HLA-DQ2 haplotype, large-cell and/or pleiomorphic cytology and that may express CD30 and type 2 characterised by less frequent association with coeliac sprue and HLA-DQ2 haplotype and monomorphic cytology with frequent CD56 expression [15,16]. Exclusion criteria were refractory coeliac sprue without high grade component, Tcell intestinal lymphoma without enteropathy and extra-intestinal T-cell lymphoma with secondary intestinal invasion. Presence of underlying coeliac disease and/or refractory coeliac disease was systematically evaluated [17–21]. Clinical, laboratory and morphologic investigations, treatment and outcome were collected. Our primary objective was to report survival of EATL patients. Our secondary objective was to report and describe the occurrence of HLH and others EATL complications and to report survival of EATL patients considering the 2 chemotherapy regimens (PNA and standard chemotherapy). 2.1.1. Characteristics of EATL Characteristics of EATL included symptoms at diagnosis, endoscopic appearance and histopathological examination, presence of HLA-DQ2 haplotype. Endoscopic evaluation included upper gastrointestinal endoscopy or double balloon enteroscopy with small intestinal biopsies. Ulcerative jejunitis was defined as previously described [21]. Villous atrophy was assessed and graded as absent, partial, subtotal, or total. The percentage of intraepithelial cells (number of IELs per 100 epithelial cells) was established on well oriented serial sections by counting at least 500 epithelial cells [21]. Immunohistochemistry was performed on serial 3-m paraffin sections, using an automated immunohistochemical stainer according to the manufacturer’s guidelines (streptavidin-peroxidase protocol; BenchMark, Ventana, Tucson, AZ), using antibodies directed against CD3, CD4, CD5, CD8, CD30, CD56, TiA-1 and granzyme-B. In situ hybridisation for EBV was also performed. Molecular detection of clonal TCR␥ chain rearrangement was performed by multiplex PCR as described [18]. 2.1.2. Lymphoma severity Staging was established according to the Ann Arbor classification, on the basis of the patient history, physical examination, blood tests, thoracic and abdominal computed tomography (CT) scan, upper and lower endoscopies, and bone marrow biopsy. During follow-up, investigations were repeated according to the chemotherapy regimen , response to treatment and clinical status. Systemic symptoms related to lymphoma, so-called B symptoms, are defined as unexplained fever for approximately 8 days and/or intense nocturnal sweating. International prognostic index (IPI) and related factors were reported at baseline [22].
HLH was diagnosed according to the criteria defined by the HLH Study Group of the Histiocyte Society, recently revised: fever, splenomegaly, cytopenia affecting at least 2 cell lineages (haemoglobin < 9 g/dl, platelets < 100 × 109 /l, neutrophils < 1 × 109 /l), hypertriglyceridaemia and/or hypofibrinogenemia (fasting triglycerides > 3 mmol/l, fibrinogen < 1.5 g/l), ferritin > 500 g/l, sCD25 ≥ 2400 U/ml, decreased or absent NK-cell activity, haemophagocytosis in bone marrow, CSF or lymph nodes (5/8 criteria are required for a positive diagnosis) [12]. Fever, hepatosplenomegaly, peripheral lymphadenopathy and other organ involvement were reported. Laboratory findings including white cell, haemoglobin and platelet counts, plasma prothrombin time, aspartate aminotransferase, LDH activity, triglyceride and ferritin as well as treatment and outcome of HLH were also specifically reported. Other complications of EATL including chemotherapy-related adverse events and intestinal complications (perforation, bleeding and obstruction) were also reported. Febrile neutropenia was defined by fever and a neutrophil count <1 × 109 /l related to chemotherapy. 2.2.1. Modalities of treatment Three types of treatment were administered alone or in association: (a) surgical resection was performed in case of intestinal complications (perforation and/or obstruction) or in case of localized EATL. During surgical procedure, systematic lymph node resection, and liver biopsy were performed when feasible. Localization, local extension, hepatosplenic involvement, and modification of digestive circuit were also reported; (b) standard chemotherapy consisted in anthracycline-based regimen (CHVpP or ACVBP) or aracytin based regimen (DHAX), for patients without contraindication, every 2–3 weeks. (c) PNA regimen consisted in 2-CDA (10 mg/m2 from day 1 to 4, repeated every 6 months when necessary) or 2 deoxycoformycin (4 mg/m2 every 2 weeks for induction phase and tapered infusion for consolidation phase). In case of relapse, second line treatment was defined by various modalities. In patients with poor clinical condition, palliative treatment with or without corticosteroids was used. 2.2.2. Statistical analysis Survival time was calculated from the date of EATL diagnosis to death or to the end of the follow-up on March 2010. The cause of death was recorded. Survival probabilities have been calculated using the Kaplan–Meier method. Survival distributions taking into account concomitant variables were compared using the log rank test, with p values of 0.05 considered statistically significant. Qualitative categories of values were defined by dichotomy from median value in 2 distinct groups of equal size. Time to remission was calculated from the date of achievement of remission to the date of recurrence or the end of the follow-up. Quantitative variables were expressed as median with ranges or as mean ± standard deviation; hazard ratios were provided with 95% confidence intervals (CI). Characteristics of patients according to chemotherapy modality (PNA or standard chemotherapy) were compared by means using non-parametric Mann–Whitney tests. 3. Results
2.2. Outcomes
3.1. Study population characteristics
Survival, complete or partial remission, disease-free survival, and occurrence of complications were studied. Complete remission (CR) was defined as a return to normal by all documented tumour sites. Partial remission (PR) was defined as more than 50% decrease in disease bulk, evaluated with CT scan, persisting for at least 1 month.
Demographic and other baseline characteristics of the patients are shown in Table 1. The median follow-up was 8.7 (1–97) months after diagnosis of EATL. Eleven (73%) patients were previously diagnosed with coeliac disease. All patients, independently of the presence of a diagnosed coeliac disease, were assigned to gluten free diet, with a good compliance in 10 (63%) cases. Seven patients
A. Amiot et al. / Digestive and Liver Disease 44 (2012) 343–349 Table 1 Baseline characteristics of the patients with enteropathy-associated T-cell lymphoma (n = 15).
Table 2 Histopathological and molecular characteristics of enteropathy-associated T-cell lymphoma (n = 15).
Patients (n = 15) Sex, female (%) Age, year (median, range) Delay before diagnosis, month (median, range) Corticosteroid before diagnosis, n (%) Immunosuppressant before diagnosis, n (%) Body mass index, kg/m2 (mean ± SD) Serum albumin, g/l (mean ± SD) Nutritional Risk Index, % (mean ± SD) Parenteral nutrition support, n (%) Elevated serum lacate dehydrogenase, n (%) Ann Arbor staging ≥3, n (%) Performance status ≥2, n (%) B symptoms, n (%) Extranodal involvement, n (%) IPI scorea (mean ± SD)
6 (40) 55 (28–81) 17 (0.1–78) 7 (47) 4 (27) 19.8 ± 2.7 26.4 ± 7 68 ± 18 12 (73) 4 (27) 7 (47%) 9 (60) 9 (60) 5 (33) 1.2 ± 1.3
a The International prognostic index (IPI) is a composite score integrating features that reflect the growth and invasive potential of the tumour and the patient’s ability to tolerate chemotherapy. One point is assigned for each of the following risk factors: Age greater than 60 years, Ann Arbor stage III or IV, elevated serum lactate dehydrogenase, performance status ≥2 and more than one extranodal involvement.
were treated with steroids, including budesonide with PPI to optimise jejunal release of enteric coated budesonide in 4 cases. A previous history of refractory coeliac sprue was reported in 7 cases (type 2: n = 6 and type 1: n = 1). Four patients with type 2 refractory coeliac sprue received immunosuppressant therapy including cyclosporine (n = 1), methotrexate (n = 1), infliximab alone (n = 1) or associated with azathioprine (n = 1), before diagnosis of EATL. All patients had malnutrition (69.5% ± 18.5) and 12/15 had severe denutrition [23]. Parenteral nutrition was required in 12 out of 15 patients but did not succeed in improving nutritional status (73% ± 14, p = 0.54).
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Patients, n (%) HLA DQ2 phenotype Type of EATL Type 1 Type 2 Histology Cells size Cells morphology Immunohistochemistry CD3 CD4 CD5 CD8 CD20 CD30 CD56 TiA-1 Granzyme-B EBV (in situ hybridisation for EBV encoded small nuclear RNAs) Clonal TCR␥ chain rearrangement
12/12 (100%) 12/15 (80%) 3/15 (20%) Large 13/15 (87%) – small 2/15 (13%) Pleomorphic 3/15 (20%) – monomorphic 12/15 (80%) 15/15 (100%) 0/15 (0%) 3/14 (21%) 1/15 (7%) 0/15 (0%) 7/13 (54%) 2/14 (14%) 13/14 (93%) 11/11 (100%) 0/11 (0%) 14/14 (100%)
3.3. Lymphoma severity Performance status was measured with ECOG score and found stage 0 or 1 in 6 (40%) cases and stage higher than 2 in 9 cases (60%). B symptoms were noticed in 9 (60%) cases. Lactate dehydrogenase (LDH) was increased in four patients (27%). Extranodal involvement was noticed in 5 (33%) patients. LDH activity was increased in 4 (27%) patients and was always associated with Ann Arbor stage IV and with further haemophagocytosis in 3 of the 4 patients. According to Ann Arbor staging criteria, disease stage was stage I in 4 patients, stage II in 4 and stage IV in 7.
3.2. Characteristics of EATL 3.4. Survival The median duration between the first occurrence of symptoms and diagnosis of EATL was 13.2 (0–52) months. Symptoms at diagnosis were diarrhoea (93%), malabsorption (80%), weight loss (67%), abdominal pain (27%) and vomiting (7%). B symptoms (fever and sweating) were noticed in 9 cases (60%) and tumoural syndrome (haematodermia, peripheral adenopathy or hepatosplenomegaly) in 5 (33%) cases. Upper endoscopy showed macroscopic abnormalities in all cases, including disappearance of folds and mosaic pattern in 12 cases, nodular lymphoid hyperplasia in 4, and ulcerative duodenitis in 10. Small-bowel biopsies showed villous atrophy in all cases, including partial in 3 cases and severe in 12. Median numbers of IELs quantified in duodenal sections were 40 (30–70)/100 epithelial cells. According to immunohistochemical examination, the phenotype of IELs was normal in 9 cases and aberrant IELs that not expressing CD4 and CD8. The diagnosis of EATL was made at laparotomy in 5 cases. The remaining 11 patients were diagnosed from small-bowel biopsies in 9 cases, peripheral lymphadenopathy biopsy in one and liver biopsy in one. Endoscopical appearance showed ulcerative jejunitis and nodular hyperplasia in 3, ulcerated stenosis in 3 and deep jejunal ulceration in 2. Diffuse enteropathy was observed in 12 cases. Life-threatening complications occurred in 6 (40%) cases with acute intestinal obstruction (n = 4), peritonitis (n = 1) or intestinal bleeding (n = 1). Histopathological and molecular details are shown in Table 2. All but one patient exhibited clonality of the TCR␥ chain. EBV in situ hybridisation was negative in all of the 11 patients tested. EATL type 1 constituted 80% (12/15) and type 2 20% (3/15) of the cases.
Amongst the 15 patients examined, 13 died during follow-up. Thirteen of these patients could be treated and only 2 (15%) survived and fulfilled a 97- and 67-month period, respectively, without any sign of recurrence. The survival rates were 40%, 27% and 20% at 1, 3 and 5 years, respectively (Fig. 1). In univariate analysis, probability of survival was significantly lower in patients with IPI score >2 (p < 0.001), disseminated disease (Ann Arbor stage IV) >2 (p = 0.01) and high LDH activity (p = 0.04). In contrast, survival was improved in case of curative surgical procedure (p = 0.006) (Fig. 1). Survival was similar in patients with EATL type 1 compared to type 2. Survival was significantly decreased in EATL patients with HLH (median survival of 1.9 ± 0.7 (0.6–3) vs. 32.4 ± 20.1 (0.1–71.8) months, p = 0.001) (Fig. 1). 3.5. Haemophagocytosis lymphohistiocytosis HLH occurred in 6 cases with a median delay of 11.2 (8–21) days before diagnosis. At the time of HLH diagnosis, 2 patients were treated with 2-DCF, 1 with CHVpP and 3 did not received any treatment. Clinical manifestations and laboratory findings are illustrated in Table 3. High grade fever (>38 ◦ C) was observed in all cases. Hepatomegaly and peripheral lymphadenopathy were reported in 5 and 3 cases, respectively. Neuropsychiatric symptoms including coma, mood disorder, delirium and cognitive dysfunction were observed in 5 cases. All cases had anaemia and thrombocytopenia whereas leucopenia was observed in 4 cases. Liver dysfunction, high LDH activity, ferritin and triglyceridaemia were systematically reported. In 2 cases, HLH was triggered by an active
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Fig. 1. Kaplan–Meier curves of overall survival after diagnosis of enteropathy T-cell associated lymphoma: (a) by occurrence of haemophagocytosis (b) by IPI score (c) by curative surgery (d) by LDH activity (e) by Ann Arbor classification (HR: hazard ratio; CI: confidence interval; NS: not significant).
infection in 2 cases including a fungal infection (mucormycosis) in one patient (patient 4) previously treated with azathioprine and infliximab and a bacterial infection (Streptococcus catheter-related bloodstream infection) in the other (patient 3). Three out of 6 patients had refractory coeliac sprue before overt EATL, treated
with steroid (patient 1), cyclosporine (patient 2) and infliximab plus azathioprine (patient 4). All our patients with HLH presented an advanced stage according to Ann Arbor classification (stage IVBb in 83%) with extra-intestinal involvement (hepatosplenic and/or cutaneous). The median IPI score was 3 (2–5). All patients died
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Table 3 Clinical manifestations and laboratory data at the onset of haemophagocytic lymphohistiocytosis. Pt Age, sex Fever >7 days
Leukocytes (×109 /l)
Haemoglobin (g/dl)
Platelets (×109 /l)
LDH (U/l)
1 2 3 4 5 6
7.2 1.4 9.0 2.0 0.8 1.2
8.7 8.4 6.7 7.1 5.6 7.3
55 66 26 34 13 32
3586 1430 628 614 610 1258
41, F 52, F 60, M 68, F 64, M 50, M
8 30 21 10 14 8
Ferritin (ng/ml) 6550 >4000 >4000 9342 12430 2334
AST (U/l) 179 119 186 123 174 185
ALP (U/l) 1072 1235 375 350 339 326
Bilirubin (M) 23 276 283 64 123 98
Prothrombin time (%)
Triglyceridaemia (g/l)
58 70 46 80 71 80
10 30 10.3 9.2 8.1 15
LDH: lactate dehydrogenase; AST: aspartate aminotransferase; ALP: alkaline phosphatase.
within 3 months. The median survival time after HLH diagnosis was 11 (1–63) days. One patient treated with vinblastine had a temporary discontinuation in HLH but a rapid flare led to death despite rescue chemotherapy with a course of CHVpP. All the other cases died before any treatment could have been initiated or after the initiation of the best supportive care for multiple organ failure. 3.6. Other complications of EATL 3.6.1. Adverse events due to chemotherapy Amongst the 4 patients treated with vincristine, one developed an acute intestinal obstruction after the third course. Ten cases of febrile neutropenia were observed including 9 cases with standard chemotherapy and 1 case with PNA chemotherapy (p = 0.06). 3.6.2. Intestinal complications Ten (66%) patients experienced at least one intestinal complication for a total of 17 complications: acute intestinal obstruction (n = 9), free peritoneal perforation (n = 5) and intestinal bleeding (n = 3). Surgery was required in 13/17 cases. Curative resection (intestinal margin free of tumour and resection of adjacent lymph nodes) was performed in 3 patients. Two out of these three patients were still free of recurrence at the end of follow-up; the last patient had a diffuse recurrence after a 63.6-month period. Ten procedures were performed in emergency (77%) and three (23%) were scheduled. 3.7. Chemotherapy Two patients died of HLH before to receive any chemotherapy. Treatment characteristics are shown in Table 4. 3.7.1. Standard chemotherapy Standard chemotherapy was used in 10 (66%) patients. Seven patients received standard chemotherapy as first line treatment and 3 patients for rescue after PNA failure. Median survival time (at the time of the first line treatment) was 7.7 (CI95% [0.1; 27.7]) months with standard chemotherapy. In the first-line group, we observed a disease progression in 5 cases and a partial remission with an 11-month survival period free of events in one case. Chemotherapy was ineffective in the 3 patients treated after PNA failure. Standard chemotherapy consisted in CHOP or CHVpP chemotherapy in 6 cases, in ACVBP in 2 cases and in other protocols (VP16-aracytine, ESHAP, BAD, and MACOP-B) in 2 cases. Only one patient reached a complete remission after curative resection and 6 courses of CHVpP with no evidence of recurrence after a follow-up of 52 months. 3.7.2. Purine nucleotide analogues chemotherapy PNA chemotherapy with 2-DCF (n = 5) and 2-CDA (n = 2) was used in 7 (47%) cases. Six patients were treated with a first line chemotherapy with a median survival time of 10.8 (CI95 % [5.5; 16.1]) months. The 2 patients treated with 2-CDA experienced a rapid disease progression with a survival time of 1.7 and 5.4
Table 4 Treatment and relative outcome of our 15 patients with enteropathy T-cell associated lymphoma. Patients, n (%) Initial treatment Nonea Standard chemotherapy Purine nucleotide analogues Surgery None Palliative Curative First line treatment resultsb Non responsive Partial response Complete response Outcome Deadc Alive
2/15 (13%) 7/15 (47%) 6/15 (40%) 5/15 (33%) 7/15 (47%) 3/15 (20%) 7/13 (54%) 1/13 (8%) 5/13 (38%) 13/15 (87%) 2/15 (13%)
a
Two patients died before to receive any chemotherapy. Complete response was observed in two patients treated with curative surgery and standard chemotherapy, one with curative surgery and purine nucleotide analogues, one with palliative surgery and standard chemotherapy and one with purine nucleotide analogues alone. Partial response was observed in one patient treated with palliative surgery and purine nucleotide analogues. c Eight patients died despite first line chemotherapy; three patients died despite 2nd to 4th line rescue chemotherapy. b
months. On the 5 patients treated with 2-DCF, 2 experienced a CR, one a PR and 2 a disease progression. The mean overall and event free survival times were 17.9 and 22 months, respectively, after treatment with 2-DCF. The survival rate was similar in patients treated with PNA (33% at 2 years) as compared to patients treated with standard chemotherapy (43% at 2 years, p = 0.60). One patient was treated with 2-DCF after the failure of standard chemotherapy but no response was observed. 4. Discussion In the present series, we described the outcome and specific complications of 15 EATL patients. The prognosis was poor with a 5-year survival rate of 20% and a high rate of serious intestinal complications (acute obstruction, intestinal bleeding or perforation). We found a very high frequency of HLH, which occurred in 40% of the cases examined and was fatal in all the cases within 3 months. Despite a relatively small number of cases and methodological bias, the tolerance was better for PNA compared to standard chemotherapy but the efficacy was similar for both therapies. Recent studies have indicated that EATL could be classified into 2 distinct subtypes, based on morphological, molecular analysis and with respect to their frequency of association with coeliac sprue [15,16]. Type 1 EATL is characterised by frequent association with coeliac sprue, an HLA-DQ2 haplotype and large-cell and/or pleiomorphic cytology and that may express CD30. In contrast, type 2 is characterised by less frequent association with coeliac sprue, HLA-DQ2 haplotype and monomorphic cytology with frequent CD56 expression. Distinct molecular abnormalities have
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been found between type 1 and type 2 EATL, suggesting distinct lymphomagenic pathway [16]. In our series, it appears that some coeliac disease patients had type 2 EATL (patients 3 and 7) and that non-coeliac disease patient had type 1 EATL (patient 5). Such confusing findings have been previously reported [2]. Similarly, despite a relatively small number of cases, we did not found any difference between the two EATL subtypes [2]. It is conceivable that complementary immunohistochemical and molecular analysis could have permitted to re-classify patients into a right EATL subtype that fit with association with coeliac sprue [16]. It is also conceivable that current criteria for coeliac sprue in EATL patients lake of specificity [17–21]. Prognosis of EATL is usually poor. The 2- and 5-year survival rates are 30–40% and 10–20%, respectively [2–6]. Standard chemotherapy, mainly an anthracycline-based regimen, has shown a modest survival improvement, but a high complication rate and a rapid relapse have been previously reported [4]. In the present series, we evaluated PNA, which are very similar cytotoxic drugs, with proven efficacy in lymphoproliferative disorders [24–27]. In our study, the survival was not different between PNA and standard chemotherapy. Although retrospective study has inherent limitation, grouping two different subtypes of EATL limits firm conclusion and the number of patients included is relatively small, we thought that our results should be considered. Indeed, PNA was associated with less febrile neutropenia compared to standard chemotherapy. Therefore, new therapeutic modalities are needed to improve EATL survival. A novel chemotherapy regimen containing high dose methotrexate and IVE (Ifosfamide, vincristine and etoposide) with first-line autologous stem cell transplantation has recently been evaluated in two prospective series including 6 and 26 patients, respectively [28,29]. In both studies, complete remission was achieved in 5/6 and 17/26 patients, respectively [28,29]. In the more recent study, overall and progression-free survival were significantly improved compared to historical group treated with anthracycline-based regimen [28]. Haemophagocytosis is characterised by the pathological finding of activated macrophages engulfing erythrocytes, leukocytes, platelets, and their precursors [12]. HLH is a distinct clinicopathological entity with a clinical presentation related to macrophage proliferation and activation, and evidence of haemophagocytosis in bone marrow and other tissues [12]. In adults, acquired HLH is associated with various conditions including non-Hodgkin’s lymphoma [12]. Amongst these conditions, most cases of lymphomaassociated HLH are associated with T and NK lymphoma [30–33]. So far, only one patient with EATL has been reported with HLH in the literature [13]. In our series, HLH was reported in 6 (40%) EATL patients. All the patients with HLH presented an advanced stage according to Ann Arbor classification, with extra-intestinal involvement, high LDH level and IPI score. Therefore, the occurrence of HLH in EATL patients may have been underestimated and its detection should be systematically assessed, especially in patients with uncontrolled disease. When untreated, HLH is a highly fatal disease [34]. A comprehensive management is required to support organ failure, especially to manage infectious complications, correct coagulation disorders and restore fluid and electrolyte balance. Life-threatening hyperinflammation, caused by excessive levels of cytokines, can be treated with corticosteroids and/or intravenous immunoglobulins [12]. Etoposide, which is very effective in monocytic and histiocytic diseases, should be added to corticosteroids in case of severe HLH [35–38]. In severe HLH, the early administration of etoposide is primordial as the time to treat the patient is associated with the severity of the outcome [35]. In case of HLH secondary to lymphoproliferative diseases, treatment should target malignant lymphocytes using combined chemotherapy regimens. In our series, only one patient was treated with vinblastine with a
temporary discontinuation of HLH but a rapid flare was fatal, despite rescue chemotherapy with a course of CHVpP. All the other cases did not receive etoposide or chemotherapy. Two patients had active infections that delayed the initiation of specific therapy. Two patients died within 1 and 2 days, respectively, before any specific treatment could have been initiated. The last patient developed HLH after the failure of the first line chemotherapy (2-DCF) and was referred to the best supportive care. The median survival time was 11 (1–63) days and it did not permit to rule-out or exclude an active infection, especially in patients receiving immunosuppressive therapy or chemotherapy. However, we hope that an earlier treatment of HLH could have improved the survival of these patients. In conclusion, EATL remained a dramatically poor condition, associated with serious intestinal adverse events (acute obstruction and intestinal perforation) and a low survival. HLH is a frequent and rapidly fatal complication of EATL. Neither standard chemotherapy nor PNA are effective to improve its poor prognosis. Surgery could be effective only if curative procedure could be feasible. Conflict of interest statement None declared.
List of abbreviations 2-CDA, cladribine; 2-DCF, 2-deoxycoformycine; IPI, International prognostic index; LDH, lactate dehydrogenase; PEACE-BOM, prednisolone, doxorubicin, cyclophosphamide, and etoposide with prednisolone, bleomycin, vincristine, and methotrexate; MACOP B, methotrexate, doxorubicin, cyclophosphamide, vincristine, predonisolone, bleomycin; CHOEP, cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisolone; PNA, purine nucleotide analogues; EATL, enteropathy T-cell lymphoma; CHVpP, cyclophosphamide 750 mg/m2 , doxorubicin 50 mg/m2 , and etoposide 100 mg/m2 day 1, prednisolone 40 mg/m2 day 1–4; ACVBP, cyclophosphamide 1200 mg/m2 and doxorubicin 50 mg/m2 day 1, vindesine 2 mg/m2 and bleomycine 10 mg/m2 day 1 and 5, prednisolone 60 mg/m2 day 1–5; DHAX, dexamethasone 40 mg/m2 day 1–4, oxaliplatin 100 mg/m2 day 1, and aracytin 2 × 2 g/m2 day 2.
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