Auto-SCT in Refractory Celiac Disease Type II Patients Unresponsive to Cladribine Therapy

ORIGINAL ARTICLE Auto-SCT in refractory celiac disease type II patients unresponsive to cladribine therapy

GJ Tack1, MJ Wondergem2, A Al-Toma3, WHM Verbeek1, A Schmittel4,5, MV Machado6, F Perri7, GJ Ossenkoppele2, PC Huijgens2, MWJ Schreurs8, CJJ Mulder1 and OJ Visser2

1Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands; 2Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands; 3Department of Gastroenterology and Hepatology, Sint Antonius hospital, Nieuwegein, The Netherlands; 4Department of Medicine IV, Charite´-University Medicine, Berlin, Germany; 5Department of Hematology and Oncology, Charite´-University Medicine, Berlin, Germany; 6Department of Gastroenterology and Hepatology, Santa Maria hospital, Lisbon, Portugal; 7Department of Gastroenterology and Digestive Endoscopy, ‘Madonna del Soccorso’ Hospital, San Benedetto del Tronto, Italy and 8Department of Clinical Pathology, VU University Medical Center, Amsterdam, The Netherlands

Autologous hematopoietic SCT (auto-SCT) has been Introduction effective therapy for refractory disease, in both malignancies and severe autoimmune diseases. It seems feasible Celiac disease (CD) is a major health care issue worldwide, and safe for refractory celiac disease (RCD) type II, with a prevalence of about 1%, affecting people of all ages.1 although long-term results have not been evaluated yet. A permanent state of intolerance to gluten-containing food With current therapies, progression into enteropathy- leads to chronic inflammation of the small intestine. associated T-cell lymphoma (EATL) occurs in 60–80% Hallmarks of CD are lymphocytic infiltration of the lamina patients, with a high mortality rate. Therefore, it is propria, expansion of the intraepithelial lymphocyte (IEL) important to evaluate new treatment strategies. Between population, hyperplasia of the crypts and atrophy of the March 2004 and February 2010, 18 RCD II patients were villi. CD occurs in genetically susceptible individuals who evaluated for auto-SCT preceded by conditioning with almost always carry the HLA-DQ 2/8 alleles.2,3 fludarabine and melphalan, as a consequence of unrespon- Although improvement is usually seen upon life-long siveness to cladribine therapy. Adverse events, survival withdrawal of dietary gluten, a small percentage (2–5%) of rate, EATL development and change in clinical, histolo- the adult-onset CD patients, especially those diagnosed gical and immunological course were monitored. Thirteen above the age of 50 years, lack clinical and histological patients were transplanted successfully and followed up response despite strict adherence to such a gluten-free diet for 42 years, 4-year survival rate was 66%. Only one for more than 12 months. Patients are classified as having patient died because of transplant-related complications. refractory celiac disease (RCD) if dietary consumption of The majority of patients showed an impressive clinical gluten and other causes of malabsorption with villous improvement and five a complete histological remission. In atrophy are ruled out.4,5 On the basis of immunophenotyp- five patients, auto-SCT could not be performed; they all ing of the IEL, we can subdivide RCD into two groups: died with a median survival of 5.5 months. EATL was type I with phenotypically normal and type II with observed in one transplanted patient, only after 4 years of phenotypically aberrant IEL, aberrance being defined as follow-up. Auto-SCT after conditioning with high-dose lack of the surface markers CD3, CD4 and CD8, but with chemotherapy in RCD II patients unresponsive to expression of cytoplasmic CD3. Clonal expansion of these cladribine therapy is feasible and seems promising. aberrant IEL is thought to be responsible for progression to Bone Marrow Transplantation (2011) 46, 840–846; enteropathy-associated T-cell lymphoma (EATL).4,6,7 The doi:10.1038/bmt.2010.199; published online 6 September 2010 genesis and expansion of these monoclonal T cells involve Keywords: auto-SCT; refractory celiac disease; entero- both inappropriate immune responses to gluten and pathy-associated T-cell lymphoma; survival; clinical course acquisition of genetic abnormalities. RCD II is in most patients resistant to most studied therapies, including corticosteroids, budesonide, infliximab, CYA, IL-10 and azathioprine/prednisone8 and has a high risk of progressing to EATL (60–80% within 5 years).9,10 This peripheral T-cell Correspondence: Dr GJ Tack, Department of Gastroenterology and lymphoma has a very poor prognosis with a 2-year survival Hepatology, VU University Medical Center, PO Box 7057, 1007 MB of only 15%, mainly because of failure to respond to Amsterdam, The Netherlands. chemotherapy.9,10 Therefore, it is of utmost importance to E-mail: [email protected] Received 29 April 2010; revised 21 June 2010; accepted 24 June 2010; evaluate new treatment strategies for RCD II patients, and published online 6 September 2010 in particular for those unresponsive to conventional SCT in refractory celiac disease GJ Tack et al 841 immunosuppressive drugs to improve the clinical course courses of cladribine, administered i.v. in a dose of 0.1 mg/ and prevent or delay development of EATL. kg per day for 5 consecutive days. Response was defined as Until 2005 in our tertiary referral center for RCD, type II clinical (improvement of signs and symptoms of malab- patients were initially treated with conventional immuno- sorption and weight gain) and histological (Marsh criteria suppressive drugs, mainly azathioprine or prednisone or 0/I) and/or immunological (420% decrease of aberrant both, and cladribine was prescribed if they were clinically IEL) remission. The diagnosis of RCD II was based on and histologically unresponsive. Cladribine is a synthetic persisting or recurring symptoms and small intestinal purine nucleoside homologue with cytotoxic activity. Since villous atrophy after a former good response despite strict 2005 a modified treatment strategy has been initiated with adherence to a gluten-free diet for at least 1 year.5,17 cladribine being drug of first choice, based on a study Furthermore, the clinically validated cutoff value of 420% showing that azathioprine combined with prednisone is not aberrant IEL detected by flow cytometric analysis was used effective in most RCD II patients.11 For patients not to distinguish RCD type I and type II.7 A lower percentage responding, an alternative was sought. High-dose chemo/ of aberrant T cells was allowed in the presence of ulcerative radiotherapy followed by auto-SCT has been effective jejunitis. T-cell receptor (TCR)-g gene rearrangement was therapy for refractory disease not only in hematological performed as previously described.7 Although this clonal malignancies, but also in severe autoimmune disease.12–14 TCR-g rearrangement is still a widely accepted additional In autoimmune disease, auto-SCT is supposed to induce method to define RCD II, Verbeek et al.7 showed that the immunoablation with subsequent regeneration of naive T percentage of aberrant IEL detected by flow cytometric lymphocytes derived from reinfused hematpoietic progenitor analysis is more accurate to define RCD II. EATL was cells.13–15 Analysis of our first seven RCD II patients treated excluded by several investigations after computed tomo- with auto-SCT showed this treatment approach is feasible and graphy (CT),18 whole-body positron emission tomogra- well tolerated in celiac patients. Survival at that time seemed phy,19 magnetic resonance imaging enteroclysis,20 upper promising, but follow-up was short.16 gastrointestinal endoscopy, video capsule endoscopy21 and/ This analysis evaluates the follow-up of 18 RCD II or double-balloon enteroscopy.22 This diagnosis was patients, including 7 patients of our pilot study, who were confirmed according to the World Health Organization selected for auto-SCT as a consequence of unresponsive- (WHO) Classification of Tumours of Haematopoietic and ness to conventional immunosuppressive and/or cladribine Lymphoid Tissues.23 WHO performance status24 had to be therapy. Fifteen patients were treated in Amsterdam, one p2, and no severe concomitant cardiac, pulmonary, renal each in Italy, Portugal and Germany. or hepatic disease was to be present. Active uncontrolled infection and HIV positivity were also exclusion criteria.

Patients and methods PBSC mobilization, conditioning and auto-SCT Mobilization of hematpoietic progenitor cells from the BM This study reports extended follow-up of the open-label into the peripheral blood was achieved using G-CSF prospective phase I study performed by Al-Toma et al.16 2 Â 10 mg/kg by s.c. injection daily for at least 4 days with six new transplanted patients added, who were without preceding chemotherapy. The minimum amount of referred after inclusion of this study was ﬁnished. Between CD34 þ cells collected was 2 Â 106 per kg. The condition- March 2004 and February 2010, 18 cladribine-unresponsive ing regimen consisted of ﬂudarabine administered orally for RCD II patients were evaluated for auto-SCT. 5 days (40 mg/m2 per day) and intermediate dose melphalan (administered i.v., 2 days, 70 mg/m2 per day), as shown in Inclusion and exclusion criteria Figure 1. At day 0 stem cells were reinfused. The purpose of Patients aged o70 years and diagnosed with RCD II were this conditioning regimen was both intensive T-cell deple- included when they showed no response to one or two tion and myeloablation by a purine analogue added to

Chemotherapy

Fludarabine Melphalan 40 mg/m2/day 70 mg/m2/day G-CSF orally i.v. Follow-up

-7 -6 -5 -4 -3 -2 -1

4 days 1 week

Leukapheresis Reinfusion of Admission Stem Cells

Figure 1 Conditioning regimen before auto-SCT.

Bone Marrow Transplantation SCT in refractory celiac disease GJ Tack et al 842 melphalan (total dose 140 mg/m2). All patients received Table 1 Patient characteristics standard antibacterial and antifungal prophylaxis during Transplanted Nottransplanted neutropenia and trimethoprim–sulfamethoxazole gluten- (n ¼ 13) (n ¼ 5) free syrup 480–960 mg daily until 6 months after transplantation. Total parenteral nutrition and blood and Gender platelet transfusions were given if indicated. Female/Male 7:6 3:2 Age at CD diagnosis (years) Follow-up and criteria of response Median (range) 50 (37–68) 63 (45–66) Before, during and after auto-SCT, a clinical assessment Age at RCDII diagnosis (years) was carried out noting in particular signs and symptoms of Median (range) 58 (42–68) 64 (47–70) malabsorption. Body mass index (BMI), WHO perfor- Age at (intention to) auto-SCT (years) mance status, and the need for transfusions, for additional Median (range) 59 (43–68) 65 (52–70) nutritional support and for additional antimicrobial treatment, were documented. Clinical remission is defined as Treatment before auto-SCT improvement of diarrhea and constant or improved WHO Cladribine 13 5 Azathioprine/Prednisone 3 2 performance status, combined with at least two of the following clinical parameters within the normal range or an Time between cladribine and improvement of X1 point: (1) BMI; (2) albumin and (3) auto-SCT (months)a Hb. Multiple duodenal biopsies were taken by upper Median (range) 6.25 (3–30) gastrointestinal endoscopy to detect histopathological Follow-up time (months) abnormalities and to perform IEL immunophenotyping Median (range) 26 (10–67) 5.5 (1–12.5) by flow cytometry analysis7,25,26 at different time points (3, 12 and 24 months) after auto-SCT. Isolation of small HLA-DQ status DQ2 heterozygous 4 2 intestinal IEL and staining for immunophenotyping were DQ2 homozygous 8 2 performed as previously described.7 Complete histological DQ2+ and DQ8+ 1 1 remission is defined as a normalization of the architecture of the small intestinal mucosa, classified as Marsh 0 or I TCR-g rearrangement 27 Monoclonal 8 4 lesion according to the modified Marsh criteria. A decline Oligoclonal 5 1 of 420% in the percentage of aberrant IEL was considered a significant immunological remission. In addition, OS and Abbreviation: CD ¼ celiac disease. the EATL occurrence were evaluated during follow-up. aDue to change in treatment strategy two patients were transplanted 2 years after cladribine therapy.

Statistical analysis was not reached for any reason, mortality in the Quantitative data were expressed as medians. Kaplan– nontransplanted cohort was high; all patients died within Meier survival curves were constructed using SPSS a median follow-up of 5.5 months (range 1–12.5 months). software (SPSS Inc., Chicago, IL, USA). In the transplanted group, however, 23% (3 of 13) patients died. There was one transplant-related death due to Ethics approval and informed consent septicemia with subsequent meningitis. The other two Approval of the medical ethics committee was obtained, patients died of chronic encephalitis and EATL, complica- and all treated patients signed an informed consent in tions associated with CD rather than transplantation. accordance with the Declaration of Helsinki Principles. Interestingly, in the latter patient EATL occurred 4 years after transplantation (Figure 2). All the ﬁve patients in whom EATL occurred died, with a mean survival of 2 months (range 0–8 months) after diagnosis. The overall Results 3- and 4-year survival after undergoing auto-SCT in case of unresponsiveness to cladribine therapy was 80 and 66%, In total, 18 RCD II patients (Table 1) who were refractory respectively (Figure 3). to cladribine therapy were eligible for auto-SCT. The Overall clinical, histological and immunological outcome median time between cladribine treatment and auto-SCT is depicted in Table 3. All transplanted patients reached was 6.25 months. All patients entered the treatment follow-up of almost 1 year to assess remission status. protocol, however ﬁve patients did not make it to auto- Within 1 year after auto-SCT, the majority of patients (11 SCT (Table 2 ): two due to unsuccessful leukapheresis and of 13) showed impressive clinical improvement with in three patients progression into EATL occurred before normalization of stool frequency, disappearance of gastro- stem cells could be collected, as depicted in Figure 2. The intestinal symptoms and normal levels of or improvement patients reaching actual transplant (n 13) had a median ¼ of X1 point in BMI, albumin and/or Hb. All patients had a follow-up time of 42 years, ranging from 10 to 67 months. WHO performance status of 0 at the end of follow-up. In addition, improvement of BMI was documented from a Survival and disease status median level of 20.1 kg/m2 at baseline to 22.5 kg/m2 after Out of the 18 patients unresponsive to cladribine, 8 patients auto-SCT. The median serum albumin level increased from died (44%), 5 of them due to EATL (28%). If auto-SCT 36 to 42 g/L (Table 3).

Bone Marrow Transplantation SCT in refractory celiac disease GJ Tack et al 843 Table 2 Transplant characteristics

Patient Duration Reinfusion Time to neutrophil Time to platelet TPN Platelet RBC admission CD34+cells recovery (days)a recovery (days)b transfusion transfusion (days) ( Â 106 per kg)

1 19 2.09 12 11 Yes 1 Â 3 Â 2 17 2.21 12 11 Yes 2 Â 6 Â 3 14 2.06 12 12 Yes 1 Â No 4 24 2.0 17 27 No No No 5162.2677No1Â 6 Â 6 29 2.21 18 17 Yes No 3 Â 7 23 2.47 19 17 Yes No 1 Â 8242.171314No1Â 6 Â 9192.961615NoNoNo 10 25 2.4 20 22 No 1 Â 2 Â 11 30 3.6 13 8 Yes No 2 Â 12 28 3.26 12 9 Yes No No 13 19 2.27 14 12 No 1 Â No Median (range) 23 (14–30) 2.26 (2–3.6) 13 (7–20) 12 (7–27)

Abbreviation: TPN ¼ total parenteral nutrition. aNeutrophil recovery: time to achieve a neutrophil count above 0.5 Â 109/L. bPlatelet recovery: time to platelet count above 20 Â 109.

RCD II unresponsive to 2-CDA 1.0 (n=18)

0.8

Successful Unsuccessful EATL before first leukapheresis leukapheresis leukapheresis attempt (n=13) (n=2) (n=3) 0.6

auSCT performed 0.4 (n=13) Overall survival

0.2

Death Death Death EATL: n=1 EATL: n=1 EATL: n=3 Other: n=2 Other: n=1 Other: n=0 0.0

Figure 2 Flow chart of cladribine-resistant RCD II patients. 04812 24 36 60 72 n=13n=12 n=7 n=6 n=4 n=2 In total, 38% (5 of 13) had a complete histological Survival (months) remission, deﬁned as Marsh 0 or I. Two of them achieved this remission within 3 months, two within 6 months and Figure 3 Survival curve of RCD II patients unresponsive to cladribine one after 2 years. One patient had a PR from a Marsh IIIB therapy who were treated with high dose of chemotherapy followed by auto-SCT. to Marsh II lesion and two patients already had a Marsh 0 and I lesion before auto-SCT. The remaining two patients showed stable and progressive histological abnormalities to EATL with dismal prognosis highlights the need for after auto-SCT. The median percentage of immunopheno- new treatment strategies. Although treatment with conven- typically aberrant intestinal T lymphocytes was 45% before tional immunosuppressive drugs, including azathioprine transplantation and 54% at the end of follow-up. Only one and prednisone, may lead to clinical remission in several patient showed a decrease in the percentage of aberrant T RCD II patients,11,28,29 most of them do not have complete lymphocytes to within the normal value. The patient showed histological improvement, do not have a beneﬁcial survival a clinical and complete histological remission as well. due to progression into EATL11,30 and/or become steroid dependent.28 Therefore, in our medical center cladribine rather than azathioprine is prescribed, showing similar Discussion clinical improvement, but with better histological response rates without any steroid dependency and need for long-term Till now there is no standardized treatment strategy medication.31 However, approximately half of the patients for RCD II.8 The high risk of subsequent progression is still clinically and histologically unresponsive to this

Bone Marrow Transplantation SCT in refractory celiac disease GJ Tack et al 844 therapy. In our analysis this speciﬁc group of RCD II patients refractory to cladribine therapy was scheduled 1 year

4 for treatment with high-dose chemotherapy followed by auto-SCT. In agreement with our pilot study,16 we report in this 4ND 1 year larger cohort of RCD II patients that the treatment o approach we described is feasible and no serious trans-

b plant-related short-term adverse events were noted. More- over, during extended follow-up no secondary malignancies and myelodysplastic disorders were observed. Treatment- related mortality was not increased compared to other 1 year before indications for auto-SCT. 4 The 5-year survival reported for RCD II, irrespective of treatment is currently 44–58%.9,28,29 In these series, patients

1 year were initially treated with different types of medication, o mainly conventional immunosuppressive drugs. In our analysis however, only RCD II patients unresponsive to these treatment options were scheduled for auto-SCT, having a 4-year survival of 66% if they manage to proceed transplantation. This survival rate seems promising so far,

1 year before as this speciﬁc group of unresponsive patients has a worse 4 prognosis. In addition, this is supported by the high mortality of the ﬁve refractory patients who could not be transplanted. 1 year

o Four patients were already diagnosed as having overt EATL before ﬁrst leukapheresis attempt, reﬂecting the quick development of this condition. The EATL rate observed in the transplanted group (1 of 13) is much better than that reported in published RCD II series (60–80%),32 however, in a small series. Even if we include the 1 year before

4 nontransplanted patients who developed EATL, the EATL rate is less than reported (30%). As one transplanted patient developed an overt EATL only after 4 years of 1 year follow-up, chemotherapy followed by auto-SCT might o possibly delay the development of this type of lymphoma. Whether progression into EATL is prevented or delayed

before must be elucidated by more prolonged follow-up.

a In addition, in two patients transplantation could not be performed because of failure of stem cell collection, most 1year World Health Organization.

) Albumin (g/L) HB (mmol/L) Marsh score Aberrant IEL (%) likely as a consequence of previous administration of 4 ¼ 2 cladribine therapy. Both cladribine and ﬂudarabine are purine nucleoside analogues. Although ﬂudarabine-con-

1 year taining regimens are well known for impairing stem cell o

BMI (kg/m mobilization, less is known about the influence of cladribine on mobilization efficacy.33 However, it seems from our data that cladribine might indeed influence stem

not determined; WHO cell collection. A solution might be mobilization after

¼ single-dose CY together with G-CSF and/or implementing plerixafor.34 This new approach should be evaluated in this

status patient group.

performance Our study results showed an impressive clinical improve- before after before ment and enhanced quality of life in almost all patients after transplantation. Approximately half of the patients had a signiﬁcant recovery of the architectural abnormalities body mass index; ND

¼ of the small intestinal mucosa. It is intriguing that a high

Monoclonal 0 0Monoclonal 19.9 1 24.5 0 25.5 21.2 19.1 37 20.0 40percentage 41 25 41 8.0 of 43 8.8 aberrant 6.2 7.4 7.4 IIIB IEL IIIA 5.2 persists I 0 after 92 IIIA auto-SCT, 86 I 37 1 c b

Overview of the clinical, histological and immunological results before and at the end of follow-up particularly in view of the improved Marsh score. These aberrant T cells reside in the intraepithelial as well as the lamina propria layer.35 Although this percentage is crucial in the diagnostic work-up for distinguishing RCD types I 12No Yes Oligoclonal 0 0 20 25.4 26.7 34 43 40 7.5 7.6 7.4 IIIA 0 0 41 62 65 89 Yes No Monoclonal Monoclonal 1 0 0 0 21.2 23.5 22.3 23.5 22.7 — 27 32 41 44 43 — 6.4 7.9 7.4 8.4 7.1 — 0 IIIB I IIIA — I 81 20 78 48 — 53 345 Yes6 Yes7No Monoclonal Yes Oligoclonal Yes 0 Oligoclonal Monoclonal 0 1 0 0 0 20.8 0 0 24.5 22.5 20.1 19.1 25.2 20.1 22.5 22.7 29.1 20.4 28 22.9 36 39 34 29 29 42 46 42 40 42 6.3 48 7.1 6.6 7.7 7.5 8.9 7.1 8.6 7.8 9.6 7.2 I 7.2 II II IIIB 0 0 IIIA 0 0 II 0 0 92 55 45 30 91 47 6 28 91 65 6 40 In this patient progression into EATL occurred.

Results at the end of follow-up, but after at least 1 year. 7 This patient had persisting ulcerative jejunitis, which is characterized by a low percentage of aberrant IEL detected by ﬂow cytometry. 101112 Yes13 Yes Oligoclonal Yes Monoclonal Yes Oligoclonal 1 2 Monoclonal 1 0 0 0 0 19.2 0 17.9 18.8 18.4 20.1 16.8 20.3 18.4 20.1 — — 36 — 36 26 41 40 36 40 44 47 — — 8.9 — 5.2 7.6 6.9 8.6 6.9 8.2 8.9 8.7 — IIIB — — IIIC IIIA 0 0 0 IIIA 0 86 I — ND — 60 — ND 40 78 40 48 — 56 — — Table 3 Patient Alive Clonality WHO Abbreviations: BMI a b c and II, our data suggest that the percentage of aberrant

Bone Marrow Transplantation SCT in refractory celiac disease GJ Tack et al 845 IEL is not suitable for monitoring therapy and predicting specific T cell responses. Proc Natl Acad Sci USA 2003; 100: prognosis, at least in this cohort and time of follow-up. In 12390–12395. fact, the percentage of aberrant T cells is not the same as 4 Cellier C, Delabesse E, Helmer C, Patey N, Matuchansky C, the overall depletion of T cells after auto-SCT. Whether the Jabri B et al. Refractory sprue, coeliac disease, and entero- absolute aberrant T-cell load, which might be quantified by pathy-associated T-cell lymphoma. French Coeliac Disease Lancet flow cytometry or by quantitative positron emission Study Group. 2000; 356: 203–208. 5 Daum S, Cellier C, Mulder CJ. Refractory coeliac disease. Best tomography scanning, instead of the percentage of aberrant Pract Res Clin Gastroenterol 2005; 19: 413–424. T cells is more suitable to predict prognosis is not clear yet. 6 Daum S, Hummel M, Weiss D, Peters M, Wiedenmann B, If histopathology or another undefined parameter should Schaper F et al. Refractory sprue syndrome with clonal be used to quantify mass needs to be investigated as well. intraepithelial lymphocytes evolving into overt enteropathy- Furthermore, clonal expansion of these aberrant IEL is type intestinal T-cell lymphoma. Digestion 2000; 62: 60–65. considered to be responsible for progression into an EATL, 7 Verbeek WH, Goerres MS, von Blomberg BM, Oudejans JJ, however in our series the persisting high percentage of Scholten PE, Hadithi M et al. Flow cytometric determination aberrant IEL after auto-SCT was not reflected in increased of aberrant intra-epithelial lymphocytes predicts T-cell lym- EATL development. In addition, the TCR-g rearrangement phoma development more accurately than T-cell clonality Clin Immunol performed after auto-SCT could not detect a clonal peak analysis in refractory celiac disease. 2008; 126: 48–56. with current available technology (data not shown). So far, 8 Verbeek WH, Schreurs MW, Visser OJ, von Blomberg BM, it is still generally accepted that aberrant T cells are the Al-Toma A, Mulder CJ. Novel approaches in the management factor responsible in EATL development. Thus, further of refractory coeliac disease. Expert Rev Clin Immunol 2008; 4: reduction of T cells or T-cell mass by intensifying 205–219. conditioning pre-auto-SCT might improve outcome. This 9 Al-Toma A, Verbeek WH, Hadithi M, von Blomberg BM, could be achieved by a higher dose of fludarabine/ Mulder CJ. Survival in refractory coeliac disease and entero- cladribine combined with anti-CD52 (alemtuzumab), anti- pathy-associated T-cell lymphoma: retrospective evaluation of thymocyte globulin or new specific anti-T-cell agents. single-centre experience. Gut 2007; 56: 1373–1378. Randomized clinical trials comparing conservative fol- 10 Bishton MJ, Haynes AP. Combination chemotherapy followed low-up to auto-SCT, if unresponsive to cladribine therapy, by autologous stem cell transplant for enteropathy-associated T cell lymphoma. Br J Haematol 2007; 136: 111–113. are not available so far. In the future, multicenter 11 Goerres MS, Meijer JW, Wahab PJ, Kerckhaert JA, Groenen randomized trials or trials with historical control groups PJ, Van Krieken JH et al. Azathioprine and prednisone will be needed to explore these new treatment strategies. combination therapy in refractory coeliac disease. 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