Combination chemotherapy followed by autologous stem cell transplant for enteropathy-associated T cell lymphoma
Dr Andrew Haynes, Consultant Haematologist, Department of Haematology, Nottingham City Hospital, Hucknall Road, Nottingham NG5 1PB, UK.
Enteropathy-associated T cell lymphoma (EATL) is a rare entity associated with coeliac disease, with a poor prognosis due to perforation and gastro-intestinal bleeding during treatment, and a high relapse risk. Six patients were treated with two cycles of IVE (ifosphamide, etoposide, epirubicin), followed by two cycles of high-dose methotrexate (3 g/m2) with folinic acid rescue and a BEAM (carmustine, etoposide, cytarabine, melphalan) autograft. Enteral feeding was given throughout treatment. Four patients remain alive in complete remission at 1·83–4·32 years; two have relapsed. Given the historically poor outcome in these patients, this regimen appears very promising in the treatment of EATL.
Enteropathy-associated T cell lymphoma (EATL) accounts for less than 1% of non-Hodgkin lymphomas and is most commonly seen in the ileum or jejunum. It is strongly associated with coeliac disease, and is more common in areas with a higher prevalence of this disease (Jaffe et al, 2003).
Most patients show the HLA DQA1*0501 or DQB1*0201 genotype that characterises coeliac disease, and there is an association with Epstein–Barr virus (Quintanilla-Martinez et al, 1998). Loss of heterozygosity at chromosome 9p21 (Obermann et al, 2004) and gain of chromosome 1q. (Verkarre et al, 2003) have also been described.
Most EATL patients have adult onset coeliac disease, or are diagnosed in the same clinical episode in which the lymphoma is diagnosed, and EATL should be considered as a cause of refractory coeliac disease (Catassi et al, 2005). Patients present with abdominal pain and weight loss, and occasionally with intestinal perforation. Diagnosis is often made at laporotomy, with ulcerating mucosal masses involving the intestine wall, but there may only be ulceration or an exophytic mass. The neoplastic cells express pan T cell markers and in most cases CD103, while the degree of enteropathy in adjacent tissue can be variable.
Traditionally, Doxorubicin-based combination chemotherapy has been used, although there is no consensus on treatment. Patients are often emaciated due to malabsorbtion and tolerate treatment poorly, with death frequently occurring due to perforation and gastro-intestinal (GI) bleeding (Gale et al, 2000), (Daum et al, 2003). There appears to be a high relapse rate, often heralded by multi-focal perforation and visceral involvement. Overall survival rates are agreed to be around 20% at 5 years.
We describe a novel regimen for EATL using two cycles of IVE (ifosphamide, etoposide, epirubicin) followed by two cycles of high-dose methotrexate, and consolidation with a peripheral blood stem cell transplant (PBSCT) with BEAM (carmustine, etoposide, cytarabine, melphalan) conditioning, in patients with biopsy proven disease.
Patients and methods
Six patients were treated (Table I), five of whom were diagnosed following laparotomy and bowel resection, while another had a computed tomography (CT)-guided lymph node biopsy. EATL was confirmed by immunohistochemistry. Three patients were previously known to have coeliac disease, although only one for longer than 1 year, and three were shown to have serological and histological evidence of coeliac disease post-diagnosis. At presentation one patient had a World Health Organization performance status score of 1, two patients a score of 2, two patients a score of 3 and one patient a score of 4.
Table I. Patient characteristics.
|Age (years)||40–59 (median 56)|
|Known coeliac disease||3|
|Laporotomy at diagnosis||5|
Once the diagnosis was made, and following recovery from laparotomy if needed, each patient was admitted to our ward. A central venous catheter and naso-jejunal (NJ) tube were inserted and patients were nil by mouth for 24 h. Intravenous fluids were started and oral ciprofloxacin and metronidazole were given in order to sterilise the gut prior to chemotherapy. The IVE regimen (McQuaker et al, 1997) with granulocyte colony-stimulating factor (G-CSF) support was started, and once the risk of perforation was considered to be over, NJ feeding began. This continued throughout treatment, with regular dietetic input, including when the patient was at home. A second course of IVE was given 4 weeks later, and stem cell mobilisation was attempted following this. Once an adequate dose of stem cells were harvested and blood counts had regenerated, two cycles of high-dose methotrexate (3 g/m2) with folinic acid rescue were given. Following this, patients were admitted for consolidation with high-dose chemotherapy using BEAM conditioning and PBSCT. Response was monitored using standard CT criteria.
All six patients tolerated treatment with no deviation from protocol and no transplant-related mortality. There were no episodes of perforation or GI bleeding. One patient was unable to be harvested due to sepsis and was mobilised with G-CSF alone prior to methotrexate. All patients suffered with severe diarrhoea and weight loss ranging from 5–11 kg during PBSCT, despite parenteral feeding.
Computed tomography restaging showed five patients achieved a complete remission (CR) and one a very good partial response. Two patients had florid relapse at 0·21 and 1·71 years post PBSCT and rapidly died due to intestinal perforation. The other four remain alive and in CR at 1·83, 3·35, 3·67 and 4·32 years following transplant respectively.
Enteropathy-associated T cell lymphoma is a rare extra nodal T cell lymphoma with a poor prognosis, and large case series take many years to build. EATL is often added to large series of other high-grade T cell lymphomas or GI non-Hodgkin lymphomas, making it difficult to determine optimal management for these tumours. It is clear that treatment with surgery alone or surgery followed by a CHOP (cyclophosphamide, hydroxydaunomycin, Oncovin, prednisone)-like regimen results in high complication rates and relapse, and that alternative treatment are needed. There are case reports using Hyper CVAD (cyclophosphamide, vincristine, adriamycin, dexamethasone) (Honemann et al, 2005) and novel therapies such as the histone deacetylase inhibitors (Piekarz & Bates, 2004), and there may be a role for the anti-CD52 antibody CAMPATH. The use of PBSCT in EATL has been reported anecdotally by Lymphoma Groups in unpublished findings but otherwise has been confined to case reports only. (Jantunen et al, 2003; Okuda et al, 2002).
In our series of patients there were no serious complications following gut sterilisation and induction chemotherapy, and despite marked weight loss, all were able to tolerate PBSCT. Four out of six patients (66.7%) remain alive and in a sustained CR, while two suffered an early relapse and rapidly died. We conclude that this regimen appears to be active in the treatment of EATL.