Annals of Oncology Advance Access originally published online on March 28, 2008
Annals of Oncology 2008 19(5):1025-1026; doi:10.1093/annonc/mdn119
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Hepatosplenic gammadelta T-cell lymphoma successfully treated with a combination of alemtuzumab and cladribine
A 41-year-old female patient suffering from fatigue due to haemolytic Coombs-negative anaemia was admitted to our department in November 2001. Computed tomography scans and sonography solely displayed a marginal hepatosplenomegaly. Bone marrow trephine biopsy (BM-TB) revealed a hypercellular marrow presenting few small nodular lymphomatous infiltrates, >50% reactive with antibodies to CD19, CD20, CD21 and bcl2. Also, numerous CD3-positive T cells, but no monoclonal T-cell receptor (TCR) rearrangement could be detected initially. Using primers for the immunoglobulin heavy chain rearrangement, a slight band was detected suggestive of B-cell monoclonality. Together with the morphology of the infiltrate, follicular lymphoma was hypothesised. Cytogenetics revealed a normal female chromosomal pattern. The follicular lymphoma international prognostic index was judged as high risk. Consequently, three cycles of R-CHOP (rituximab–cyclophosphamide–doxorubicin–vincristine–prednisolone) were administered leading to a good partial remission.
None the less, transfusion-dependent haemolytic anaemia and neutropenia reoccurred 1 year later and was symptomatically treated by repetitive red blood cell transfusions—108 units within 1 year. Concomitantly, massive hepatosplenomegaly in conjunction with B-type symptoms developed. At that time, the BM-TB showed a hypercellular marrow with multiple nodular lymphomatous infiltrates revealing the typical hepatosplenic gammadelta (
) T-cell lymphoma-specific phenotype: CD2+, CD3+, CD4-, CD5-, CD7+, CD8- and a bright CD52 positivity. PCR-based analysis of the TCR chain rearrangement by two different methods revealed a clear positive band on gel electrophoresis in peripheral blood as well as bone marrow specimens and a confirmative monoclonal peak in the automated fluorescent fragment analysis. These findings established the diagnosis of hepatosplenic T-cell lymphoma. Because of the rarity of this lymphoma type, no published guidelines for the treatment of this entity exist. Since a bright CD52 expression suggested the use of a specific mAb [1, 2], we choose the anti-CD52 antibody alemtuzumab in combination with cladribine, a nucleoside analogue with a pronounced cytotoxic and T-cell depletory activity [3].
A total of six cycles were given. Cladribine was administered at a dose of 0.12 mg/kg body weight by i.v. infusion over 2 h and alemtuzumab at a dose of 10 mg absolute by i.v. infusion over 1 h, both on days 1–3 of each cycle, repeated every 4 weeks. This treatment was followed by alemtuzumab maintenance therapy (10 mg by i.v.infusion over 1 h, three times a week) for a further 18 weeks. Premedication for alemtuzumab consisted of mefenamic acid and dimethindene maleate. Pneumocystis jiroveci pneumonia and herpes virus prophylaxis was administered as outlined in the manufacturer's recommendations.
Shortly after start of chemotherapy, the transfusion demand dropped and was entirely suspended at the beginning of alemtuzumab maintenance. Since harvest of CD 34-positive stem cells was insufficient, high-dose therapy with consecutive autologous stem-cell transplantation could not be considered as part of the initial treatment strategy. The entire treatment was well tolerated and no toxicity of more than World Health Organisation (WHO) grade 2 occurred. Because of pre-existent disease-related leukopenia and anaemia, haematologic toxicity was difficult to estimate. However, with addition of prophylactic granulocyte colony-stimulating factor after each treatment cycle, an absolute neutrophil count nadir of no more than two WHO grades—compared with each pretreatment value—developed and no serious infections necessitating dose reductions occurred. Platelet counts were not affected by the chemotherapy.
After an observation period of 27 months, the patient is in a continuous clinical and molecular remission with normal peripheral blood counts. Hepatosplenomegaly resolved and bone marrow and peripheral blood examination revealed a complete disappearance of the TCR rearrangement.
Hepatosplenic -T-cell lymphoma is a distinct rare entity first described in 1990 [4]. It is characterised by hepatosplenomegaly, lack of lympadenopathy and evidence of TCR chain rearrangement. The clinical course is usually aggressive. Despite chemotherapy, the majority of patients die with a median survival of 
8 months [4]. Aggressive treatments, occasionally also including stem-cell transplantation are required, nevertheless induction of complete remission is rare [5].
Combination therapy of lymphoma-active mAbs in conjunction with established cytotoxic chemotherapies is a highly effective strategy in the treatment of lymphomas of B- [6] and T-cell type [1, 2]. Different mechanisms of actions exert a synergistic effect without adding significant toxicity, thus, optimising therapeutical success. An international phase III first-line trial of the Competence Network Malignant Lymphomas (http://www.lymphome.de/en/) evaluating this strategy in peripheral T-cell lymphoma by combining CHOP ± alemtuzumab has recently been started. Nevertheless, to date no such combination treatments have been employed yet in this entity [1, 2, 5]. By combining both alemtuzumab and cladribine, a continuing lasting clinical and molecular remission, of more than 2 years, was be achieved in this aggressive lymphoma. However, to confirm the promising results of this therapy, further evaluation in more patients is necessary.
1 Division of Haematology, Department of Internal Medicine, Medical University of Graz, Graz
2 Institute of Pathology, Medical University of Graz, Graz
3 Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University Vienna, Vienna, Austria
* (E-mail: gerald.jaeger{at}meduni-graz.at)
References
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2. Gallamini A, Zaja F, Patti C, et al. Alemtuzumab (Campath-1H) and CHOP chemotherapy as first-line treatment of peripheral T-cell lymphoma: results of a GITIL (Gruppo Italiano Terapie Innovative nei Linfomi) prospective multicenter trial. Blood (2007) 110:2316–2323.
3. Petzer AL, Bilgeri R, Zilian U, et al. Inhibitory effect of 2-chlorodeoxyadenosine on granulocytic, erythroid, and T-lymphocytic colony growth. Blood (1991) 78:2583–2587.
4. Farcet JP, Gaulard P, Marolleau JP, et al. Hepatosplenic T-cell lymphoma: sinusal/sinusoidal localization of malignant cells expressing the T-cell receptor gamma delta. Blood (1990) 75:2213–2219.
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