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• W2041688661 abstract "T-cell large granular lymphocytic (T-LGL) leukaemia is a low-grade lymphoproliferative disorder that results from the clonal proliferation of cytotoxic T-cells. Transformation of T-LGL leukaemia to a high grade T-cell lymphoma is rare but has been documented (Matutes et al, 2001). However, development of a large B-cell non-Hodgkin lymphoma (B-NHL) on the background of T-LGL leukaemia has not been reported previously. We present a patient with T-LGL leukaemia who developed a high grade B-NHL whilst on methotrexate, and discuss the possible pathogenetic role of immunosuppression. Incidental lymphocytosis of 8·8 × 109/l and neutropenia of 0·4 × 109/l were noted on routine blood tests on a 74-year-old man. There was no lymphadenopathy or hepatosplenomegaly and the rest of the full blood count was normal. A peripheral blood film showed numerous circulating large granular lymphocytes (LGLs) (Fig 1A). His autoimmune profile including rheumatoid factor was negative. Serology for hepatitis B, hepatitis C, Epstein-Barr virus (EBV), human T-lymphotropic viruses (HTLV-I and HTLV-II) and human herpes viruses (HHV-6 and HHV-7) were negative. (A) LGL in blood with an eccentric nucleus and azurophilic granules (May-Grünwald Giemsa stain; ×100). (B) Bone marrow with interstitial infiltrate of CD8+ LGLs (×10). (C) Inguinal lymph node heavily infiltrated by DLBCL (Haematoxylin & Eosin (H&E); ×40). (D) Bone marrow showing large lymphoid cells strongly positive for CD20, consistent with involvement by DLBCL (×10). (E) Bone marrow biopsy section showing clearance of DLBCL with treatment (H&E; ×10). (F) Post-treatment bone marrow with residual CD8+ LGL infiltrate (×10). A diagnostic bone marrow aspirate showed a mild infiltration by LGLs with good haematopoietic reserve. Sections of the trephine biopsy showed a reactive intertrabecular lymphoid nodule composed of both B and T-cells together with an interstitial infiltrate of CD8+ T-cells with variable CD57 staining (Fig 1B), consistent with a low level of infiltration by T-LGL leukaemia. Flow cytometry on bone marrow aspirate and peripheral blood demonstrated the presence of CD2+ CD3+ CD5+ CD7+ CD8+ CD57+ T-cells that were CD4, CD16, CD56, CD25, CD19 and HLA-DR negative. Molecular studies with polymerase chain reaction confirmed the clonal nature of the LGLs with TCRB and TCRG gene rearrangements. In view of the neutropenia, a low dose of oral methotrexate was commenced at 5 mg/week. Due to a lack of response, the dose was gradually increased to 30 mg/week, which improved the neutrophil counts to consistently above 1·2 × 109/l. A repeat bone marrow examination a year from diagnosis showed a similar residual level of interstitial infiltration by LGLs, confirming that the mechanism of action of methotrexate is by immunomodulation and suppression of cytokines rather than by direct cytotoxicity. Two years after the diagnosis of LGL leukaemia and initiation of methotrexate, the patient presented with inguinal lymphadenopathy in the absence of B symptoms. A staging computed tomography (CT) scan demonstrated bulky inguinal and pelvic lymph nodes along with omental, peritoneal and hepatic low attenuation masses, consistent with lymphomatous infiltration. His full blood count was normal but serum lactate dehydrogenase was elevated to 356 (normal 98–192 μ/l). Excision biopsy of the inguinal lymph node revealed a diffuse proliferation of large lymphoid cells with abundant cytoplasm and pleomorphic nuclei (Fig 1C). The cells were CD20+ CD10+ BCL6+ BCL2− and showed a high proliferation rate, consistent with a diffuse large B-cell lymphoma (DLBCL). EBV markers LMP-1 and EBER-ISH were negative. Concurrent bone marrow biopsy showed a sheet-like intertrabecular infiltrate of CD20+ CD10+ BCL6+ large lymphoid cells, confirming infiltration by DLBCL (Fig 1D). An interstitial infiltrate of CD3+ CD5+ CD8+ T-LGLs was also noted. Combination chemotherapy with 6 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) with three doses of prophylactic intrathecal methotrexate achieved complete resolution of the DLBCL. Post treatment CT scan and a bone marrow biopsy showed clearance of the high grade lymphoma (Fig 1E). Interestingly, the low-level infiltration by T-LGL leukaemia persisted unchanged in spite of intensive chemotherapy (Fig 1F). The patient is currently well 5 years after completion of R-CHOP chemotherapy and is on a watch and wait policy of management, off all treatment including methotrexate and successfully maintaining a neutrophil count around 2·5 × 109/l. LGL leukaemias have occasionally been reported to pursue an aggressive course, particularly when associated with a Natural Killer-cell phenotype and germline configuration of the T-Cell Receptor chain genes (Ohno et al, 1988; Imamura et al, 1990). EBV-related proliferation of LGLs and B-cells have also been described in LGL leukaemia (Hart et al, 1992; Toba et al, 1997). We have previously documented a patient with untreated LGL leukaemia, whose disease showed transformation into an aggressive peripheral T-cell lymphoma 11 years later (Matutes et al, 2001). This is the first report of a high grade B-cell lymphoma arising on the background of a T-LGL leukaemia. This present case is different to the patient who developed high-grade T-cell transformation in that the lymphoma was of B-cell origin and hence unlikely to have evolved from the original T-LGL clone. There is some evidence in the literature for the occurrence of EBV-driven B-NHL as a complication of long term immunosuppressive therapy with methotrexate (Feng et al, 2004; Miyazaki et al, 2007). However, large prospective population studies have failed to establish a causal relationship between immunomodulatory doses of methotrexate and subsequent development of NHL (Mariette et al, 2002; Wolfe & Michaud, 2007). In our patient, serological, molecular and histopathological markers for EBV infection were negative and hence his DLBCL was not triggered by this virus. Whether the long term immunosuppression per se had a contributory role in the aetiopathogenesis of the lymphoma is debatable. Interestingly, intensive chemotherapy with 6 cycles of R-CHOP completely cleared the high grade B-NHL, but had practically no effect on the LGLs. Patients with LGL leukaemia generally do not benefit from cytotoxic treatment as LGLs are extremely chemotherapy-resistant cells. The cytopenias in LGL leukaemia are thought to be driven by cytokine release rather than by severe bone marrow infiltration (Osuji et al, 2006). Another point of note is that despite showing initial resistance to methotrexate at diagnosis and needing dose increments up to 30 mg/week, the patient is now paradoxically maintaining a normal neutrophil count after 5 years off all medications. Though many clinicians would prefer to continue immunomodulation indefinitely to maintain the response, our experience with this patient may be regarded as corroborative evidence to the contrary. LGL leukemias have a variable natural history and it may thus be feasible to take patients off immunomodulation for a trial of watch and wait policy management once a stable neutrophil count has been achieved with initial treatment. We express our gratitude to Mr John Maynard, for help with editing the manuscript. We also wish to thank Dr Chloe Anthias and Dr Radovan Saso, for their involvement with clinical management of the above patient." @default.
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• W2041688661 title "Epstein-Barr virus negative large B-cell lymphoma during long term immunomodulatory therapy for T-cell large granular lymphocytic leukaemia" @default.
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