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• Rituximab is effective and safe in RA-associated LGLL. • Repeated rituximab infusion seems to be effective in LGLL relapse. • Potentials mechanisms include: decreased inflammatory cytokine production, reduced T-cell stimulation and direct T-cell depletion. To assess the efficacy and tolerance profile of rituximab in rheumatoid arthritis (RA)-associated large granular lymphocyte leukemia (LGLL). Multicenter retrospective case series. Inclusion criteria were RA defined by the ACR/EULAR 2010 criteria and LGLL defined by absolute LGL count ≥ 0.3 × 109/L with evidence of an expanded clonal LGL population (flow cytometry, TCR-γ polymerase chain reaction, or Stat3 mutation). Fourteen patients (10 women, mean age 55.2 ± 14.2 years) included; 13 were seropositive for anti-cyclic citrullinated peptides (n = 11) or rheumatoid factor (n = 10). LGLL diagnosis was made 9.5 [IQR: 3.25;15.5] years after RA diagnosis. Thirteen patients had T-LGLL. Rituximab was the first-line therapy for LGLL for 4 patients. Previous treatment lines included methotrexate (n = 7), cyclophosphamide (n = 2), cyclosporin A (n = 1), or granulocyte colony-stimulating factor (n = 4). Rituximab was used in monotherapy (n = 8) or associated to methotrexate (n = 3), granulocyte colony-stimulating factor (n = 2), or alkylating agents (n = 1). The number of rituximab cycles ranged from 1 to 11 (median 6), with high heterogeneity in dosing regimens. Median duration response after rituximab initiation was 35 [IQR: 23.5;41] months. The overall response rate was 100%: 8 patients experienced complete response (normalization of blood count and LGL ≤ 0.3 × 109/L) and 6 experienced partial responses (improvement in blood counts without complete normalization). The tolerance profile was good, with no infectious complications. rituximab appears as a valuable therapeutic option for RA-associated LGLL. [ABSTRACT FROM AUTHOR]

Abstract: Large granular lymphocyte (LGL) leukemia is a spectrum of rare lymphoproliferative diseases of T lymphocytes and natural killer cells. These diseases frequently present with splenomegaly, neutropenia, and autoimmune diseases like rheumatoid arthritis. LGL leukemia is more commonly of a chronic, indolent nature; however, rarely, they have an aggressive course. LGL leukemia is thought to arise from chronic antigen stimulation, which drives long-term cell survival through the activation of survival signaling pathways and suppression of pro-apoptotic signals. These include Jak-Stat, Mapk, Pi3k-Akt, sphingolipid, and IL-15/Pdgf signaling. Treatment traditionally includes immunosuppression with low dose methotrexate, cyclophosphamide, and other immunosuppressive agents; however, prospective and retrospective studies reveal very limited success. New studies surrounding Jak-Stat signaling suggest this may reveal new avenues for LGL leukemia therapeutics. [Copyright &y& Elsevier]

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Abstract: Objective: The association between vasculitis and large granular lymphocyte (LGL) leukemia has rarely been reported or investigated. Thus, we assessed the clinical and biological phenotypes of LGL leukemia associated with vasculitis. Results: We studied a series of 11 patients displaying LGL leukemia associated with vasculitis (LAV). The mean age at diagnosis of LGL leukemia was 60.3 years; there were nine women and two men. The mean follow-up period was 45 months. The main LGL lineage was T-LGL (10 patients), and only one NK-LGL was identified. Clinical and biological features of T-LGL leukemia were compared with those from the 2009 French T-LGL registry. We did not find any relevant differences except that patients with LAV were predominantly female (p < 0.05). The most frequently observed vasculitis was cryoglobulinemia (n = 5). Three patients presented with cutaneous leukocytoclastic angiitis, two patients had ANCA-negative microscopic polyangiitis, and one patient had giant cell arteritis. The main clinical features involved the skin, e.g., purpura (91%), arthralgia (37%), peripheral neuritis (27%), and renal glomerulonephritis (18%). The most frequent histologic finding was leucocytoclastic vasculitis (54%). The rate of complete remission was high; i.e., 80%. A minority of patients had a vasculitis relapse (27%). Three patients (27%) died; one death was related to LGL leukemia (acute infection) and the two other deaths were related to vasculitis (both with heart failure). Conclusion: We conclude that vasculitis is overrepresented in the population of LGL patients, LAV predominantly affects women, vasculitis preferentially affects the small vessels, and LAV has high rate of complete response. [Copyright &y& Elsevier]

Clonal disorders of large granular lymphocytes (LGL) represent a rare spectrum of biologically distinct lymphoproliferative diseases originating either from mature T cells or natural killer cells. Both subtypes can manifest as indolent or aggressive disorders. We report a 77-year-old woman with rheumatoid arthritis, splenomegaly, and neutropenia who developed a painful leg ulcer refractory to treatment and thigh telangiectatic lesions. Because of the association of rheumatoid arthritis, splenomegaly, and nonspecific neutropenia, the diagnosis of Felty syndrome was initially made. Further investigation allowed the diagnosis of a CD56– natural killer–cell LGL leukemia and documented skin infiltration by natural killer cells. Cutaneous manifestations of LGL leukemia have been rarely reported. This report of pseudo-Felty syndrome with CD56– LGL leukemia, presenting with a leg ulcer and telangiectasia, enhances the role of dermatology in the diagnosis of hematologic neoplasia. [Copyright &y& Elsevier]

Summary: T-cell large granular lymphocyte leukemia (TLGL) is an atypical chronic lymphoproliferative disorder derived from cytotoxic T-cells (CTL). Unlike most forms of leukemia, the pattern of bone marrow infiltration in TLGL may be subtle and the cytopenias are often lineage specific, with neutropenia dominating. Both granulocytic survival and proliferation defects are observed and are mediated by humoral and cell-mediated mechanisms respectively. Splenic production of immune complexes induces a neutrophil survival defect, where as Fas expression by leukemic CTL results in a marrow based proliferation defect. These humoral and cell-mediated pathways induce granulocytic apoptosis through independent intracellular mechanisms which are not mutually exclusive and may be observed concurrently in individual patients with either TLGL or FS. A variety of therapeutic interventions have been utilized in the management of TLGL and Felty syndrome, including methotrexate, cyclosporine A, cyclophosphamide, glucocorticoids, myeloid colony stimulating factors and splenectomy. Their efficacy and mechanisms of action are reviewed. [Copyright &y& Elsevier]

Objective: Patients with T-cell (CD3+) large granular lymphocyte (LGL) leukemia have a high prevalence of autoantibodies and associated autoimmune diseases. Sjogren’s syndrome may not be diagnosed unless specifically looked for. We set to determine the prevalence of Sjogren’s syndrome in LGL leukemia and its cytokine profile. Methods: Every patient with a confirmed diagnosis of LGL leukemia diagnosed at a single academic medical center over the last 15 years was evaluated for Sjogren’s syndrome by questioning about sicca symptoms. In symptomatic patients, Schirmer’s test, rose bengal corneal staining, salivary flow rate measurement, autoantibody screening, and minor salivary gland biopsy were performed. Supernatants obtained from T-LGL leukemic cells following phytohemagglutinin (PHA) activation were analyzed for cytokine production by enzyme-linked immunosorbent assay and patients with or without Sjogren’s syndrome were compared with controls. Results: Of 48 patients, 21 reported sicca symptoms and were enrolled in the study. In 8 patients Sjogren’s syndrome was ruled out. Thirteen patients had clear evidence of Sjogren’s syndrome according to accepted criteria (27%). None had rheumatoid arthritis, but 1 had limited scleroderma. Thus, 12/48 patients had primary Sjogren’s syndrome. Other autoimmune diseases were frequently present, in particular, immune cytopenias (n = 7) or thyroid autoimmunity (n = 6). Supernatants of T-LGL leukemia cells incubated with PHA revealed markedly increased levels of multiple cytokines (especially soluble interleukin 2 receptor, tumor necrosis factor alpha, IL-6, IL-8) compared with healthy controls. However, this increase was common to LGL leukemia patients with or without Sjogren’s syndrome. Conclusions: Sjogren’s syndrome was commonly identified in the patients with T-cell LGL leukemia in this study. Upregulated cytokine production by the neoplastic cells may underlie some of the immune-mediated disorders common in these patients. [Copyright &y& Elsevier]