Genomics of LGL leukemia and select other rare leukemia/lymphomas.

Genomic analysis of cancer offers the hope of identifying new treatments or aiding in the selection of existing treatments. Rare leukemias pose additional challenges in this regard as samples may be hard to acquire and when found the underlying pathway may not be attractive to drug development since so few individuals are affected. In this case, it can be useful to identify common mutational overlap among subsets of rare leukemias to increase the number of individuals that may benefit from a targeted therapy. This chapter examines the current mutational landscape of large granular lymphocyte (LGL) leukemia with a focus on STAT3 mutations, the most common mutation in LGL leukemia to date. We examined the linkage between these mutations and autoimmune symptoms and disorders, in cases of obvious and suspected LGL leukemia. We then summarized and compared mutations in a set of other rare leukemias that also have JAK/STAT signaling pathway activation brought about by genomic changes. These include T-cell acute lymphoblastic leukemia (T-ALL), T-cell prolymphocytic leukemia (T-PLL), cutaneous T-cell lymphoma (CTCL), select peripheral T-cell lymphoma (PTCL), and adult T-cell leukemia/lymphoma (ATLL). Though STAT3 activation is common in these leukemias, the way in which it is achieved, such as the activating cytokine pathway and/or the co-mutational background, is quite diverse.

Somatic STAT3 mutations in Felty syndrome: an implication for a common pathogenesis with large granular lymphocyte leukemia.

Felty syndrome is a rare disease defined by neutropenia, splenomegaly, and rheumatoid arthritis. Sometimes the differential diagnosis between Felty syndrome and large granular lymphocyte leukemia is problematic. Recently, somatic STAT3 and STAT5B mutations were discovered in 30-40% of patients with large granular lymphocyte leukemia. Herein, we aimed to study whether these mutations can also be detected in Felty syndrome, which would imply the existence of a common pathogenic mechanism between these two disease entities. We collected samples and clinical information from 14 Felty syndrome patients who were monitored at the rheumatology outpatient clinic for Felty syndrome. Somatic STAT3 mutations were discovered in 43% (6/14) of Felty syndrome patients with deep amplicon sequencing targeting all STAT3 exons. Mutations were located in the SH2 domain of STAT3, which is a known mutational hotspot. No STAT5B mutations were found. In blood smears, overrepresentation of large granular lymphocytes was observed, and in the majority of cases the CD8+ T-cell receptor repertoire was skewed when analyzed by flow cytometry. In bone marrow biopsies, an increased amount of phospho-STAT3 positive cells was discovered. Plasma cytokine profiling showed that ten of the 92 assayed cytokines were elevated both in Felty syndrome and large granular lymphocyte leukemia, and three of these cytokines were also increased in patients with uncomplicated rheumatoid arthritis. In conclusion, somatic STAT3 mutations and STAT3 activation are as frequent in Felty syndrome as they are in large granular lymphocyte leukemia. Considering that the symptoms and treatment modalities are also similar, a unified reclassification of these two syndromes is warranted.

Cell size variations of large granular lymphocyte leukemia: Implication of a small cell subtype of granular lymphocyte leukemia with STAT3 mutations.

Large granular lymphocyte leukemia (LGL-L) has been morphologically defined as a group of lymphoproliferative disorders, including T-cell large granular lymphocytic leukemia (T-LGL-L), chronic lymphoproliferative disorders of NK cells (CLPD-NK) and aggressive NK cell leukemia. We investigated the morphological features of LGL leukemic cells in 26 LGL-L patients in order to elucidate relationships with current classifications and molecular backgrounds. LGL-L cells were mostly indistinguishable from normal LGL. Patients with STAT3 SH2 domain mutations showed significantly smaller cells compared with patients without STAT3 mutations. Four patients with T-LGL-L showed smaller granular lymphocytes with a median diameter of less than 13µm, which were rarely seen in normal subjects. This small subtype of T-LGL-L was recognized among rather young patients and was associated with D661Y mutations in the STAT3 gene SH2 domain. In addition, all of them showed anemia including two cases with pure red cell aplasia. These results suggest the heterogeneity of T-LGL-L and a specific subtype with small variants of T-LGL-L.

[The understanding of Epstein-Barr virus associated lymphoproliferative disorder].

In recent years, there are increasing articles concerning Epstein-Barr virus associated lymphoproliferative disorder (EBV+ LPD), and the name of EBV+ LPD is used widely. However, the meaning of EBV+ LPD used is not the same, which triggered confusion of the understanding and obstacles of the communication. In order to solve this problem. Literature was reviewed with combination of our cases to clarify the concept of EBV+ LPD and to expound our understanding about it. In general, it is currently accepted that EBV+ LPD refers to a spectrum of lymphoid tissue diseases with EBV infection, including hyperplasia, borderline lesions, and neoplastic diseases. According to this concept, EBV+ LPD should not include infectious mononucleosis (IM) and severe acute EBV infection (EBV+ hemophagocytic lymphohistiocytosis, fatal IM, fulminant IM, fulminant T-cell LPD), and should not include the explicitly named EBV+ lymphomas (such as extranodal NK/T cell lymphoma, aggressive NK cell leukemia, Burkitt lymphoma, and Hodgkin lymphoma, etc.) either. EBV+ LPD should currently include: (1) EBV+ B cell-LPD: lymphomatoid granulomatosis, EBV + immunodeficiency related LPD, chronic active EBV infection-B cell type, senile EBV+ LPD, etc. (2) EBV+ T/NK cell-LPD: CAEBV-T/NK cell type, hydroa vacciniforme, hypersensitivity of mosquito bite, etc. In addition, EBV+ LPD is classified, based on the disease process, pathological and molecular data, as 3 grades: grade1, hyperplasia (polymorphic lesions with polyclonal cells); grade 2, borderline (polymorphic lesions with clonality); grade 3, neoplasm (monomorphic lesions with clonality). There are overlaps between EBV+ LPD and typical hyperplasia, as well as EBV+ LPD and typical lymphomas. However, the most important tasks are clinical vigilance, early identification of potential severe complications, and treating the patients in a timely manner to avoid serious complications, as well as the active treatment to save lives when the complications happened.

[CD4⁺/CD8⁻ T- cell large granular lymphocytic leukemia: one case report and literatures reviews].

OBJECTIVE: Presenting the clinical features of one patient with CD4⁺/CD8⁻ T-cell large granular lymphocytic leukemia, to improve the understanding of the disease. METHODS: Clinical data of one patient hospitalized for skin rush and leukocytosis were analyzed, and the related literatures were reviewed. RESULTS: The patient was hospitalized for skin rush and leukocytosis. Routine blood test showed remarkable elevated white blood cell counts and mild anemia. Subsequent hematological examination led to a diagnosis of T- cell large granular lymphocytic leukemia with CD4⁺/CD8⁻ immunophenontype. CONCLUSION: CD3⁺/CD4⁺/CD8⁻ T- cell large granular lymphocytic leukemia is a kind of variant subtype, and is relatively rare, it has different clinical features with classic CD3⁺/CD4⁻/CD8⁺/TCRαß⁺T- cell large granular lymphocytic leukemia, so differentiating diagnosis is of great importance.

Chronic natural killer lymphoproliferative disorders: characteristics of an international cohort of 70 patients.

BACKGROUND: The 2008 World Health Organization (WHO) classification distinguishes three entities among the large granular lymphocytic leukemia (LGL leukemia): T-cell LGL leukemia (T-LGL leukemia), aggressive natural killer (NK) cell leukemia, and chronic NK lymphoproliferative disorders (LPD), the later considered as a provisional entity. Only a few and small cohorts of chronic NK LPD have been published. PATIENTS AND METHODS: We report here clinicobiological features collected retrospectively from 70 cases of chronic NK LPD, and compared with those of T-LGL leukemia. RESULTS: There were no statistical differences between chronic NK LPD and T-LGL leukemia concerning median age [61 years (range 23-82 years)], organomegaly (26%), associated autoimmune diseases (24%), and associated hematological malignancies (11%). Patients with chronic NK LPD were significantly less symptomatic (49% versus 18%, P < 0.001) and the association with rheumatoid arthritis was more rarely observed (7% versus 17%, P = 0.03). The neutropenia (<0.5 × 10(9)/l) was less severe in chronic NK LPD (33% versus 61%, P < 0.001) without difference in the rate of recurrent infections. STAT3 mutation was detected in 12% of the cohort, which is lower than the frequency observed in T-LGL leukemia. Thirty-seven percent of the patients required specific therapy. Good results were obtained with cyclophosphamide. Overall and complete response rates were, respectively, 69% and 56%. Overall survival was 94% at 5 years. CONCLUSION: This study suggests very high similarities between chronic NK LPD and T-LGL leukemias. Since chronic NK LPD is still a provisional entity, our findings should be helpful when considering further revisions of the WHO classification.

[Large granular lymphocyte leukemia].

Large granular lymphocytic (LGL) leukaemia is an uncommon clonal lymphoproliferative disorder. The WHO classification recognizes three distinct disorders of LGLs: T-cell large granular lymphocytic leukaemia (T-LGL), chronic lymphoproliferative disorders of NK-cells (CLPD-NK) and aggressive NK-cell leukaemia. Despite the different origin of cells, there is considerable overlap between T-LGL and CLPD-NK in terms of clinical presentation and treatment. Majority of these patients are asymptomatic and may not need treatment. When significant cytopenias occur, the application of immunosuppressive therapy often should be considered. In contrast, aggressive NK cell leukemia and the rare CD56(+) aggressive T-LGL leukemia have a fulminant clinical course and an earlier age of onset, therefore, more intensive combination chemotherapy is required, followed by allogeneic hematopoietic stem cell transplantation. However, these diseases are relatively rare, there are few clinical trials to guide management. In this review, the pathogenesis, diagnosis, treatment and prognosis of this leukemia are summarized and discussed.

T-cell and natural killer-cell large granular lymphocyte leukemia neoplasias.

Large granular lymphocyte (LGL) leukemia is a rare disorder of cytotoxic lymphocytes. LGL cells play an integral role in the immune system and are divided into two major lineages of CD3(-)natural killer (NK) cells and CD3(+) T cells that circulate throughout the blood in search of infected cells, in which they will make contact through a receptor ligand and induce cell death. LGL cells are also programmed to undergo apoptosis after contact with an infected target cell; however, they continue to survive in individuals with LGL leukemia. This unchecked proliferation and cytotoxicity of LGLs in patients results in autoimmunity or malignancy. Rheumatoid arthritis is the most common autoimmune condition seen in individuals with LGL leukemia; however, LGL leukemia is associated with a wide spectrum of other autoimmune diseases. Patients may also suffer from other hematological conditions including hemolytic anemia, pure red cell aplasia, and neutropenia, which lead to recurrent bacterial infections. Currently, the only established treatment involves a low dose of an immunosuppressive regimen with methotrexate, in which 40-50% of patients are either resistant or do not respond. In order to establish new therapeutics it is important to understand the current state of LGL leukemia both in the clinic and in basic research.

Large granular lymphocyte leukemia.

Clonal diseases of large granular lymphocytes (LGLs) represent a spectrum of clinically rare lymphoproliferative malignancies arising from either mature T-cell (CD3(+)) or natural killer (NK)-cell (CD3(-)) lineages. The clinical behavior of these disorders ranges from indolent to very aggressive. Patients with symptomatic indolent T-cell or NK-cell LGL leukemia are usually treated with immunosuppressive therapies; in contrast, aggressive T-cell or NK-cell LGL leukemias require intensive chemotherapy regimens. Novel targeted therapies are currently being tested in clinical studies.