Clustering of Expression Data in Chronic Lymphocytic Leukemia Reveals New Molecular Subdivisions.

Although the identification of inherent structure in chronic lymphocytic leukemia (CLL) gene expression data using class discovery approaches has not been extensively explored, the natural clustering of patient samples can reveal molecular subdivisions that have biological and clinical implications. To explore this, we preprocessed raw gene expression data from two published studies, combined the data to increase the statistical power, and performed unsupervised clustering analysis. The clustering analysis was replicated in 4 independent cohorts. To assess the biological significance of the resultant clusters, we evaluated their prognostic value and identified cluster-specific markers. The clustering analysis revealed two robust and stable subgroups of CLL patients in the pooled dataset. The subgroups were confirmed by different methodological approaches (non-negative matrix factorization NMF clustering and hierarchical clustering) and validated in different cohorts. The subdivisions were related with differential clinical outcomes and markers associated with the microenvironment and the MAPK and BCR signaling pathways. It was also found that the cluster markers were independent of the immunoglobulin heavy chain variable (IGVH) genes mutational status. These findings suggest that the microenvironment can influence the clinical behavior of CLL, contributing to prognostic differences. The workflow followed here provides a new perspective on differences in prognosis and highlights new markers that should be explored in this context.

Small lymphocytic lymphoma and chronic lymphocytic leukemia: are they the same disease?

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world, characterized by peripheral blood B-cell lymphocytosis as well as lymphadenopathy, organomegaly, cytopenias, and systemic symptoms. Chronic lymphocytic leukemia cells have a distinctive immunophenotype, and the disease has a characteristic pattern of histological infiltration in the lymph node and bone marrow. The clinical course of CLL is heterogeneous, with some patients presenting with very indolent disease and other patients having a more aggressive malignancy. It is known that genetic abnormalities underlie this difference in clinical presentation. Some patients may present solely with lymphadenopathy, organomegaly, and presence of infiltrating monoclonal B cells with the same immunophenotype as CLL cells, but lacking peripheral blood lymphocytosis. This disease is called small lymphocytic lymphoma (SLL) and has been considered for almost 2 decades to be the tissue equivalent of CLL. Both CLL and SLL are currently considered different manifestations of the same entity by the fourth edition of the World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. It is suspected that differential expression of chemokine receptors (e.g., reduced expression of R1 and CCR3 in SLL cells), integrins (e.g., CLL cells have lower expression of integrin αLß2), and genetic abnormalities (a higher incidence of trisomy 12 and lower incidence of del(13q) is found in SLL) may explain some of the clinical differences between these 2 disorders. However, there is still a lack of knowledge on the precise biological basis underlying the different clinical presentations of CLL and SLL. It is expected that future studies will shed light on the pathophysiology of both disorders.

Leucemia linfocítica crônica: classificação marcadores de risco e tratamento / Chronic lymphocytic leukemia: markers of risk classification and treatment

Revisão sobre leucemia linfocítica crônica, enfoque em estadiamento, novos marcadores prognósticos e novas abordagens terapêuticas.

Is assessment of surface CD38 expression worthwhile as a prognostic factor in chronic lymphocytic leukemia patients?

We studied the clinical impact of CD38 expression in 226 chronic lymphocytic leukemia patients (CLL) at disease presentation and during follow up to determine its prognostic significance, progression free survival (PFS) and overall survival (OS), and to verify whether this parameter changed over time. Various patients' characteristics were studied including gender, Rai and Binet stages, immunoglobulin light chain expression, lymphocyte doubling time and CD38 expression. After a median follow up of 53 months (range 6-282), 62% CD38 positive(+) patients required therapy. PFS and OS at 84 months were significantly lower for CD38(+) patients: 20 and 71% respectively, compared to CD38 negative(-): 70 and 96%. At multivariate analysis CD38(+) showed to be the best factor for predicting progression: HR 3.3, 95%CI 2.10-5.14, p = 0.000. Its expression did not change in 98% re-evaluated patients. We confirm that CD38(+) is a stable parameter for the identification of CLL patients with a more aggressive disease course.

Contribution of immunohistochemistry to small B-cell lymphoma classification.

Although the small B-cell lymphomas show major morphologic overlapping, they have been recently shown to be distinct entities with several biologic and clinical differences. Therefore, the utility of a panel of paraffin-reactive antibodies in differentiating these neoplasms was investigated. Using clinical data and morphologic criteria, 134 cases of small B-cell lymphomas were grouped as those with (1) one strongly suggested diagnosis, (2) differential diagnosis between two types of lymphomas, and (3) small B-cell lymphoma without hints for further subclassification. With a panel of antibodies including CD5, CD10, CD23, CD43, bcl-2, and cyclin D1, most but not all cases could be precisely categorized. This panel confirmed the diagnosis in 96.5% of the cases from group 1. In group 2 it confirmed one of the two diagnoses in 81.5% of the cases. In group 3 it established a definitive diagnosis in 55% of the cases. When all groups were considered, a correct diagnosis could be established for 88.1% of cases; for 6.7% of them the authors remained with two possible diagnosis, and the broad "small B-cell lymphoma" was the only diagnosis for 5.2% of cases. CD10 separated most follicular lymphomas from other small B-cell lymphoid neoplasms. CD23 separated small lymphocytic lymphoma/chronic lymphocytic leukemia. Cyclin D1 separated mantle cell lymphoma. The present study selected CD10, CD23, and cyclin D1 as a minimal panel for the classification of small B-cell lymphomas, yielding a final diagnosis in 88.1% of the cases.