Advances in the Clinical Staging of Chronic Lymphocytic Leukemia

Kanti, R.; Jain, Preetesh

doi:10.1373/clinchem.2010.159004

Cited by 117 publications

(139 citation statements)

References 6 publications

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“…1 Staging was performed according to Rai classification. 2 The time to initial treatment was defined according to the period between first diagnosis and first CLL-specific treatment. No deaths (CLL-related or unrelated) occurred during the observation period.…”

Section: Patientsmentioning

confidence: 99%

Regulatory T cells predict the time to initial treatment in early stage chronic lymphocytic leukemia

Weiß

Melchardt

Egle

et al. 2010

Cancer

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BACKGROUND: Early stage chronic lymphocytic leukemia is characterized by a highly variable course of disease. Because it is believed that regulatory T cells (T regs ) are potent suppressors of antitumor immunity, the authors hypothesized that increased T regs may favor disease progression. METHODS: T reg levels (cluster of differentiation 3 [CD3]-positive, [CD4]-positive, CD25-positive, and CD127-negative) in peripheral blood from 102 patients were analyzed by flow cytometry. Statistical analysis was used to evaluate correlations with clinical data. RESULTS: The relative T reg numbers in CD4-positive T cells were significantly greater in patients with chronic lymphocytic leukemia compared with the numbers in a control group of 170 healthy individuals (P ¼ .001). Patients were divided into 2 groups using a median T reg value of 9.7% (the percentage of CD4-positive T cells). Patients with higher T reg levels had a significantly shorter time to initial treatment (median, 5.9 years) compared with patients who had lower T reg levels (median, 11.7 years; log-rank P ¼ .019). Furthermore, T reg levels (the percentage of CD4-positive T cells) had significant prognostic power to predict the time to initial treatment in univariate analysis (P ¼ .023) and in multivariate Cox regression analysis that included the variables Rai stage, immunoglobulin heavy-chain variable region gene mutational status, chromosomal aberrations, and CD38 expression (P ¼ .028). CONCLUSIONS: Higher T reg levels had significant and independent prognostic power for predicting the time to initial treatment in patients with low to intermediate stage chronic lymphocytic leukemia.

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Section: Patientsmentioning

confidence: 99%

Regulatory T cells predict the time to initial treatment in early stage chronic lymphocytic leukemia

Weiß

Melchardt

Egle

et al. 2010

Cancer

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“…Several prognostic markers, such as the Rai and Binet staging systems (3,4), immunoglobulin V H gene mutational status (5), ZAP70 expression (6,7), and cytogenetic abnormalities (8) like Del 13q14, Del 17p, and Del 11q, can be used to predict the survival outcome and direct treatment strategies for patients with CLL (9).…”

Section: Introductionmentioning

confidence: 99%

PIM Kinases Are Essential for Chronic Lymphocytic Leukemia Cell Survival (PIM2/3) and CXCR4-Mediated Microenvironmental Interactions (PIM1)

Decker

Finter

Forde

et al. 2014

Molecular Cancer Therapeutics

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Overexpression of the CXCR4 receptor is a hallmark of chronic lymphocytic leukemia (CLL) and is important for CLL cell survival, migration, and interaction with their protective microenvironment. In acute myelogenous leukemia (AML), PIM1 was shown to regulate the surface expression of the CXCR4 receptor. Here, we show that PIM (proviral integration site for Moloney murine leukemia virus) kinases 1-3 are overexpressed and that the CXCR4 receptor is hyperphosphorylated on Ser339 in CLL compared with normal lymphocytes. Furthermore, CXCR4 phosphorylation correlates with PIM1 protein expression and PIM1 transcript levels in CLL. PIM kinase inhibition with three different PIM kinase inhibitors induced apoptosis in CLL cells independent of the presence of protective stromal cells. In addition, PIM inhibition caused dephosphorylation of the CXCR4 receptor on Ser339, resulting in enhanced ligand-dependent CXCR4 internalization and reduced re-externalization after withdrawal of CXCL12. Furthermore, PIM inhibition in CLL cells blocked CXCR4 functions, such as migration toward CXCL12-or CXCL12-induced extracellular signal-regulated kinase (ERK) phosphorylation. In concordance, pretreatment of CLL cells with PIM kinase inhibitors strongly reduced homing of CLL cells toward the bone marrow and the spleen of Rag2

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“…3 The remaining one-third are characterised by an initial indolent phase followed by disease progression. Disease staging systems developed by Rai 4 and Binet, 5 which enable classification of patients into good, intermediate and poor prognostic outcome groups have facilitated the determination of treatment course. However, neither provide the means for early stage diagnosis nor the discrimination of stable and progressive forms of CLL.…”

Section: Introductionmentioning

confidence: 99%

Serum metabolome analysis by 1H-NMR reveals differences between chronic lymphocytic leukaemia molecular subgroups

et al. 2010

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Chronic lymphocytic leukaemia (CLL) is a heterogeneous disease exhibiting variable clinical course and survival rates. Mutational status of the immunoglobulin heavy chain variable regions (IGHVs) of CLL cells offers useful prognostic information for high-risk patients, but time and economical costs originally prevented it from being routinely used in a clinical setting. Instead, alternative markers of IGHV status, such as zeta-associated protein (ZAP70) or messenger RNA levels are often used. We report a 1 H-NMR-based metabolomics approach to examine serum metabolic profiles of early stage, untreated CLL patients (Binet stage A) classified on the basis of IGHV mutational status or ZAP70. Metabolic profiles of CLL patients (n ¼ 29) exhibited higher concentrations of pyruvate and glutamate and decreased concentrations of isoleucine compared with controls (n ¼ 9). Differences in metabolic profiles between unmutated (UM-IGHV; n ¼ 10) and mutated IGHV (M-IGHV; n ¼ 19) patients were determined using partial least square discriminatory analysis (PLS-DA; R 2 ¼ 0.74, Q 2 ¼ 0.36). The UM-IGHV patients had elevated levels of cholesterol, lactate, uridine and fumarate, and decreased levels of pyridoxine, glycerol, 3-hydroxybutyrate and methionine concentrations. The PLS-DA models derived from ZAP70 classifications showed comparatively poor goodness-of-fit values, suggesting that IGHV mutational status correlates better with diseaserelated metabolic profiles. Our results highlight the usefulness of 1 H-NMR-based metabolomics as a potential non-invasive prognostic tool for identifying CLL disease-state biomarkers.

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Advances in the Clinical Staging of Chronic Lymphocytic Leukemia

Cited by 117 publications

References 6 publications

Regulatory T cells predict the time to initial treatment in early stage chronic lymphocytic leukemia

Regulatory T cells predict the time to initial treatment in early stage chronic lymphocytic leukemia

PIM Kinases Are Essential for Chronic Lymphocytic Leukemia Cell Survival (PIM2/3) and CXCR4-Mediated Microenvironmental Interactions (PIM1)

Serum metabolome analysis by 1H-NMR reveals differences between chronic lymphocytic leukaemia molecular subgroups

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