Abdominal Computed Tomography Predicts Progression in Patients With Rai Stage 0 Chronic Lymphocytic Leukemia

2007 ◽  
Vol 25 (12) ◽  
pp. 1576-1580 ◽  
Author(s):  
Ana Muntañola ◽  
Francesc Bosch ◽  
Pedro Arguis ◽  
Eduardo Arellano-Rodrigo ◽  
Carmen Ayuso ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Chronic Lymphocytic Leukemia ◽  
Early Stage ◽  
Strong Predictor ◽  
Clinical Stage ◽  
Prognostic Significance ◽  
Clinical Information ◽  
Lymphocytic Leukemia ◽  
Abdominal Ct ◽  
Work Up

Purpose Whether computed tomography (CT) should be routinely included in the diagnostic work-up in patients with chronic lymphocytic leukemia (CLL) has not yet been determined. The aim of this study was to analyze the prognostic significance of abdominal CT in patients with CLL in Rai clinical stage 0. Patients and Methods Abdominal CT was performed at diagnosis in 140 patients consecutively diagnosed with CLL in Rai stage 0 disease. Results An abnormal abdominal CT was found in 38 patients (27%). Abnormal CT correlated with increased bone marrow infiltration (P = .024), high lymphocyte count (P = .001), increased ZAP-70 expression (P = .003), and short lymphocyte doubling time (LDT; P = .007). Patients with abnormal CT progressed more frequently and had a shorter time to progression than those with normal CT (median, 3.5 years v not reached, respectively; P < .001) and required earlier treatment intervention. In a multivariate analysis, only high ZAP-70 expression (relative risk = 3.60) and an abnormal abdominal CT (RR = 2.71) correlated with disease progression. Conclusion In this series, an abnormal abdominal CT was a strong predictor of progression in patients with early-stage CLL. The inclusion of CT scans in the initial work-up of patients with early clinical stage on clinical grounds can, therefore, provide relevant clinical information.

scholarly journals Prognostic significance of immunoglobulin phenotype in B cell chronic lymphocytic leukemia

Blood ◽  
1985 ◽  
Vol 65 (2) ◽  
pp. 340-344 ◽  
Author(s):  
L Baldini ◽  
R Mozzana ◽  
A Cortelezzi ◽  
A Neri ◽  
F Radaelli ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Clinical Stage ◽  
Prognostic Significance ◽  
Prognostic Index ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Clinical Prognosis ◽  
Delta Type ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Seventy-six consecutive untreated patients with B cell chronic lymphocytic leukemia (B-CLL) and classified according to Binet's staging system were studied at the clinical presentation. Several immunologic parameters (number of total and T circulating lymphocytes and their surface membrane immunoglobulin [Smlg] phenotypes and levels of serum Ig) were evaluated with the aim of identifying a biologic marker of prognostic relevance. In this series of persons, Binet staging confirmed its usefulness as a prognostic index (P less than .001). With regard to Smlg, they were mu-type in 41 cases (53.9%), mu- type plus delta-type in 29 cases (38.2%), alpha-type in one case, and not detectable in five cases. No correlations were found between clinical stage and immunoglobulin phenotype, although all but one patient in stage C showed mu-type Smlg alone. On analyzing the survival curves of our patients according to different Smlg phenotypes, we found that patients with only mu-type Smlg had a poorer prognosis (P less than .05) than those with mu-type plus delta-type; this difference was even more significant (P less than .01) in patients in stage A, whereas there were no statistical differences in those in stages B and C. Because the appearance of surface heavy chain of delta-type could be an expression of cell maturation, these results suggest that in B-CLL the presence of phenotypically more mature leukemic cells may correlate with better clinical prognosis, particularly in the early phase of the disease.

Global Methylation Provides Independent Prognostic Information in Chronic Lymphocytic Leukemia and Is Associated with a Microrna Signature

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3873-3873
Author(s):  
Alfons Navarro ◽  
Gerardo Ferrer ◽  
Marina Díaz-Beyá ◽  
Carmen Muñoz ◽  
Rut Tejero ◽  
...  
Keyword(s):  
Dna Methylation ◽  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Mirna Expression ◽  
Clinical Stage ◽  
Prognostic Significance ◽  
Surrogate Marker ◽  
Lymphocytic Leukemia ◽  
Prognostic Impact ◽  
Global Methylation

Abstract Abstract 3873 Introduction: Disruption of normal DNA methylation, including both gene specific hypermethylation and genome-wide hypomethylation, is found in most malignant tumors. Most epigenetic studies in chronic lymphocytic leukemia (CLL) have been focused in CpG islands and gene promoter regions, and have identified hypomethylated genes, such as BCL2 or TCL1, and hypermethylated genes, such as GRM7. However, the quantification of overall methylation measured as levels of 5-methylCytosine (5mC) has been poorly explored. As compared to their normal counterparts (CD19+ B cells), overall hypomethylation has been observed in CLL neoplastic cells. Importantly, the overall methylation varies among patients but its clinical significance has not been widely investigated. In addition, it is known that microRNA (miRNA) expression is altered in CLL, and that and epigenetic mechanisms, such as methylation, can affect miRNA expression. Aim: To investigate the prognostic impact of overall methylation in patients with CLL and to analyze the correlation of 5mC levels with miRNAs expression. Methods: We analyzed 73 CLL patients (median age, 69 [range, 34–86]; 43% males) diagnosed in our institution between 1992 and 2007. The median follow up was 10.5 years. The level of global methylation in total DNA was estimated after determination of percentage of 5mC using anti-5mC monoclonal antibodies (MethylFlash Methylated DNA Quantification Kit, Epigentek). The expression of 377 mature miRNAs was analyzed using TaqMan Array Human MicroRNA A Card v2.0 (Applied Biosystems). Statistical analysis was performed with SPSS version 15.0.1 and R software version 2.9.0. MaxStat package of R were used to determine the optimal cutoffs and Quantitative trail function in BRB array tools to correlate miRNA expression and methylation levels. Results: The analysis of methylation levels showed a wide distribution of methylation degree among patients (median: 3.02%, range: 0.58–6.14%). From the clinical standpoint, methylation levels were only correlated with Binet clinical stage, patients with C stage showing a higher degree of methylation (p=0.015). Using MaxStat, we identified two cutoffs which classified patients as having low, medium or high degree of methylation. Mean progression-free survival (PFS) was 8.4 years (95% CI: 6.4–10.4), 6.2 years (95% CI: 4.7–7.7) and 3.2 years (95% CI: 2.4–4.8) for patients with low, medium, and high methylation levels, respectively (p=0.013). In the multivariate analysis for PFS (including ZAP70, IGHV, Age≤65, cytogenetics and global methylation), high ZAP70 expression (HR: 3; 95%CI: 1.1–7.9; p=0.026) and high global methylation (HR: 5.4 95%CI: 1.7–17.1; p=0.004) were independent unfavorable prognostic factors, while a significant trend was observed for high-risk cytogenetics (17p-, 11q-, +12) (p=0.054). Interestingly, methylation levels retained its prognostic significance in subgroup analysis: clinical stage A (p=0.06) and B/C (p=0.009); mutated (p=0.008) and unmutated IGHV (p=0.028); low (p=0.028) and high ZAP70 (p=0.001); and low-risk (normal karyotype, 13q-)(p=0.008) and high-risk (17p-, 11q-, +12) cytogenetics (p=0.001). Finally, we identified a 4-miRNA signature associated with global methylation levels: miR-103 (Spearman correlation [SC]: −0.821;p=0.03), miR-132 (SC: 0.786;p=0.05), miR-494 (SC: −0.786; p=0.02), and miR-193a-5p (SC: 0.786; p=0.05). Interestingly, miR-103, miR-132 and miR-494 are located in subtelomeric regions, which are known to be more susceptible to overall methylation changes. Conclusions: In this study, the degree of global DNA methylation was an independent prognostic factor for PFS in patients with CLL. The analysis of overall methylation could be useful not only for the prognosis of patients with CLL but also in the monitoring of clinical trials in which hypomethylating agents (e.g., decitabine) are being investigated as CLL therapy. The correlation between overall methylation levels and certain miRNAs may be a surrogate marker of epigenetic lesions and deserves further investigation. Disclosures: No relevant conflicts of interest to declare.

Chronic lymphocytic leukemia: An Indian experience.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e19007-e19007
Author(s):  
Ajay Gogia ◽  
Ritu Gupta ◽  
Atul Sharma ◽  
Lalit Kumar ◽  
Vinod Raina ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Early Stage ◽  
Indian Subcontinent ◽  
Clinical Stage ◽  
Lymphocytic Leukemia ◽  
Adverse Impact ◽  
Stage Iii ◽  
Total Leukocyte Count ◽  
Female Ratio ◽  
Free Survival

e19007 Background: Chronic lymphocytic leukemia (CLL) is the most common lymphoproliferative disorder in the West accounting for about 30% of leukemias, whereas in Indian subcontinent it accounts for 3-5% of all leukemias. We aimed to evaluate biological and molecular prognostic parameters as well as therapeutic considerations in CLL patients in India. Methods: We retrospectively analyzed 510 patients with CLL, who presented at our institute over a period of 18 years. Results: The median age of CLL patients at presentation was 60 years (range: 28 - 92 years) with male: female ratio = 3:1. The median total leukocyte count was 45X109/L . As per clinical Rai stage distribution 55 (10.08%) patients were in Stage 0, 92 (18%) in stage I, 174 (34%) in stage II, 92 (18%) in stage III and 97 (19%) were in stage IV. ZAP-70 was positive ( > 20%) in 206 (57% , n = 361) , CD 38( > 30%) in 107 (29% , n = 363), and CD49d was positive ( > 30%) in 63 (50.3%, n = 127) cases. Beta-2 microglobulin (B2M) was elevated (≥3.5 mg/L) in 243 patients (70%, n = 347). One hundred and fifty six cases (57%, n = 273) were IGHV mutated and Del (17p) by FISH was observed in 18 cases (12%, n = 150). A total of 331 (64.9 %) patients required treatment wherein 155 patients (46.8%) received Chlorambucil-based, 110 ( 33.2%) received BR, 42 (12.6%) received Fludarabine based ( FC-7,FCR-35) and 41 patients received others regimen. Overall response rate seen with Chlorambucil, BR and Fludarabine based regimen was 67% ( CR-3.2%), 90% ( CR-45%) & 88% ( CR-44%) respectively. Median event free survival (EFS) and overall survival (OS) and was 3.5 years and 5.5 years respectively, with median follow up period of 3.9 years. Clinical stage (Rai III/IV), elevated B2 M, IGHV-unmutated had statistically significant adverse impact on OS and EFS. Fludarabine based chemotherapy appeared toxic as half of patients developed febrile neutropenia and various infections whereas in BR , cutaneous side effects were more common(p = 0.001) . In early stage CLL, median time to first treatment was 22 months and; IGHV-unmutated, elevated B2M and CD38 positivity were significantly associated with shorter treatment free survival. Conclusions: This is the largest series of CLL reported from Asia. Clinical Rai Stage III/IV, unmutated IGHV and elevated B2M have statistically significant adverse impact on survival of patients with CLL. BR was better tolerated than fludarabine based regimen with similar responses and events.

Serum Tumor Markers in Non-Hodgkin's Lymphomas and Chronic Lymphocytic Leukemia

1993 ◽  
Vol 8 (1) ◽  
pp. 14-20 ◽  
Author(s):  
A.N. Pavlidis ◽  
J. Kalef-Ezra ◽  
L.C. Bourantas ◽  
A. Lambrou ◽  
A. Mavridis
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Tumor Markers ◽  
Clinical Stage ◽  
Prognostic Significance ◽  
Interleukin 2 ◽  
Serum Levels ◽  
Lymphocytic Leukemia ◽  
Mean Values ◽  
Hodgkin's Lymphomas ◽  
Normal Controls

The levels of soluble interleukin-2 receptors (sIL-2R), beta-2 microglobulin (β-2M), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were measured in the serum of 50 previously untreated patients with non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL) as well as in 25 age and sex-matched normal controls. Compared to normal controls, mean serum levels of sIL-2R and β-2M were significantly increased in both NHL and CLL (p < 0.001) while the increase in ESR and CRP was less marked (p < 0.01 and p < 0.05, respectively). Comparison of these tumor markers with histologic grading showed statistically significant differences only for CRP between low, intermediate and high-grade lymphomas (p < 0.001 and p < 0.05). More advanced stages exhibited higher mean values of all serum markers than early stages (p < 0.001 for sIL-2R, β-2M and ESR and p < 0.05 for CRP). An association with the presence of b-symptoms was observed only for sIL-2R (p < 0.05). In addition, sIL-2R as well as β-2M were able to predict time to progression in patients with diffuse large-cell lymphomas. We conclude that of the four tumor markers tested sIL-2R and β-2M more frequently showed increased serum levels and were associated with clinical stage and/or presence of b-symptoms. Both sIL-2R and β-2M were also found to have prognostic significance for survival.

Angiopoietin-2 mRNA Expression Is Elevated in Chronic Lymphocytic Leukemia Patients with Poor Prognostic Features

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4182-4182
Author(s):  
Filip Vrbacky ◽  
Lukas Smolej ◽  
Vladimira Vroblova ◽  
Sona Pekova ◽  
Monika Hrudkova ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Mononuclear Cells ◽  
Statistical Significance ◽  
Clinical Stage ◽  
Prognostic Significance ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Mrna Levels ◽  
Prognostic Features ◽  
Angiopoietin 2

Abstract Several studies have demonstrated potential prognostic importance of angiogenesis in chronic lymphocytic leukemia (CLL). Elevated expression of angiogenic activator angiopoietin-2 (Ang-2) was recently reported in CLL but data regarding prognostic significance of Ang-2 in CLL is limited. Therefore, we evaluated potential relationship between Ang-2 expression and other prognostic factors in patients with CLL. Ang-2 mRNA was quantified by real-time quantitative PCR in purified mononuclear cells of 33 untreated CLL patients. Ang-2 transcript levels were further analyzed with regard to clinical stage, disease course, IgVH mutation status, CD38 and ZAP-70 expression. Elevated Ang-2 mRNA was detected in 12 cases; twenty-one patients had very low or undetectable levels of Ang-2 transcript. High Ang-2 mRNA levels were significantly associated with unmutated IgVH genes (p=0.010) and high CD38 expression (p=0.011) but not with ZAP-70 expression (p=0.784), Rai stage (p=0.305) or stable vs. progressive clinical course (p=0.443). Interestingly, there was a trend towards shorter progression-free survival in patients with high Ang-2 expression, but it did not reach statistical significance (median 15 months vs. not reached; p=0.090). In conclusion, our data show that Ang-2 mRNA is differentially expressed in patients with CLL and its increased expression appears to be associated with poor prognostic features.

scholarly journals Differential Induction of Apoptosis by Fludarabine Monophosphate in Leukemic B and Normal T Cells in Chronic Lymphocytic Leukemia

Blood ◽  
1998 ◽  
Vol 91 (5) ◽  
pp. 1742-1748 ◽  
Author(s):  
Ugo Consoli ◽  
Iman El-Tounsi ◽  
Alex Sandoval ◽  
Virginia Snell ◽  
Hans-Dieter Kleine ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Lymphocytic Leukemia ◽  
T Lymphocytes ◽  
Early Stage ◽  
Clinical Stage ◽  
Lymphocytic Leukemia ◽  
Clinical Samples ◽  
Spontaneous Apoptosis ◽  
Induced Apoptosis

Fludarabine (F-ara-A), an adenine nucleoside analog with efficacy in B-cell chronic lymphocytic leukemia (B-CLL), has also been shown to have a long-lasting suppressive effect on T lymphocytes. In heterogeneous clinical samples, apoptosis cannot be detected by standard methods in small cellular subsets. We developed, therefore, a combined assay of in situ end-labeling of nicked DNA by terminal deoxynucleotide transferase, with measurements of cellular DNA content and surface antigens (CD3, CD4, CD8, and CD19) by multiparametric flow cytometry. This assay was used to determine F-ara-A–induced apoptosis in different lymphocyte subsets from CLL patients and normal controls treated with F-ara-A in vitro. Apoptosis was also correlated to bcl-2 protein levels. We observed a direct effect of F-ara-A on both B-CLL and T lymphocytes. The response to F-ara-A in B-CLL lymphocytes in vitro was Rai stage–dependent, the early-stages being more responsive (P = .01). Higher levels of spontaneous apoptosis were observed in B-CLL lymphocytes from early stage patients (P = .02). No difference was observed in spontaneous apoptosis of normal T cells in B-CLL, although T lymphocytes in late-stage disease were more sensitive to F-ara-A–induced apoptosis. Incubation with cyclosporin A did not affect B-CLL and T-lymphocyte survival compared with control cultures. Results suggested a direct apoptotic effect of F-ara-A on B-CLL lymphocytes that decreases with increasing clinical stage. No correlation was found between bcl-2 and spontaneous or F-ara-A–induced apoptosis. Apoptosis occurred at all cell-cycle stages and was not restricted to cells in S phase. The mechanisms of this stage-dependent apoptosis in CLL remain to be elucidated.

scholarly journals Prognostic significance of immunoglobulin phenotype in B cell chronic lymphocytic leukemia

Blood ◽  
1985 ◽  
Vol 65 (2) ◽  
pp. 340-344
Author(s):  
L Baldini ◽  
R Mozzana ◽  
A Cortelezzi ◽  
A Neri ◽  
F Radaelli ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Clinical Stage ◽  
Prognostic Significance ◽  
Prognostic Index ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Clinical Prognosis ◽  
Delta Type ◽  
Cell Chronic Lymphocytic Leukemia

Seventy-six consecutive untreated patients with B cell chronic lymphocytic leukemia (B-CLL) and classified according to Binet's staging system were studied at the clinical presentation. Several immunologic parameters (number of total and T circulating lymphocytes and their surface membrane immunoglobulin [Smlg] phenotypes and levels of serum Ig) were evaluated with the aim of identifying a biologic marker of prognostic relevance. In this series of persons, Binet staging confirmed its usefulness as a prognostic index (P less than .001). With regard to Smlg, they were mu-type in 41 cases (53.9%), mu- type plus delta-type in 29 cases (38.2%), alpha-type in one case, and not detectable in five cases. No correlations were found between clinical stage and immunoglobulin phenotype, although all but one patient in stage C showed mu-type Smlg alone. On analyzing the survival curves of our patients according to different Smlg phenotypes, we found that patients with only mu-type Smlg had a poorer prognosis (P less than .05) than those with mu-type plus delta-type; this difference was even more significant (P less than .01) in patients in stage A, whereas there were no statistical differences in those in stages B and C. Because the appearance of surface heavy chain of delta-type could be an expression of cell maturation, these results suggest that in B-CLL the presence of phenotypically more mature leukemic cells may correlate with better clinical prognosis, particularly in the early phase of the disease.

scholarly journals Differential Induction of Apoptosis by Fludarabine Monophosphate in Leukemic B and Normal T Cells in Chronic Lymphocytic Leukemia

Blood ◽  
1998 ◽  
Vol 91 (5) ◽  
pp. 1742-1748 ◽  
Author(s):  
Ugo Consoli ◽  
Iman El-Tounsi ◽  
Alex Sandoval ◽  
Virginia Snell ◽  
Hans-Dieter Kleine ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Lymphocytic Leukemia ◽  
T Lymphocytes ◽  
Early Stage ◽  
Clinical Stage ◽  
Lymphocytic Leukemia ◽  
Clinical Samples ◽  
Spontaneous Apoptosis ◽  
Induced Apoptosis

Abstract Fludarabine (F-ara-A), an adenine nucleoside analog with efficacy in B-cell chronic lymphocytic leukemia (B-CLL), has also been shown to have a long-lasting suppressive effect on T lymphocytes. In heterogeneous clinical samples, apoptosis cannot be detected by standard methods in small cellular subsets. We developed, therefore, a combined assay of in situ end-labeling of nicked DNA by terminal deoxynucleotide transferase, with measurements of cellular DNA content and surface antigens (CD3, CD4, CD8, and CD19) by multiparametric flow cytometry. This assay was used to determine F-ara-A–induced apoptosis in different lymphocyte subsets from CLL patients and normal controls treated with F-ara-A in vitro. Apoptosis was also correlated to bcl-2 protein levels. We observed a direct effect of F-ara-A on both B-CLL and T lymphocytes. The response to F-ara-A in B-CLL lymphocytes in vitro was Rai stage–dependent, the early-stages being more responsive (P = .01). Higher levels of spontaneous apoptosis were observed in B-CLL lymphocytes from early stage patients (P = .02). No difference was observed in spontaneous apoptosis of normal T cells in B-CLL, although T lymphocytes in late-stage disease were more sensitive to F-ara-A–induced apoptosis. Incubation with cyclosporin A did not affect B-CLL and T-lymphocyte survival compared with control cultures. Results suggested a direct apoptotic effect of F-ara-A on B-CLL lymphocytes that decreases with increasing clinical stage. No correlation was found between bcl-2 and spontaneous or F-ara-A–induced apoptosis. Apoptosis occurred at all cell-cycle stages and was not restricted to cells in S phase. The mechanisms of this stage-dependent apoptosis in CLL remain to be elucidated.

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