scholarly journals Elevated serum levels of soluble CD44 can identify a subgroup of patients with early B-cell chronic lymphocytic leukemia who are at high risk of disease progression

Cancer ◽  
2001 ◽  
Vol 92 (4) ◽  
pp. 713-719 ◽  
Author(s):  
Stefano Molica ◽  
Gaetano Vitelli ◽  
Domenico Levato ◽  
Diana Giannarelli ◽  
Giuseppe Maria Gandolfo
Keyword(s):  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Disease Progression ◽  
Elevated Serum ◽  
Serum Levels ◽  
Lymphocytic Leukemia ◽  
Soluble Cd44 ◽  
Risk Of Disease ◽  
Cell Chronic Lymphocytic Leukemia

Serum Insulinlike Growth Factor Is Not Elevated in Patients with Early B-Cell Chronic Lymphocytic Leukemia but Is Still a Prognostic Factor for Disease-Progression.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4786-4786
Author(s):  
Stefano Molica ◽  
Gaetano Vitelli ◽  
Rosanna Mirabelli ◽  
Giovanna Digiesu ◽  
Diana Giannarelli ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Growth Factor ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Disease Progression ◽  
Adhesion Molecule ◽  
Serum Levels ◽  
Lymphocytic Leukemia ◽  
Cell Chronic Lymphocytic Leukemia ◽  
Igfbp 3

Abstract Insulin like growth factor 1 (IGF-1) is an important growth and antiapoptotic factor for the cancer cells in several malignancies and in multiple myeloma recent studies support the hypotesis of a role for IGF-1 in disease progression. Clinico-biological relevance of IGF-1 was never studied in B-cell chronic lymphocytic leukemia (CLL). Using a quantitative sandwich immunoassay technique (ELISA)(QUANTIKINE®, Human IGF-1 and IGFBP-3, R & D Systems), we measured the concentration of IGF-1 and its major binding protein IGF-binding protein 3 (IGFBP-3) in serum drawn at the time of diagnosis from 77 Binet stage A CLL patients. Either IGF-1 or IGFBP-3 were significantly decreased compared to healthy age- and sex-matched controls (P<0.0001 for both; Mann-Whitney test). Serum levels of IGF-1 and IGFBP-3 paralleled each other (P=0.002); in contrast, no significant correlation was found between serum levels of IGF-1 and clinico-hematological variables including age (P=0.253), sex (P=0.270), Rai clinical substages (P=0.140), LDH (P=0.956), β2-microglobulin (P=0.368), lymphocyte count (P=0.703) and lymphocyte doubling time [LDT](P=0.233). When correlation were attempted with circulating levels of angiogenic cytokines such as vascular endothelial growth factor (VEGF)(P=0.971), basic fibroblastic growth factor (FGF-2)(P=0.695), angiogenin (P=0.282) or adhesion molecules such as vascular cell adhesion molecule-1 [VCAM-1] (P=0.318), intercellular adhesion molecule-1 [ICAM-1] (P=0.883) and platelet endothelial cell adhesion-1 [PECAM-1] (P=0.772) similar results were found. Serum levels of IGF-1 were further evaluated as a dichotomous variable with respect to progression-free survival (PFS), an endpoint surrogate for overall survival in early B-cell CLL. The best separation of curves was seen with the cutoff point at the 75th percentile of IGF-1 levels (i.e., 93 pg/ml). Median PFS was 63 months in the patient group with low IGF-1, compared to a median PFS of 40 months in the remaining patients (P=0.002; HR, 0.311, 95% C.I, 0.085–0.630). In the multivariate analysis performed including variables significant at univariate analysis [i.e., Rai substage (P=0.002); LDT (P=0.004), IGF-1 (P=0.01)], only Rai substage retained prognostic significance (P=0.006). However, after removing from analysis LDT (only 6 out of 77 had an LDT< 12 months), either IGF-1 or Rai substage entered the model at a significant level ((P=0.03 and P=0.01, respectively). In conclusion, IGF-1 did not correlate with markers of tumor burden or clinical status in CLL thus suggesting that levels of this cytokine do not reflect the intrinsic malignancy of disease. Results of the present study highlight, however, its involvement in mechanisms of disease-progression in early CLL.

scholarly journals Role of interleukin-10 and interleukin-24 in the pathogenesis of В-cell chronic lymphocytic leukemia

2018 ◽  
pp. 56-61
Author(s):  
Т.Н. Жевак ◽  
Н.П. Чеснокова ◽  
Т.В. Шелехова ◽  
О.Е. Царева ◽  
И.А. Будник ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Serum Level ◽  
B Cell ◽  
Serum Levels ◽  
Lymphocytic Leukemia ◽  
Disease Stage ◽  
Enzyme Linked Immunosorbent Assay ◽  
Control Group ◽  
Patient Groups ◽  
Cell Chronic Lymphocytic Leukemia

Цель. Изучить закономерности изменения экспрессии интерлейкина-10 и интерлейкина-24, обладающих иммуномодулирующим эффектом, при развитии B-клеточного хронического лимфолейкоза. С учетом этого выявить информативные прогностические критерии развития гемобластоза и/или нового подхода к терапии заболевания. Методы. У 120 больных с разными стадиями В-клеточного хронического лимфолейкоза методом твердофазного иммуноферментного анализа исследована динамика уровней интерлейкина-10 и интерлейкина-24 в сыворотке крови. Результаты. Обнаружено закономерное повышение содержания интерлейкина-10 и интерлейкина-24 в сыворотке крови пациентов уже на начальной стадии B-клеточного хронического лимфолейкоза и сохранение их достоверно высоких уровней на последующих стадиях заболевания. Заключение. Обнаруженный нами факт повышения содержания интерлейкина-10 в сыворотке крови пациентов с В-клеточным хроническим лимфолейкозом является фактором риска снижения противоопухолевой защиты организма вследствие подавления им механизмов клеточного иммунитета и способности ингибировать апоптоз малигнизированных клеток. Напротив, повышение экспрессии интерлейкина-24, обладающего проапоптотической активностью и стимулирующего дифференцировку клеток, может способствовать повышению эффективности механизмов противоопухолевой резистентности организма. Устранение дисбаланса продукции и/или содержания указанных цитокинов в сыворотке крови может создать условия повышения эффективности терапии пациентов с В-клеточным хроническим лимфолейкозом. Aim. To study serum levels of immunosuppressive cytokines (interleukin (IL)-10 and IL-24) in patients with B-cell chronic lymphocytic leukemia for assessment of the disease progression and elaboration of a new treatment strategy. Methods. 120 patients with B-cell chronic lymphocytic leukemia were enrolled in the study and divided into four groups according to the disease stage (Rai stage I-IV). Control group included 30 healthy volunteers. Concentrations of IL-10 and IL-24 were measured in serum using the enzyme-linked immunosorbent assay (ELISA). Results. Serum levels of IL-10 and IL-24 levels were significantly increased in all patient groups compared to the control. No difference in the cytokines levels between the patient groups was observed. Conclusion. In patients with B-cell chronic lymphocytic leukemia, the increased serum level of IL-10 might impair the antitumor defence by inhibiting the cell immune response and preventing apoptosis of malignant lymphocytes. On the other hand, the increased serum level of IL-24 might oppose these effects by promoting cellular differentiation and inducing apoptosis in malignant cells. Therefore, correction of IL-10/IL-24 imbalance may be a beneficial therapeutic strategy for patients with B-cell chronic lymphocytic leukemia.

Characteristics and Outcome of B-Cell Chronic Lymphocytic Leukemia in HCV-Positive Patients.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4986-4986
Author(s):  
Stefano Molica ◽  
Rosanna Mirabelli ◽  
Demetrio Misuraca ◽  
Caterina Battaglia
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Monoclonal Gammopathy ◽  
Absolute Lymphocyte Count ◽  
Serum Levels ◽  
Autoimmune Disorders ◽  
Lymphocytic Leukemia ◽  
Severe Infections ◽  
Hodgkin's Lymphomas ◽  
Cell Chronic Lymphocytic Leukemia

Abstract HCV-associated B-cell non-Hodgkin’s lymphomas (NHL) show distinctive clinico-pathological features such as older age, liver damage, presence of monoclonal gammopathy, increased incidence of autoimmune disorders, extranodal localizations and restricted histological subtypes. As far as B-cell chronic lymphocytic leukemia (CLL) is concerned, information dealing with either characteristics or outcome of HCV-associated CLL are limited. With this background we compared clinico-hematological features and outcome of 34 HCV-positive patients diagnosed at our institution as having immunologically typical B-cell CLL (i.e., CD5+/CD23+/CD79b-/SmIg dim) with 161 unselected CLL HCV-negative patients followed-up in the last 10 years. The two groups were alike with respect to main clinico-hematological features such as age (P=0.780), sex (P=0.650), absolute lymphocyte count (P=0.788), platelet count (P=0.362), haemoglobin level (P=0.704), β2-microglobulin (P=0.192), Binet stage distribution (P=0.224) and lymphocyte doubling time (LDT)(P= 0.620). As expected either ALT or AST serum levels at the time of CLL diagnosis were significantly higher in HCV-positive patients in comparison to HCV-negative ones (P<0.0001 for both). In contrast, no difference was found in the incidence of monoclonal gammopathy between HCV-positive and HCV-negative patients (10.3% versus 7.7%; P=0.708). The same applied for autoimmune disorders which were homogeneously distributed in the two subgroups (P=0.711) and accounted, more frequently, for autoimmune emolytic anemia (AEA)(HCV-negative subgroup, 5.5%; HCV-positive subgroup, 9.0%). The proportion of severe infections registered did not reflect the HCV-status (HCV-negative subgroup, 9.6%; HCV-positive subgroup 6.4%; P= 0.510). Also second tumours were equally distributed among HCV-positive and HCV-negative subgroups (10% versus 6.8%; P=0.655). Survival curves projected at 10 years did not show any statistical in terms overall survival (Hazard Risk, 0.690; 95% CI: 0.216–1.304; P=0.167). Finally, the short term hepatic toxicity of chemotherapy did not increase among HCV-positive patients (P=0.671). In conclusion, HCV-positive patients with B-cell CLL do not differ from other patients both for presentation and clinical outcome. The need to activate specific protocols of antiviral therapy appears less urgent in comparison to NHL, however, younger CLL patients HCV-positive who are eligible for therapies at higher immunosuppressive potential (i.e., chemo-immunotherapy) should be taken in special consideration.

Rituximab Consolidation and Maintenance Immunotherapy Improve Outcome in B-Cell Chronic Lymphocytic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2035-2035 ◽  
Author(s):  
Giovanni Del Poeta ◽  
Maria Ilaria Del Principe ◽  
Luca Maurillo ◽  
Francesco Buccisano ◽  
Gianfranco Catalano ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Maintenance Therapy ◽  
B Cell ◽  
Response Duration ◽  
Lymphocytic Leukemia ◽  
Induction Treatment ◽  
Hematologic Toxicity ◽  
Grade 3 ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Monoclonal antibodies in combination with chemotherapy allowed us to obtain more responses and longer response duration in B-cell chronic lymphocytic leukemia (B-CLL), reducing disease burden to levels detectable only by flow cytometry. Moreover, it has been reported that low-dose rituximab decreases CD20 antigen loss via shaving and promotes enhanced targeting in CLL (Williams, 2006). We performed a phase II study that added rituximab to fludarabine (Flu) as therapy for symptomatic, untreated CLL. Remission status was assessed by a multiparametric flow cytometric method based on the detection of CD19+CD5+CD79b– residual B-CLL lymphocytes. VH mutational status, CD38, ZAP-70 and cytogenetics were obtained in all pts before treatment. We defined as “high risk” pts having at least two of the following markers: unmutated IgVH, CD38>30%, ZAP-70>20%, intermediate/unfavorable cytogenetics (trisomy 12 or del11q or del17p). Eighty-two CLL pts, median age 61 years, received six monthly courses of Flu (25 mg/m2 for 5 days) and four weekly doses of rituximab (375 mg/m2) starting after completion of Flu therapy. According to modified Rai stages, 8 pts had a low stage, 70 an intermediate stage and 4 a high stage. Based on NCI criteria, 66/82 (80%) pts achieved a complete remission (CR), 12/82 (15%) a partial remission (PR) and 4/82 (5%) no response or progression. Hematologic toxicity included mainly neutropenia (grade 3 and/or 4 in 42 pts) and thrombocytopenia (grade 3 and/or 4 in 4 pts). Thirty-five pts in clinical CR or PR, either with CD5+CD19+CD79b– bone marrow (BM) cells >1% (MRD+, n=20 pts) or MRD negative but presenting CD5+CD19+ peripheral blood lymphocytes (PBL) >1000/microl (n=15 pts) within 1 year after completion of the induction treatment, underwent consolidation/maintenance therapy with four monthly cycles of rituximab at 375 mg/m2 followed by twelve monthly doses of rituximab at 150 mg/m2. The median follow-up duration was 46 months. Noteworthy, all B-CLL pts experienced a long progression-free survival (PFS) from the end of induction treatment (68% at 5 years). Nevertheless, CLL pts that underwent consolidation and maintenance therapy (n=35) showed a significant longer response duration (85% at 5 years, Figure). On the other hand, BM and PBL persistently MRD negative (>1 year) pts (n=29) showed a response duration similar to that of the consolidated pts (87% at 5 years). A significant shorter PFS was observed within CD38+ pts (39% vs 78% at 5 years, P=0.002), unmutated pts (45% vs 94% at 2.5 years, P=0.001) and ZAP-70+ pts (36% vs 88% at 6 years; P=0.00002). Notably, within the “high risk” subset (n=30), considering only MRD+ pts in CR or PR (n=20), MRD+ consolidated pts (n=11) showed a significant longer response duration (64% vs 13% at 2 years, P=0.006) in comparison with MRD+ unconsolidated pts (n=9). In conclusion, consolidation/maintenance therapy with rituximab prolongs significantly the response duration in B-CLL, improving also the outcome of the “high risk” subset. Figure Figure

Serum BAFF (B-Cell Activating Factor of the TNF Family) Compared with Immunoglobulin Heavy-Chain Mutation Status, ZAP-70 and CD38 as a Predictor of Time to First Treatment in Early B-Cell Chronic Lymphocytic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3093-3093
Author(s):  
Stefano Molica ◽  
Gaetano Vitelli ◽  
Giovanna Cutrona ◽  
Giovanna Digiesi ◽  
Rosanna Mirabelli ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Heavy Chain ◽  
Immunoglobulin Heavy Chain ◽  
Serum Levels ◽  
Lymphocytic Leukemia ◽  
B Cell Activating Factor ◽  
Mutational Status ◽  
Time To First Treatment ◽  
Cell Chronic Lymphocytic Leukemia

Abstract We analyzed the correlation between well-established biological parameters of prognostic relevance in B-cell chronic lymphocytic leukemia [CLL] (i.e, mutational status of the immunoglobulin heavy chain variable region [IgVH], ZAP-70- and CD38-expression) and serum levels of BAFF (B-cell activating factor of the TNF family) by evaluating the impact of these variables on the time to first treatment [TFT] in a series of 69 previously untreated Binet stage A B-cell CLL patients. By using a commercial ELISA (R & D Systems, USA) we found that higher levels of BAFF characterized more frequently patients with Rai stage 0 (P=0.008) and mutated IgVH (P=0.03). In contrast, peripheral blood lymphocytosis (P=0.06), serum β2-m (P=0.159), LDH (P=0.333) and percentage of ZAP-70-positive (P=0.242) or CD38-positive B-CLL cells (P=0.142) did not reflect circulating levels of BAFF. The relationship among various bio-pathological parameters, analyzed by the multiple correspondence analysis (MCA), showed two different clinico-biological profiles. The first, characterized by higher BAFF serum levels (i.e., > 336 ng/mL), presence of mutation in the IgVH, low percentage of CD38-positive B-CLL cells (< 30%) and low LDH was associated with a stable pattern of disease generally not requiring therapy. The second, defined by lower BAFF levels, absence of mutation in the IgVH, high percentage of CD38- positive B-CLL cells and high LDH was associated with a more progressive pattern of disease and a shorter TFT. After a median follow-up time of 35 months (range, 2–120 months) 26 (37.6%) out of 69 patients experienced a need for chemotherapy. Kaplan-Meier estimates of patientsTFT, plotted after searching the best cut-off for BAFF (i.e., 336 ng/mL), demonstrated that low BAFF concentration was associated with a shorter TFT (median TFT 36 months) while median was not reached by patients with BAFF levels higher than 336 ng/mL (P<0.0001). Along with lower serum levels of BAFF (Hazard Ratio [HR], 0.19; P<0.0001), the univariate Cox proportional hazard model identified absence of mutation in IgVH (HR, 0.17; P<0.0001), CD38-positivity (HR, 3.32; P=0.01) and lower platelet count (HR, 0.19; P=0.03) as predictor of shorter TFT. Finally, in multivariate analysis only mutational status of IgVH (HR, 0.25; P=0.007) and serum concentration of BAFF (HR, 034; P=0.04) affected significantly TFT. Our results indicate that in early B-cell CLL clinico-biological profile including among other parameters BAFF may provide a useful insight into the complex interrelationship of prognostic variables and semplify their interpretation. The possible presence of BAFF isoform in B-CLL could peraphs account for the unexpected correlation between low soluble BAFF levels and poor clinical outcome in patients with early disease.

Monoclonal B-Cell Lymphocytosis (MBL) Is a Precursor State for Chronic Lymphocytic Leukemia (CLL) with 1% Progression Per Year.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 749-749
Author(s):  
Andy C. Rawstron ◽  
Fiona L. Bennet ◽  
Sheila J.M. O’Connor ◽  
Marwan Kwok ◽  
James A.L. Fenton ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
General Population ◽  
B Cell ◽  
Cell Count ◽  
Disease Progression ◽  
Lymphocyte Count ◽  
Progressive Disease ◽  
Lymphocytic Leukemia ◽  
Risk Of Disease

Abstract The 2007 IWCLL guidelines indicate that a diagnosis of Chronic Lymphocytic Leukemia (CLL) requires a B-cell count above 5,000/μL in the absence of other features; below this level the diagnosis is Monoclonal B-cell Lymphocytosis (MBL). There is little outcome data for MBL patients and it is not clear whether the detection of low levels of CLL cells, seen in 3% of the general population, is of clinical relevance. We have therefore investigated two hospital populations: the first with normal blood counts and no history of cancer; and the second MBL patients referred for investigation of a current or prior lymphocytosis. Blood samples from 1520 outpatients aged 60–80 with a normal blood count were screened: CLL cells were detected in 78/1520 (5.1%) with a median CLL cell count of 140/μL (range 15 – 1,248). Chromosomal abnormalities were frequently detected in purified CLL-phenotype cells (deletion 13q14 in 15/38, trisomy 12 in 4/22) although poor-risk abnormalities (deletion 11q or 17p) were not detected. The median IgVH mutation was 6.6% (range 0.5 – 13.7%) with 85% of cases showing >2% mutation from germline. The IgVH gene usage was heavily biased with a similar profile to mutated CLL. Detection of CLL cells in individuals with a normal count was not associated with increased mortality (estimated yearly rate 6.2% vs. 8.9% for matched controls, P=0.76) or risk of developing CLL as subsequent lymphocyte counts remained normal in all cases. A diagnosis of MBL was established in 309 of 2228 referrals for investigation of lymphocytosis between 1995 and 2000. A cohort of 185 MBL patients was monitored for a median 6.7 years (range 0.2 – 11.8): the presenting B-cell count was a median 3,100/μL (range 30 – 5,000), age 73 years (range 42 – 96); IgVH mutation rate was 7.1% (range 1.3 – 9.3%) with 96% of cases showing >2% mutation from germline. Progression to a lymphocyte count above 30,000/μL occurred in 15% of cases (28/185) and chemotherapy for progressive CLL was required in 7% (13/185). The absolute B-cell count was the only independent risk factor for an increasing disease levels. Neither IgVH mutation status nor CD38 expression predicted risk of disease progression or requirement for treatment. During follow-up 33% died: age above 70, hemoglobin concentration below 11 g/dL and T-lymphopenia (CD3+ <1,000/μL) predicted shorter survival, whereas patients presenting with a T-lymphocytosis (>2,400μL) had significantly longer survival. Development of progressive disease did not predict overall survival: 7/13 patients requiring therapy remain alive at a median 1.9 years (range 0–8.6 years) after initiation of treatment. The total lymphocyte count had no impact on the risk of disease progression, time to treatment or overall survival. CLL-phenotype cells are genetically equivalent to CLL even when detected in the general population but are not associated with increased mortality or risk of progression to CLL when present below 1,500/μL. MBL patients with higher levels of CLL cells show a steady increase in disease levels over time with 1–2% per year requiring chemotherapy for progressive disease. As such, periodic monitoring is indicated but this should have a minimal impact on lifestyle as MBL patients are often elderly with multiple health issues. MBL is a newly described disorder which is related to CLL in a similar way that MGUS is related to myeloma.

Sign in / Sign up

Export Citation Format

Share Document