Cytogenetic abnormalities in chronic lymphocytic leukemia

Trisomy of chromosome 12 is one of the commonest cytogenetic abnormalities in the karyotype in chronic lymphocytic leukemia (CLL). It is associated with atypical morphology of lymphocytes, progressing disease and poor survival. A high incidence abnormality in the B-cell CLL is deletion of chromosome 13 (13q14) detected by using modern diagnostic methods such as southern blot hybridization and fluorescence in situ hybridization. It occurs in 51% of the CLL patients and in as much as 70% in mantle-cell lymphoma. The deletion of 13q14.3 affects a locus telomeric to the RB1 gene (retinoblastoma gene) and the marker D13S25 which bear relation to a candidate tumour suppressor gene. Also common are the chromosome 14 abnormalities which are expressed as the translocation t(11;14)(q13;q32) and which correlate with a high leukocytes count, adverse response to cytostatic therapy and increased risk of prolymphocytic proliferation. The oncogene BCL-1 is activated in this translocation. Deletions of the long arm of chromosome 18 (18q21)(q32;q13.1) activate the BCL-2 oncogene, while the translocation t(14;19)(q32;q13.1) activates the BCL-3 oncogene. Essential role in the pathogenesis of CLL is played by the aberrations in chromosome 17 and the p53 mutations (17p13.1). The gene p53 is defined as a tumour suppressor gene; mutations of this gene leads to a CLL characterized with rapid progression, aggressive course, poor prognosis and low survival. The deletions in chromosome 7 are associated with the multidrug resistance gene which causes resistance to doxorubicin, vinblastine and colchicine. All these abnormalities are characteristic of the B-cell chronic lymphocytic leukemia. In the T-cell leukemia characteristic deletions are 11q22-q23, a.14q23.1, as well as the inversion inv(14)(11q32) and some rarer aberrations.     

Multidrug resistance in chronic lymphocytic leukemia

INTRODUCTION: New prognostic factors discovered in chronic lymphocytic leukemia have recently got into the center of clinical interest. While the predictive value of cytogenetical abnormalities, immunoglobulin heavy chain gene mutation status, CD38 and ZAP70 expression is already well known, the significance of multi-drug resistance in chronic lymphocytic leukemia is not well characterized. AIMS: The goal of this study was to characterize the multidrug resistance features in 82 patients with chronic lymphocytic leukemia at the genetical, expression- and functional level and to compare it with the patient's clinical behavior (survival and response to therapy). METHODS: Light Cycler Real Time PCR based "Single Nucleotide Polymorphism" analysis of the MDR1 gene, as a biological predictor of the expression level of P-glycoprotein was tested in 66 patients with chronic lymphocytic leukemia. P-glycoprotein expression and MDR-function was detected in 82 cases by flow cytometry (by use of anti-P-glycoprotein monoclonal antibody and calcein-verapamil functional test). Response to therapy was analyzed by statistical Fisher-test in the treated 35 patients. The survival analysis (Log-rank test) was performed on the whole population ( n = 82). RESULTS: No significant correlation was found between the three levels of multidrug resistance (genetics, phenotype, function) in our patients with chronic lymphocytic leukemia. P-glycoprotein positive cases (n = 9) were predominantly non-responders (8/9, 89%). There must be, however, other mechanisms causing non-response (total non-responders: 13/35 treated cases). Most of P-glycoprotein negative CLL patients (n = 26) responded well (21/26, 80%) to chemotherapy (responders: 22/35 treated CLL) (p < 0,001). The tendency was the same in the average expected survival rate between P-glycoprotein positive and negative patients (84 vs 203 months) but the difference was not significant (p = 0,106). CONCLUSIONS: This study proved the clinical prognostic significance of P-glycoprotein expression of leukaemic cells predicting the chemotherapy response and partially estimating the general survival of patients suffering from chronic lymphocytic leukemia.     

Ionizing radiation and chronic lymphocytic leukemia

The U.S. government recently implemented rules for awarding compensation to individuals with cancer who were exposed to ionizing radiation while working in the nuclear weapons complex. Under these rules, chronic lymphocytic leukemia (CLL) is considered to be a nonradiogenic form of cancer. In other words, workers who develop CLL automatically have their compensation claim rejected because the compensation rules hold that the risk of radiation-induced CLL is zero. In this article we review molecular, clinical, and epidemiologic evidence regarding the radiogenicity of CLL. We note that current understanding of radiation-induced tumorigenesis and the etiology of lymphatic neoplasia provides a strong mechanistic basis for expecting that ionizing radiation exposure increases CLL risk. The clinical characteristics of CLL, including prolonged latency and morbidity periods and a low case fatality rate, make it relatively difficult to evaluate associations between ionizing radiation and CLL risk via epidemiologic methods. The epidemiologic evidence of association between external exposure to ionizing radiation and CLL is weak. However, epidemiologic findings are consistent with a hypothesis of elevated CLL mortality risk after a latency and morbidity period that spans several decades. Our findings in this review suggest that there is not a persuasive basis for the conclusion that CLL is a nonradiogenic form of cancer.     

Molecular biology examination in chronic lymphocytic leukemia

Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia characterised by the accumulation of monoclonal CD5 + B-lymphocytes. The pathogenesis and the biology of CLL is complex and many details are still unknown. Several molecular biological methods have been used in the investigation of CLL, among them the study of apoptosis appears to be one of the most important. Initial experiences obtained by the spontaneous and fludarabine induced apoptosis, multidrug resistance (MDR)-test and fluorescent in situ hybridization (FISH) are reported by the authors. Apoptosis of CLL cells could be induced by fludarabine, while more studies should be performed to determine the exact role of MDR-test and FISH.     

Antigenic stimulation and the occurrence of chronic lymphocytic leukemia.

Data from a population-based case-control study of chronic lymphocytic leukemia were analyzed to assess the possible etiologic role of chronic antigenic stimulation. The study, conducted in four geographic areas of the United States (the metropolitan areas surrounding Seattle, Washington, Salt Lake City, Utah, Detroit, Michigan, and Atlanta, Georgia) sought to identify all incident cases (n = 430) among residents diagnosed between July 1, 1977 and December 31, 1981. The responses of these cases to questions about possible sources of antigenic stimulation were compared with the responses of controls selected from the populations of these areas. Little difference between cases and controls was present for a history of most forms of viral and bacterial infection and for a history of allergies or allergy treatment. However, a relation was observed with antecedent syphilis infection (odds ratio (OR) = 5.0, 95% confidence interval (Cl) 2.0-12.9). Associations of smaller magnitude were observed with a history of tuberculosis (OR = 1.9, 95% Cl 1.0-3.7) and of urinary tract infection (OR = 1.4, 95% Cl 1.1-1.9). Overall, however, the authors found little evidence of a relation between chronic antigenic stimulation and the occurrence of chronic lymphocytic leukemia. Nonetheless, because the measure of prior antigenic stimulation was restricted to that obtained through interviews and undoubtedly was an insensitive one, these negative results should not be interpreted as ruling out antigenic stimulation as a possible cause of some cases of chronic lymphocytic leukemia.     

Complex analysis of prognostic factors in chronic lymphocytic leukemia

INTRODUCTION: Many new prognostic factors established in recent years in chronic lymphocytic leukemia. May help predicting survival. AIMS: The goal of the present study was to determine the frequency and the correlation of these novel prognostic factors in samples of 419 leukemia patients. METHODS: The mutation status of the IgH gene was evaluated in 160 cases. RESULTS: In 62% of cases, non-mutated IgH gene was found, the heavy chain family usage was different in mutated and non-mutated cases. The CD38 expression demonstrated 78% concordance with the mutation status, the ZAP-70 expression failed to show any correlation. Cytogenetic abnormalities were seen in 76% of cases, the most frequent were del(13q) (57%), trisomy 12 (15%), del(11q) (12%) and del(17p) (6%). 95% of cases with del(11q) harbored non-mutated, 74% of cases with del(13q) as the sole anomaly demonstrated mutated IgH genes. CONCLUSIONS: The parameters analysed are not independent of each other, utilization of them in the clinical routine needs careful planning.     

Familial study of chronic lymphocytic leukemia: aggregation of different malignant processes in families with individuals affected with chronic lymphocytic leukemia

There has been evidence that familial factors play a certain role in some cases of chronic lymphocytic leukemia. It is possible in one or more family members to observe chronic lymphocytic leukemia alone, other malignant disorders or combination of both of them. THE AIM: of our study was to analyze the association of family history of malignances with the onset of chronic lymphocytic leukemia. PATIENTS AND METHODS: We conducted a case-control study through direct inquiry of the families of 126 patients with chronic lymphocytic leukemia. The control group consisted of 124 patients with benignant disorders. For statistic data processing we used Fisher's exact test in 2x2 table and Kaplan-Meier survival analyses. RESULTS: 35.71% of the investigated individuals had first degree relatives with malignant disorders, while in the control group their percentage was 17.7%. Significant correlation between positive family history of malignancy and the onset of chronic lymphocytic leukemia was found (P = 0.0016). The risk of development of chronic lymphocytic leukemia in individuals with family history of malignant disorders was 1.69 times higher than in individuals with negative family history RR = 1.697, 95% C.I. [1.177; 2.448]. There was no significant difference in the general survival between groups with positive and negative family history of malignancy. Stomach cancer was particularly often diagnosed in families with individuals affected with chronic lymphocytic leukemia. Other lymphoproliferative disorders were also registered in 3.9% of the families from the control group. CONCLUSION: Our data show that there is a high risk of getting chronic lymphocytic leukemia in close relatives of affected individuals with malignant disorders. There was no data for greater aggressiveness of chronic lymphocytic leukemia in patients with positive family history of malignancy.     

Evaluating treatment strategies in chronic lymphocytic leukemia: use of quality-adjusted survival analysis.

To assess comparatively, in terms of quality-adjusted survival, three front-line treatments in patients with stage B- or C-chronic lymphocytic leukemia (CLL). To describe better and compare the survival after randomization of patients from the CLL90 trial that randomly compared ChOP (cyclophosphamide, doxorubicin, oncovin, prednisone), CAP (cyclophosphamide, doxorubicin, prednisone) and fludarabine in advanced CLL, we performed a quality-adjusted survival analysis. This consisted of defining four clinical states (toxicity, treatment free of toxicity, no treatment nor symptoms, relapse), then summing up the average times spent in each state weighted by utility coefficients that reflect relative value according to quality of life. The resulting quality-adjusted time without symptoms or toxicity (Q-TWIST) was compared between randomized groups, and sensitivity (threshold) analyses to the choice of utility coefficients was performed. Over 73 months after randomization, the fludarabine group gained a mean of 45 days of toxicity-free survival at CAP, and 61 days over ChOP. The mean TWIST was 27.05 months with CAP, 31.5 months with ChOP and 32.95 months with fludarabine. The threshold analyses showed that, whatever the utility weights, the mean Q-TWIST was always greater with ChOP or fludarabine as compared to CAP. Fludarabine was consistently a better treatment than ChOP, except in the unlikely case of high utility weights attributed to toxicity and low utility weights attributed to treatment. Nevertheless, from a clinical point of view, differences between ChOP and fludarabine were moderate or event slight (mean difference in TWIST of 1.45 months). We conclude that patients with advanced CLL have a moderate benefit in terms of Q-TWIST when treated with fludarabine over ChOP. These two treatments are always superior to CAP.     

Occupation and risk of non-Hodgkin's lymphoma and chronic lymphocytic leukemia

To investigate the association between occupation and the risk of non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL), and to test whether the associations may vary by histological type of NHL, we analyzed data from two population-based, case-control studies of NHL performed in Kansas and Nebraska. A total of 555 incident NHL cases, 56 CLL cases, and 2380 population-based controls were included in the analysis. Information on occupation and other confounding factors was collected through telephone interviews. Study pathologists reviewed slides of tumor tissues in all cases. In men, we found an increased risk of NHL and CLL for those working in agricultural, forestry, and logging industries (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.2 to 2.1). The OR was 1.9 (95% CI, 1.4 to 2.6) for those producing crops. An increased risk was also observed for industries involving metalworking machinery and equipment (OR, 8.4; 95% CI, 1.4 to 50.6), motor vehicles and motor vehicle equipment (OR, 4.2; 95% CI, 1.3 to 13.9), and telephone communications (OR, 3.1; 95% CI, 1.2 to 8.0), and for teachers (OR, 2.5; 95% CI, 1.0 to 6.5), farmers (OR, 2.0; 95% CI, 1.5 to 2.8), and welders and solderers (OR, 2.9; 95% CI, 1.2 to 6.9). The risks for these associations increased by duration of employment and seem to vary by histological type. Work in the printing and publishing industry was also associated with an increased risk of NHL among women. These data suggest that the workers employed in these industries or occupations experienced an increased risk of NHL and CLL, and the risks associated with these industries or occupations may vary by histological type of NHL.     

Long-term results with fludarabine monotherapy in chronic lymphocytic leukemia]

Fludarabine has widely been studied in chronic lymphocytic leukemia (CLL), with impressive remission rates in refractory, relapsed or untreated disease. In our study the clinical response and survival of 9 patients with a mean follow-up time of 28 months after treatment with fludarabine as a single agent for CLL has been evaluated. Seven patients were previously treated. Partial remission was achieved in 8 patients. No complete remission was seen. The cytoreductive activity of fludarabine was excellent in all the 9 patients. The median time to progression was 13.5 months. The median survival time from entering the trial was 27.9 months. Our patients tolerated the fludarabine treatment extremely well. Although fludarabine has been established as the most active single agent in CLL, most patients will have recurrent disease. 7/9 patients relapsed in our study, and they were given further chemotherapy. Grade 4 hematologic toxicity was observed in 2 patients. During the fludarabine treatment the frequency of infections decreased, but in the following 12 months increased again. Three fludarabine-treated patients developed high-grade non-Hodgkin lymphoma. It is concluded that fludarabine is a highly useful agent in CLL.     

Secondary cutaneous infiltration in B-cell chronic lymphocytic leukemia (B-CLL)

Authors report here on a case presenting as B-CLL and complicated with cutaneous infiltration involving the legs and the trunk a year later. Immunohistochemic analysis and the immunoglobulin heavy chain gene rearrangement confirmed cell invasion into the skin identical with the underlying disorder. After failure of conventional chemotherapy, interferon alpha 2b therapy has been started with satisfactory result. Few cases presenting cutaneous infiltration in the course of B-CLL has already been reported in the literature. Secondary cutaneous B-cell lymphoma represents an entity of the poorest prognosis in comparison with primary cutaneous form treated with conventional therapy as well as with lymphomas lacking skin manifestations. Interferon alpha 2b therapy cleans up the skin and yields a favourable survival so it's introduction recommended in this entity. Authors summarise the characteristics of secondary cutaneous B-cell lymphomas on the basis of literature survey. According to authors investigations histidine decarboxylase activity was found to be absent from the lymphocytes infiltrating the skin in contrast to those remaining in the circulation. This seems to be a newly recognised feature of these cells. The changing character of the disease raises the possibility of an altered gene expression pattern of the cells invading the skin. Authors summarise data from the literature concerning suspected molecular mechanism of tissue invasion.     

Familial cancer history and chronic lymphocytic leukemia. A case-control study

In a population-based case-control study carried out in the Baltimore, Maryland metropolitan area, family cancer history for 342 chronic lymphocytic leukemia cases diagnosed in 1969-1982 revealed significantly higher risks of leukemia as well as other hematolymphoproliferative neoplasms and breast cancer among their first-degree relatives compared with reported occurrence of these neoplasms in first-degree relatives of 342 matched cancer controls and 342 matched controls without cancer. Siblings of case subjects also had a significant elevation of kidney cancer compared with siblings of controls. Only one of the affected case families (and no control family) included more than one additional member with leukemia. The results suggest a genetic component for leukemia occurrence in several case families, although the majority of cases of chronic lymphocytic leukemia appeared to be sporadic. The similarity of findings between the two comparisons (cases vs. cancer controls and cases vs. controls without cancer) diminishes the likelihood of recall bias as an explanation for the observed excess risks.     

Acute lymphocytic leukemia in the adolescent: diagnosis, treatment, and outcomes

Leukemia remains the most common cancer in childhood, and while great strides have been made in increasing event-free survival in the past 20 years, patients with high-risk features still pose a challenge for successful disease-free survival. Older children and adolescents are included in that high-risk group. Approximately 80-85% of cases of leukemia in the pediatric population are of the lymphocytic subtype. Overall disease-free survival rates for acute lymphocytic leukemia have increased to 80% for those with standard or low-risk disease and 65-70% for those with high-risk disease. This is a product of both a better understanding of the molecular pathophysiology of ALL and the development of better treatment strategies based on risk. In acute myelogenous leukemia, we have not achieved such success, and disease-free survival rates are in the 30-40% range. This article discusses the diagnosis of leukemia in the adolescent population with attention to pathogenesis, prognostic risk factors, therapy, outcome, and late effects of acute lymphocytic leukemia.     

Anti-mutagenic and pro-apoptotic effects of apigenin on human chronic lymphocytic leukemia cells

Diet can play a vital role in cancer prevention. Nowadays the scientists are looking for food materials which can potentially prevent the cancer occurrence. The purpose of this research is to examine anti-mutagenic and apoptotic effects of apigenin in human lymphoma cells. In present study human chronic lymphocytic leukemia (Eheb cell line) were cultured in RPMI 1640 (Sigma), supplemented with 10% fetal calf serum, penicillin-streptomycin, L-glutamine and incubated at 37 oC for 2 days. In addition cancer cell line was treated by and apigenin and cellular vital capacity was determined by MTT assay. Then effect of apigenin in human lymphoma B cells was examined by flow cytometry techniques. The apigenin was subsequently evaluated in terms of anti-mutagenic properties by a standard reverse mutation assay (Ames test). This was performed with histidine auxotroph strain of Salmonella typhimurium (TA100). Thus, it requires histidine from a foreign supply to ensure its growth. The aforementioned strain gives rise to reverted colonies when exposed to sodium azide as a carcinogen substance. During MTT assay, human chronic lymphocytic leukemia revealed to have a meaningful cell death when compared with controls (P<0.01) Apoptosis was induced suitably after 48 hours by flow cytometry assay. In Ames test apigenin prevented the reverted mutations and the hindrance percent of apigenin was 98.17%.These results have revealed apigenin induced apoptosis in human lymphoma B cells in vitro.     

Prognositc value of CD38 cell surface marker in chronic lymphocytic leukemia

CD38 is expressed on the surface of leukemic cells in a significant percentage of patients with B-cell chronic lymphocytic leukaemia (CLL). From the literature it is known that CD38 expression has prognostic value in CLL, suggesting an association between CD38 expression and the mutational status of IgV genes. Peripheral blood samples from 82 patients with CLL were analyzed by flow cytometry for CD38 expression on CD19+ leukemic cells. CD38 was expressed in 30% or more of leukemic cells in 26 patients (patients with 30% or more B cells coexpressing CD19/CD38 were considered positive). Seven of the 26 patients with high CD38 expression and eight of the 56 patients with low CD38 expression had advanced-stage disease (RAI III-IV). Higher than 4 mg/l levels of beta 2-microglobulin was measured in the serum of nine of 26 CD38+ and seven of 56 CD38- patients. Our analyses showed that the high CD38 expression is associated with other risk factors, identifying an aggressive disease, which require treatment. It will be important to conduct further studies to establish the prognostic value of the high CD38 expression in early-stage disease.     

Cancer mortality of family members of patients with chronic lymphocytic leukemia

European Journal of Epidemiology - A case-control study comprised 130 cases affected by chronic lymphocytic leukemia and the same number of individually matched controls, with accidental injuries...