Chronic Lymphocytic Leukemia

In recent years, important progress has been made in understanding the pathophysiology, and in improving the diagnosis and treatment, of chronic lymphocytic leukemia (CLL). The characteristics of the B lymphocyte clone are now better defined and disclose great heterogeneity in the mechanisms involved in the development of lymphocytic tumours: both proliferative and apoptotic abnormalities are involved, and a single or recurrent triggering feature is not recognized. Accordingly, the course of the disease is highly variable. Although treatment abstention or deferral for a long period is convenient for many patients, others who present with, or progress to, active CLL will ultimately die from the disease. Clinico-hematological staging systems have greatly clarified the prognostic factors of interest to clinicians, but they remain imprecise in a large category of patients. Recently, other characteristics such as cytogenetics, immunoglobulin gene sequencing, and serum levels of soluble CD23, thymidine kinase and lymphocyte p27 have been recognized as powerful prognostic factors and should now be evaluated in prospective clinical trials. It remains unclear whether any of the available treatments, when indicated, could offer long-term survival benefits for patients. Chlorambucil, purine analogues (including fludarabine or cladribine) and anthracyclinecontaining regimens [i.e. cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP)] have been evaluated in large prospective controlled trials, which demonstrated some differences according to response rates, but which failed to disclose any survival advantage, irrespective of the first-line drug treatment allocated. These disappointing results emphasize the need to develop other treatment strategies. Progress could be anticipated in two main ways. Firstly, new, effective and well tolerated treatments with greater specificity are now, or should soon be, available in the clinic: monoclonal antibodies, apoptotic inducers and vaccine systems. Preliminary data suggest that the best use of such treatments is as adjuvant therapy for patients with residual disease, thus complementing the results of chemotherapy. Secondly, intensive treatments with stem-cell rescue (autologous or allogenic) have provided evidence that clonal extinction is an obtainable goal in selected patients, some of whom remain free of any clonal molecular signal for many years. Whether such patients could be considered cured is still unresolved, and this point deserves longer follow-up. Controlled trials are currently exploring this important question. Finally, optimum therapy also aims to improve quality of life, and clinical trials dealing with this important issue, especially in elderly patients, are needed.     

Refractory Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is a common malignancy often managed by the practicing oncologist rather than at a tertiary referral center. Since no standard treatment has been shown to be curative, patients are frequently observed without treatment for many years. In the past, first-line therapy with an alkylating agent, particularly chlorambucil, was standard when treatment became necessary. Because of its superior activity in achieving remission and extending the time to relapse and disease progression compared with alkylating agents, the purine nucleoside analog fludarabine is now commonly used as first-line treatment. Historically, salvage treatment with combination chemotherapy included an alkylating agent, anthracycline, vinca alkyloid, and/or corticosteroid. Currently, salvage regimens often incorporate a purine nucleoside analog and an alkylating agent. Two monoclonal antibodies, rituximab and alemtuzumab, have become available and have made further advances in both first-line and salvage treatment of patients with CLL. In this article we review the agents and regimens that have been studied as salvage treatment of CLL. With the development of purine nucleoside analogs and monoclonal antibodies, incremental progress has been made in the therapy of previously treated patients with CLL. Newer strategies will aim to further improve the complete remission rate, which may have a positive impact on survival.     

Immune Reconstitution in Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is associated with a profound immune defect, which results in increased susceptibility to recurrent infections as well as a failure to mount effective antitumor immune responses. Current chemotherapy-based regimens are not curative and often worsen this immune suppression, so their usefulness is limited, particularly in the frail and elderly. This article reviews the immune defect in CLL and discusses strategies aimed at repairing or circumventing this defect. In particular, it focuses on recent developments in the areas of CD40 ligand (CD40L/CD154) gene therapy, immunomodulatory agents such as lenalidomide, and adoptive transfer of T cells bearing chimeric antigen receptors.     

TNF Receptors in Chronic Lymphocytic Leukemia

Two transmembrane receptors for tumor necrosis factor (TNF) with different molecular weight, 55 kD (p55) and 75 kD (p75), have been identified. In addition, the extracellular part of both receptors are shedded by proteolytic cleavage and exist as soluble receptors which bind to TNF in plasma and other biological fluids. Normal B cells produce TNF and express TNF receptors (R), mainly p75, upon stimulation. TNF costimulates DNA synthesis via the p75 receptor in normal B cells. The B cells from patients with chronic lymphocytic leukemia (CLL) produce TNF and have the capacity to express both receptor types. Also in malignant B cells the p75 receptor is dominant. TNF induce DNA synthesis in CLL cells via both receptors. CLL patients have elevated serum levels of soluble (s) TNFR and this is more pronounced in advanced disease. In conclusion, there is considerable support for TNF as an autocrine growth factor in CLL. However, the net effect of TNF is determined by the quan titative relationship between TNFR on the cell surface, TNF in plasma and sTNFR in plasma, and the affinities between TNF-p55 and TNF-p75. Due to increasing serum levels of sTNFR the significance of TNF as a growth factor is probably less important in advanced disease.     

Prognostic Factors for Chronic Lymphocytic Leukemia

As novel strategies for treatment and prognostication of chronic lymphocytic leukemia (CLL) evolve, the traditional Rai and Binet systems can now be updated with more modern prognostic markers. This is a review of the latest articles which combine studies from major CLL centers to summarize major prognostic factors for patients diagnosed with CLL. The prognostic information can be categorized into three categories: genetic abnormalities which include 17p, 11q, and immunoglobulin heavy chain variable (IGHV) abnormalities; biochemical abnormalities and cell surface markers which include serum thymidine kinase, β-2-microglobulin, CD49d, CD38, and ZAP-70 levels; and patient characteristics which include sex, age, and performance status.     

Richter Syndrome in Chronic Lymphocytic Leukemia

The term Richter syndrome (RS) indicates the transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma. RS is a rare complication with an aggressive clinical course, bearing an unfavorable prognosis. In the majority of cases, CLL transforms into RS as diffuse large B cell lymphoma (DLBCL), and a clonal relation between the two processes can be found. However, clonally unrelated RS can occur and transformations to other histologies beside DLBCL have been described. Recent data have shed some light on genetic characteristics that can influence and drive the transformation from CLL to RS. This molecular information has not been translated yet into significant treatment advances, and currently the therapy regimens for RS continue to rely on intensive chemotherapy combinations followed by stem cell transplant in suitable candidates. Based on the rapid pace of discoveries in the field of hematological malignancies and on the recent revolution in the therapeutic landscape for CLL and B cell lymphomas, new therapeutic options for RS might be available in the upcoming years.     

New Agents in Chronic Lymphocytic Leukemia

Despite advances in treatment, chronic lymphocytic leukemia (CLL) remains incurable with standard therapies. Novel therapeutic agents are needed, particularly for patients with high-risk cytogenetic abnormalities such as del(17p13). The past year has seen several advances in this field. The immunomodulatory drug lenalidomide and the cyclin-dependent kinase inhibitor flavopiridol demonstrated clinical activity in fludarabine-refractory CLL patients with high-risk cytogenetic features and bulky lymphadenopathy, but they were associated with toxicities such as tumor flare and tumor lysis. Second-generation monoclonal anti-CD20 antibodies in clinical trials include ofatumumab, which demonstrated activity in fludarabine-refractory patients with bulky lymphadenopathy. Oblimersen, obatoclax, and ABT-263 target the antiapoptotic protein Bcl-2. Investigational agents with novel therapeutic targets include the anti-CD37 small modular immunopharmaceutical TRU-016, the oral spleen tyrosine kinase (Syk) inhibitor fostamatinib, and the oral phosphatidylinositol-3-kinase (PI3K) inhibitor CAL-101; all of these have all shown preliminary evidence of clinical activity. The development of novel agents for treating CLL remains an active, exciting area of research.     

Chylous Effusion Complicating Chronic Lymphocytic Leukemia

We present a case of chylous effusion (CE) occurring in a patient with chronic lymphocytic leukemia (CLL), an observation which has rarely been reported. Therefore, CLL should be added to the differential diagnosis of nontraumatic chylothorax. CE in CLL can be successfully managed by irradiation of the mediastinum.     

Chronic Lymphocytic Leukemia and Prognostic Factors

Background: The clinical course of individual chronic lymphocytic leukemia (CLL) is highly variable andclinical staging systems do not help us to predict if and at what rate there will be disease progression in anindividual patient diagnosed with early stage disease. Recently, several important observations related to otherprognostic factors including lymphocyte doubling time (LDT), ß2-microglobulin (ß2-MG), and percent of smudgecell in peripheral blood smears, cytogenetic and molecular analysis have been made. The aim of this study wasto evaluate a range of prognostic factors in our CLL patients. Design and methods: Seventy patients with CLLwere enrolled. Prognostic factors of disease including Binet staging, LDT, ß2-MG, ESR, LDH, percent of smudgecell in peripheral blood smear, absolute lymphocyte count, and conventional cytogenetic (CC) analysis wereevaluated at diagnosis, and the patients were followed up to determine their outcome. We compared factors witheach other and with Binet staging and prognosis. Results: Enrolled patients aged 37–85 years at diagnosis orduring follow up. There was no relationship between serum LDH level (P=0.3), ESR (P=0.11), percent of smudgecells in peripheral blood smear (P=0.94), and absolute lymphocyte count (P=0.18) with the stage of disease andprognosis, but the β2 macroglobulin level (p<0.0001), LDT (p<0.001) had direct and significant relation withstaging and outcome. In 19% of patients cytogenetic alteration were seen. Conclusion: The detection of cytogeneticalteration only using the CC method is not sufficient and we need to use FISH, but because FISH study is anexpensive method not available in all areas, instead we believe that β2 MG can be applied in its place as a goodprognostic factor for CLL at diagnosis and during follow up. We suggest to add it to Binet staging for prognosticsubgrouping of CLL.     

Chlorambucil in Chronic Lymphocytic Leukemia: Mechanism of Action

Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries but the clinical presentation and rate of disease progression are highly variable. When treatment is required the most commonly used therapy is the nitrogen mustard alkylating agent, chlorambucil (CLB), with or without prednisone. Although CLB has been used in the treatment of CLL for forty years the exact mechanism of action of this agent in CLL is still unclear. Studies in proliferating model tumor systems have demonstrated that CLB can bind to a variety of cellular structures such as membranes, RNA, proteins and DNA; however, DNA crosslinking appears to be most important for antitumor activity in these systems. In addition, a number of different mechanisms can contribute to CLB resistance in these tumor models including increased drug metabolism, DNA repair and CLB detoxification resulting from elevated levels of glutathione (GSH) and glutathione S-transferase (GST) activity. However, unlike tumor models in vitro, CLL cells are generally not proliferating and studies in CLL cells have raised questions about the hypothesis that DNA crosslinking is the major mechanism of antitumor action for CLB in this disease. CLB induces apoptosis in CLL cells and this appears to correlate with the clinical effects of this agent. Thus, alkylation of cellular targets other than DNA, which can also induce apoptosis, may contribute to the activity of CLB. Alterations in genes such as p53, mdm-2, bcl-2 and bax which control entry into apoptosis may cause drug resistance. Loss of wild-type p53 by mutation or deletion occurs in 10 to 15% of CLL patients and appears to correlate strongly with poor clinical response to CLB. The induction of apoptosis by CLB is paralleled by an increase in P53 and Mdm-2 but this increase is not observed in patients with p53 mutations indicating that with high drug concentrations CLB can produce cell death through P53 independent pathways. The level of Mdm-2 mRNA in the CLL cells is not a useful predictor of drug sensitivity. In addition, although Bax and Bcl-2 are important regulators of apoptosis and the levels of these proteins are elevated in CLL cells compared with normal B cells, the levels of Bax and Bcl-2, ortheBax:Bcl-2 ratio, are not important determinants of drug sensitivity in this leukemia. Finally, whereas CLB and nucleoside analogs may produce cell death in CLL by a P53 dependent pathway other agents, such as dexamethasone or vincristine, may act through P53-independent pathways.     

Infections in Chronic Lymphocytic Leukemia: Risk Factors, and Impact on Survival, and Treatment

Patients with chronic lymphocytic leukemia (CLL) are at an increasing risk of infectious morbidity and mortality. Infections are generally due to bacteria and influenced by the degree of hypogammaglobulinemia; although, in more advanced stages of disease they may also be contributed by neutropenia due to bone marrow infiltration and/or cytotoxic therapy. Furthermore, defect in cell-mediated immunity appears to be a predisposing factor to infections in patients treated with newer purine analogues. Controversies surrounding the pathogenesis of infectious complications in CLL raise several questions on their management. Patients with advanced disease who receive cytotoxic therapy might qualify for antibacterial prophylaxis. Intravenous immunoglobulin (IVIG), although of scientific interest, may be of little relevance at the present time. The new growth factors should be tested in well-designed prospective studies.     

Survival and Clinical Aspects for Patients with Chronic Lymphocytic Leukemia in Kermanshah,Iran

Chronic lymphocytic leukemia (CLL)is the most common leukemia in adults in Western countries but is relatively rare in Asia. Immune hemolytic anemia, Evan’s syndrome, lymphadenopathy, organomegaly and B symptoms are the main complaints of patients in CLL. The present retrospective analysis evaluated a group of 109 patients with CLL over a 9-year period, studying correlations between sex, age and overall survival. The patients were hospitalized in the Clinic of Hematology and Oncology, Kermanshah, Iran, between 2006 and 2014. Data analysis for sex and age was performed using IBM SPSS19 and overall survival was plotted by Kaplan- Meier plot, Log-rank test in Graph Pad prism 5 Software for five-year periods. The mean age of diagnosis for CLL patients was 60.73 years, 59.6% male. Survival rate patients was 64% and mean overall survival was 38.5 months. In the Rai system, fourteen patients (12.8%) had stage ΙΙΙ and twenty eight patients (25.7%) had stage IV. Most frequent clinical features in patients with CLL were lymphadenopathy (38.7%) and organomegaly (34%), respectively. There is not relationship between sex and age in patients but overall survival rate in females was higher than in males. In Asian countries, CLL is more in male and in age above 60 years. Complaints about lymphadenopathy and virus infection are prevalent.