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PubMed2003

Advances in the therapy of chronic lymphocytic leukemia.

Chronic lymphocytic leukemia therapy has changed dramatically over the past decade, with recent studies supporting the use of fludarabine as the initial therapy for symptomatic disease. New findings relative to the use of fludarabine and complications arising from this therapy are reviewed. Exciting combination approaches using monoclonal antibodies such as rituximab or Campath-1H in combination with fludarabine offer the opportunity to improve the complete response rate further in chronic lymphocytic leukemia. Furthermore, the field of experimental therapeutics for chronic lymphocytic leukemia was advanced by the description of a new mouse model of human chronic lymphocytic leukemia and identification of several disrupted signal transduction pathways in this disease. The description of therapies that target AKT, protein kinase C, phosphodiesterase 4, mammalian target of rapamycin, histone deacetylase, and methyltransferase offer the opportunity to utilize molecularly targeted therapy for this disease. Such targeted approaches offer hope that we might be on the threshold to changing the natural history of chronic lymphocytic leukemia.

Antineoplastic Agents↗

PubMed2005

Multicentric glial brain tumors of a varying degree of differentiation in patient with chronic lymphocytic leukemia.

Chronic lymphocytic leukemia is associated with an increased incidence of secondary neoplasms. Primary brain tumors are rarely seen; however, an increased risk relative to the general population has been observed in male patients with chronic lymphocytic leukemia. A case report of a 62-year-old man with progressive chronic lymphocytic leukemia and pronounced neurologic symptoms is presented. Richter's syndrome or brain infiltration with leukemia cells was clinically suspected and suggested by computed tomography findings. Progression of the neurologic symptoms rapidly continued and the patient died. Neuropathologic examination revealed multicentric glial tumors of a varying degree of differentiation located throughout the brain and cerebellum.

Brain Neoplasms↗

PubMed2006

Narrative review: initial management of newly diagnosed, early-stage chronic lymphocytic leukemia.

Chronic lymphocytic leukemia is one of the most common malignant lymphoid diseases in the western world and is frequently diagnosed by internists. There have been clinically significant changes in method of diagnosis, prognostic tools, supportive care, and treatment over the past 2 decades. Most patients with chronic lymphocytic leukemia now have Rai stage 0 or I disease at diagnosis. Patients with early-stage disease are a heterogeneous group: Approximately 30% to 50% will have accelerated disease progression, and the remainder may live for decades and possibly never require therapy. Recent insights into the biological characteristics of leukemic B cells have led to the discovery of new prognostic tools (immunoglobulin variable-region heavy chain gene mutation status, cytogenetic abnormalities assessed by fluorescent in situ hybridization, and Z-chain-associated protein kinase-70 protein expression) that can identify patients with early-stage disease who are at high risk for early disease progression. These tools allow physicians to individualize counseling, follow-up, and management on the basis of disease risk. In addition, new treatments developed over the past 2 decades (purine nucleoside analogues, monoclonal antibodies, and combination chemoimmunotherapy regimens) have dramatically improved response rates and appear to prolong survival. In this review, the authors discuss the current work-up of lymphocytosis and highlight how to use recently identified prognostic tools to stratify risk in patients with newly diagnosed, early-stage chronic lymphocytic leukemia. Recommendations for patient counseling, follow-up, supportive care, and initial treatment are presented for each risk category.

Biomarkers↗

PubMed1993

Coronary artery bypass grafting in patients with chronic lymphocytic leukemia.

Chronic lymphocytic leukemia is a disease of the elderly. It tends to have a variable clinical course. Because of the patients' immunologically dysfunctional state, there has been reluctance to perform open cardiac procedures because of concern about early postoperative sepsis leading to death. To assess the risk of coronary artery bypass grafting in elderly patients, the records of 26 patients (mean age, 69.6 +/- 4.9 years) with chronic lymphocytic leukemia who underwent coronary artery bypass grafting between January 1975 and July 1990 were retrospectively reviewed. Nineteen underwent isolated coronary artery bypass grafting, and 7 had combined procedures. The operative mortality rate was 7.7%. Postoperative infections developed in 6 patients (23.1%): pneumonia in 3 and sternal osteomyelitis, acute parotiditis, and bacteremia in 1 each. One of these 6 patients died of acute Serratia pneumonitis. Twenty-four patients (92.3%) were discharged from the hospital an average of 10.6 +/- 7.7 days postoperatively. Patients with chronic lymphocytic leukemia can undergo coronary artery bypass grafting with acceptable mortality but with increased risk of postoperative infection.

Aged↗

PubMedDate not supplied

Chromosome 6 abnormalities associated with prolymphocytic acceleration in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is most characteristically associated with the cytogenetic abnormalities +12, 13q14, and 14q32. Recently abnormalities of chromosome 6 have been reported in patients with mantle zone lymphoma, CLL mixed type, and a CLL variant with larger prolymphocytoid cells in the peripheral blood. The purpose of this study was to review the cases of CLL karyotyped at the University of Texas M. D. Anderson Cancer Center (UTMDACC) and to determine the number and type of chromosome 6 abnormalities. Precisely 830 cases of CLL with karyotypes were reviewed. Among these, 257/830 (31 percent) had abnormal karyotypes, 56/257 (22 percent) had an abnormality of 6, 18/56 (32 percent) had translocations involving 6 and, in most instances, a different chromosome was involved, 37/56 (66 percent) had deletion 6 or loss of at least a portion of 6q, and 9/56 (16 percent) had an abnormality of 6p. The losses of 6q were in the q13 to q25 regions. Of these, 13/56 (23.2 percent) of patients with 6q abnormalities had > or = 10 percent prolymphocytes (PL) in the bone marrow (BM) and/or peripheral blood (PB), 10/56 (17.9 percent) had > or = 10 percent PL in the bone marrow, 8/56 (14.3 percent) had > or = 10 percent PL in the peripheral blood, and 5/56 (9 percent) had > or = 10 percent PL in both (see table I). The 201 CLL patients with chromosome abnormalities other than 6 contained 23 with excess PL (11.9 percent). A subset of karyotypic changes of 6 associated with increased PL is recognizable and may be useful in aiding in clinical diagnosis and therapy.

Adult↗

PubMed2000

Sister chromatid exchange frequency in B-cells stimulated by TPA in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is characterised by the clonal proliferation and accumulation of neoplastic B-lymphocytes. The median age of the patients is 65 years, and more men than women are affected. The overwhelming majority of CLLs are of B-cell origin. Chromosomal aberrations have been detected in more than 50% of the B-cells obtained from peripheral blood samples after appropriate stimulation with polyclonal B-cell mitogens. The analysis of sister chromatid exchange is a cytogenetic technique used to show DNA damage due to an exchange of DNA fragments between sister chromatids. In this study, lymphocytes from 22 patients with CLL-B (7 female, 15 male; mean age 64.09 +/- 7.56 years) were stimulated by a B-cell mitogen (TPA) and BrdU added at the 24 h of the culture. Metaphase chromosomes were stained with a fluorescence plus Giemsa technique after a standard harvest procedure. The frequency of sister chromatid exchange was found to be increased significantly P =.02) in patients with CLL-B (8.24 +/- 1.36 per metaphase) compared to controls (7.25 +/- 1.42 per metaphase). We conclude that the increased frequency of sister chromatid exchange in chronic lymphocytic leukemia after stimulation with a B-cell mitogen (TPA) may reflect DNA instability and defective DNA repair in these patients.

Aged↗

PubMed1993

Mechanism of autoimmune hemolytic anemia in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is a malignant clonal expansion of CD5+B lymphocytes. The CD5+B lymphocytes have been postulated to produce autoantibodies. CLL patients may demonstrate features of autoimmunity including autoimmune hemolytic anemia. However, the origin of the autoantibodies causing the hemolysis is not clear. The present studies were performed to determine whether these autoantibodies are the products of the neoplastic B-CLL clones. Immunoglobulins (Ig) were eluted from washed red blood cells (RBC) obtained from two CLL patients at the time they had autoimmune (DAT-direct antiglobulin test-positive) hemolytic anemia. The light chain phenotypes of these eluted autoantibodies were determined and found to be monotypic with exact correlation to the light chain expressed on the surface of the B-CLL clones. Elutions from RBC of DAT negative patients or normal volunteers failed to demonstrate measurable amounts of Ig. In contrast, Ig eluted from RBC obtained from SLE patients with DAT positive hemolytic anemia found to be polyclonal autoantibodies exhibiting both light chain types. Furthermore, CD5+B lymphocytes obtained from the same two CLL patients (DAT+) produce, in vitro understimulation with phorbal myristate acetate (PMA), monoclonal antibodies which react and bind to RBC. Thus these studies provide direct evidence demonstrating that the antibodies causing the autoimmune hemolytic anemia in our two CLL patients are the products of the B-CLL neoplastic clones.

Aged↗

PubMed2006

Clinical implications of ZAP-70 expressionin chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is a disease with an extremely heterogeneous prognosis. Because of this and because of the lack of a truly effective therapy, treatment of CLL must be adapted to the individual risk of each patient. Over the last quarter of century, prognosis of patients with CLL has been based on clinical features. In the last few years a number of biological prognostic parameters have been identified. Among them, the expression of ZAP-70 in neoplastic B lymphocytes is increasingly being recognized as of paramount importance to predict outcome. Patients with a low percentage (<20%) of ZAP-70 positive neoplastic B lymphocytes have a much better prognosis that those with a higher proportion (>20%) of ZAP-70 positive neoplastic B lymphocytes.

Biomarkers, Tumor↗

PubMed2005

Advances in the diagnosis and treatment of chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is a low-grade B-lineage lymphoid malignancy, which is often not treated until patients become symptomatic or develop signs of rapid progression. Even in this setting, treatment is non-curative and is directed at reducing the symptoms from an increasing disease burden. Newer treatment regimens incorporating purine nucleoside analogs have increased the rate of successful remission induction in CLL patients. Recent combination chemoimmunotherapy regimens have produced frequent complete molecular remissions, and early evidence suggests this may result in an improved long-term survival. Allogeneic hematopoietic cell transplantation is the only curative therapy for CLL but is infrequently used due to the older age of most patients, although reduced intensity conditioning regimens have reduced the toxicity of allogeneic transplantation. This review will summarize recent advances in the management of CLL, including prognostic factors, combination chemotherapy including nucleoside analogs and monoclonal antibodies, and reduced intensity allogeneic transplant conditioning regimens.

Age Factors↗

PubMed2002

HSV amplicon-mediated delivery of LIGHT enhances the antigen-presenting capacity of chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is a B lymphocyte malignancy that remains a largely incurable disease. CLL B cells possess the ability to process and present tumor antigens but lack expression of costimulatory molecules, rendering them inefficient effectors of T-cell activation. We previously demonstrated that helper virus-free preparations of herpes simplex virus (HSV) amplicon vectors encoding CD40L efficiently transduce CLL B cells and render them capable of eliciting specific anti-tumor T-cell responses. LIGHT (TNFSF14), a member of the tumor necrosis factor (TNF) superfamily, efficiently activates both T cells and antigen-presenting cells (APCs). We employed an HSV amplicon vector expressing human LIGHT (hf-HSV-LIGHT) to transduce CLL B cells and compared the immunomodulatory function and T-cell activation induced by hf-HSV-LIGHT transduction to that observed with a CD40L-expressing HSV amplicon (hf-HSV-CD40L). hf-HSV-LIGHT transduction induced expression of endogenous B7.1, B7.2, and ICAM.1 on CLL cells, albeit to a lesser degree than that observed in response to transduction with hf-HSV-CD40L. hf-HSV-LIGHT enhanced the antigen-presenting capacity of CLL B cells, as measured by induction of T-cell proliferation in an allogeneic mixed lymphocyte tumor reaction. Finally, hf-HSV-LIGHT-transduced CLL B cells successfully stimulated the outgrowth of autologous cytotoxic T-lymphocytes in vitro. In aggregate, these data suggest that hf-HSV-LIGHT transduction may be useful for induction of immune responses to CLL and other B-cell lymphoid malignancies.

Antigen Presentation↗

PubMed2001

New aspects on the pathogenesis, diagnostic procedures, and therapeutic management of chronic lymphocytic leukemia.

Chronic lymphocytic leukemia of the B-cell type (B-CLL) is the most frequently occurring leukemia in the Western hemisphere. Until 10 years ago, the basic medical approach to this disease was expectative and palliative. Chemotherapy with alkylating agents such as chlorambucil used to be the main therapeutic option, and only patients at advanced stages of B-CLL were treated. With the advent of new treatments such as purine analogs, high-dose therapy followed by hematopoietic progenitor support, monoclonal antibodies, and further immunotherapies, this paradigm is about to change. By using these combinations, younger patients with active disease are now treated with the goal of a long-lasting remission. More sophisticated techniques allow characterization of some of the underlying molecular genetic aberrations and (together with new serum parameters) more accurate prediction of individual prognoses than with the clinical staging systems. With the help of these developments, patients with B-CLL will be managed according to their individual risk with a watch-and-wait strategy in patients with the most indolent form of the disease, conventional chemotherapy with alkylating agents and/or purine analogs in patients at intermediate risk, and aggressive high-dose chemotherapy (followed by immunotherapy) in patients with the most aggressive form of the disease.

Antineoplastic Agents↗

PubMed2006

[Therapy-resistant cutaneous infiltrates in chronic lymphocytic leukemia].

Chronic lymphocytic leukemia (CLL) is a low-grade B-cell non-Hodgkin lymphoma. Skin involvement is observed in up to 25% of patients. A 70-year-old men with presented with prominent erythematous facial infiltrates. After the diagnosis of CLL was established, he showed a good hematologic response to the monoclonal antibody rituximab, but the skin infiltrates were therapy-resistant.

Aged↗

PubMed2001

Autoimmunity in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is associated with the immune-mediated disorders autoimmune hemolytic anemia and immune thrombocytopenia. Initial treatment with corticosteroids is often successful in controlling these manifestations, but splenectomy should be considered if a rapid and complete response is not obtained. For those with persistent anemia or thrombocytopenia after splenectomy, treatment directed against the underlying CLL may be considered, although the use of purine analogues has also precipitated autoimmune hemolytic anemia. Pure red cell aplasia has been reported in CLL, and usually responds to immunosuppressive therapy.

Adrenal Cortex Hormones↗

PubMed2003

Immunologic monitoring in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is characterized by progressive defects in humoral- and cell-mediated immunity. These defects are manifested as a propensity to develop infections with encapsulated bacteria, and less frequently, with gram-negative enterics. In addition, reactivation of viruses such as herpesvirus is not uncommon. Treatment of the disease further exacerbates immunosuppression by depleting immune effectors and broadening the spectrum of potentially offending pathogens. Risk of infection can potentially be reduced by administration of intravenous immunoglobulin and use of prophylactic antibiotics for individuals who are at high risk. Current work focuses on development of cellular and cytokine therapy to facilitate immune reconstitution in patients with CLL, thereby reducing morbidity and mortality and potentially improving survival.

Anti-Bacterial Agents↗

PubMed2004

Advances in the understanding of biology and prognosis in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) has a heterogeneous clinical course and outcome. Recent advances in the diagnosis and molecular characterization of CLL permit improved prediction of disease prognosis, which could result in better management. We review the biology and diagnosis of CLL and the role of analysis of immunoglobulin heavy-chain variable region mutation status, molecular cytogenetics (interphase fluorescence in situ hybridization), and the expression of CD38 and ZAP-70 in the evaluation and management of patients with CLL.

ADP-ribosyl Cyclase 1↗

PubMed1989

Studies on drug resistance in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia is a neoplastic disease in which drug resistance invariably occurs. We have studied the uptake and interaction with molecular targets of two drugs, chlorambucil and adriamycin, in CLL lymphocytes and CHO cell lines. Resistance does not appear related to uptake for either drug. Exposure to CLB causes DNA cross-links in the sensitive but not in the resistant cell line. The GSH content of B-CLL lymphocytes is depleted after a 20-hr incubation. An inability to maintain its GSH content may contribute to this cell's vulnerability to CLB. The resistance of CLL lymphocytes to ADR may be related to the undetectable levels of its target enzyme DNA topoisomerase II. Future approaches may involve study of novel anthracyclines, DNA topoisomerase I inhibitors and the development of in vitro predictive tests.

Animals↗

PubMed1991

New modalities of therapy in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is the most cormmon form of leukemia in adults in Western countries. After several decades of relative inactivity, important progress has been made in our understanding of the biology and immunology of this disorder. In addition, exciting therapeutic results have been achieved with several new, unique, and effective therapies. The most interesting chemotherapeutic agent is fludarabine, a purine analogue which achieves complete remission in 13% of relapsed or refractory patients and in greater than 30% of previously untreated patients; the overall response rates of 60% and 75%, respectively, are superior to reports with other single agents or combination regimens. Related drugs with promising activity are 2'-deoxycoformycin, and 2-chlorodeoxyadenosine. Preliminary studies are evaluating allogeneic and autologous bone marrow transplantation as potentially curative therapy. Biological approaches exploiting new insights into the immunology of CLL include the use of lymphoid growth factors. Interpretation of results of CLL studies has suffered from variability in eligibility and response criteria, especially definitions of complete remission. Recently published standardized guidelines for CLL clinical trials will facilitate comparisons among therapies and help identify those which are most promising. Continued progress will require integration of laboratory science and clinical investigation.

Antineoplastic Agents↗

PubMed2005

The value of fluorescence in situ hybridization in the diagnosis and prognosis of chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia. Prognosis is related to clinical staging and cytogenetic findings. Conventional cytogenetic analysis of CLL reveals abnormalities in approximately one third of patients. Fluorescence in situ hybridization (FISH) is analytically more sensitive than conventional cytogenetics for specific chromosomal abnormalities. To evaluate the usefulness of FISH in CLL, a study of 100 CLL patients comparing conventional cytogenetics and a commercially available multiprobe FISH kit was undertaken. One hundred consecutive CLL patients (67 males, 33 females) were studied. The male-female patient ratio was approximately 2.0 to 1. Twenty-eight percent (28/98) of patients had abnormal karyotypes by conventional cytogenetics (one patient had no specimen for conventional cytogenetics and one had an unanalyzable karyotype), and of those 19/100 (19%) had more than one chromosomal abnormality. Sixty-four percent (64/100) of the patients were positive for at least one abnormality by the FISH probes used. The following abnormalities were noted with FISH: 11q22 ATM, 23/100 (23%); trisomy 12, 11/100 (11%); 13q14.3, 40/100 (40%); 13q34.3, 4/100 (4%); 17p13.1, 12/100 (12%). Conventional karyotypes revealed 2 patients with abnormalities of chromosome 6 (which FISH did not address); 11 with abnormalities of 11 or 11q; 6 with trisomy 12; and 4 with abnormalities of 17. Aberrations of 11q and 17p are reported to have a poor prognosis in CLL. FISH can identify abnormalities missed with conventional cytogenetics and is helpful in diagnosis, prognosis, and evaluation of therapy for CLL. Additional chromosomal changes are identified with conventional cytogenetics that are not addressed by the multiprobe FISH kit.

Female↗