Clinical Profile

The largest series (39 cases) addressing RS emerged from a retrospective analysis of the M.D. Anderson Cancer Center computerized database of1374 CLL cases diagnosed between 1972 and 1992 (21). The authors included in their definition of RS cases of immunoblastic non-Hodgkin's lymphomas. The median interval between the initial diagnosis and the onset of RS was approximately 4 yr. Salient presenting features included male predominance (62 ), progressive lym-phadenopathy (64 ), systemic symptoms...

Immunizations

Live attenuated virus vaccines are contraindicated in patients with CLL. Vaccinations have not been successful in many patients with CLL because poor antibody responses correlate with hypo GG and advanced disease, those groups of patients who most need protection. Immunization with the pneumococcal polysaccharide vaccine has also produced disappointing results because patients can be infected with serotypes of S. pneumoniae that are not incorporated in the vaccine (81). Attempts at immunizing...

Overview Of The Immune Deficits In Bcll

To set the stage for a description of the immune deficits in B-CLL, we provide a brief, relevant review of the normal immune system. An intact immune system will include both humoral and cellular components. The humoral component is comprised of circulating antibodies (i.e., IgA, IgG, IgM) that have reactivity to specific antigens and are important in the host defense against infectious microbes. A polyclonal population of B-lymphocytes residing primarily in the lymph nodes, spleen, and...

Second Primary Cancers and Richters Syndrome

The association of a second primary malignancy with CLL is well known. Epidemiological studies were carried out on large series of CLL patients enrolled in tumor registries participating in the National Cancer Institute Surveillance, Epidemiology, and End Results program. CLL patients were found to have a significantly increased risk, constant over time, of developing second cancers, with an overall observed expected ratio of 1.2 (46,47). In our series, we recorded an overall incidence of 8.3...

History

The pioneering work of Winifred Ashby (3) established a technique to determine the life span of red blood cells. Transfusion of compatible but serologically distinct red cells allowed them to be tracked by differential agglutination. In nine patients with CLL, Berlin (4) used this technique to demonstrate a shortened red cell survival, even though only one had a reticulocytosis. This was probably the first demonstration that the anemia of CLL might be hemolytic in nature. According to Ehrlich...

DNA Vaccination

DNA plasmid expression vectors can be used for gene transfer. Generally, the transgene is placed downstream of a strong promoter, such as the heterologous cytomegalovirus promoter enhancer region, and upstream of a polyadenylation signal sequence, to allow for appropriate RNA processing and transport from the nucleus. Transfection of cells with such plasmid DNA can effect high-level expression of the transgene, provided the RNA has appropriate Kozak sequences for initiating effective...

Fungal Infections

The association between cryptococcosis and CLL has been recognized for many years. In a study from 1956 to 1972, the estimated occurrence of cryptococcosis among CLL patients was 24 episodes 1000 admissions, the highest among all cancers (57). The most common form of infection is meningitis, but some patients have fulminant pneumonia, fungemia, disseminated infection, or skin and subcutaneous lesions. P. carinii (now considered to be a fungus) occasionally caused pneumonia in CLL patients prior...

References

National Institutes of Health, Office of Biotechnology Activities. Clinical Trials in Human Gene Transfer-Recom-binant and Gene Transfer, 2002, 2. Dunbar CE, Cottler-Fox M, O'Shaughnessy JA, et al. Retrovirally marked CD34-enriched peripheral blood and bone marrow cells contribute to long-term engraftment after autologous transplantation. Blood 1995 85 3048-3057. 3. Verhasselt B, De Smedt M, Verhelst R, Naessens E, Plum J. Retrovirally transduced CD34++ human cord blood cells generate T cells...

Clinical Stage

The clinical staging systems independently developed by Rai et al. (3) and Binet et al. (4) in the early 1980s, which are based on easily obtainable biological and clinical parameters, are extremely useful for assessing prognosis in patients with CLL. These staging systems not only facilitate the treatment of patients according to individual prognosis, but also make it possible to conduct and compare trials based on the risk of disease. Rai's stages were further classified as low (Rai stage 0),...

CD40 Ligand CD154

As noted above, CLL cells express high levels of the MHC class I and II molecules required for antigen presentation but lack expression of important costimulatory molecules for T-cell activation. In addition, leukemic B-cells can downmodulate T-cell surface molecules that are required to induce expression of such molecules on antigen-presenting cells (73). As a consequence, the leukemic B-cell has a tolerogenic influence on T-cells, even on those isolated from normal allogeneic donors. For any...

Conclusions

Anemia, thrombocytopenia, and neutropenia are important features of CLL and usually herald a poor prognosis since their usual cause is bone marrow suppression by infiltrating lymphocytes. Although neither the Binet nor the Rai scoring system specifies it, cytopenias with other causes do not necessarily have such dire consequences. The two most important other causes are autoim-munity and hypersplenism. Autoimmune hemolytic anemia and thrombocytopenia are relatively common complications of CLL,...

Binet

After publication of the Rai staging system and the general realization that patients with anemia and thrombocytopenia defined high-risk CLL, the question arose as how to define the nonanemic, nonthrombocytopenic patients who constitute 75 of CLL patients. It was felt that the large variability in this group was not well explained. The French CLL group, under the leadership of Binet, proposed in 1977, revised in 1981, and presented in 1981 a new classification based on three prognostic groups...

Ethical And Emotional Aspects

Physicians should recall that a diagnosis of CLL can have a devastating effect on the pateint's quality of life, independently of age, clinical stage, and the therapy requirements. A leukemia diagnosis at a relatively young age may cause worries about the future course of the disease, the need for therapy, the potential complications, the ability to face professional and familial engagements, and, most of all, the risk of premature death. This is particularly so in light of the progressive...

Preface

Chronic lymphocytic leukemia (CLL) is usually described as the most common leukemia in the United States, Canada, and Western Europe, whereas it is rare in Japan (1) and infrequent in other Asian societies (2). In the United States, CLL remained the most common leukemia between 1973 and 1991 with a mean age- and population-adjusted incidence of 4.4 100,000, whereas it was 3.2 100,000 for acute myelocytic leukemia (AML), the second most frequent leukemia during that time. However, the incidence...

Herpes Simplex Virus

Herpesviruses are promising vehicles for transferring genes into cells. Among this virus family, herpes simplex virus type 1 (HSV-1) is the most extensively studied for potential use in human gene therapy. Its genome is comprised of 152 kb of linear dsDNA containing at least 84 contiguous genes of which only 50 are essential for virus replication. For this reason, HSV-1 vectors can carry very large transgene inserts (approximately 30 kb), potentially allowing HSV-1 vectors to contain multiple...

Second Malignancies

CLL has long been known to be associated with an increased risk for second malignancies (15,17,48). A recent report, based on 16,367 patients with CLL registered in the SEER program of the National Cancer Institute between 1973 and 1996, represents the largest study to date addressing this issue (48). The mean patient follow-up was 5.2 yr, representing 84,667 person-years of follow-up data. Follow-up end points were the dates of diagnosis of a second cancer, death, or the study cutoff (December...

Prognostic Relevance of Genomic Aberrations and VH Mutation Status

To examine the individual prognostic value of genomic aberrations, the VH mutation status, and other clinical and laboratory features, a multivariate analysis was made of the survival time by means of a Cox regression (10). The VH mutation status, 17p deletion, 11q deletion, age, leukocyte count and lactate dehydrogenase levels were identified as independent prognostic factors in this analysis. When the VH mutation status, and 11q and 17p aberrations were included, the clinical stage of disease...

Management

At present the management of RS is unsatisfactory. Most successfully treated patients have received conventional chemotherapy appropriate for the treatment of DLCL, such as cyclophosphamide, Adriamycin, vincristine, and prednisone (CHOP) or the equivalent. Anecdotal reports of treatment results are skewed toward success, and only three series have been published from which to assess treatment success rates and patient outcomes. In the first one, published in 1981 (19), of the 19 cases of RS...

Rai

Rai (2) notes that the roots of the Rai staging system for CLL can be traced back to the work of Galton presented in a Burroughs Wellcome Lecture in 1965 and subsequently published by the Canadian Medical Association in 1966 (27). Galton presented data on 88 CLL patients followed for 15 yr classifying them into four groups Fig. 29. Kanti Rai (left) and Jacque Louis Binet (right). This digital image was taken with permission at the IWCLL March 2002 meeting in San Diego outside the poster display...

New Therapies 41 Anti Idiotypic Vaccines

Since all major chemotherapeutic treatments in CLL induce good responses but are unable to effect a cure, one of the major questions that needs to be answered is whether there is a place for immunotherapeutic approaches like anti-idiotypic vaccines. Since each B-cell undergoes a unique, characteristic, rearrangement and since malignant B-cell hemopathies are characterized by clonal expansion of a clone displaying a unique rearrangement, idiotype constitutes a privileged tumor antigen. One of...

Deficiencies in Humoral Immunity

Humoral immunity has been studied extensively in CLL patients, ever since decreased immu-noglobulin concentrations, associated with increased risk of infection, were discovered in these patients. Complement deficiencies have also been identified in CLL patients and may also increase susceptibility to infectious complications. Deficiencies in complement components have been reported to enhance the risk of acquiring infection in CLL patients with hypogamma-globulinemia. The most prominent and...

Viral Infections

Herpes zoster is the most common severe viral infection associated with CLL (48). Less than 10 of patients experience cutaneous dissemination, and only a few develop visceral dissemination. About 20 suffer from postherpetic neuralgia, and a few develop polyradiculopathy or meningoencephalitis (55,60). Herpes simplex infections of the circumoral area and oropharynx are more common than herpes zoster but are usually not as severe. A chronic indolent form of orofacial herpes simplex infection has...

Purine Analog Based Combination Chemotherapy

Fludarabine has produced high overall response rates when used as initial therapy of CLL and has shown greater activity than chlorambucil. However, most responses are partial, with only a minority of patients achieving a complete response. This has led to the use of fludarabine in combination with other agents to improve efficacy. 3.4.1. Fludarabine and Doxorubicin or Mitoxantrone The combination of fludarabine and doxorubicin with or without prednisone was investigated in 30 patients with...

Pathogenesis of Autoimmunity in CLL

Autoantibodies Secreted by the Tumor 2.4.1.1. Warm Antibodies. The most obvious explanation for autoimmune disease in CLL would be that the autoantibodies were the product of the tumor. I am constantly surprised by the many eminent immunologists who believe this to be so. The CLL cell does secrete immunoglobulin. Stevenson et al. (59) demonstrated secretion of small amounts of idiotypic IgM by CLL cells using a highly sensitive radioimmunoassay. The immunoglobulin secreted by CLL cells...

Defects in Phagocytic Cell

Impairment in monocyte and neutrophil function have been detected in CLL patients, but these seem to have no important consequences. Neutropenia from the disease or its therapy is of overriding importance in predisposing to infection. In the absence of neutrophils, many of the defects in humoral immunity have little significance, since their function is to facilitate phagocytosis. 2.1.1. Defects in Phagocytic Cell Function Defects in both granulocytes and monocytes have been detected in CLL...

Second Era 19241973 Initial Clinical Investigations Into CLL 221 Major Contributors

In the first era, CLL was separated from leukemia, and its separation from lymphomas was initiated. The second era, between 1924 and 1973, was marked by significant contributions to our understanding of the natural history of the disease, the diagnosis, and (as poor as they were) the various treatments for this disease. It should be noted that chronic leukemia was often the subject of a given report and that both forms (myelogenous and lymphocytic) were studied. Just before...

Deletions of Bands 11q22q23 With ATM As the Candidate Gene

In a study using FISH, a critical region was identified around the neural cell adhesion molecule (NCAM) gene in band 11q23.1 in 15 hematological tumors (51). In another study, the extent of 11q deletions among 40 B-CLL cases was determined using a FISH probe set of overlapping yeast artificial chromosome (YAC) clones spanning bands 11q14-q24 (52,53). All aberrations affected a minimal consensus region of 2-3 Mb in size in bands 11q22.3-q23.1. In the minimal deleted region, the ataxia...

Malignant BCells CD5CD19

Leagel Dising Thinking

The malignant B-CLL B-cell has been well characterized by surface immunophenotype. This latter feature gives us a potential clue as to its origin and functional capacity. In addition to the common B-cell antigens CD19, CD20, and CD21, these malignant cells have been demonstrated to express CD5 and variable amounts of surface-bound immunoglobulin (sIg). In normal hosts, CD5+ B-cells occur at the edge of germinal centers in the mantle zone of lymphoid follicles (14) and are found in cord blood....

Treatment of Autoimmunity in CLL

Treatment of the autoimmune complications of CLL is not guided by good data. In general, the same treatments have been applied as when the disease occurs spontaneously. However, some treatments are less appropriate, and there is also the question of whether and how to treat the CLL itself. The possibility that the immunosuppression caused by the disease or its treatment has triggered the autoimmunity has to be weighed against the prospect that treating the disease will eliminate the...

Myeloablative Regimens

Natuurkunde Druk

Although encouraging results have been observed after high-dose chemotherapy alone followed by autologous SCT, in the vast majority of published data on SCT for CLL, the Fig. 1. Autologous transplants in CLL survival effect of interval diagnosis-transplant adjusted for source of stem cell . Data from EBMT database. Fig. 1. Autologous transplants in CLL survival effect of interval diagnosis-transplant adjusted for source of stem cell . Data from EBMT database. Fig. 2. CLL. MRC pilot study D....

Treatment of Advanced CLL

Early treatment is prescribed for most patients with advanced forms of CLL, including 1 classical chemotherapeutic regimens, 2 purine analogs, 3 monoclonal antibodies, 4 autologous or allogeneic bone marrow transplantation, and 5 other treatments. 2.3.1. Classical Chemotherapeutic Regimens CB alone or associated with corticosteroids using a daily or intermittent schedule has been traditionally used to treat CLL. Ten randomized trials 14 , involving 2035 patients mostly with Binet stage B or C...

Alkylating Agent Based Combination Chemotherapy

Various alkylating agent-based drug combinations have been used in CLL, mainly in patients with advanced-stage disease. Frequently used combination regimens include COP or CVP and CHOP. The results of the largest alkylator-based combination studies are shown in Table 2. The French Cooperative Group compared the COP CVP regimen with chlorambucil in patients with Binet stage B disease and found similar times to disease progression and overall survival 11 . Large Randomized Studies of Alkylating...

Introduction of Monoclonal Antibodies Into Clinical Practice

Several problems have limited the successful introduction of monoclonal antibody therapies into clinical practice. These obstacles include 1 identification of tumor-specific antigens, 2 antigen surface density, 3 antibody production, 4 internalization of antigen or antigen-antibody complex, 5 antigenicity of the antibody resulting in host sensitization, 6 infusion toxicity from host humoral response, and 7 delivery of antibody to bulky tumors. An ideal antigen should be expressed at relatively...

Guy B Faguet md

Tamura K, Sawada H, Izumi Y, et al. Kyushu Hematology Organization for Treatment K-HOT Study Group. Chronic lymphocytic leukemia CLL is rare, but the proportion of T-CLL is high in Japan. Eur J Haematol 2001 67 152-157, 2. Boggs DR, Chen SC, Zhang ZN, Zhang A. Chronic lymphocytic leukemia in China. Am J Hematol 1987 25 349-354. 3. SEER Cancer Statistics Review, 1975-2000, 4. American Cancer Society Facts amp Figures for Professionals, 5. Jemal A, Murray T, Samuels A, Ghaffor A, Ward E, Thun...

Symeonidis A And Immune Function Parameters

Manusow D, Weinerman BH, Hisada M, et al. Subsequent neoplasia in chronic lymphocytic leukemia. JAMA 1975 232 267-269. 2. Hisada M, Biggar RJ, Greene MH, Fraumeni JF, Jr., Travis LB. Solid tumors after chronic lymphocytic leukemia. Blood 2001 98 1979-1981. 3. Rozman C, Montserrat E, Vinolas N. Serum immunoglobulins in B-CLL natural history and prognostic significance. Cancer 1988 61 279-283. 4. Rozman C, Montserrat E. Chronic lymphocytic leukemia. N Engl J Med 1995 333 1052-1057. 5. Shaw R,...

Chronic Lymphocytic Leukemia

Indolent B-cell lymphoproliferative disorders such as CLL are ideal targets for monoclonal antibody therapies. Although CLL responds to cytotoxic chemotherapy, only a proportion of patients achieve complete remission CR , and treatment is palliative. For many years, therapy for CLL consisted of oral alkylating agents such as chlorambucil and combination chemo-therapeutic regimens, such as cyclophosphamide, vincristine, and prednisone CVP 8-10 . In recent years the purine analog fludarabine and...

Binet et al

Binet et al. 11 recognized the need for a staging system with fewer stages than in the Rai schema and proposed another CLL staging system originally in 1977 and revised in 1981 Table 2 . Binet's system divided patients into three stages. Stage C included patients with anemia hemoglobin lt 10 g dL or thrombocytopenia platelet count lt 100,000 L or both. All the remaining non-stage C patients were subdivided on the basis of whether they had three or more areas of lymphoid enlargement stage B , or...

Treatment of Smoldering CLL

The French group proposed a classification that segregated stage A into A' and A'' 11,15,23 . Criteria for A' were hemoglobin level higher than 120 g L and lymphocyte count lower than 30,000 mm3 and for A'' they were hemoglobin under 120 g L and or lymphocyte count higher than 30,000 mm3. The survival of these two groups was clearly different, with a 5-yr survival of 82 in the A' group and 62 in the A'' group. Interestingly, the survival of the A' group was very close to that of a sex- and...

IgVH Mutations

Cll Igvh Zap70

CLL has long been considered a homogeneous disease of CD5 B-cells, which are pregerminal cells that have not been exposed to antigenic stimulation. In 1999, two different groups reported an important breakthrough in CLL 29,88 . These groups clearly showed that the mutational status of the somatic mutations of the variable region of the immunoglobulin genes IgVH correlates with different disease subsets. Thus, those patients with unmutated IgVH genes have a poorer prognosis than those displaying...

Treatment of Indolent CLL

It is not clear whether early therapy benefits patients with indolent CLL. This form of the disease includes patients with a median age of 64 yr displaying a survival greater than 10 yr. In indolent CLL, Chlorambucil CB given daily or intermittently, alone or combined with corticosteroids, is the most commonly used drug. It often provides a period of relief from any symptoms, even in advanced disease. However, there has been much uncertainty as to whether such chemotherapy should be started...