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

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...

References

Cronkite ER, et al. Clinical staging of chronic lymphocytic leukemia. Blood 1975 46 219-234. 2. Binet, J-L, Leporier M, Dighiero G, et al. A clinical staging system for chronic lymphocytic leukemia. Cancer 1977 40 855-864. 3. Ashby W. Determination of the length of life of transfused blood corpuscles in man. J Exp Med 1919 29 267-281. 4. Berlin R. Red cell survival studies in normal and leukaemic subjects latent hemolytic syndrome in leukaemia with splenomegaly nature of...

Myeloablative Regimens

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...

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...

First Era 18451924 Recognition of CLL As a Distinct Entity

Subleukemic Leukemia

The reports of Rai 2 , Galton 3 , Gunz 4 , Hamblin 5 , Piller 6 , and Videbaek 7 are useful in reconstructing this early historical period. Gunz 4 attributes the first accurate description of a case of leukemia to Dr. Velpeau, who in 1827 8 described a 63-yr-old florist and lemonade seller Monsieur Vernis, who had abandoned himself to the abuse of spirituous liquor and women 8 . Hamblin 5 shed further light on this subject by noting that in this profession and in his former job as a florist,...