Clinical Relevance of Deletion 6q
In B-CLL patients with deletion 6q, shorter therapy-free intervals could be demonstrated, reflecting more rapid progression of the disease 18 . By contrast, however, no association of deletion 6q with shorter survival time was proved in the IWCCLL studies 19,21 . An interphase FISH study on 285 B-CLL patients revealed a correlation between deletion 6q and greater tumor mass, measured by leukocyte count median 49.3 x 109 L vs 31.7 x 109 L p 0.036 and lymphadenopathy 95 . The sum of the products...
References Pzd
1. Morrison VA. The infectious complications of chronic lymphocytic leukemia. Semin Oncol 1998 25 98-106. 2. Molica S, Levato D, Levato L. Infections in chronic lymphocytic leukemia. Analysis of incidence as a function of length of follow-up. Haematologica 1993 78 374-377. 3. Tsiodras S, Samonis G, Keating MJ, Kontoyiannis DP. Infection and immunity in chronic lymphocytic leukemia. Mayo Clin Proc 2000 75 1039-1054. 4. Zeya HI, Keku E, Richards F II, Spurr CL. Monocyte and granulocyte defect in...
Genomic Aberrations In Bcll
Two major subjects can be differentiated with respect to the genetic analysis of B-CLL on the one hand, genomic aberrations, which, as acquired changes, may be involved in the initiation and progression of the disease, and, on the other hand, the mutation status of the variable segments of immunoglobulin heavy chain genes VH , which may reflect the cellular origin of B-CLL. Since the early 1980s, chromosome banding analyses of malignant B-cells have been performed using B-cell mitogens 11-18 ....
Interleukin10
IL-10 is a cytokine produced by type 2 helper T-cells, as well as by monocytes and B-lympho-cytes, with strong immunosuppressive effects via inhibition of Thl-type cytokines, including IFN-y and IL-2 60-62 . It has a potent stimulating effect on B-cells and is capable of inducing proliferation and differentiation 63 . The role of IL-10 in the pathogenesis and clinical course of CLL is one of the more controversial within the cytokines potentially connected with this disease Fig. 1 . Leukemic...
Distribution of Genomic Aberrations in the VH Subgroups
Using interphase FISH, genomic aberrations were demonstrable in 246 of 300 82 B-CLL cases with known VH mutation status in our series 10 . The incidences of the individual genomic aberrations in the total group and in dependence on the VH mutation status are shown in Table 2. The incidences of genomic aberrations overall and of trisomy 12 in the two VH subgroups were comparable by contrast, prognostically unfavorable aberrations 11q-, 17p- occurred almost exclusively in the VH unmutated, and...
First Clinical Study Of Immune Gene Therapy For Patients With Cll
Because Ad-CD154-infected CLL B-cells could induce autologous T-cells to generate cytotoxic T-cells against the patient's leukemia cells in vitro, we developed a phase I clinical trial to examine this effect in patients with CLL 78 . Leukemia cells were harvested by pheresis and then infected ex vivo with Ad-CD154 in a good-manufacturing practice facility. The cells were examined for expression of the CD154 and immune costimulatory molecules. After sterility testing, some of the modified...
References Fke
1. Dighiero G, Maloum K, Desablens B, et al. Chlorambucil in indolent chronic lymphocytic leukemia. French Cooperative Group on Chronic Lymphocytic Leukemia. N Engl J Med 1998 338 1506-1514. 2. Chemotherapeutic options in chronic lymphocytic leukemia a meta- analysis of the randomized trials. CLL Trialists' Collaborative Group. J Natl Cancer Inst 1999 91 861-868. 3. Rai KR, Peterson BL, Appelbaum FR, et al. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic...
Clinical Characteristics of Trisomy 12
In a large comparison of individual chromosomal aberrations in banding analysis, B-CLL with trisomy 12 had the shortest survival time 19,21 . However, the negative prognostic relevance of trisomy 12 could not be confirmed in further studies 18,68,69,73 . In interphase FISH studies, trisomy 12 was associated with atypical morphology and immunophenotype in B-CLL 77,79,81 . An effect of trisomy 12 on survival time was found in a series of 83 B-CLL patients 78 . Patients with trisomy 12 had a mean...
STAGING SYSTEMS 31 Rai et al
In 1975, my colleagues and I KRR proposed a system of clinical staging, stratifying CLL patients into five stages 5 Table 1 . The criteria of our staging system were based on Galton and Dameshek's postulate that CLL is characterized by a continuous accumulation of immu-nologically inert lymphocytes thus, with increasing tumor burden, clinical disease would progress from observable enlarged lymphoid masses, with relatively preserved marrow function in early stages, to severely impaired marrow...
AdenoAssociated Viruses
Adeno-associated virus AAV is a human parvovirus that was initially discovered as a contaminant in adenovirus preparations. AAV requires a helper virus, such as adenovirus, to mediate a productive infection 18 . There are six known human virus serotypes, of which AAV-2 is the best studied. No known human disease is associated with AAV. AAV vectors have a number of qualities that make them highly suitable for gene therapy. AAV vectors can effect transgene expression in nondividing cells. Also,...
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....
AntiCD23
CD23 is another potential target of monoclonal antibody therapy like CD20 and CD5, CD23 is expressed on the overwhelming majority of CLL cells. A chimeric macaque-derived anti-CD23 antibody, p6G5G1, has been developed 154 . Although these antibodies have been developed as possible therapies for asthma and other allergic disorders, the ubiquitous expression of CD23 on CLL cells indicates that preclinical studies of these compounds in CLL should be pursued. Recently, in vitro studies of a...
Hairy Cell Leukemia 1
HCL was initially described in 1958 under the term leukemic reticulosis 59 . Because of the unique morphologic features of the leukemic B-cells, with their highly characteristic hairy cytoplasmic projections, the term hairy cell leukemia was finally accepted in 1966 60 . HCL Immunophenotypic Patterns of the Most Common Leukemic B-Cell Chronic Lymphoproliferative Disorders Other Than CLL CD19 CD22 CD20 FMC7 CD5 CD10 CD23 CD79b sIg CD103 CD11c CD43 CD24 HC2 CD25 CD38 - weak - - weak - - weak -...
Immunological Classification
Flow cytometry FCM has played a crucial role in CLL and B-cell identification. We 66 have recently reviewed the technology, its quantitative aspects, the application of FCM to BCLL, and its potential for the detection of early disease in familial CLL. With regard to the identification of the B-cell in CLL, the original work of Aisenberg and Block in 1972 67 and that of Preud'homme and Seligmann also in 1972 68 , are usually cited. In the ensuing years, the work by Geisler et al. in 1991 69 ,...
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...
CELL CYCLE KINETICS OF CLL 21 Techniques to Determine Cell Growth Kinetics
Cell growth kinetics is an important parameter in assessing the potential aggressiveness of tumors and in the prediction of clinical outcome of patients with neoplastic diseases. Slowly proliferating tumors generally have a longer course and a better prognosis than rapidly growing ones, which may require a more aggressive therapy for their control. Different methods have been used over the years to measure the proliferation characteristics of neoplastic cells with the purpose of providing a...
Allotransplantation In Cll
Although allotransplantation adds immunotherapeutic effects to the cytotoxic effects and might thus be curative, its use in patients with CLL has been difficult and contentious, partly because many patients with CLL are older and or have indolent disease, which does not justify aggressive treatment. Even in experienced centers, the treatment-related mortality TRM of allogeneic SCT in patients with CLL has been reported to be as high as 36 6,7,10,11 . A recent update of the EBMT database...
Immunoglobulin Genes
Nearly all patients with CLL have leukemia cells that express low levels of surface monoclonal immunoglobulin, usually both IgM and IgD isotypes. Sixty percent of cases express k, and 40 express X light chain 143 . Rare cases of CLL 7 lack allelic exclusion and therefore may express two different Ig heavy chain genes 144 . The immunoglobulins expressed by CLL cells usually have broad or overlapping antigen specificity, often with a propensity to bind self-antigens such as those on hematopoietic...
Immunophenotypic Differential Diagnosis of CLL
As mentioned above, immunophenotyping has emerged as an essential tool in the diagnosis of CLL 4-6 . A classic phenotype of typical CLL has been defined see Subheading 1.2.2. . When demonstrated, this characteristic phenotype does not present diagnostic difficulties. The caveat lies in the fact that, absent this characteristic pattern, the overlap with other lymphoid proliferations may be quite substantial. Diagnostic dilemmas most often arise when the diagnostician is faced with a case of...
References Hpm
1. Juliusson G, Oscier DG, Fitchett M, et al. Prognostic subgroups in B-cell chronic lymphocytic leukemia defined by specific chromosomal abnormalities. N Engl J Med 1990 323 720-724. 2. Dohner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 2000 343 1910-1916. 3. Chapman RM, Corcoran MM, Gardiner A, Hawthorn LA, Cowell JK, Oscier DG. Frequent homozygous deletions of the D13S25 locus in chromosome region 13q14 defines the...
Alkylating AgentBased 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...
194. Catovsky D Et Al. Semin Hematol 36 148 1999
1. Harris N, Jaffe E, Diebold J, et al. World Health Organization Classification of Neoplastic Diseases of the Hematopoietic and Lymphoid Tissues Report of the Clinical Advisory Committee Meeting Airlie House, Virginia, November 1997. J Clin Oncol 1999 17 3835-3849. 2. Harris NL, Jaffe ES, Stein H, et al. A revised european-american classification of lymphoid neoplasms a proposal from the international lymphoma study group. Blood 1994 84 1361-1392. 3. Di Giuseppe JA, Borowitz MJ. Clinical...
Lymphocyte Morphology 1
Numerous morphological variants of CLL have been described, although their prognostic significance is controversial. Lymphocyte size, number of prolymphocytes, and the presence of cleaved and or lymphoplasmocytic cells have all been associated with poor prognosis 41-43 . Melo et al. 41 showed that CLL cases with an absolute prolymphocyte count of 15 x 109 L or less have standard-prognostic risk, whereas the survival outlook for the cases with prolymphocytes more than 15 x 109 L was as bad as...
Guy B Faguet md
1. 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...
Immunophenotypic Characteristics of Normal Mature BCells
Many studies have been reported, in which the phenotypic features of normal, mature PB 25,28,31 , and or BM B-cells 32-36 have been analyzed. These studies systematically show that virtually all PB and a substantial part of BM B-cells are mature sIg lymphocytes. Most of these correspond to naive sIgM sIgD 80-90 and, to a lesser extent 10-15 , immature sIgM B-lymphocytes 37-43 . In contrast, sIgM , sIgG , or sIgA memory B-cells only represent a minor fraction of the total sIg lymphocytes lt 10...
References Cot
1. Montserrat E. Classical and new prognostic factors in chronic lymphocytic leukemia where to now Hematol J 20002 3 7-9. 2. Caligaris-Cappio F, Hamblin TJ. B-cell chronic lymphocytic leukemia a bird of a different feather. J Clin Oncol 1999 17 399-408. 3. Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia. Blood 1975 46 219-234. 4. Binet JL, Auquier A, Dighiero G, Chastang C, Piguet H, Goasguen J, et al. A new prognostic...
Symeonidis A And Immune Function Parameters
1. 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,...
Cll Research Consortium And Cll List Serve
Two developments in the recent history of CLL bear further mention. The first is the evolution of the CLL Research Consortium CRC under the direction of Thomas Kipps. As Cheson 175 notes in the preface of his new book, Chronic Lymphoid Leukemias, the CRC is a highly interactive collaboration among some of the foremost basic and clinical researchers in the United States and this new integrated research model is likely to result in major progress. At the time of this writing, the CRC had...
Changing Natural History Of Cll
Molica and Levato 173 analyzed 518 CLL patients diagnosed between 1970 and 1998 by forming three groups. Group I consisted of 75 patients, group II consisted of 149 patients, and group III consisted of 293 patients diagnosed with CLL in the time periods 1970-1979, 1980-1989, and 1990-1998, respectively. As expected, there was no difference between age and sex in these three time periods. The median survival values were 38, 54, and 93 mo for the time periods 1970-1979, 1980-1989, and 1990-1998,...
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...
Deletion 17p13 and Mutation of the p53 Gene in BCLL
Involvement of p53 in band 17p13 in B-CLL was found in molecular genetic studies. Because of its role in nearly all kinds of tumors, p53 was examined as a candidate gene in B-CLL. By means of single-strand conformational polymorphism analyses and direct DNA sequencing, p53 mutations could be proved, with a prevalence between 10 and 15 in B-CLL 94,97-100 . 17p13 deletions were found in 4-9 in B-CLL 9,101 . To examine the relationship of 17p13 deletion and p53 inactivation by mutation in the...
Atypical CLL
Atypical CLL aCLL is an ill-defined term applied to cases that mimic CLL but do not have the classical morphological or immunophenotypic features. Uniformly accepted criteria for aCLL do not exist. Historically the term aCLL has been used primarily for lymphocytosis with morphologically atypical cells lymphoplasmacytoid features, irregular clefted nuclei 13 . Numerous studies have attempted to correlate the morphological definition of aCLL with immunophenotype 7,14,15 , but these studies have...
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 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...
Contributors
Julia Almeida, md, phd Service of Cytometry, Department of Medicine and Cancer Research Center, University of Salamanca, Salamanca, Spain Gerald P. Bodey, md Department of Infectious Diseases, The University of Texas M.D. Anderson Cancer Center, Houston, TX Francesc Bosch, md Department of Hematology, Hospital Clinic, University of Barcelona, Barcelona, Spain Raul C. Braylan, md Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville,...
First Era 18451924 Recognition of CLL As a Distinct Entity
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,...
Trisomy 12
The first nonrandom chromosome abnormality discovered in CLL was trisomy 12 12 7 , which is found in about one-third of those who show clonal abnormalities, i.e., about 17 of all patients Fig. 1 . Using FISH analysis, a somewhat higher percentage is achieved 8 about 24 of over 600 CLL patients studied showed evidence of trisomy 12 for review, see ref. 9 , whereas 16 had 12 in the German FISH study 10 . Half of all patients with trisomy 12 have no additional abnormality, and although 12 may...
Immunophenotypic Characteristics of Leukemic BCells in CLPD Other Than CLL
Among the B-CLPD, CLL is the most common disease, its differential diagnosis from other leukemic B-cell CLPD being a constant challenge. Typically, CLL exhibits a highly characteristic phenotype, different from that found in other B-CLPD 44-48 , including weak expression of CD22, CD20 FMC7, CD79b and sIg, together with a relatively high reactivity for the CD5 and CD23 antigens for more details, see Chapter 7 . In the last decade, scoring systems based on the above mentioned markers 46,48 have...