• Successful treatment of refractory disseminated Mycobacterium avium complex infection with the addition of linezolid and mefloquine.

• Bendamustine in the treatment of chronic lymphocytic leukemia: results and future perspectives.

• Do B-cell chronic lymphocytic leukemia patients with Ig VH3-21 genes constitute a new subset of chronic lymphocytic leukemia?

• CXCR4 expression is associated with survival in familial chronic lymphocytic leukemia, but CD38 expression is not.

• Phase II trial of subcutaneous anti-CD52 monoclonal antibody alemtuzumab (Campath-1H) as first-line treatment for patients with B-cell chronic

• CD38 expression distinguishes two groups of B-cell chronic lymphocytic leukemias with different responses to anti-IgM antibodies and propensity

• Apoptosis or plasma cell differentiation of CD38-positive B-chronic lymphocytic leukemia cells induced by cross-linking of surface IgM or

• Survival of leukemic B cells promoted by engagement of the antigen receptor.

• Nucleolated variant of mantle cell lymphoma with leukemic manifestations mimicking prolymphocytic leukemia.

• Analysis of resveratrol-induced apoptosis in human B-cell chronic leukaemia.

• B-CLL: is the enigma of disease heterogeneity about to be revealed?

• Multivariate analysis of prognostic factors in CLL: clinical stage, IGVH gene mutational status, and loss or mutation of the p53 gene are

• The clinical significance of tumor necrosis factor-alpha plasma level in patients having chronic lymphocytic leukemia.

• Relationship between p53 dysfunction, CD38 expression, and IgV(H) mutation in chronic lymphocytic leukemia.

• V(H) mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia.

• Clonal relation in a case of CLL, ALCL, and Hodgkin composite lymphoma.

• Chronic lymphocytic leukaemia--the haematologic basis for diagnosis and treatment.

• What are we learning from familial chronic lymphocytic leukemia?

• Telomere length and heavy-chain mutation status in familial chronic lymphocytic leukemia.

• Regulation of CD23 isoforms on B-chronic lymphocytic leukemia.

• Quantitative analysis of Cyclin D1 and CD23 expression in mantle cell lymphoma and B-chronic lymphocytic leukemia.

• From chronic lymphocytic leukemia to Hodgkin's disease: a case of prognostically favorable transformation.

• Intracellular T cell cytokines in patients with B cell chronic lymphocytic leukaemia (B-CLL).

• DNA-dependent protein kinase in leukaemia cells and correlation with drug sensitivity.

• Efficient gene transfer of CD40 ligand into primary B-CLL cells using recombinant adeno-associated virus (rAAV) vectors.

• A high-resolution allelotype of B-cell chronic lymphocytic leukemia (B-CLL).

• Protection of CLL B cells by a follicular dendritic cell line is dependent on induction of Mcl-1.

• Modulation of the activity of calcium-activated neutral proteases (calpains) in chronic lymphocytic leukemia (B-CLL) cells.

• Spontaneous and drug-induced apoptosis is mediated by conformational changes of Bax and Bak in B-cell chronic lymphocytic leukemia.

• Angiogenesis in B-cell chronic lymphocytic leukemia: methods of study, clinical significance and prognostic implications.

• Morphologically typical and atypical B-cell chronic lymphocytic leukemias display a different pattern of surface antigenic density.

• Richter's syndrome following cladribine therapy for chronic lymphocytic leukemia first manifested as pathologic fracture of the femur.

• Prognostic value of plasma interleukin-6 levels in patients with chronic lymphocytic leukemia.

• [Fludarabine as primary therapeutic drug in chronic lymphatic leukemia]

• Primary leukemia cells resistant to alpha-interferon in vitro are defective in the activation of the DNA-binding factor

• Anthropometric characteristics, physical activity, and risk of non-Hodgkin's lymphoma subtypes and B-cell chronic lymphocytic leukemia:

• Clinical tumor cell distribution pattern is a prognostically relevant parameter in patients with B-cell chronic lymphocytic leukemia.

• CD69 expression in B-cell chronic lymphocytic leukemia: a new prognostic marker ?

• CD5-negative chronic lymphocytic leukemia or monoclonal B-lymphocytosis of undetermined significance?

• Diffuse plane normolipaemic xanthomatosis in a patient with chronic lymphatic leukaemia and monoclonal gammopathy.

• Cladribine decreases the level of angiogenic factors in patients with chronic lymphocytic leukemia.

• Surface membrane antigen expression changes induced in vitro by exogenous growth factors in chronic lymphocytic leukemia cells.

• DNA profiling and cytogenetic analysis of cell line WSU-CLL reveal cross-contamination with cell line REH (pre B-ALL).

• Mechanisms of resistance to nucleoside analogue chemotherapy in mantle cell lymphoma: a molecular case study.

• Genetic imbalances in progressed B-cell chronic lymphocytic leukemia and transformed large-cell lymphoma (Richter's syndrome).

• Immunoglobulin genes in chronic lymphocytic leukemia.

• CD40-ligand (CD154) gene therapy for chronic lymphocytic leukemia.

• Interleukin-15 as a potential costimulatory cytokine in CD154 gene therapy of chronic lymphocytic leukemia.

• Fludarabine-related pulmonary toxicity: a distinct clinical entity in chronic lymphoproliferative syndromes.

• Cell cycle regulatory proteins and apoptosis in B-cell chronic lymphocytic leukemia.

1
UI - 12099753
AU - Nannini EC; Keating M; Binstock P; Samonis G; Kontoyiannis DP
TI - Successful treatment of refractory disseminated Mycobacterium avium complex infection with the addition of linezolid and mefloquine.
SO - J Infect 2002 Apr;44(3):201-3
AD - Department of Infectious Diseases, The University of Texas, M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Execpt in patients with AIDS, disseminated MAC infection has been rare. We describe a patient with chronic lymphatic leukemia who developed disseminated cutaneous MAC lesions refractory to conventional antimycrobial therapy. The lesions responded to the addition of compounds that were recently discovered to have anti-MAC activity (linezolid, moxifloxacin) as well as GM-CSF. Copyright 2002 The British Infection Society.

2
UI - 12170428
AU - Aivado M; Schulte K; Henze L; Burger J; Finke J; Haas R
TI - Bendamustine in the treatment of chronic lymphocytic leukemia: results and future perspectives.
SO - Semin Oncol 2002 Aug;29(4 Suppl 13):19-22
AD - Department of Hematology, Oncology, and Clinical Immunology, Heinrich Heine-University, Moorenstrasse 5, 40225 Dusseldorf, Germany.
Chronic lymphocytic leukemia (CLL) occurs predominantly in elderly patients. The treatment options for patients with CLL have increased with the introduction of purine analogs, and promising results have been reported with fludarabine and cladribine when these agents are used in newly diagnosed and relapsed disease. Monoclonal antibodies such as alemtuzumab and rituximab are also clinically active in CLL. The use of purine analogs in combination with monoclonal antibodies may provide additional treatment options and this strategy is being studied in patients with relapsed and refractory CLL. Bendamustine is an alkylating agent with properties of a purine analog and is a promising agent in the treatment of CLL. Bendamustine reduces the number of circulating B lymphocytes by over 90% and shows only partial cross-resistance with other alkylating agents, making it an ideal candidate for the treatment of CLL and for use in combination with other alkylating agents. Bendamustine monotherapy can be given to patients whose disease is refractory to standard therapies. The results of a trial using bendamustine as a salvage treatment in patients with relapsed or refractory, heavily pretreated CLL are discussed here. Bendamustine 100 mg/m(2) (days 1 and 2) was found to be an effective treatment for older patients with advanced CLL, with 14 of 21 patients responding. Complete hematologic remission was achieved in six of 21 patients and a further eight patients achieved a partial hematologic remission. The main toxicities were hematologic; nonhematologic side effects were mild and uncommon. Copyright 2002, Elsevier Science (USA). All rights reserved.

3
UI - 12130479
AU - Nollet F; Cauwelier B; Billiet J; Selleslag D; Van Hoof A; Louwagie A;
TI - Criel A Do B-cell chronic lymphocytic leukemia patients with Ig VH3-21 genes constitute a new subset of chronic lymphocytic leukemia?
SO - Blood 2002 Aug 1;100(3):1097-8; discussion 1098-9

4
UI - 12150154
AU - Ishibe N; Albitar M; Jilani IB; Goldin LR; Marti GE; Caporaso NE
TI - CXCR4 expression is associated with survival in familial chronic lymphocytic leukemia, but CD38 expression is not.
SO - Blood 2002 Aug 1;100(3):1100-1

5
UI - 12130484
AU - Lundin J; Kimby E; Bjorkholm M; Broliden PA; Celsing F; Hjalmar V;
TI - Mollgard L; Rebello P; Hale G; Waldmann H; Mellstedt H; Osterborg A Phase II trial of subcutaneous anti-CD52 monoclonal antibody alemtuzumab (Campath-1H) as first-line treatment for patients with B-cell chronic lymphocytic leukemia (B-CLL).
SO - Blood 2002 Aug 1;100(3):768-73
AD - Department of Hematology, Karolinska Hospital, and Huddinge University Hospital, Stockholm, Sweden.
This phase II study determined the efficacy and safety of alemtuzumab, a humanized anti-CD52 monoclonal antibody, delivered subcutaneously as first-line therapy, over a prolonged treatment period of 18 weeks in 41 patients with symptomatic B-cell chronic lymphocytic leukemia (B-CLL). Injections were administered subcutaneously 3 times per week, from week 2 to 3 onward. An overall response rate (OR) of 87% (95% CI, 76%-98%; complete remission [CR], 19%; partial remission [PR], 68%) was achieved in 38 evaluable patients (81% of intent-to-treat population). CLL cells were cleared from blood in 95% patients in a median time of 21 days. CR or nodular PR in the bone marrow was achieved in 66% of the patients and most patients achieved this after 18 weeks of treatment. An 87% OR (29% CR) was achieved in the lymph nodes. The median time to treatment failure has not yet been reached (18+ months; range, 8-44+ months). Transient injection site skin reactions were seen in 90% of patients. Rigor, rash, nausea, dyspnea, and hypotension were rare or absent. Transient grade IV neutropenia developed in 21% of the patients. Infections were rare, but 10% patients developed cytomegalovirus (CMV) reactivation. These patients rapidly responded to intravenous ganciclovir. One patient, allergic to cotrimoxazole prophylaxis, developed Pneumocystis carinii pneumonia. Alemtuzumab is highly effective as first-line treatment in patients with B-CLL. Prolonged treatment is important for maximal bone marrow response. Subcutaneous administration induced very few "first-dose" flulike symptoms and may reduce health care costs in comparison with the intravenous infusions.

6
UI - 8695855
AU - Zupo S; Isnardi L; Megna M; Massara R; Malavasi F; Dono M; Cosulich E;
TI - Ferrarini M CD38 expression distinguishes two groups of B-cell chronic lymphocytic leukemias with different responses to anti-IgM antibodies and propensity to apoptosis.
SO - Blood 1996 Aug 15;88(4):1365-74
AD - Servizio di Immunologia Clinica, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
The expression of CD38 by B cells chronic lymphocytic leukemia (B-CLL) was studied in 20 untreated patients. The cells expressed abundant CD38 (relative fluorescence intensity range, 6 to 15) in 6 cases (group I patients), whereas CD38 expression was low to absent (relative fluorescence intensity range, 0 to 3) in the remaining cases (group II patients). Exposure of the cells from group I patients to goat antihuman mu chain antibodies (Ga mu-ab) resulted in the elevation of intracellular free Ca2+ concentration([Ca2+]i) followed by apoptosis. In contrast, exposure of group II cells to Ga mu-ab was not followed by increased levels of [Ca2+]i, programmed cell death or cell proliferation. No differences in the expression of surface IgM were noted in the two groups of B-CLL cells. Normal peripheral blood B cells, which expressed low to absent CD38, were capable of mobilizing [Ca2+]i and of proliferating after exposure to Ga mu-ab. The collected data suggest that, although group I B-CLL cells were able to transduce the signals delivered by IgM crosslinking, this pathway was severely impaired in group II B-CLL cells. However, unlike that observed in normal circulating B cells, stimulation of group I cells with Ga mu-ab resulted in apoptosis rather than proliferation. CD38 did not appear to be directly involved in [Ca2+]i mobilization induced by Ga mu-ab in group I B-CLL cells because their exposure to anti-CD38 monoclonal antibodies failed to cause [Ca2+]i mobilization or to block the [Ca2+]i response induced by Ga mu-ab. These data indicate that CD38 expression identified a particular subset of B-CLL cells with defined functional properties, including the propensity to undergo apoptosis.

7
UI - 10666191
AU - Zupo S; Massara R; Dono M; Rossi E; Malavasi F; Cosulich ME; Ferrarini M
TI - Apoptosis or plasma cell differentiation of CD38-positive B-chronic lymphocytic leukemia cells induced by cross-linking of surface IgM or IgD.
SO - Blood 2000 Feb 15;95(4):1199-206
AD - Servizio di Immunologia Clinica, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy. szupo@hp380.ist.unige.it
Previously, we demonstrated that B-chronic lymphocytic leukemia (B-CLL) cells could be divided into 2 groups depending on the expression of CD38 by the malignant cells. The 2 groups differed in their signal-transducing capacities initiated by cross-linking of surface IgM; only in CD38-positive cells was an efficient signal delivered, invariably resulting in cell apoptosis. In this study, we investigated the effect of surface IgD cross-linking in 10 patients with CD38-positive B-CLL. Exposure of the malignant cells to goat antihuman delta-chain antibodies (Gadelta-ab) caused [Ca(++)]i mobilization and tyrosine kinase phosphorylation in a manner not different from that observed after goat antihuman mu-chain antibody (Gamu-ab) treatment in vitro. However, Gadelta-ab-treated cells failed to undergo apoptosis and instead displayed prolonged survival in culture and differentiated into plasma cells when rIL2 was concomitantly present. Cross-linking of surface IgD failed to induce proliferation of the malignant cells in vitro. Moreover, treatment with Gadelta-ab did not prevent apoptosis of B-CLL cells induced by Gamu-ab. Collectively, these experiments demonstrated that IgM and IgD expressed by the same cell may deliver opposite signals under particular circumstances and provide some clues for the understanding of the pathophysiology of B-CLL. (Blood. 2000;95:1199-1206)

8
UI - 11698290
AU - Bernal A; Pastore RD; Asgary Z; Keller SA; Cesarman E; Liou HC;
TI - Schattner EJ Survival of leukemic B cells promoted by engagement of the antigen receptor.
SO - Blood 2001 Nov 15;98(10):3050-7
AD - Immunology Program, Weill Graduate School of Medical Sciences of Cornell University, and Department of Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA.
Chronic lymphocytic leukemia (CLL) is an incurable leukemia characterized by the slow but progressive accumulation of cells in a CD5+ B-cell clone. Like the nonmalignant counterparts, B-1 cells, CLL cells often express surface immunoglobulin with the capacity to bind autologous structures. Previously there has been no established link between antigen-receptor binding and inhibition of apoptosis in CLL. In this work, using primary CLL cells from untreated patients with this disease, it is demonstrated that engagement of surface IgM elicits a powerful survival program. The response includes inhibition of caspase activity, activation of NF-kappaB, and expression of mcl-1, bcl-2, and bfl-1 in the tumor cells. Blocking phosphatidylinositol 3-kinase (PI3-K), a critical mediator of signals through the antigen receptor, completely abrogated mcl-1 induction and impaired survival in the stimulated cells. These data support the contention that CLL cell survival is promoted by antigen for which the malignant clone has affinity, and suggest that pharmacologic interference with antigen-receptor-derived signals has potential for therapy in patients with CLL.

9
UI - 11865846
AU - Wong KF; So CC; Chan JK
TI - Nucleolated variant of mantle cell lymphoma with leukemic manifestations mimicking prolymphocytic leukemia.
SO - Am J Clin Pathol 2002 Feb;117(2):246-51
AD - Department of Pathology, Queen Elizabeth Hospital, Hong Kong, People's Republic of China.
Chronic lymphoproliferative disorders sometimes can be difficult to classify. We report 4 cases characterized by large cells with distinct central nucleoli, reminiscent of prolymphocytic leukemia, but shown on further workup to represent mantle cell lymphoma. At initial examination, the patients had generalized lymphadenopathy, splenomegaly, and a leukemic blood picture. The peripheral blood showed many large cells with round to slightly irregular nuclei, single central nucleoli, and a fair amount of pale cytoplasm. The picture was not typical of prolymphocytic leukemia because of the presence of generalized lymphadenopathy and the large size of the circulating abnormal cells. Immunophenotypic study showed that the large lymphoid cells were CD5+ CD23- mature B cells with overexpression of cyclin D1, and cytogenetic study demonstrated the translocation t(11;14)(q13;q32) in 3 patients. Lymph node biopsy confirmed a diagnosis of mantle cell lymphoma, pleomorphic variant, in all 4 patients. This study documents the existence of an unusual leukemic form of mantle cell lymphoma with prominent nucleoli; the clinicopathologic features that distinguish it from other chronic lymphoproliferative disorders are discussed.

10
UI - 12060119
AU - Roman V; Billard C; Kern C; Ferry-Dumazet H; Izard JC; Mohammad R;
TI - Mossalayi DM; Kolb JP Analysis of resveratrol-induced apoptosis in human B-cell chronic leukaemia.
SO - Br J Haematol 2002 Jun;117(4):842-51
AD - U.365 INSERM, Institut Curie, 26 rue d'Ulm, 75248 Paris cedex 05, France.
Trans-resveratrol was analysed for its apoptotic and growth inhibitory activity in human B-cell lines derived from chronic B-cell malignancies (WSU-CLL and ESKOL), and in leukaemic lymphocytes from patients with B-cell chronic lymphocytic leukaemia (B-CLL). Resveratrol displayed antiproliferative activity on both B-cell lines, as estimated by the decrease in cell recovery and inhibition of thymidine uptake. Furthermore, resveratrol induced apoptosis in the two cell lines as well as in B-CLL patients' cells, as evidenced by the increase in annexin V binding, caspase activation, DNA fragmentation and decrease of the mitochondrial transmembrane potential DeltaPsim. We previously reported that nitric oxide (NO), endogenously released by an iNO synthase (iNOS) spontaneously expressed in these leukaemic cells, contributed to their resistance towards apoptosis. We show here that resveratrol inhibited both iNOS protein expression and in situ NO release in WSU-CLL, ESKOL and B-CLL patients'cells. In addition, Bcl-2 expression was also inhibited by resveratrol. Thus, downregulation of the two anti-apoptotic proteins iNOS and Bcl-2 can contribute to the apoptotic effects of resveratrol in leukaemic B cells from chronic leukaemia. Our data suggest that this drug is of potential interest for the therapy of B-CLL.

11
UI - 12149185
AU - Kay NE; Jelinek DF
TI - B-CLL: is the enigma of disease heterogeneity about to be revealed?
SO - Blood 2002 Aug 15;100(4):1110-1
AD - Mayo Clinic, USA.

12
UI - 12149195
AU - Oscier DG; Gardiner AC; Mould SJ; Glide S; Davis ZA; Ibbotson RE;
TI - Corcoran MM; Chapman RM; Thomas PW; Copplestone JA; Orchard JA; Hamblin TJ Multivariate analysis of prognostic factors in CLL: clinical stage, IGVH gene mutational status, and loss or mutation of the p53 gene are independent prognostic factors.
SO - Blood 2002 Aug 15;100(4):1177-84
AD - Department of Haematology, Royal Bournemouth Hospital, Bournemouth, United Kingdom. david.oscier@lineone.net
This study evaluates the prognostic significance of genetic abnormalities (detected at or shortly after presentation), clinical stage, lymphocyte morphology, CD38 expression, and IGVH gene status in 205 patients with chronic lymphocytic leukemia (B-CLL). Deletion of chromosome 11q23, absence of a deletion of chromosome 13q14, atypical lymphocyte morphology, and more than 30% CD38 expression are significantly associated with the presence of unmutated IGVH genes. Advanced stage, male sex, atypical morphology, more than 30% CD38 expression, trisomy 12, deletion of chromosome 11q23, loss or mutation of the p53 gene, and unmutated IGVH genes are all poor prognostic factors in a univariate analysis. However, only 98% or more homology of IGVH genes to the germline sequence, loss or mutation of the p53 gene, and clinical stage retain prognostic significance in a multivariate analysis. The median survival of patients with mutated IGVH genes, unmutated IGVH genes, and loss or mutation of the p53 gene regardless of IGVH gene status is 310, 119, and 47 months, respectively. These data should facilitate the design of new trials for the management of patients presenting with advanced disease or poor prognosis early stage disease.

13
UI - 12149200
AU - Ferrajoli A; Keating MJ; Manshouri T; Giles FJ; Dey A; Estrov Z; Koller
TI - CA; Kurzrock R; Thomas DA; Faderl S; Lerner S; O'Brien S; Albitar M The clinical significance of tumor necrosis factor-alpha plasma level in patients having chronic lymphocytic leukemia.
SO - Blood 2002 Aug 15;100(4):1215-9
AD - Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Tumor necrosis factor-alpha (TNF-alpha), a cytokine possessing pleiotropic biological activities, is produced by leukemic lymphocytes in patients with chronic lymphocytic leukemia (CLL) and acts as an autocrine and paracrine growth factor in this disease. In this study, TNF-alpha levels were determined in 150 patients with CLL and correlated with disease characteristics, prognostic factors, and survival. The mean TNF-alpha plasma concentration in the patients with CLL was significantly higher than in the healthy control population (16.4 versus 8.7 pg/mL; P <.0001). Patients having an elevated TNF-alpha level had more advanced Rai and Binet stage disease, higher serum beta(2)-microglobulin (beta(2)M) levels, a greater percentage of cells expressing CD38, and lower hemoglobin and platelet levels. Patients having chromosomal abnormalities such as 11q deletion, trisomy 12, and chromosome 17 aberrations had a higher mean TNF-alpha level (27.5 pg/mL) than patients having a diploid karyotype or other miscellaneous cytogenetic abnormalities (14.2 pg/mL; P <.001). The TNF-alpha level was a predictor of survival when the Cox proportional hazards model was used with TNF-alpha entered as a continuous variable (P =.0001). Also, patients having a TNF-alpha level above the mean value of 14 pg/mL had significantly shorter survival duration (P =.00001). The TNF-alpha level remained predictive of survival in Cox multivariate analysis independent of Rai staging and beta(2)M, hemoglobin, prior therapy, white cell count, and platelet level (P =.005). We conclude that the TNF-alpha level serves as a prognostic factor in patients with CLL and that inhibition of TNF-alpha in these patients could have therapeutic importance.

14
UI - 12149224
AU - Lin K; Sherrington PD; Dennis M; Matrai Z; Cawley JC; Pettitt AR
TI - Relationship between p53 dysfunction, CD38 expression, and IgV(H) mutation in chronic lymphocytic leukemia.
SO - Blood 2002 Aug 15;100(4):1404-9
AD - Department of Haematology, Royal Liverpool University Hospital, United Kingdom.
Established adverse prognostic factors in chronic lymphocytic leukemia (CLL) include CD38 expression, relative lack of IgV(H) mutation, and defects of the TP53 gene. However, disruption of the p53 pathway can occur through mechanisms other than TP53 mutation, and we have recently developed a simple screening test that detects p53 dysfunction due to mutation of the genes encoding either p53 or ATM, a kinase that regulates p53. The present study was conducted to examine the predictive value of this test and to establish the relationship between p53 dysfunction, CD38 expression, and IgV(H) mutation. CLL cells from 71 patients were examined for IgV(H) mutation, CD38 expression, and p53 dysfunction (detected as an impaired p53/p21 response to ionizing radiation). Survival data obtained from 69 patients were analyzed according to each of these parameters. Relative lack of IgV(H) mutation (less than 5%; n = 45), CD38 positivity (antigen expressed on more than 20% of malignant cells; n = 19), and p53 dysfunction (n = 19) were independently confirmed as adverse prognostic factors. Intriguingly, all p53-dysfunctional patients and all but one of the CD38(+) patients had greater than 5% IgV(H) mutation. Moreover, patients with p53 dysfunction and/or CD38 positivity (n = 31) accounted for the short survival of the less mutated group. These findings indicate that the poor outcome associated with having less than 5% IgV(H) mutation may be due to the overrepresentation of high-risk patients with p53 dysfunction and/or CD38 positivity within this group, and that CD38(-) patients with functionally intact p53 may have a prolonged survival regardless of the extent of IgV(H) mutation.

15
UI - 12149225
AU - Krober A; Seiler T; Benner A; Bullinger L; Bruckle E; Lichter P; Dohner
TI - H; Stilgenbauer S V(H) mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia.
SO - Blood 2002 Aug 15;100(4):1410-6
AD - Abteilung Innere Medizin III, University of Ulm, Germany.
In chronic lymphocytic leukemia (CLL), biologic risk factors such as immunoglobulin variable heavy chain gene (V(H)) mutation status, CD38 expression level, and genomic aberrations have recently been identified, but the relative prognostic impact of the individual parameters is unknown. In the current study, we analyzed V(H) mutation status by polymerase chain reaction and sequencing (n = 300), genomic aberrations by fluorescence in situ hybridization (+3q, 6q-, +8q, 11q-, +12q, 13q-, t(14q), 17p-) (n = 300), and CD38 expression by triple-color FACS (CD5, CD19, CD38) (n = 157) in a unicentric CLL cohort. The prognostic influence of V(H) mutation rate and CD38 expression level was tested by maximally selected log-rank statistics. A corrected P value (P(cor)) for a cutoff level allowing the best separation of 2 subgroups with different survival probabilities was identified at 97% V(H) homology (95% confidence interval [CI], 96%-98% homology, P(cor) <.001) and at 7% CD38 expression (95% CI, 20%-71% expression, P(cor) =.02). In univariate analyses, unmutated V(H) genes and high CD38 expression levels predicted for shorter survival times. The overall incidence of genomic aberrations was similar in the V(H) unmutated and V(H) mutated subgroups. High-risk genomic aberrations such as 17p- and 11q- occurred almost exclusively in the V(H) unmutated subgroup, whereas favorable aberrations such as 13q- and 13q- as single abnormalities were overrepresented in the V(H) mutated subgroup. In multivariate analysis, unmutated V(H), 17p deletion, 11q deletion, age, WBC, and LDH were identified as independent prognostic factors, indicating a complementary role of V(H) mutation status and genomic aberrations to predict outcome in CLL.

16
UI - 12149227
AU - van den Berg A; Maggio E; Rust R; Kooistra K; Diepstra A; Poppema S
TI - Clonal relation in a case of CLL, ALCL, and Hodgkin composite lymphoma.
SO - Blood 2002 Aug 15;100(4):1425-9
AD - Department of Pathology and Laboratory Medicine, University and University Hospital Groningen, Groningen, The Netherlands.
Large cell lymphomas and Hodgkin disease may develop during the course of chronic lymphocytic leukemia (CLL). In some cases the transformed cells are Epstein-Barr virus (EBV)-positive and not clonally related to the CLL cells. In other cases the transformed cells have the same clonal rearrangements as the CLL cells. Here we describe a composite lymphoma in a patient with CLL that exhibits a combination of CLL/small lymphocytic lymphoma, large cell lymphoma with anaplastic morphology, and Hodgkin lymphoma (HL). Although the large cell lymphoma cells are CD45R0 and TIA-1-positive, suggesting a T- or 0-cell anaplastic large cell lymphoma (ALCL), the genetic analysis demonstrates immunoglobulin heavy chain (IgH) gene rearrangements for both alleles, carrying the same somatic mutations as observed in the CLL component. The Reed-Sternberg (R-S) cells in the Hodgkin component also strongly express TIA-1 but differ from the anaplastic large cells by the expression of CD15 and TARC and the presence of a prominent lymphocytic infiltrate. The ALCL and HL components both are EBV negative. Analysis of the IgH gene rearrangements in micromanipulated R-S cells revealed identical Ig gene rearrangements carrying the same somatic mutations as the CLL and the large cell components. The findings indicate transformation of the CLL cells into a large cell lymphoma with anaplastic morphology and a Hodgkin component.

17
UI - 12171775
AU - Jacobs P; Wood L
TI - Chronic lymphocytic leukaemia--the haematologic basis for diagnosis and treatment.
SO - Hematol 2002 Feb;7(1):33-41
AD - The Department of Haematology and Boone Marrow Transplant Unit incorporating the Searll Research Laboratory for Cellular and Molecular Biology, Constantiaberg Medi-Clinic, Cape Town, South Africa. haematol@icon.co.za
Clinically diagnosis may be incidental when absolute lymphocytosis is uncovered at routine medical examination. More usually there is a recurrent sinopulmonary infection reflecting a varying degree of humoral and cellular immune deficiency. Autoimmune phenomena may result in haemolytic anaemia or thrombocytopenia. Expanding tumour bulk underlies the lymphadenopathy which may be prominent. Diagnosis is confirmed on morphology of the smear where atypical variants need to be distinguished from other indolent lymphoproliferative disorders. Immunophenotyping is indispensable in classification. Prognosis is predicated by cytogenetics and markers of tumour biology that include beta-2 microglobulin and peripheral blood lymphocyte doubling time. Management is dictated by symptoms and signs of progression superimposed upon performance status that includes age. Disease that is asymptomatic and truly indolent, particularly in the elderly, qualifies for a careful watch-and-wait policy. In other circumstances stratification to therapy requires entry into peer-reviewed protocols if optimal outcome is to be achieved. Established regimens, of demonstrably equal efficacy, are pulsed single-agents exemplified by chlorambucil or combinations of cyclophosphamide with vincristine and prednisone. The purine analogues, particularly when administered with an alkylating agent and mitoxantrone, are emerging as superior options. In selected patients any properly accredited program will make provision for escalation in chemotherapy requiring haematopoietic stem cell transplantation on the one hand or use of serotherapy with CD52 antibodies on the other. Less commonly, but in a defined subgroup, immunoglobulins directed against membrane CD20 may be effective. Perspective for the generalist is anchored in recognising that the previous cavalier approach to drug medication, with or without radiotherapy, is unwise whereas integrated management is now the international standard of practice. The previous anachronism of dabbling by occasional therapists is to be deprecated since this will generally deny patients access to proper diagnosis and risk-adjusted multi-disciplinary treatment.

18
UI - 12127549
AU - Caligaris-Cappio F
TI - What are we learning from familial chronic lymphocytic leukemia?
SO - Leuk Res 2002 Sep;26(9):779-80
AD - Department of Oncological Sciences, Division of Clinical Immunology and Hematology, Torino and Laboratory of Tumor Immunology, University of Torino, Ospedale Mauriziano Umberto I, IRCC, Candiolo, 10128 Torino, Italy. fcaligaris@mauriziano.it

19
UI - 12127552
AU - Ishibe N; Prieto D; Hosack DA; Lempicki RA; Goldin LR; Raffeld M; Marti
TI - GE; Caporaso NE Telomere length and heavy-chain mutation status in familial chronic lymphocytic leukemia.
SO - Leuk Res 2002 Sep;26(9):791-4
AD - Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 6120 Executive Blvd, MSC 7236, Rockville, MD 20892, USA. ishiben@exchange.nih.gov
We examined whether telomere lengths of peripheral blood mononuclear cells are associated with immunoglobulin gene usage in 21 familial chronic lymphocytic leukemia (CLL) patients. Subjects with unmutated V genes tended to have shorter telomeres than those with somatic mutations, especially after adjusting for age. Unlike V(H) mutation status, telomere length was not predictive for survival. Our results suggest that telomere length is associated with V(H) gene mutation status and provides further evidence that the biological basis of familial B-CLL is similar to that of sporadic patients.

20
UI - 12127553
AU - Goller ME; Kneitz C; Mehringer C; Muller K; Jelley-Gibbs DM; Gosselin
TI - EJ; Wilhelm M; Tony HP Regulation of CD23 isoforms on B-chronic lymphocytic leukemia.
SO - Leuk Res 2002 Sep;26(9):795-802
AD - Department of Rheumatology and Immunology, Medizinische Poliklinik, University of Wurzburg, Klinikstrasse 6-8, Wurzburg, Germany.
CD23 is constitutively and atypically expressed on malignant B-cells in patients with chronic lymphocytic leukemia. It exists in two isoforms that differ only in a short amino acid sequence at the N-terminus. The CD23a isoform exhibits an endocytosis signal, that renders it more efficient in antigen uptake than CD23b. Therefore, we analyzed the regulation of CD23 isoforms and tested the ability to stimulate T-cell clones by targeting antigen to CD23 on CLL B-cells. Investigation of several stimulators to promote CD23a expression on CLL versus normal B-cells confirmed a different CD23 regulation in B-CLL. We did not find any evidence for a differential regulation of the two CD23 isoforms in B-CLL. However, CD23a is always predominantly expressed with a constant ratio of CD23a:CD23b. We show that antigen targeted to CD23 on CLL B-cells is very efficiently presented. Therefore, CD23 is likely to provide a suitable target for receptor-mediated antigen presentation in B-CLL which can be used to activate a T-cell response.

21
UI - 12127555
AU - Koiso H; Tsukamoto N; Miyawaki S; Shinonome S; Nojima Y; Karasawa M
TI - Quantitative analysis of Cyclin D1 and CD23 expression in mantle cell lymphoma and B-chronic lymphocytic leukemia.
SO - Leuk Res 2002 Sep;26(9):809-15
AD - Third Department of Internal Medicine, Gunma University School of Medicine, 3-39-15 Showa-cho, Maebashi, Gunma, Japan. hkoiso@med.guna-u.ac.jp
We studied Cyclin D1 (CyD1) and CD23 mRNA expression with real-time quantitative reverse transcription polymerase chain reaction (RQ-PCR) method. CyD1 expression in peripheral blood of seven mantle cell lymphoma (MCL) patients was found to be 1305.4 times higher than in 24 B-chronic lymphocytic leukemia (CLL) patients. CD23 expression in CLL was found to be 54.8 times higher than in MCL. These differences were statistically significant, and no overlap was found in CyD1 expression intensities between MCL and CLL. RQ-PCR allows rapid, simple and accurate quantification of CyD1 and CD23 expression, even from small samples, and is thus useful for the diagnosis of MCL and CLL.

22
UI - 12191574
AU - Zinzani PL; Tani M; Stefoni V; Piccaluga PP; Baccarani M; Ascani S;
TI - Pileri S From chronic lymphocytic leukemia to Hodgkin's disease: a case of prognostically favorable transformation.
SO - Leuk Res 2002 Aug;26(8):775-6

23
UI - 12144536
AU - Rossmann ED; Lewin N; Jeddi-Tehrani M; Osterborg A; Mellstedt H
TI - Intracellular T cell cytokines in patients with B cell chronic lymphocytic leukaemia (B-CLL).
SO - Eur J Haematol 2002 May;68(5):299-306
AD - Immune and Gene Therapy Laboratory, Cancer Center Karolinska, Karolinska Hospital, SE-171 76 Stockholm, Sweden.
Analysis of cytokine production is a tool to functionally characterise T cells. In this study, spontaneous and polyclonal activation induced cytokine production in T cells were assessed by flow cytometry in patients with B-CLL. Patients with progressive disease had a significantly increased number of T cells spontaneously producing IL-2, IL-4 and GM-CSF as compared to healthy donors and patients with non-progressive CLL, which was not the case for TNF-alpha and IFN-gamma producing T cells. However, no difference in the frequency of T cells producing these cytokines was seen comparing patients with non-progressive disease to control donors. Polyclonal activation of B-CLL T cells in vitro induced an increased proportion of T cells producing these five cytokines in patients as well as in control donors, indicating that T cells in CLL patients might have a relatively well preserved functional capacity. However, the increase in GM-CSF, TNF-alpha and IL-4 producing T cells was more marked in CLL patients than in controls. Furthermore, following activation, a higher frequency of cytokine-producing T cells was noted in patients with progressive disease as compared to those with non-progressive disease. The augmented number of cytokine-producing T cells in CLL may indicate an up-regulated capability of T cells to secrete cytokines, especially in patients with progressive CLL. The increased production of the T cell derived cytokines GM-CSF, TNF-alpha, IL-4 and IL-2 is interesting, as these cytokines have previously been shown to support growth of B-CLL leukaemic cells in vitro and as T cells might specifically recognise the autologous leukaemic B cells in vivo. The findings may suggest a role for T cells in the pathogenesis of B-CLL.

24
UI - 12168870
AU - Eriksson A; Lewensoh R; Larsson R; Nilsson A
TI - DNA-dependent protein kinase in leukaemia cells and correlation with drug sensitivity.
SO - Anticancer Res 2002 May-Jun;22(3):1787-93
AD - Department of Oncology and Pathology, Cancer Centre Karolinska, Karolinska Hospital, Stockholm, Sweden.
We investigated whether the levels of the DNA-dependent protein kinase (DNA-PK) activity and content correlate with drug sensitivity in different tumour materials and if this can be utilised in predicting treatment outcome. DNA-PK activity and expression were investigated in tumour cells from 8 patients with chronic lymphocytic leukaemia (CLL) and 18 patients with acute myeloid leukaemia (AML), using Western blot and DNA-PK kinase activity assay. Tumour cells from the patients were investigated for their drug sensitivity to topoisomerase II inhibitors (doxorubicin and etoposide), DNA reactive agents (melphalan, 4-hydroxycyclophosphamide and cisplatinum), an antimetabolite (cytosine arabinoside) and an antimicrotubule agent (vincristine) by fluorometric microculture cytotoxicity assay (FMCA). Within each group of leukaemia there was a large variation in both DNA-PK activity and DNA-PKcs expression, while the Ku subunits were expressed more homogeneously. In CLL cells, sensitivity to topoisomerase II inhibitors correlated with DNA-PKcs protein expression (r=0.7174, p=0.0452). In AML samples, sensitivity to DNA cross-linking alkylating agents correlated with Ku86 (r=-0.7512, p=0.0031) and Ku70 (r=-0.6134, p=0.0258) expression. Unexpectedly, DNA-PK activity was found to correlate with sensitivity to vincristine in both CLL (r=0.8557, p=0.0067) and AML (r=0.5480, p=0.0228) cells. The results indicate that DNA-PK is not only involved in the recognition of DNA double-strand breaks (DSB), but also other DNA lesions.

25
UI - 12176885
AU - Wendtner CM; Kofler DM; Theiss HD; Kurzeder C; Buhmann R; Schweighofer
TI - C; Perabo L; Danhauser-Riedl S; Baumert J; Hiddemann W; Hallek M; Buning H Efficient gene transfer of CD40 ligand into primary B-CLL cells using recombinant adeno-associated virus (rAAV) vectors.
SO - Blood 2002 Sep 1;100(5):1655-61
AD - Medical Clinic III, University Hospital Grosshadern and Gene Center, Ludwig-Maximilians-University, Munich, Germany.
B cells of chronic lymphocytic leukemia (B-CLL) are resistant to transduction with most currently available vector systems. Using an optimized adenovirus-free packaging system, recombinant adeno-associated virus (rAAV) vectors coding for the enhanced green fluorescent protein (AAV/EGFP) and CD40 ligand (AAV/CD40L) were packaged and highly purified resulting in genomic titers up to 3 x 10(11)/mL. Cells obtained from 24 patients with B-CLL were infected with AAV/EGFP or AAV/CD40L at a multiplicity of infection (MOI) of 100 resulting in transgene expression in up to 97% of cells as detected by flow cytometry 48 hours after infection. Viral transduction could be specifically blocked by heparin. Transduction with AAV/CD40L resulted in up-regulation of the costimulatory molecule CD80 not only on infected CLL cells but also on noninfected bystander leukemia B cells, whereas this effect induced specific proliferation of HLA-matched allogeneic T cells. Vaccination strategies for patients with B-CLL using leukemia cells infected ex vivo by rAAV vectors now seems possible in the near future.

26
UI - 12176901
AU - Novak U; Oppliger Leibundgut E; Hager J; Muhlematter D; Jotterand M;
TI - Besse C; Leupin N; Ratschiller D; Papp J; Kearsey G; Aebi S; Graber H; Jaggi R; Luthi JM; Meyer-Monard S; Lathrop M; Tobler A; Fey MF A high-resolution allelotype of B-cell chronic lymphocytic leukemia (B-CLL).
SO - Blood 2002 Sep 1;100(5):1787-94
AD - Department of Clinical Research and Medical Oncology/Hematology, Inselspital (University Hospital), Bern, Switzerland.
The most frequent chromosomal aberrations in B-cell chronic lymphocytic leukemia (B-CLL) are deletions on 13q, 11q, and 17p, and trisomy 12, all of which are of prognostic significance. Conventional cytogenetic analysis and fluorescence in situ hybridization (FISH) are used for their detection, but cytogenetic analysis is hampered by the low mitotic index of B-CLL cells, and FISH depends on accurate information about candidate regions. We used a set of 400 highly informative microsatellite markers covering all chromosomal arms (allelotyping) and automated polymerase chain reaction (PCR) protocols to screen 46 patients with typical B-CLL for chromosomal aberrations. For validation, we compared data with our conventional karyotype results and fine mapping with conventional single-site PCR. All clonal cytogenetic abnormalities potentially detectable by our microsatellite PCR (eg, del13q14 and trisomy 12) were picked up. Allelotyping revealed additional complex aberrations in patients with both normal and abnormal B-CLL karyotypes. Aberrations detectable in the samples with our microsatellite panel were found on almost all chromosomal arms. We detected new aberrant loci in typical B-CLL, such as allelic losses on 1q, 9q, and 22q in up to 25% of our patients, and allelic imbalances mirroring chromosomal duplications, amplifications, or aneuploidies on 2q, 10p, and 22q in up to 27% of our patients. We conclude that allelotyping with our battery of informative microsatellites is suitable for molecular screening of B-CLL. The technique is well suited for analyses in clinical trials, it provides a comprehensive view of genetic alterations, and it may identify new loci with candidate genes relevant in the molecular biology of B-CLL.

27
UI - 12176902
AU - Pedersen IM; Kitada S; Leoni LM; Zapata JM; Karras JG; Tsukada N; Kipps
TI - TJ; Choi YS; Bennett F; Reed JC Protection of CLL B cells by a follicular dendritic cell line is dependent on induction of Mcl-1.
SO - Blood 2002 Sep 1;100(5):1795-801
AD - The Burnham Institute, La Jolla, CA 92037, USA.
Chronic lymphocytic leukemia (CLL) B cells have defects in apoptosis pathways and therefore accumulate in vivo. However, when removed from the patient and cultured in vitro, these malignant cells rapidly undergo apoptosis. Recent studies suggest that leukemia cell survival is influenced by interactions with nonleukemia cells in the microenvironment of lymph nodes, marrow, and other tissues. To model such cell-cell interactions in vitro, we cultured freshly isolated CLL B cells with a follicular dendritic cell line, HK. CLL B cells cocultured with HK cells were protected from apoptosis, either spontaneous or induced by treatment with anticancer drugs. Protection against spontaneous apoptosis could also be induced by coculturing the CLL B cells with normal dendritic cells (DCs) or with a CD40-ligand (CD154)-expressing fibroblast cell line. Examination of the expression of several apoptosis-regulatory proteins revealed that coculture with HK cells or DCs induced up-regulation of the antiapoptotic Bcl-2 family protein Mcl-1 in CLL B cells, whereas CD40 ligation increased expression of Bcl-X(L). Cell-cell contact was required for HK-induced protection, and introducing neutralizing antibodies against various adhesion molecules showed that CD44 was involved in HK-mediated survival, whereas CD40, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were not. Anti-CD44 antibodies also blocked Mcl-1 induction by HK cells. Mcl-1 antisense oligonucleotides reduced leukemia cell expression of Mcl-1, and significantly suppressed HK-induced protection against apoptosis, whereas control oligonucleotides had no effect. Thus, HK cells protect CLL B cells against apoptosis, at least in part through a CD44-dependent mechanism involving up-regulation of Mcl-1, and this mechanism is distinct from that achieved by CD40 ligation. Consequently, the particular antiapoptotic proteins important for CLL survival may vary depending on the microenvironment.

28
UI - 12176903
AU - Witkowski JM; Zmuda-Trzebiatowska E; Swiercz JM; Cichorek M; Ciepluch H;
TI - Lewandowski K; Bryl E; Hellmann A Modulation of the activity of calcium-activated neutral proteases (calpains) in chronic lymphocytic leukemia (B-CLL) cells.
SO - Blood 2002 Sep 1;100(5):1802-9
AD - Department of Pathophysiology, Medical University of Gdansk, Poland. jawit@amedec.amg.gda.pl
Decreased susceptibility to apoptosis and impaired proliferative control are thought to be responsible for prolonged life span and accumulation of chronic lymphocytic leukemia (B-CLL) cells. The activity of calpains (calcium-dependent, neutral proteases, active in the cells responding to signals inducing a rise of cytoplasmic Ca(++)) is involved in the regulation of apoptosis of some cell types by interaction with caspase-3. This work verifies the hypothesis of the abnormal activity of calpains and its role in reduced apoptosis of the B-CLL cells. Casein zymography, reverse transcriptase-polymerase chain reaction, and Western blotting were used for identification and quantification of the activity and expression of calpains in B-CLL cells and purified normal B lymphocytes. The activity and expression of mu-calpain (requiring micromolar Ca(++) for activation) are significantly higher in the leukemic than in nonmalignant cells. Contrarily, the activity and expression of m-calpain (requiring millimolar Ca(++)) as well as the expression of calpastatin (an endogenous inhibitor of calpains) are unchanged or reduced in the B-CLL lymphocytes. Correspondingly, the activity of caspase-3 is many times lower in the B-CLL cells than in normal B lymphocytes. Inhibition of overexpressed mu-calpain in living B-CLL cells in vitro results in doubling of the proportion of the cells undergoing spontaneous apoptosis. This observation suggests a possible role for calpains in longer survival of the B-CLL cells and may open new therapeutic possibilities.

29
UI - 12176904
AU - Bellosillo B; Villamor N; Lopez-Guillermo A; Marce S; Bosch F; Campo E;
TI - Montserrat E; Colomer D Spontaneous and drug-induced apoptosis is mediated by conformational changes of Bax and Bak in B-cell chronic lymphocytic leukemia.
SO - Blood 2002 Sep 1;100(5):1810-6
AD - Department of Hematology, Institute of Hematology and Oncology from Hospital Clinic, Postgraduate School of Hematology Farreras-Valenti, Barcelona, Spain.
The role of Bax and Bak, 2 proapoptotic proteins of the Bcl-2 family, was analyzed in primary B-cell chronic lymphocytic leukemia (CLL) cells following in vitro treatment with fludarabine, dexamethasone, or the combination of fludarabine with cyclophosphamide and mitoxantrone (FCM). A strong correlation was found between the number of apoptotic cells and the percentage of cells stained with antibodies recognizing conformational changes of Bax (n = 33; r = 0.836; P <.001) or Bak (n = 10; r = 0.948; P <.001). Preincubation of CLL cells with Z-VAD.fmk (N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone), a broad caspase inhibitor, abolished caspase-3 activation, exposure of phosphatidylserine residues, and reactive oxygen species generation; partially reversed the loss of transmembrane mitochondrial potential (DeltaPsim); but did not affect Bax or Bak conformational changes. These results indicate that the conformational changes of Bax and Bak occur upstream of caspase activation or are caspase independent. Following drug-induced apoptosis, Bax integrates into mitochondria, as demonstrated by fluorescence microscopy and Western blot, without changes in the total amount of Bax or Bak protein. Fludarabine and FCM induce p53 stabilization, but do not seem to be essential in inducing Bax and Bak conformational changes, as they are also observed in dexamethasone-treated CLL cells. These results demonstrate that, in CLL cells, the change in the intracellular localization of Bax from cytosol to mitochondria and the conformational changes of Bax and Bak are among the early steps in the induction of cell d

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