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NCI CANCERLIT^® Search: Chronic Lymphocytic Leukemia - August 2002

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National Cancer Institute^®
Ultima Vez Modificado: 1 de agosto del 2002

Chronic lymphocytic leukaemia: one cell, two diseases?
Molecular diversity of gammadelta T cells in peripheral blood from patients with B-cell chronic lymphocytic leukaemia.
Berlex Laboratories to market new treatment for B-CLL.
Immunotherapy of chronic lymphocytic leukemia.
Update on prophylaxis and therapy of infection in patients with chronic lymphocytic leukemia.
T type 1/type 2 subsets balance in B-cell chronic lymphocytic leukemia--the three-color flow cytometry analysis.
T-cell responses against chronic lymphocytic leukemia cells: implications for immunotherapy.
Modulation of malignant B cell activation and apoptosis by bcl-2 antisense ODN and immunostimulatory CpG ODN.
CD23 negative chronic lymphocytic leukemia of the tonsil: report of a case.
Chromosomal DNA and p53 stability, ubiquitin system and apoptosis in B-CLL lymphocytes.
Association of CD38 antigen expression with other prognostic parameters in early stages of chronic lymphocytic leukemia.
Rituximab toxicity in patients with peripheral blood malignant B-cell lymphocytosis.
Immunophenotype changes and loss of CD52 expression in two patients with relapsed T-cell prolymphocytic leukaemia.
Selection and expansion of T cell from untreated patients with CLL: source of cells for immune reconstitution?
CAMPATH (alemtuzumab) for the treatment of chronic lymphocytic leukemia and beyond.
Role of surface IgM and IgD on survival of the cells from B-cell chronic lymphocytic leukemia.
Campath-1H-induced complete remission of chronic lymphocytic leukemia despite p53 gene mutation and resistance to chemotherapy.
Differential expression of alpha-smooth muscle actin molecule in a subset of bone marrow stromal cells, in b-cell chronic lymphocytic
Ionizing radiation and cancer risk: evidence from epidemiology.
Molecular study of an IgG1kappa cryoglobulin yielding organized microtubular deposits and glomerulonephritis in the course of chronic
High-dose chemotherapy plus allogeneic stem cells to treat chronic lymphocytic leukemia or small lymphocytic lymphoma.
Multiple neoplasms: a case report.
Simultaneous diagnosis of hairy cell leukemia and chronic lymphocytic leukemia/small lymphocytic lymphoma: a frequent association?
Chronic lymphocytic leukaemia: one disease or two?
Analysis of age, estimated creatinine clearance and pretreatment hematologic parameters as predictors of fludarabine toxicity in patients
[Experience with fludarabine treatment and review of the literature]
Leukemic mantle cell lymphoma with cells resembling prolymphocytes.
CD34+-enriched-CD19+-depleted autologous peripheral blood stem cell transplantation for chronic lymphoproliferative disorders: high purging
ATM mutations are rare in familial chronic lymphocytic leukemia.
Monoclonal B lymphocytes with the characteristics of "indolent" chronic lymphocytic leukemia are present in 3.5% of adults with normal blood

1
UI - 12133650
AU - Fegan C
TI - Chronic lymphocytic leukaemia: one cell, two diseases?
SO - Lancet 2002 Jul 20;360(9328):184-6
AD - Department of Haematology, Birmingham Heartlands and Solihull National Health Service Trust, Birmingham B9 5SS, UK. feganc@heartsol.wmids.nhs.uk

2
UI - 12088111
AU - Bartkowiak J; Kulczyck-Wojdala D; Blonski JZ; Robak T
TI - Molecular diversity of gammadelta T cells in peripheral blood from patients with B-cell chronic lymphocytic leukaemia.
SO - Neoplasma 2002;49(2):86-90
AD - Department of Oncology, Medical University of Lodz, Poland. j.bartkowiak@pro.onet.pl
To characterize circulating gammadelta T cell subpopulations in B chronic lymphocytic leukaemia patients (n=30), TCR Vgamma and Vdelta gene-segment use was analyzed by RT-PCR using a panel of subfamily-specific oligonucleotide primers. All results were compared with those obtained with specimens from healthy donors (n=10). The cells expressing Vdelta1+ TCR displayed the highest relative increase in B-CLL patients (particularly observed in 60% of cases), but Vdelta3+ T lymphocytes also expanded in leukaemic peripheral blood (10% of studied cases). Both mentioned gammadelta T cell subsets were significantly more frequent in the most severe stages of disease--Rai III+IV. The analysis of Vgamma region usage in TCR formation revealed that gammadelta T cells from B-CLL patients predominantly expressed a Vgamma9 segment (26 of 30 cases), usually linked to Cgamma1 region. It should be noticed that the dominant TCR genes expression in a 50% of healthy donors was Vdelta2+/Vgamma9+, however, Vgamma4 and Vgamma8 transcripts were also observed (2 and 3 of 10 cases, respectively). The above results indirectly indicate that gammadelta T lymphocyte expansion was driven by the oligo- or polyclonal proliferation and can reflect specific response against the autologous tumor cells.

3
UI - 12113127
AU - Anonymous
TI - Berlex Laboratories to market new treatment for B-CLL.
SO - Expert Rev Anticancer Ther 2001 Jun;1(1):3

4
UI - 12113136
AU - Wierda WG; O'Brien S
TI - Immunotherapy of chronic lymphocytic leukemia.
SO - Expert Rev Anticancer Ther 2001 Jun;1(1):73-83
AD - UT MD Anderson Cancer Center, Department of Leukemia, 1515 Holcombe Boulevard, Box 428, Houston, TX 77030, USA.
Chronic lymphocytic leukemia (CLL) is typically an indolent B-cell malignancy, primarily affecting the aging population. Standard cytotoxic treatment with alkylating agents or purine analogs is very effective at inducing remission. However, curative treatment is not yet available. Immunotherapy is emerging as an exciting modality with significant potential to advance the treatment of this disease. This review discusses the different modalities of immunotherapy under investigation for the treatment of CLL. These modalities include passive immunotherapy with monoclonal antibodies against antigens on CLL B-cells including CD52 and CD20. Active immunotherapy by vaccination with genetically modified autologous leukemia cells is being evaluated in clinical trials. Allogeneic stem cell transplant for adoptive immunotherapy of CLL is yet another modality being investigated. While this modality may have limited application due to morbidity in older patients, it may result in improved survival and possibly cure. The use of immunotherapy in CLL is in the early stages of development. It is likely that this approach will significantly improve the treatment of CLL and possibly contribute to the cure of this disease.

5
UI - 12113137
AU - Morrison VA
TI - Update on prophylaxis and therapy of infection in patients with chronic lymphocytic leukemia.
SO - Expert Rev Anticancer Ther 2001 Jun;1(1):84-90
AD - University of Minnesota, Sections of Hematology/Oncology and Infectious Disease, Veterans Affairs Medical Center, Minneapolis, MN 55417, USA. morri002@tc.umn.edu
Infections remain a major cause of morbidity and mortality in patients with chronic lymphocytic leukemia. These patients are predisposed to infection due to the immune compromise inherent to the primary disease and to therapy-related immunosuppression. The introduction of purine analogs and agents such as Campath-1H into the therapeutic armamentarium for chronic lymphocytic leukemia has altered the spectrum of infections. Although bacterial infections are most common, opportunistic infections, such as those caused by Candida, Pneumocystis and herpesviruses, may occur, related to T-cell immunosuppression induced by these agents. We will review the pathogenesis of infection, spectrum of infections, risk factors for infection and approaches for infection prophylaxis and therapy.

6
UI - 12008083
AU - Podhorecka M; Dmoszynska A; Rolinski J; Wasik E
TI - T type 1/type 2 subsets balance in B-cell chronic lymphocytic leukemia--the three-color flow cytometry analysis.
SO - Leuk Res 2002 Jul;26(7):657-60
AD - Department of Clinical Immunology, University School of Medicine in Lublin, Jaczewskiego 8, 20-950, Lublin, Poland. mpodhor@asklepios.am.lukin.pl
The impairments in immune cell functions as well as changes in cytokine network are the cause of malignant cell accumulation and secondary immune deficiencies in B-cell chronic lymphocytic leukemia (B-CLL). To broaden the knowledge of immune system in B-CLL we tried to evaluate the Th1/Th2 and Tc1/Tc2 balance in B-CLL patients in comparison with healthy individuals and changes of this pattern during disease progression. The three-color flow cytometry technique was used to analyze IL-4 and IFNgamma expression in peripheral blood CD3+CD4+ and CD3+CD8+ cells.The results indicate the dominance of T type 1 cells and T-cell-mediated immunity in B-CLL patients that is however shifted towards T type 2 during disease progression.

7
UI - 12070023
AU - Krackhardt AM; Harig S; Witzens M; Broderick R; Barrett P; Gribben JG
TI - T-cell responses against chronic lymphocytic leukemia cells: implications for immunotherapy.
SO - Blood 2002 Jul 1;100(1):167-73
AD - Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Chronic lymphocytic leukemia (CLL) cells are ineffective antigen-presenting cells (APCs) although CD40-activated CLL cells can stimulate proliferation of autologous and allogeneic T cells. We examined the antigen-presenting capacity of CD40-activated CLL cells as well as dendritic cells pulsed with apoptotic bodies of CLL cells to generate autologous and allogeneic immune responses against CLL cells. Both APC types were capable of generating T-cell lines that proliferate specifically in response to unstimulated CLL cells. Whereas cytotoxic responses against stimulated and unstimulated CLL cells could be repeatedly generated by allogeneic healthy donors, autologous cytotoxic immune responses against CD40-activated and native CLL cells were rarely detected. However, T cells isolated from patients with CLL could recognize and lyse allogeneic stimulated and unstimulated CLL cells, demonstrating that cytotoxic T cells from these tumor-bearing patients are functionally intact.

8
UI - 12101266
AU - Jahrsdorfer B; Jox R; Muhlenhoff L; Tschoep K; Krug A; Rothenfusser S;
TI - Meinhardt G; Emmerich B; Endres S; Hartmann G Modulation of malignant B cell activation and apoptosis by bcl-2 antisense ODN and immunostimulatory CpG ODN.
SO - J Leukoc Biol 2002 Jul;72(1):83-92
AD - Division of Clinical Pharmacology, Department of Internal Medicine, University of Munich, Ziemssenstrasse 1, 80336 Munich, Germany.
Inhibition of bcl-2 expression by antisense oligodeoxynucleotides (ODN) might render bcl-2 overexpressing malignant B cells more susceptible to chemotherapy. ODN containing unmethylated CG dinucleotides (CpG) are known to activate B cells. We studied the effects of two bcl-2 antisense ODN, with (G3139) or without CG dinucleotides (NOV 2009) within the sequence, and the effects of a nonantisense, CpG-containing ODN (ODN 2006) on activation and apoptosis of malignant B cell lines and primary B-CLL cells. Without cationic lipids, no antisense-mediated inhibition of bcl-2 synthesis was achieved with G3139 and NOV 2009. Instead, G3139, but not NOV 2009, induced similar changes as ODN 2006 in proliferation, expression of costimulatory and antigen-presenting molecules, as well as in bcl-2 and bcl-xL levels of primary B-CLL cells. G3139 and ODN 2006 inhibited in vitro, spontaneous apoptosis in B-CLL cells of patients with high serum thymidine kinase activity (s-TK, marker for proliferative activity of malignant B cells), whereas in patients with low s-TK activity, apoptosis was induced. In conclusion, our results suggest that modulation of malignant B cell apoptosis by G3139 depends on its immunostimulatory properties rather than on antisense-mediated reduction of bcl-2 expression. Immunostimulatory CpG ODN may have a therapeutic potential in patients with B-CLL, especially those with low s-TK activity.

9
UI - 12139359
AU - Ampil FL; Veillon DM; Nordberg ML; Nathan CA; Kunjumoideen K; Cotelingam
TI - JD CD23 negative chronic lymphocytic leukemia of the tonsil: report of a case.
SO - J La State Med Soc 2002 May-Jun;154(3):141-3
We present the case of atypical chronic lymphocytic leukemia presenting as a tonsillar mass in an elderly man. Histological examination of the tumor revealed diffuse submucosal infiltration by small lymphocytes. On flow cytometry, a monoclonal B lymphocytic population expressing CD5, CD19, lambda light chain, but not expressing CD10, CD23, or FMC7 activities, was observed. A diagnostic conundrum occurred with the demonstration on molecular cytogenetic analysis of the chromosomal translocation abnormality, t(11;14)(q13;q32). The diagnosis of CD23 negative chronic lymphocytic leukemia was made after further molecular studies failed to detect the bcl-1 gene rearrangement.

10
UI - 11911398
AU - Blaise R; Masdehors P; Lauge A; Stoppa-Lyonnet D; Alapetite C;
TI - Merle-Beral H; Binet JL; Omura S; Magdelenat H; Sabatier L; Delic J Chromosomal DNA and p53 stability, ubiquitin system and apoptosis in B-CLL lymphocytes.
SO - Leuk Lymphoma 2001 Nov-Dec;42(6):1173-80
AD - Laboratoire de Radiobiologie et Oncologie (CEA-DSV/DRR), Fontenay aux Roses, France.
The ubiquitin system regulates diverse biological processes such as DNA replication and repair, biogenesis of ribosome, peroxisome and nucleosome, cell cycle, stress response and signal transduction pathways. Thus, the reported role of the ubiquitin system in apoptotic death control as well the alteration of its control in carcinogenesis should come as no surprise. Indeed, we and other groups have reported that the ubiquitin system is involved in apoptotic cell death of normal human lymphocytes and that this control is altered in B lymphocytes derived from chronic lymphocytic leukemia patients (B-CLL), rendering these malignant cells hypersensitive to specific inhibition of protein degradation/processing through proteasomal function. This approach recently allowed us to demonstrate that the stability of the tumor suppressor and pro-apoptotic protein p53 is differentially regulated in B-CLL versus normal lymphocytes and that this difference might at least partly explain the impaired response of B-CLL lymphocytes to apoptotic death activation. These results strongly suggest an imbalance in p53 regulation in B-CLL cells that leads to a variable response to DNA damage and constitutively expressed chromosomal instability. The question we and others would like to address is whether this alteration, or more likely a subset of alterations of the ubiquitin-proteasome pathway, is specific to B-CLL malignancy or if it is a hallmark of cancer cells in general. In either case, a better understanding of the ubiquitin-dependent control of apoptosis should pave the way towards a methodological approach for in vitro development of discriminating treatments which may be of potential usefulness in clinical trials of B-CLL.

11
UI - 11911414
AU - Heintel D; Schwarzinger I; Chizzali-Bonfadin C; Thalhammer R;
TI - Schwarzmeier J; Fritzer-Szekeres M; Weltermann A; Simonitsch I; Lechner K; Jaeger U Association of CD38 antigen expression with other prognostic parameters in early stages of chronic lymphocytic leukemia.
SO - Leuk Lymphoma 2001 Nov-Dec;42(6):1315-21
AD - Department of Internal Medicine I, The University of Vienna School of Medicine, Austria.
The expression of the surface molecule CD38 on B cell chronic lymphocytic leukemia (B-CLL) cells has recently been described as a prognostic marker for patient survival. We have analyzed CD19/CD38 expression in 81 patients with predominantly early stages of B-CLL (69 Binet A, seven Binet B, five Binet C). Sixty-two patients (77%) had less than 30% CD38+/CD19+ cells, while 19 (23%) had > or = 30%. There was a significant association between Binet stages (A vs. B+C, p < 0.0001), Rai stages (0-II vs. III+IV, p < 0.001) and CD38 expression, confirming the published cut-off level of 30%. A particularly strong association between CD38 expression was found with soluble CD23 (sCD23) levels of > or = 2000 U/ml (p < 0.0001) and beta2-microglobulin (beta2 MG) serum levels of > or = 3 mg/l (p < 0.0001) indicating that CD38 is a marker of tumor mass as well as disease progression. A borderline association was found with lymphocyte doubling time (LDT) < 12 months (p = 0.05) due to low patient numbers, while there was no association with age, sex or immunoglobulin deficiency. Discordant results were obtained in a number of patients: 10 of 69 patients (14%) with Binet A had a CD38 > or = 30% while three of seven patients with Binet B had a CD38 < 30%. In these two subgroups CD38 and other prognostic factors gave discrepant results. Due to the early stage and short median observation time (12 months. range 1-24 months), calculations concerning patient survival were not performed. However, our data show a strong association between CD38 and other known prognostic factors. The results also suggest that this factor is not always reliable in Binet A patients.

12
UI - 11911416
AU - Kanelli S; Ansell SM; Habermann TM; Inwards DJ; Tuinstra N; Witzig TE
TI - Rituximab toxicity in patients with peripheral blood malignant B-cell lymphocytosis.
SO - Leuk Lymphoma 2001 Nov-Dec;42(6):1329-37
AD - Faculty of Medicine, Charles University, Hradec Kralove, Czech Republic.
Infusion related adverse events (AE) with day 1 rituximab in patients with B-cell non-Hodgkin's lymphoma (NHL) are common. The purpose of this study was to evaluate the AE occurring in patients with malignant B-cell lymphocytosis who received rituximab. Patients with a > or = 3 x 10(9)/L absolute lymphocyte count (ALC) receiving rituximab from 1998 to 1999 or participating in a phase I study of rituximab and interleukin-12 were reviewed. The AE occurring on the day of rituximab, the treatment provided (including hospitalization), and the subsequent ALC responses were recorded. Twenty-seven patients were identified; 14 had NHL, one Waldenstrom's macroglobulinemia, and 12 patients had chronic lymphocytic leukemia. The baseline median ALC was 9.58 x 10(9)/L (mean, 49.31; range, 3.56-380.95). All patients received rituximab as an outpatient. There were only two AE > or = grade 3. One patient was hospitalized for 1 day for i.v. fluids to treat an increase in creatinine that occurred with tumor lysis. A second patient developed a pulmonary syndrome five days after day 1 rituximab and required mechanical ventilation, but had no long-term lung toxicity. This study demonstrates that patients with high numbers of circulating blood B-lymphocytes can usually safely receive rituximab as outpatients. Patients who experience a rapid drop in ALC should be monitored closely for tumor lysis and the pulmonary syndrome.

13
UI - 11911422
AU - Tuset E; Matutes E; Brito-Babapulle V; Morilla R; Catovsky D
TI - Immunophenotype changes and loss of CD52 expression in two patients with relapsed T-cell prolymphocytic leukaemia.
SO - Leuk Lymphoma 2001 Nov-Dec;42(6):1379-83
AD - Academic Department of Haematology and Cytogenetics, The Royal Marsden NHS Trust, London, UK.
T-cell prolymphocytic leukaemia (T-PLL) is an aggressive disease often resistant to conventional chemotherapy. Long lasting remissions with the monoclonal antibody CAMPATH-1H (anti-CD52) have been documented. We describe two unusual T-PLL patients treated successfully first with CAMPATH-1H in whom, at the time of relapse, the cells underwent a phenotypic switch with loss of CD52 expression. In one of them, cytogenetic analysis demonstrated the same chromosome abnormalities in the cells at diagnosis and relapse. The reasons for the immunophenotypic changes are unknown but it is likely that loss of CD52 antigen expression contributed to the resistance to CAMPATH-1H in one of the patients when re-treated.

14
UI - 12042041
AU - Husebekk A; Fellowes V; Read EJ; Williams J; Petrus MJ; Gress RE; Fowler
TI - DH Selection and expansion of T cell from untreated patients with CLL: source of cells for immune reconstitution?
SO - Cytotherapy 2000;2(3):187-93
AD - Department of Transfusion Medicine, Clinical Center, National Cancer Institute/NIH, Bethesda, MD, USA.
BACKGROUND: Lymphocyte-derived malignancies can be treated with combinations of drugs that efficiently eradicate normal and malignant lymphocytes. Lack of T lymphocytes after treatment of B lymphocyte CLL (B-CLL) makes the patients susceptible to serious infections and may limit the benefit of the therapy. The aim of the study was to purify and culture-expand normal T lymphocytes from B-CLL patients prior to therapy. These cells could be frozen and given to the patients in the lymphopenic period post-chemotherapy. METHODS: T lymphocytes were isolated from the mononuclear cell apheresis products from five patients with previously untreated B-CLL. The apheresis products were red-cell depleted by density gradient centrifugation. B-lymphocyte purging was performed by incubating with MAbs to four different B-cell epitopes, followed by magnetic-bead depletion. One round of negative selection removed >90% of the B lymphocytes. The T-lymphocyte enriched cell suspension was cultured for 10/11 days in the presence of IL-2 and the anti-T cell receptor Ab OKT3. In addition, in some cultures anti-CD22 ricin immunotoxin was added. RESULTS: T cells from CLL patients expanded 4.7-21-fold over a 10/11 days culture interval. After culture, CLL cells could no longer be identified by flow cytometric evaluation. The cultured T lymphocytes were predominantly CD8(+), and were capable of lysing autologous CLL cells through a fas-dependent mechanism. DISCUSSION: Selection and expansion of T lymphocytes by this method may represent a strategy for enhancing immunity in the lymphopenic period following CLL treatment.

15
UI - 12113063
AU - Dumont FJ
TI - CAMPATH (alemtuzumab) for the treatment of chronic lymphocytic leukemia and beyond.
SO - Expert Rev Anticancer Ther 2002 Feb;2(1):23-35
AD - Merck Research Laboratories, RY80W107, 126 East Lincoln Avenue, Rahway 07065, NJ, USA. Francis_Dumont@merck.com
CAMPATH (CAMPATH-1H, alemtuzumab, MabCAMPATH), is a lymphocyte-depleting humanized monoclonal antibody that was recently approved in the USA and Europe for the treatment of chronic lymphocytic leukemia (CLL). It targets CD52--a small glycosylphosphatidylinositol-anchored glycoprotein that is highly expressed on normal T- and B-lymphocytes and on a large proportion of lymphoid cell malignancies--but not on hematopoietic progenitor cells. CAMPATH was shown to be effective against CLL refractory to chemotherapy with an acceptable toxicity profile. CAMPATH is also active against T-cell prolymphocytic leukemia and has been extensively used to prevent graft-versus-host disease associated with bone marrow transplantation. CAMPATH is owned by ILEX Pharmaceuticals LP and distributed by Schering AG and its US affiliate Berlex Laboratories.

16
UI - 11902141
AU - Zupo S; Cutrona G; Mangiola M; Ferrarini M
TI - Role of surface IgM and IgD on survival of the cells from B-cell chronic lymphocytic leukemia.
SO - Blood 2002 Mar 15;99(6):2277-8

17
UI - 12167696
AU - Stilgenbauer S; Dohner H
TI - Campath-1H-induced complete remission of chronic lymphocytic leukemia despite p53 gene mutation and resistance to chemotherapy.
SO - N Engl J Med 2002 Aug 8;347(6):452-3

18
UI - 11874079
AU - Papadopoulos N; Simopoulos C; Kotini A; Lambropoulou M; Tolparidou I;
TI - Tamiolakis D Differential expression of alpha-smooth muscle actin molecule in a subset of bone marrow stromal cells, in b-cell chronic lymphocytic leukemia, autoimmune disorders and normal fetuses.
SO - Eur J Gynaecol Oncol 2001;22(6):447-50
AD - Department of Histology-Embryology, Democritus University of Thrace, Alexandroupolis, Greece.
Lymphocytes are a constituent of normal marrow. Both B and T lymphocytes are derived from bone marrow stem cells. Lymphocytes are found in normal marrow as single cells and in lymphoid aggregates or follicles. Lymphocytes and precursors are particularly prominent in bone marrow from children in which they may account for up to 40% of the bone marrow cells. The development of hematopoetic cells within the bone marrow (BM) occurs in intimate association with cells of the bone marrow microenvironment. This phenotypically diverse population of connective tissue-type cells includes fibroblasts, macrophages, adipocytes and endothelial cells and, collectively, represents the stromal tissue of the bone marrow. The presence of myoid cells in human bone marrow has been observed during hemopoiesis in embryonic life, whereas during adult life, it is strictly related to different pathologic conditions such as metastatic carcinoma, Hodgkin's disease, hairy cell leukemia and chronic myelo-proliferative diseases. Under normal circumstances, lymphoid cells may constitute up to 20% of the population of nucleated cells in the bone marrow. However, there may be an absolute or a relative increase, the latter due to a reduction in hematopoietic tissue, as in some skeletal areas in advancing age, or in hypoplastic conditions. The aim of this study was to examine the presence, distribution and quantitation of cells expressing alpha-smooth muscle actin in the stroma of the BM of patients with nodular type b-cell chronic lymphocytic leukemia (B-CLL), patients with autoimmune disorders and embryos (gestational age 15 to 25 weeks). For this reason, we investigated the presence of myoid cells (MCs) in a series of 20 trephine bone marrow biopsies from adult patients and ten fetal specimens of the spine and femur, using a monoclonal antibody recognizing alpha-smooth muscle actin, a contractile microfilament expressed exclusively by smooth muscle cells, myofibroblasts and related cells. The results of our study showed that: 1. BM stromal myoid cells represent a distinct subpopulation of reticular cells in the bone marrow, undergoing cytoskeletal remodeling in response to various stimuli (fetuses). 2. The appearance of BM stromal myoid cells is not only seen as a characteristic feature in B-CLL, but is also seen, to a lesser degree, in the stroma of bone marrow in patients with autoimmune disorders. 3. Stromal cells with phenotypic smooth muscle features appear in bone marrow during pathological situations in a manner reminiscent of what occurs during normal development.

19
UI - 11956701
AU - Ron E
TI - Ionizing radiation and cancer risk: evidence from epidemiology.
SO - Pediatr Radiol 2002 Apr;32(4):232-7; discussion 242-4
AD - Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, 6120 Executive Boulevard, Rockville, MD 20852, USA. eron@mail.nih.gov

20
UI - 12100030
AU - Galea HR; Bridoux F; Aldigier JC; Paraf F; Bordessoule D; Touchard G;
TI - Cogne M Molecular study of an IgG1kappa cryoglobulin yielding organized microtubular deposits and glomerulonephritis in the course of chronic lymphocytic leukaemia.
SO - Clin Exp Immunol 2002 Jul;129(1):113-8
AD - Department of Immunology (CNRS UMR6101), University Hospital, Limoges, France.
Glomerulonephritis with organized microtubular monoclonal immunoglobulin deposits (GOMMID) and glomerulonephritis related to type I cryoglobulin are well-known but rare complications of B cell derived chronic lymphocytic leukaemia. In these disorders, monoclonal Ig have never been studied at the molecular level. We conducted a pathological and molecular analysis in a patient with chronic lymphocytic leukaemia, glomerulonephritis and a single circulating monoclonal Ig. Unusual IgG1kappa kidney deposits were observed. The heavy and light chain variable region sequences of that cryoprecipitating monoclonal Ig were characterized. Light microscopy revealed glomerulonephritis typical of cryoglobulinaemia, with neutrophil and macrophage infiltration, endocapillary hyperplasia and few protein thrombi. Electron microscopic study clearly evidenced numerous subepithelial mixed granular and organized deposits with a unique microtubular organization, reminiscent of the GOMMID. The Ig molecule sequence revealed alterations of charge and hydrophobicity potentially promoting a crystal-like aggregation and the aggregation of microtubules.This description suggests that common mechanisms are involved in various forms of precipitation and/or deposition of complete Ig molecules, with a variable extent of organization and with a possible overlap between pathological patterns of either glomerulonephritis with microtubular deposits or type I cryoglobulinic glomerulonephritis.

21
UI - 12166460
AU - Anonymous
TI - High-dose chemotherapy plus allogeneic stem cells to treat chronic lymphocytic leukemia or small lymphocytic lymphoma.
SO - TEC Bull (Online) 2002 Apr 5;19(1):5-9

22
UI - 12029570
AU - Pigeaud-Klessens ML; van der Valk P
TI - Multiple neoplasms: a case report.
SO - Orbit 2002 Jun;21(2):145-8
AD - Department of Ophthalmology, VU-Medical Center, Amsterdam, The Netherlands.
Patients diagnosed with Chronic Lymphocytic Leukemia (CLL) have an increased risk of developing second primary cancers. However, as far as we know, more than one type of subsequent malignancy in one patient has not been described. We report a case of two different skin cancers following CLL. A 68-year-old female patient, in whom CLL was diagnosed 5 years earlier, presented with a pigmentation in the left lower eyelid. Biopsy showed a melanoma. The tumor was excised and histopathological examination revealed a superficial spreading melanoma. Half a year later, a new pigmented tumor was seen in the transplant of the left lower eyelid. Biopsy was performed and histopathological examination showed an intraepithelial squamous cell carcinoma. This was treated with 5 fluorouracil 1% eyedrops.

23
UI - 12145685
AU - Gine E; Bosch F; Villamor N; Rozman M; Colomer D; Lopez-Guillermo A;
TI - Campo E; Montserrat E Simultaneous diagnosis of hairy cell leukemia and chronic lymphocytic leukemia/small lymphocytic lymphoma: a frequent association?
SO - Leukemia 2002 Aug;16(8):1454-9
AD - Institute of Hematology and Oncology, Department of Hematology, Hospital Clinic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
The association of hairy cell leukemia (HCL) with other neoplasms, mainly non-Hodgkin's lymphomas, is well known. However, the simultaneous diagnosis of HCL and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is rare, with only few cases of such an association having been reported. We describe three patients with a well-characterized HCL in whom a CLL/SLL population was detected. Of note, these cases represent a significant proportion (11.5%; 95% CI: 0% to 24%) of the total number of HCL cases diagnosed in our institution during the same period of time. All three patients were treated with deoxycoformycin. They achieved a complete response of the HCL, whereas the CLL/SLL population persisted in all cases. The immunoglobulin gene rearrangement analysis, in two informative cases, suggested that the HCL and CLL/SLL populations arose from different B cell clones. This study indicates that the association of HCL and CLL/SLL might be much more frequent than previously recognized. Therefore, a large panel of monoclonal antibodies, including those necessary to detect CLL/SLL, should be employed when studying patients with HCL.

24
UI - 12107557
AU - Hamblin T
TI - Chronic lymphocytic leukaemia: one disease or two?
SO - Ann Hematol 2002 Jun;81(6):299-303
AD - Department of Haematology and Oncology, Royal Bournemouth Hospital, Castle Lane East, Bournemouth BH7 7DW, UK. terjoha@aol.com
The discovery that the presence or absence of somatic mutations in immunoglobulin variable region genes separates chronic lymphocytic leukaemia (CLL) into benign and malignant subsets has raised the question as to whether CLL is one disease or two. Although there are similarities between morphology, immunophenotype and gene expression profiles between the two subsets, the very different natural histories and the immutability of one to the other suggests two diseases deriving from a common stem. It is proposed that a single intrinsic defect of B-lymphocytes dictates a particular reaction pattern -- partially activated, anergic and anti-apoptotic -- when the B-cell receptor is stimulated. The difference between the two subsets is determined by whether the receptor is stimulated conventionally within the germinal centre or unconventionally, outside it. The further differences, including CD38 expression and chromosomal abnormalities, are the consequences of further ongoing stimulation of the receptor leading to low-grade proliferation.

25
UI - 12111110
AU - Martell RE; Peterson BL; Cohen HJ; Petros WP; Rai KR; Morrison VA; Elias
TI - L; Shepherd L; Hines J; Larson RA; Schiffer CA; Hurwitz HI Analysis of age, estimated creatinine clearance and pretreatment hematologic parameters as predictors of fludarabine toxicity in patients treated for chronic lymphocytic leukemia: a CALGB (9011) coordinated intergroup study.
SO - Cancer Chemother Pharmacol 2002 Jul;50(1):37-45
AD - Geriatrics Research, Education and Clinical Center, Veterans Affairs Medical Center and Hematology/Oncology Division, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
PURPOSE: Fludarabine is a renally excreted agent that is an effective treatment for chronic lymphocytic leukemia (CLL), a disease predominantly of the elderly. We sought to determine whether age, renal function or pretreatment hematologic status predicted toxicity of fludarabine treatment for CLL. METHODS: We evaluated 192 patients with previously untreated B-cell CLL who were entered onto the fludarabine treatment arm (25 mg/m(2) daily for 5 days every 28 days) of CALGB study 9011, an intergroup study with participation from SWOG, CTG/NCI-C and ECOG. Patients were required to have serum creatinine within 1.5 times normal. Hematologic indices and infections were recorded during the first 28-day cycle of treatment. A time-to-toxicity endpoint was evaluated over the entire course of fludarabine treatment. Creatinine clearance (CrCl(est)) was estimated using serum creatinine, age and body mass index. RESULTS: The median age was 64 years (range 37-87 years) and median CrCl(est) was 62 ml/min (range 27-162 ml/min, interquartile range 52-79 ml/min). We found no association between age and incidence of hematologic toxicity or infection during the first cycle of treatment. There was a strong association between CrCl(est) and the time-to-toxicity endpoint. Patients with CrCl(est) below 80 ml/min had increased incidence of toxicity during their treatment course ( P<0.0001). Pretreatment anemia, thrombocytopenia and Rai stage were highly associated with the incidence of neutrophil toxicity and grade III/IV hematologic toxicities during the first cycle of treatment ( P<0.0001). CONCLUSIONS: Patient age was not an independent risk factor for fludarabine-related toxicity, but CrCl(est) was associated with time to toxicity.

26
UI - 12138643
AU - Telek B; Rejto L; Kiss A; Batar P; Remenyi G; Rak K; Udvardy M
TI - [Experience with fludarabine treatment and review of the literature]
SO - Orv Hetil 2002 Jun 16;143(24):1459-65
AD - Debreceni Orvos- es Egeszsegtudomanyi Centrum, II. Belgyogyaszati Klinika, Hematologiai Tanszek.
INTRODUCTION: Fludarabine is the most commonly used purine analog, its mechanism of action is complex. Fludarabine inhibits DNA synthesis, acts on non-dividing (G0 phase) cells influencing apoptosis. PATIENTS, RESULTS, CONCLUSIONS: In our institute 47 patients were treated with fludarabine or fludarabine based combination chemotherapy. Fludarabine was given in 19 patients with chronic lymphocytic leukaemia (CLL), complete remission (CR) was achieved in one case, partial remission (PR) was obtained in 10 patients. Fludarabine was more effective in patients who received less intensive chemotherapy prior to fludarabine therapy and in those patients who had less advanced diseases. Elderly patients (over sixty years of age) also responded to fludarabine therapy. Fludarabine and cyclophosphamide combination (FCy) were used in three lymphocytic lymphoma patients, two of them obtained PR, in the third case the disease progressed. Fludarabine + mitoxantrone (Novantrone) + dexamethasone (FND) regimen was administered in nine patients who were previously heavily treated (one patient with B-CLL, one with T-CLL, one with peripheral T-cell lymphoma and six with indolent B-cell lymphoma). More patients and longer follow up is needed to determine the efficacy of FCy and FND protocol. FLAG-IDA (fludarabine, high dose Ara-C, granulocyte colony-stimulating factor, idarubicin) was applied in 16 acute leukaemia patients with poor prognosis including therapy refractory and relapsing cases. Three CR and two PR, one CR and three PR was achieved in nine patients with acute myeloid leukaemia and in seven patients with acute lymphoid leukaemia, respectively. For this reason, despite the short period of remission, this regimen can be recommended to patients who are candidate for stem cell transplantation.

27
UI - 12162692
AU - Onciu M; Schlette E; Bueso-Ramos C; Medeiros LJ
TI - Leukemic mantle cell lymphoma with cells resembling prolymphocytes.
SO - Am J Clin Pathol 2002 Aug;118(2):305-6; discussion 306

28
UI - 12135682
AU - Altes A; Sierra J; Esteve J; Martin-Henao G; Marin P; Sureda A; Briones
TI - J; Martino R; Villamor N; Colomer D; Carreras E; Garcia J; Brunet S; Montserrat E CD34+-enriched-CD19+-depleted autologous peripheral blood stem cell transplantation for chronic lymphoproliferative disorders: high purging efficiency but increased risk of severe infections.
SO - Exp Hematol 2002 Jul;30(7):824-30
AD - Clinical Hematology Division, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain. aaltesh@hsp.santpau.es
OBJECTIVE: The main objective of this work was to decrease the incidence of relapse after autologous stem cell transplantation with a "double purging" procedure. METHODS: We used a "positive" (CD34) and "negative" (CD19) double selection method to improve the efficacy of "single purging" of hematopoietic harvests in poor-prognosis lymphoproliferative disorders. All patients included in the study had a positive molecular marker of their disease. Minimal residual disease (MRD) was studied by flow cytometry and PCR techniques during the purging procedure and after transplantation. RESULTS: Twenty-six patients fulfilled entry criteria. Median age of patients was 50 years (range: 33-66); 17 were male and 9 female. Thirteen (50%) of the patients mobilized an adequate number of CD34+ cells (>or=3 x 10(6)/kg) to proceed with the double-selection protocol. Twelve of the 13 harvests became PCR negative after purging. Ten patients were grafted with the selected products and all but one engrafted without delay. After a median follow-up of 30 months, 2 of 10 patients suffered a molecular relapse at 7 and 19 months respectively. The earlier relapse was observed in the patient who received a MRD+ product. Only one patient experienced a clinical relapse. Three patients died due to obliterans bronchiolitis, pneumococcal sepsis, and septic shock of unknown origin, respectively, and three others presented life-threatening infections. CONCLUSION: Therefore, CD34+/CD19+ positive/negative selection is an effective purging approach in patients with chronic lymphoproliferative disorders. This favorable effect is, however, counterbalanced by the high frequency of life-threatening infections.

29
UI - 12091354
AU - Yuille MR; Condie A; Hudson CD; Bradshaw PS; Stone EM; Matutes E;
TI - Catovsky D; Houlston RS ATM mutations are rare in familial chronic lymphocytic leukemia.
SO - Blood 2002 Jul 15;100(2):603-9
AD - Academic Department of Haematology and Cytogenetics, Institute of Cancer Research, Sutton, Surrey, United Kingdom.
It is now recognized that a subset of B-cell chronic lymphocytic leukemia (CLL) is familial. The genetic basis of familial CLL is poorly understood, but recently germ line mutations in the Ataxia Telangiectasia (ATM) gene have been proposed to confer susceptibility to CLL. The evidence for this notion is, however, not unequivocal. To examine this proposition further we have screened the ATM gene for mutations in CLLs from 61 individuals in 29 families. Truncating ATM mutations, including a known ATM mutation, were detected in 2 affected individuals, but the mutations did not cosegregate with CLL in the families. In addition, 3 novel ATM missense mutations were detected. Common ATM missense mutations were not overrepresented. The data support previous observations that ATM mutation is associated with B-CLL. However, ATM mutations do not account for familial clustering of the disease.

30
UI - 12091358
AU - Rawstron AC; Green MJ; Kuzmicki A; Kennedy B; Fenton JA; Evans PA;
TI - O'Connor SJ; Richards SJ; Morgan GJ; Jack AS; Hillmen P Monoclonal B lymphocytes with the characteristics of "indolent" chronic lymphocytic leukemia are present in 3.5% of adults with normal blood counts.
SO - Blood 2002 Jul 15;100(2):635-9
AD - Haematological Malignancy Diagnostic Service, Academic Unit of Haematology and Oncology, Algernon Firth Building, University of Leeds, United Kingdom. andy.rawstron@hmds.org.uk
Molecular and cellular markers associated with malignant disease are frequently identified in healthy individuals. The relationship between these markers and clinical disease is not clear, except where a neoplastic cell population can be identified as in myeloma/monoclonal gammopathies of undetermined significance (MGUS). We have used the distinctive phenotype of chronic lymphocytic leukemia (CLL) cells to determine whether low levels of these cells can be identified in individuals with normal complete blood counts. CLL cells were identified by 4-color flow cytometric analysis of CD19/CD5/CD79b/CD20 expression in 910 outpatients over 40 years old. These outpatients were age- and sex-matched to the general population with normal hematologic parameters and no evident history of malignant disease. CLL phenotype cells were detectable in 3.5% of individuals at low level (median, 0.013; range, 0.002- 1.458 x 10(9) cells/L), and represented a minority of B lymphocytes (median, 11%; range, 3%-95%). Monoclonality was demonstrated by immunoglobulin light-chain restriction in all cases with CLL phenotype cells present and confirmed in a subset of cases by consensus-primer IgH-polymerase chain reaction. As in clinical disease, CLL phenotype cells were detected with a higher frequency in men (male-to-female ratio, 1.9:1) and elderly individuals (2.1% of 40- to 59-year-olds versus 5.0% of 60- to 89-year-olds, P =.01). The neoplastic cells were identical to good-prognosis CLL, being CD5+23+20(wk)79b(wk)11a(-)22(wk)sIg(wk)CD38-, and where assessed had a high degree (4.8%-6.6%) of IgH somatic hypermutation. The monoclonal CLL phenotype cells present in otherwise healthy individuals may represent a very early stage of indolent CLL and should be useful in elucidating the mechanisms of leukemogenesis.

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