National Cancer Institute®
Last Modified: May 1, 2002
UI - 11960343
AU - Oudat R; Keating MJ; Lerner S; O'Brien S; Albitar M
TI - Significance of the levels of bone marrow lymphoid infiltrate in chronic lymphocytic leukemia patients with nodular partial remission.
SO - Leukemia 2002 Apr;16(4):632-5
AD - Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Patients with chronic lymphocytic leukemia (CLL) are considered in nodular partial remission (nPR) when they are in remission but bone marrow biopsies show rare nodules. The significance of the level of residual disease in nPR is not known. We studied 91 previously untreated CLL patients who were treated with fludarabine alone, fludarabine with prednisone, or fludarabine with cyclophosphamide and achieved nPR at the end of six courses. We compared bone marrow lymphoid infiltration before therapy and at the end of three and six courses of therapy as evaluated by a pathologist in retrospective fashion with that of the routine evaluation at the time of performing bone marrow biopsy. We then compared these results with those obtained by computer-aided histomorphometry in 28 patients in nPR. There was significant correlation (P < 0.05) between pathologists as well as between pathologists and histomorphometry. Upon correlation with clinical characteristics, there was significant correlation (P 0.01) between marrow involvement before therapy and white blood cell counts (wbc), hemoglobin (hgb), absolute lymphocyte counts, and beta2-microglobulin (beta2-m) but none of these parameters correlated with the lymphoid infiltrate at the end of three or six courses of therapy. more importantly, lymphoid infiltration after three and six courses did not correlate with time to progression (ttp) or overall survival (os). however, patients with >70% marrow involvement before therapy had a significantly shorter TTP (P = 0.02). All 91 patients showed similar results. However, we found reverse correlation between marrow lymphoid infiltrate at the end of three courses and OS (P = 0.01).
UI - 11960344
AU - Bende RJ; Aarts WM; Pals ST; van Noesel CJ
TI - Immunoglobulin diversification in B cell malignancies: internal splicing of heavy chain variable region as a by-product of somatic hypermutation.
SO - Leukemia 2002 Apr;16(4):636-44
AD - Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands.
In this study we describe alternative splicing of somatically mutated immunoglobulin (Ig) variable heavy chain (V(H)) genes in three distinct primary B cell non-Hodgkin's lymphomas (B-NHL). In two V4-34 expressing lymphomas, ie a post-germinal center type B cell chronic lymphocytic leukemia (B-CLL) and a follicular lymphoma (FL), internally spliced V(H) gene transcripts were found in which a sequence stretch of 116 bp between the framework region 1 (FR1) and complementarity determining region 2 (CDR2) had been deleted. We provide evidence that for this alternative IgV(H) mRNA processing a known cryptic 5' splice donor site and a previously unidentified cryptic 3' splice acceptor site were used. Site-directed mutagenesis showed that the cryptic 3' splice acceptor site had been activated by specific somatic point mutations. The B-CLL further harbored a triplication of the rearranged JH3 gene segment including the putative N region and part of the JH3-JH4 intron sequence. This triplication probably took place via a repeated mechanism of DNA double strand break followed by homologous recombination, a mechanism which was recently proposed also involved in the somatic hypermutation process and is compatible with the post-germinal center derivation of this B-CLL. Finally, in a V4-34 expressing diffuse large B cell lymphoma, we observed alternative IgV(H) mRNA processing using the same cryptic 5' splice donor site and the normal splice acceptor site of the CH1-C(mu) exon. The significance of alternative IgV(H) processing in B cell malignancies and as a potential mechanism of somatic Ig diversification is discussed.
UI - 10779422
AU - Mauro FR; Foa R; Cerretti R; Giannarelli D; Coluzzi S; Mandelli F;
TI - Girelli G Autoimmune hemolytic anemia in chronic lymphocytic leukemia: clinical, therapeutic, and prognostic features.
SO - Blood 2000 May 1;95(9):2786-92
AD - Dipartimento di Biotecnologie Cellulari ed Ematologia and Dipartimento di Medicina Sperimentale, University "La Sapienza," Rome, Italy. firstname.lastname@example.org
Fifty-two cases of autoimmune hemolytic anemia (AHA) were observed within a series of 1203 patients (4.3%) with chronic lymphocytic leukemia (CLL) followed at a single institution. Nineteen were observed at the time of CLL diagnosis and 33 during the clinical follow-up. Ninety percent of the patients with CLL/AHA showed active CLL and 25% had been treated previously. The antierythrocyte autoantibody (AeAb) was an IgG in 87% of cases and an IgM in 13%. A lymphocyte count more than 60 x 10(9)/L (P <.00001), age above 65 years (P <.01), and male gender (P <.01) emerged as independent parameters that correlated significantly with an increased rate of AHA at CLL diagnosis. Patients previously treated with chlorambucil (CB) plus prednisone (PDN) and with fludarabine plus PDN showed a similar rate of AHA (1.8% and 2.5%, respectively). After steroid therapy associated with CB in case of active CLL, 70% of patients achieved the complete disappearance of the AeAb. The actuarial AHA relapse-free survival probability was 54% at 5 years and the median survival probability after AHA was 41 months. Infections represented the main cause of morbidity and mortality. IgG AHA and the occurrence of AHA at the same time of CLL diagnosis emerged as independent factors significantly correlated with a better survival probability of AHA/CLL patients. Taken together, this study indicates that in CLL, AHA is a rare event with no independent effect on survival for which steroids, associated with CB if required, and a careful management of infections may successfully control the 2 conditions. Cooperative studies are needed to better define the optimal steroid schedule and the therapeutic role of other immunosuppressive agents and splenectomy. (Blood. 2000;95:2786-2792)
UI - 11822361
AU - Iannitto E; Ammatuna E; Marino C; Cirrincione S; Greco G; Mariani G
TI - Sustained response of refractory chronic lymphocytic leukemia in progression complicated by acute hemolitic anemia to anti-CD20 monoclonal antibody.
SO - Blood 2002 Feb 1;99(3):1096-7
UI - 11920165
AU - Parrado A; Noguera ME; Delmer A; McKenna S; Davies J; Le Gall I; Bentley
TI - P; Whittaker JA; Sigaux F; Chomienne C; Padua RA Deregulated expression of promyelocytic leukemia zinc finger protein in B-cell chronic lymphocytic leukemias does not affect cyclin A expression.
SO - Hematol J 2000;1(1):15-27
AD - Laboratoire de Biologie Cellulaire Hematopoietique, Universite Paris 7, France. email@example.com
INTRODUCTION: The promyelocytic leukemia zinc finger (PLZF) gene encodes a transcription factor expressed in myeloid, lymphoid and CD34(+) progenitor cells. Structurally related to BCL-6, which is involved in human lymphoma, PLZF may have a role in proliferation, differentiation and survival of hematopoietic cells, that could be mediated by transcriptional repression of the cyclin A gene. MATERIALS AND METHODS: Quantitative competitive reverse transcription-polymerase chain reaction was used to measure the levels of expression of PLZF and cyclin A in normal leukocyte subsets (including CD19(+) lymphocytes, n=21) and malignant B lymphocytes (including B-chronic lymphocytic leukemias [B-CLL], n=63). Results obtained with this method were confirmed by Western and Northern blot analysis. Transactivation assays were performed using an expression construct for PLZF and two cyclin A promoter luciferase reporters in an Epstein-Barr virus (EBV)-transformed B-cell line. Cyclin A expression, cell growth kinetics, and cell cycle were analysed in stable clones of the Burkitt lymphoma (BL) B-cell line DG75 with inducible expression of PLZF, generated using the tetracycline-regulated expression system. RESULTS: Expression of PLZF was 100-fold downregulated in 90% B-CLL (56/63) compared to normal B lymphocytes (P<0.001). B-CLL patients with the highest levels of PLZF had a poorer survival (P<0.013). In transactivation assays, PLZF inhibited the activity of the cyclin A reporters by 50%, demonstrating that PLZF can repress cyclin A expression in non-malignant B lymphocytes. However, in B-CLL patients, the level of cyclin A expression was found to be within the normal range. Altered PLZF function in B lymphoid malignancies was further corroborated in the PLZF-regulatable DG75 clones, where induction of PLZF expression did not significantly alter the levels of cyclin A expression, the cell growth kinetics, or the cell cycle phase distribution. CONCLUSION: The lower survival of patients with the highest levels of PLZF suggests that this protein may be a marker of progression in B-CLL. The absence of co-ordinated regulation of PLZF and cyclin A genes in B-CLL and in a malignant B-cell line may indicate a loss of cyclin A control by PLZF in B-CLL and other B-cell disorders. Deregulation of PLZF could thus play a role in B-cell malignancy.
UI - 11920168
AU - Hetet G; Dastot H; Baens M; Brizard A; Sigaux F; Grandchamp B; Stern MH
TI - Recurrent molecular deletion of the 12p13 region, centromeric to ETV6/TEL, in T-cell prolymphocytic leukemia.
SO - Hematol J 2000;1(1):42-7
AD - Unite INSERM U409 and Centre de recherche Claude Bernard, Hopital Bichat, Paris, France.
INTRODUCTION: T-cell prolymphocytic leukemia is a rare form of mature leukemia which occurs in adults and in younger patients suffering ataxia telangiectasia. Among others, complex chromosome aberrations of chromosome 12 have been described in this disease. We searched for deletions of the 12p13 region as the result of these chromosome rearrangements. MATERIAL AND METHODS: Paired leukemic and non-leukemic cells were obtained from a series of 21 patients suffering T-cell prolymphocytic leukemia. Loss of heterozygosity was searched for by microsatellite typing using a fluorescent automated laser DNA sequencer to analyze the amplification products. Proteins were analyzed by Western blot. Southern blot analysis of one patient was conducted. RESULTS AND CONCLUSION: Loss of heterozygosity of the 12p13 region, including the ETV6 and CDKN1B genes, was detected in nine of these 21 cases (43%). Western and Southern blot analyses of one case demonstrated a biallelic deletion which did not include ETV6. Taken together, our results defined a minimal region of deletion of less than one Mb flanked by the markers b312C2T7 and D12S320, excluding ETV6 as a candidate gene. Deletion of the 12p13 region is thus a highly recurrent genetic event in T-cell prolymphocytic leukemia.
UI - 11760820
AU - Roberts JC; Roberts GH
TI - B-Prolymphocytic leukemia: a case study.
SO - Clin Lab Sci 2001 Fall;14(4):233-7
AD - St Francis Medical Center, Monroe LA 71210, USA.
The case study reported is of a patient initially misdiagnosed as chronic lymphocytic leukemia. Immunophenotyping studies ultimately identified the nature of the disease as B-cell prolymphocytic leukemia with concomitant warm autoimmune hemolytic anemia. The leukemia and hemolytic anemia were refractory to all conventional treatments administered. The patient survived a significantly shorter period of time than the median time of three years reported in the literature. The patient expired from complications resulting from B-cell PLL, warm autoimmune hemolytic anemia, and combination chemotherapy.
UI - 11921024
AU - Smith E; Hallman JR; Pardasani A; McMichael A
TI - Multiple herpetic whitlow lesions in a patient with chronic lymphocytic leukemia.
SO - Am J Hematol 2002 Apr;69(4):285-8
AD - Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
Herpetic whitlow, a herpes simplex virus infection involving the digits, most commonly presents as a vesicular eruption involving a single digit. Diagnosis of herpetic whitlow can usually be made with the history of exposure, the characteristic vesicular eruption, and a positive Tzank smear and/or viral culture. We describe a case of herpetic whitlow in a patient finishing 6 cycles of chemotherapy for refractory chronic lymphocytic leukemia that presented with a bilateral, multi-digit, crusted eruption of the hands. This is an illustrative case of an immunocompromised host status altering appearance and course of cutaneous disease such that the history and physical exam alone may not help in diagnosing atypical presentations of herpetic infections. This case underscores the necessity for clinico-histopathologic correlation. Copyright 2002 Wiley-Liss, Inc.
UI - 11880188
AU - Bessler H; Bergman M; Salman H; Cohen AM; Fenig E; Djaldetti M
TI - Factor(s) released from irradiated B-CLL cells induce apoptosis in leukemic lymphocytes.
SO - Cancer Lett 2002 May 8;179(1):103-8
AD - Laboratory for Immunology and Hematology Research, Rabin Medical Center, Golda Campus, Petah Tiqva and the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Photon irradiation of peripheral blood lymphocytes from 25 patients with untreated B-chronic lymphocytic leukemia (B-CLL) induced an increase in apoptotic response by 270%. No significant increase in apoptosis was observed after irradiation of peripheral blood mononuclear cells from 15 healthy volunteers. Supernatants (sups) derived from irradiated leukemic cells incubated with non-irradiated autologous cells induced a 75% enhancement in number of apoptotic cells, as compared with sups from non-irradiated CLL cells. The level of tumor necrosis factor alpha, a cytokine known to prevent apoptosis, was reduced in the sups of irradiated CLL cells in comparison to that of non-irradiated lymphocytes. The interleukin (IL)-10 level, an IL reported to induce apoptosis, was similar in the sups of irradiated and non-irradiated lymphocytes from B-CLL patients. No change in IL-2 levels was observed. The significance of these findings and the role of factor(s) in the sups of irradiated leukemic lymphocytes as inducers of apoptosis are discussed.
UI - 11917501
AU - Hara T; Choraku M; Hashimoto N; Kosaka M; Wakatsuki S
TI - [A longer prognosis of B-CLL with mutation of IgVH gene]
SO - Nippon Naika Gakkai Zasshi 2002 Feb 10;91(2):743-5
AD - Tokushima Prefecture Hospital of Kaifu, Tokushima.
UI - 11979092
AU - Asplund SL; McKenna RW; Howard MS; Kroft SH
TI - Immunophenotype does not correlate with lymph node histology in chronic lymphocytic leukemia/small lymphocytic lymphoma.
SO - Am J Surg Pathol 2002 May;26(5):624-9
AD - University of Texas Southwestern Medical School, Dallas, Texas, USA. Sheryl.Asplund@UTSouthwestern.edu
The presence of prominent proliferation centers (PCs) in lymph nodes (LNs) involved with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has been associated with atypical blood smear morphology. Atypical CLL has in turn been associated with variant immunophenotypes and poor outcome. However, the significance of abundant PCs remains controversial. We have analyzed the flow cytometric immunophenotypic features of 54 CLL/SLL LNs and correlated these findings with the morphologic and clinical features. The LN histology was assigned to one of two groups based on the prominence of PCs: Group I LNs contained scattered small, sometimes ill-defined PCs in a background of monotonous small round lymphocytes. Group II LNs had increased numbers and sizes of PCs resulting in an obviously nodular appearance at low magnification. Flow cytometry was performed using broad three- or four-color antibody panels that included anti-CD5, CD19, CD20, CD23, CD38, FMC7, and surface immunoglobulin (sIg). The intensity of expression of all markers was scored semi-quantitatively using isotypic controls and internal positive and negative populations as standards. There were 32 group I and 22 group II LNs that, by definition, expressed CD19, CD5, and CD23. Little variability was seen in the intensity of expression of CD19, and the majority of cases expressed CD23 brightly. CD5 varied from very dim to an intensity similar to that of normal T cells; the majority had an intermediate level of CD5 expression. FMC7 was expressed to a significant extent in 11 cases (21%). CD20 was relatively bright in 17 cases (32%). sIg was dim in 29 cases (55%) and moderate or bright in 24 cases (45%). CD38 was expressed significantly in 25 cases (47%). There was no correlation between histologic group and intensity of expression of any individual marker or with an immunophenotypic atypia score based on FMC7, CD20, and sIg. There was also no correlation between morphology or immunophenotype and clinical features. These findings do not support the interpretation that the prominence of proliferation centers in CLL/SLL LNs defines biologically distinct subtypes.
UI - 11418459
AU - Rawstron AC; Kennedy B; Evans PA; Davies FE; Richards SJ; Haynes AP;
TI - Russell NH; Hale G; Morgan GJ; Jack AS; Hillmen P Quantitation of minimal disease levels in chronic lymphocytic leukemia using a sensitive flow cytometric assay improves the prediction of outcome and can be used to optimize therapy.
SO - Blood 2001 Jul 1;98(1):29-35
AD - Haematological Malignancy Diagnostic Service, Leeds General Infirmary, Leeds, United Kingdom. firstname.lastname@example.org
Previous studies have suggested that the level of residual disease at the end of therapy predicts outcome in chronic lymphocytic leukemia (CLL). However, available methods for detecting CLL cells are either insensitive or not routinely applicable. A flow cytometric assay was developed that can differentiate CLL cells from normal B cells on the basis of their CD19/CD5/CD20/CD79b expression. The assay is rapid and can detect one CLL cell in 10(4) to 10(5) leukocytes in all patients. We have compared this assay to conventional assessment in 104 patients treated with CAMPATH-1H and/or autologous transplant. During CAMPATH-1H therapy, circulating CLL cells were rapidly depleted in responding patients, but remained detectable in nonresponders. Patients with more than 0.01 x 10(9)/L circulating CLL cells always had significant (> 5%) marrow disease, and blood monitoring could be used to time marrow assessments. In 25 out of 104 patients achieving complete remission by National Cancer Institute (NCI) criteria, the detection of residual bone marrow disease at more than 0.05% of leukocytes in 6 out of 25 patients predicted significantly poorer event-free (P =.0001) and overall survival (P =.007). CLL cells are detectable at a median of 15.8 months (range, 5.5-41.8) posttreatment in 9 out of 18 evaluable patients with less than 0.05% CLL cells at end of treatment. All patients with detectable disease have progressively increasing disease levels on follow-up. The use of sensitive techniques, such as the flow assay described here, allow accurate quantitation of disease levels and provide an accurate method for guiding therapy and predicting outcome. These results suggest that the eradication of detectable disease may lead to improved survival and should be tested in future studies.
UI - 11699197
AU - D'Arena G; Musto P; Cascavilla N; Dell'Olio M; Di Renzo N; Perla G;
TI - Savino L; Carotenuto M CD38 expression correlates with adverse biological features and predicts poor clinical outcome in B-cell chronic lymphocytic leukemia.
SO - Leuk Lymphoma 2001 Jun;42(1-2):109-14
AD - Division of Hematology, IRCCS Casa Sollievo della Sofferenza Hospital, 71013 San Giovanni Rotondo, Italy. email@example.com
CD38 identifies a surface molecule with multi-functional activity. Its prognostic importance in B-cell chronic lymphocytic leukemia (B-CLL) is currently under investigation in view of the fact that two different groups have recently indicated that CD38 expression could be an independent prognostic marker in B-CLL. We analyzed the clinico-biological features of 61 immunologically typical (CD5+CD23+) B-CLL patients stratified according to the CD38 expression. Twenty-two (36%) patients expressed CD38 in more than 30% of CD19-positive cells and were considered as CD38-positive B-CLL. Atypical morphology (p 0.02), peripheral blood lymphocytosis (p 0.01) and diffuse histopathologic bone marrow pattern (p 0.003) were findings found to be closely associated with CD38 expression. On the other hand, A and B Binet stages (p 0.02) and interstitial bone marrow involvement (p 0.005) were more represented in the CD38-negative B-CLL group. Trisomy 12 was detected more frequently in the CD38-positive B-CLL group, while 13q14 deletions mainly occurred in CD38-negative group (p 0.005). Finally, median survival of CD38-positive B-CLL patients was 90 months, while it was not reached at 180 months in CD38-negative patients. Taken together, our data strongly suggest that the evaluation of CD38 expression may identify two groups patients with B-CLL greatly differing in their clinico-biological features.
UI - 11699204
AU - Stahl D; Lacroix-Desmazes S; Sibrowski W; Kazatchkine MD; Kaveri SV
TI - Broad alterations of self-reactive antibody-repertoires of plasma IgM and IgG in B-cell chronic lymphocytic leukemia (B-CLL) and B-CLL related target-restricted autoimmunity.
SO - Leuk Lymphoma 2001 Jun;42(1-2):163-76
AD - INSERM U430, Universite Pierre et Marie Curie, Hopital Broussais, Paris, France. firstname.lastname@example.org
B-cell chronic lymphocytic leukemia (B-CLL) is characterized by a malignant CD5+ B-cell clone. The leukemic clone commonly expresses IgM antibodies exhibiting reactivity toward a wide range of self-antigens. However, B-CLL associated autoimmunity is typically restricted to self-antigens expressed by blood cells, and mediated by IgG autoantibodies of polyclonal origin. In the present study, we addressed the question whether self-reactive antibody repertoires of plasma IgM and IgG are disturbed by monoclonal immunoglobulins of B-CLL patients, and whether antibody repertoires of patients exhibiting B-CLL associated target-restricted autoimmune disease (AID) differ from those of B-CLL patients without AID. We investigated antibody repertoires at a global level, using a technique of quantitative immunoblotting that allows for the quantitative screening of antibody reactivities in complex antibody mixtures toward a large panel of antigens derived from homologous tissue extracts, followed by multiparametric statistical analysis of the data. We demonstrate that self-reactive antibody repertoires of plasma IgM and IgG are broadly altered in patients with B-CLL, that alterations in self-reactive antibody repertoires are not restricted to B-CLL patients exhibiting AID, and that target-restricted autoimmunity in B-CLL patients is associated with altered antibody repertoires not restricted to the target organ. We conclude that monoclonal alterations of immunoglobulin production in B-CLL are associated with broad defects of self-reactive antibody repertoires. Our observations suggest that the application of therapeutic IVIg preparations might influence B-CLL by restoring normal self-reactive antibody repertoires in plasma.
UI - 11699207
AU - Tsimanis A; Shvidel L; Klepfish A; Shtalrid M; Kalinkovich A; Berrebi A
TI - Over-expression of the functional interleukin-11 alpha receptor in the development of B-cell chronic lymphocytic leukemia.
SO - Leuk Lymphoma 2001 Jun;42(1-2):195-205
AD - Department of Hematology, Kaplan Medical Center, POB 1, Rehovot, 76100, Israel. Yehudats@netvision.net.il
Several cytokines have been found to play a role in the pathogenesis of B-CLL. In the present study using reverse-transcriptase polymerase chain reaction (RT-PCR), FACS analysis and immunofluorescence we have shown the constitutive expression of IL-11 and IL-11R alpha in B-chronic lymphocytic leukemia (B-CLL). The expression level of IL-11R alpha in B-CLL cells is much higher than in PBL of normal donors. Recombinant human IL-11 (rhIL-11) activates B-CLL cells, leading to morphologic alterations of the cells and increase in cell number and size. Short-term cultivation in the presence of rhIL-11 did not lead to quantitative changes in the ratio of the living vs apoptotic and dead cells. However, in contrast to rhIL-6, pretreatment with rhIL-11, did not cause B-CLL cells to be resistant to the action of dexamethasone. These data suggest an essential role for the IL-11/IL11 R alpha system in the pathogenesis of the malignant B-CLL cells.
UI - 11699221
AU - Gu B; Dao LP; Wiley J
TI - Impaired transendothelial migration of B-CLL lymphocytes: a defect linked to low L-selectin expression.
SO - Leuk Lymphoma 2001 Jun;42(1-2):5-12
AD - Sydney University, Department of Medicine, Nepean Hospital, Penrith, NSW 2750, Australia.
The emigration of lymphocytes from blood into lymph nodes is regulated by the expression of the adhesion molecule, L-selectin on the lymphocyte surface which arrests the rolling of the cell on the vessel wall and allows firmer adhesive interactions to develop. The expression of L-selectin on B-CLL lymphocytes is less than half that on normal lymphocytes and this difference correlates with an impaired capacity of B-CLL lymphocytes to migrate beneath a monolayer of human umbilical vein endothelial cells. Both the B-cell and T-cell lymphocytes from normal subjects and B-CLL patients show down-regulation of L-selectin and CD23 after transendothelial migration. The reduced expression of L-selectin on B-CLL lymphocytes leads to a relative "trapping" of these cells in the vascular space and is one factor contributing to the elevation of peripheral lymphocyte count.
UI - 11699227
AU - Ishibe N; Sgambati MT; Fontaine L; Goldin LR; Jain N; Weissman N; Marti
TI - GE; Caporaso NE Clinical characteristics of familial B-CLL in the National Cancer Institute Familial Registry.
SO - Leuk Lymphoma 2001 Jun;42(1-2):99-108
AD - Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 6120 Executive Blvd., MSC 7236, Rockville, MD 20852, USA.
In an ongoing study, families with two or more living cases of B-CLL in first-degree relatives have been recruited through physician and self-referral. Since 1967, 28 kindreds with 73 cases of B-CLL have been enrolled within the National Cancer Institute (NCI) Familial B-CLL Registry. Medical, clinical, and demographic information have been obtained from private physicians, patient interview, hospital records, and death certificates. We used SEER Registry data to compare characteristics of sporadic B-CLL to familial B-CLL. The mean age at diagnosis was approximately 10 years younger among familial cases (57.9 +/- 12.1) than that observed in sporadic cases (70.1 +/- 11.9). A higher percentage of second primary tumors among familial CLL cases compared to reports in sporadic was also observed (16% vs. 8.8%). However, the transformation rate to non-Hodgkin's lymphoma does not appear to be different from that reported for sporadic cases. In conclusion, we observed some differences between familial and sporadic cases; whether any of these characteristics affect survival time or severity of disease is unknown. The study of families with multiple B-CLL cases will aid in delineating the genes and environmental factors that may play a role in the development of both forms of B-CLL.
UI - 11871387
AU - Esteve J; Villamor N; Colomer D; Montserrat E
TI - Different clinical value of minimal residual disease after autologous and allogenic stem cell transplantation for chronic lymphocytic leukemia.
SO - Blood 2002 Mar 1;99(5):1873-4
UI - 11916516
AU - Kivekas I; Hulkkonen J; Hurme M; Vilpo L; Vilpo J
TI - CD80 antigen expression as a predictor of ex vivo chemosensitivity in chronic lymphocytic leukemia.
SO - Leuk Res 2002 May;26(5):443-6
AD - Leukemia Research Laboratory, Department of Clinical Chemistry, Laboratory Center, Tampere University Hospital and University of Tampere Medical School, P.O. Box 2000, FIN-33521, Tampere, Finland.
We investigated the correlation between expression of 31 surface membrane antigens and chemosensitivity of peripheral blood mononuclear cells from 36 patients with CLL. The sensitivity of CLL cells to nine drugs (2'-chlorodeoxyadenosine, cisplatin, chlorambucil, cyclosporin A, doxorubicin, fludarabine, prednisolone, verapamil and vincristine) and two types of irradiation (gamma and UV-irradiation) was determined from dose-response curves of 4-day cultures ex vivo. The results indicated that the CLL cases responding to purine analogs (2'-chlorodeoxyadenosine and fludarabine) can be identified according to CD80 expression: all resistant cases had low or negative CD80 expression. No other correlations were revealed. CD80 may be a surrogate chemosensitivity marker for purine analogs.
UI - 11916525
AU - Zhou R; Frostvik Stolt M; Kronenwett U; Gruber A; Liliemark J; Liliemark
TI - E Real-time RT-PCR for the determination of topoisomerase II mRNA level in leukaemic cells.
SO - Leuk Res 2002 May;26(5):487-94
AD - Department of Oncology-Pathology, Cancer Center Karolinska at CCK, Karolinska Institute and Hospital, R8:00, SE-171 76 Stockholm, Sweden. email@example.com
We developed a real-time RT-PCR assay for the quantification of topoisomerase II (topo II) mRNA level. It was applied on peripheral leukaemic cells from 23 patients with acute myelogenous leukaemia (AML) and 23 with chronic lymphocytic leukaemia (CLL). RNA template dilutions from 0.25 to 25ng per reaction were used as standard curves for topo IIalpha, beta and the internal control 18S rRNA. About 57% (26/46) and 26% (12/46) of the specimens had detectable topo IIbeta and alpha mRNA, respectively. The correlation between these two factors was rho=0.7 and P=0.0001. No relationship between topo IIalpha or beta mRNA level and response to chemotherapy was found in AML patients (n=19 assessable for response).Our method is rapid and convenient for quantification of topo IIalpha and beta mRNA levels, and could be suitable for investigation in a larger population.
UI - 11769960
AU - Keating MJ
TI - Progress in CLL, chemotherapy, antibodies and transplantation.
SO - Biomed Pharmacother 2001 Nov;55(9-10):524-8
AD - The University of Texas M. D. Anderson Cancer Center, Department of Leukemia, Houston 77030, USA.
Over the last decade, major advancements in our understanding of chronic lymphocytic leukemia (CLL) and its variants have occurred. It has become apparent that there is diversity in types of CLL including those patients that do or do not have hyper-mutation of their immunoglobulin genes. Mutated genes confer a favorable prognosis. One of the major advances in our therapy has been the discovery of the activity of purine analogs, which have been demonstrated to be more active than conventional therapy in achieving complete remission, prolonged remission duration, and a suggestion of improved survival. More recently, based on information that purine analogs inhibit DNA repair, rational combinations have been developed. In particular, fludarabine plus cyclophosphamide appeared to have added activity compared to either drug given alone or in sequence. This has led to a higher response rate, longer time to progression, and an improvement in survival in patients treated following prior alkylating agents. Two monoclonal antibodies, Rituximab and Campath-1H, have become available for clinical use and research. Rituximab has modest activity as a single agent, with higher response rates being noted in patients who receive more intensive regimens. Rituximab has been successfully combined with chemotherapy, and in association with fludarabine plus cyclophosphamide (FCR) has a very high response rate and the ability to obtain polymerase chain reaction (PCR) negativity for the immunoglobulin heavy chain region. Campath-1H is very active as a single agent and is being recommended for treatment for patients with fludarabine refractory disease and will receive increased attention as a research agent in earlier-stage patients. Autologous and allogeneic bone marrow transplantation have emerged as significant treatments in CLL. The ability to achieve responses in bone marrow and peripheral blood with newer regimens has given the opportunity to collect stem cells from patients. There is a suggestion that intensification of remissions with autologous transplant can lead to PCR negativity and prolonged remissions. Allogeneic transplantation has been demonstrated to be effective with a strong suggestion of graph versus leukemia effect. This has been utilized in the development of non-ablative marrow allogenaic bone marrow transplant programs. Non-ablative transplants appear to be as effective as ablative transplants in the most recent analysis. Thus, multiple modalities have been brought together to achieve high-quality complete remissions in CLL, giving the prospect of improved survival.
UI - 11869948
AU - De Fanis U; Dalla Mora L; Romano C; Sellitto A; Tirelli A; Lucivero G
TI - Altered constitutive and activation-induced expression of CD95 by B- and T-cells in B-cell chronic lymphocytic leukemia.
SO - Haematologica 2002 Mar;87(3):325-7
Expression of CD95, a molecule involved in activation-induced cell death (AICD), might contribute to explain accumulation of leukemic B-cells and functional impairment of T-cells in B-cell chronic lymphocytic leukemia (B-CLL). There-fore, we compared constitutive and activation-induced expression of CD95 and CD69 by B- and T-cells in CLL patients and in healthy donors.
UI - 11877305
AU - Kennedy B; Rawstron A; Carter C; Ryan M; Speed K; Lucas G; Hillmen P
TI - Campath-1H and fludarabine in combination are highly active in refractory chronic lymphocytic leukemia.
SO - Blood 2002 Mar 15;99(6):2245-7
AD - Haematological Malignancy Diagnostic Service, Institute of Pathology, Algernon Firth Building, University of Leeds, Leeds LS2 9JT, West Yorkshire, UK. firstname.lastname@example.org
Campath-1H (alemtuzumab) is the most effective monoclonal antibody in single-agent use in B-cell chronic lymphocytic leukemia (CLL) with reported response rates of 33% to 70%. Combination therapy is now the conventional treatment for most hematologic malignancies. Monoclonal antibody treatments may sensitize tumor cells to subsequent chemotherapy. We report the combination of Campath-1H with fludarabine in patients with CLL refractory to each agent used singly. Six patients who had received a median of 8 courses of fludarabine (range, 4-10 courses) and 16 weeks of Campath-1H (range, 8-32 weeks) were treated. Five patients responded, including one who had a complete response by National Cancer Institute criteria. The responses observed were better in each patient than responses after each agent used singly. Complete morphologic bone marrow responses were seen in 3 patients, including eradication of disease measured by sensitive flow cytometry in 2. Campath-1H combined with fludarabine is a highly promising novel therapy for refractory CLL.
UI - 11877310
AU - Tobin G; Thunberg U; Johnson A; Thorn I; Soderberg O; Hultdin M; Botling
TI - J; Enblad G; Sallstrom J; Sundstrom C; Roos G; Rosenquist R Somatically mutated Ig V(H)3-21 genes characterize a new subset of chronic lymphocytic leukemia.
SO - Blood 2002 Mar 15;99(6):2262-4
AD - Department of Genetics and Pathology, Uppsala University, SE-751 85 Uppsala, Sweden.
Recent studies on the immunoglobulin variable heavy chain (IgV(H)) genes have revealed that B-cell chronic lymphocytic leukemia (B-CLL) consists of at least 2 clinical entities with either somatically mutated or unmutated V(H) genes. We have analyzed the V(H) gene mutation status and V(H) gene usage in 119 B-CLL cases and correlated them to overall survival. A novel finding was the preferential use of the V(H)3-21 gene in mutated cases, whereas biased V(H)1-69 gene usage was found in unmutated cases as previously reported. Interestingly, the subset of mutated cases using the V(H)3-21 gene displayed distinctive genotypic/phenotypic characteristics with shorter average length of the complementarity determining region 3 and clonal expression of lambda light chains. In addition, this mutated subset showed significantly shorter survival than other mutated cases and a similar clinical course to unmutated cases. We therefore suggest that B-CLL cases with mutated V(H)3-21 genes may constitute an additional entity of B-CLL.
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
UI - 11839681
AU - Moon E; Lee R; Near R; Weintraub L; Wolda S; Lerner A
TI - Inhibition of PDE3B augments PDE4 inhibitor-induced apoptosis in a subset of patients with chronic lymphocytic leukemia.
SO - Clin Cancer Res 2002 Feb;8(2):589-95
AD - Department of Medicine, Section of Hematology and Oncology, Boston Medical Center, 650 Albany Street, Boston, MA 02118, USA.
PURPOSE: cAMP phosphodiesterase (PDE) 4 is a family of enzymes the inhibition of which induces chronic lymphocytic leukemia (CLL) apoptosis. However, leukemic cells from a subset of CLL patients are relatively resistant to treatment with the PDE4 inhibitor rolipram, particularly when this drug is used in the absence of an adenylate cyclase stimulus such as forskolin. Elevated cAMP levels induce compensatory up-regulation of several cyclic nucleotide PDE families in other model systems. We here examine the hypothesis that CLL cells that survive treatment with rolipram do so as a result of residual PDE activity that is not inhibited by this drug. EXPERIMENTAL DESIGN: We examined by Western analysis the effect of rolipram treatment on CLL expression of PDE3B, PDE4A, PDE4B, PDE4D, and PDE7A. We also examined the ability of rolipram (PDE4 inhibitor) or cilostamide (PDE3 inhibitor), alone or together, to induce apoptosis or elevate cyclic AMP in leukemic cells from patients with CLL. RESULTS: Rolipram increased levels of PDE4B and, to a variable extent, PDE4D. When combined with forskolin, rolipram also increased levels of a second family of PDEs, PDE3B. Addition of the specific PDE3 inhibitor, cilostamide, modestly augmented rolipram-induced apoptosis in five of seven "rolipram-resistant" CLL samples. CONCLUSIONS: Although this work confirms that PDE4 appears to be the most important PDE target for induction of apoptosis in CLL, combination therapy with PDE3 and PDE4 inhibitors or use of dual-selective drugs may be of benefit in a subset of relatively PDE4-inhibitor resistant CLL patients.
UI - 11997030
AU - Nardini E; Rizzi S; Capello D; Vitolo U; Gaidano G; Menard S; Balsari A
TI - Most immunoglobulin heavy chain switch mu rearrangements in B-cell chronic lymphocytic leukemia are internal deletions.
SO - FEBS Lett 2002 May 8;518(1-3):119-23
AD - Department of Experimental Oncology, Molecular Targeting Unit, National Cancer Institute, Via Venezian 1, 20133, Milan, Italy.
We investigated 38 cases of B-cell chronic lymphocytic leukemia (B-CLL) for the presence of non-productive rearrangements in the S(mu) regions and defined for the first time the molecular nature of these rearrangements. Southern blot analysis revealed S(mu) region rearrangements in 13 cases (34%) and polymerase chain reactions (PCRs) indicated that these rearrangements consisted of internal deletions of the S(mu) region. Long-distance PCRs localized the S(mu) deletions in the V(H)DJ(H) rearranged allele in most cases. We investigated if S(mu) deletions were related to V(H) somatic mutations that, together with isotype switch recombination, are indicative of the B-cell maturation stage. No significant correlation between the presence of S(mu) deletions and V(H) somatic mutations was found, indicating that the two processes are independent in B-CLL. Moreover no significant correlation between S(mu) deletions and prognosis was observed. Having shown that S(mu) internal deletions are not chromosome translocations rules out their involvement in the onset of malignancy, while their localization in the V(H)DJ(H) rearranged alleles suggests a possible role in the stabilization of the isotype of the expressed immunoglobulin.
UI - 10477712
AU - Damle RN; Wasil T; Fais F; Ghiotto F; Valetto A; Allen SL; Buchbinder A;
TI - Budman D; Dittmar K; Kolitz J; Lichtman SM; Schulman P; Vinciguerra VP; Rai KR; Ferrarini M; Chiorazzi N Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia.
SO - Blood 1999 Sep 15;94(6):1840-7
AD - Department of Medicine, North Shore University Hospital, Manhasset, NY, USA.
Cellular immunophenotypic studies were performed on a cohort of randomly selected IgM(+) B-chronic lymphocytic leukemia (B-CLL) cases for which Ig V(H) and V(L) gene sequences were available. The cases were categorized based on V gene mutation status and CD38 expression and analyzed for treatment history and survival. The B-CLL cases could be divided into 2 groups. Those patients with unmutated V genes displayed higher percentages of CD38(+) B-CLL cells (>/=30%) than those with mutated V genes that had lower percentages of CD38(+) cells (<30%). Patients in both the unmutated and the >/=30% CD38(+) groups responded poorly to continuous multiregimen chemotherapy (including fludarabine) and had shorter survival. In contrast, the mutated and the <30% CD38(+) groups required minimal or no chemotherapy and had prolonged survival. These observations were true also for those patients who stratified to the Rai intermediate risk category. In the mutated and the <30% CD38(+) groups, males and females were virtually equally distributed, whereas in the unmutated and the >/=30% CD38(+) groups, a marked male predominance was found. Thus, Ig V gene mutation status and the percentages of CD38(+) B-CLL cells appear to be accurate predictors of clinical outcome in B-CLL patients. These parameters, especially CD38 expression that can be analyzed conveniently in most clinical laboratories, should be valuable adjuncts to the present staging systems for predicting the clinical course in individual B-CLL cases. Future evaluations of new therapeutic strategies and drugs should take into account the different natural histories of patients categorized in these manners.
UI - 10477713
AU - Hamblin TJ; Davis Z; Gardiner A; Oscier DG; Stevenson FK
TI - Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia.
SO - Blood 1999 Sep 15;94(6):1848-54
AD - Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK. email@example.com
Despite having several characteristics of naive B cells, chronic lymphocytic leukemia (CLL) cells have been shown in some cases to have somatically mutated Ig variable region genes, indicating that the cell of origin has passed through the germinal center. A previous study of patients with CLL found an association between lack of somatic mutation and trisomy 12 and, therefore, possibly with a less favorable prognosis. We have sequenced the Ig V(H) genes of the tumor cells of 84 patients with CLL and correlated our findings with clinical features. A total of 38 cases (45.2%) showed >/= 98% sequence homology with the nearest germline V(H) gene; 46 cases (54.8%) showed >2% somatic mutation. Unmutated V(H) genes were significantly associated with V1-69 and D3-3 usage, with atypical morphology; isolated trisomy 12, advanced stage and progressive disease. Survival was significantly worse for patients with unmutated V(H) genes irrespective of stage. Median survival for stage A patients with unmutated V(H) genes was 95 months compared with 293 months for patients whose tumors had mutated V(H) genes (P =.0008). The simplest explanation is that CLL comprises 2 different diseases with different clinical courses. One, arising from a memory B cell, has a benign course, the other, arising from a naive B cell, is more malignant.
UI - 11263438
AU - Thunberg U; Johnson A; Roos G; Thorn I; Tobin G; Sallstrom J; Sundstrom
TI - C; Rosenquist R CD38 expression is a poor predictor for VH gene mutational status and prognosis in chronic lymphocytic leukemia.
SO - Blood 2001 Mar 15;97(6):1892-4
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