Relevant bibliographies by topics / Chronic lymphocitic leukemia (CLL)

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Academic literature on the topic 'Chronic lymphocitic leukemia (CLL)'

Author: Grafiati
Published: 11 March 2023

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Journal articles on the topic "Chronic lymphocitic leukemia (CLL)"

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Delioukina, Maria L., and Stephen J. Forman. "ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION IN THE TREATMENT OF CHRONIC LYMPHOCITIC LEUKEMIA : WHY AND WHEN ?" Mediterranean Journal of Hematology and Infectious Diseases 2, no. 2 (June 30, 2010): e2010018. http://dx.doi.org/10.4084/mjhid.2010.018.

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Chronic lymphocytic leukemia (CLL) is the most common hematologic malignancy in adults with an incidence rate of 4.2 per 100,000 per year. CLL frequently takes an indolent course, with some patients not requiring treatment for years, yet is incurable by currently available chemo- and immuno-therapeutic modalities. Despite high initial response rates, particularly to purine analogues, patients invariably relapse and subsequently develop resistance to therapy. The traditional “watchful waiting” approach to CLL is being challenged by data showing that treatments used early in the disease course impact long-term overall and progression-free survivals . The only curative treatment for CLL currently, is allogeneic hematopoeietic cell transplantation (alloHCT). In contrast to autologous transplant, myeloablative alloHCT for CLL patients generates durable remissions with promising survival plateaus; however, significant transplant related mortality (TRM) is also observed (25-50%) . At present the fact remains that for poor-risk CLL, alloHCT is the only treatment with the potential of providing long-term disease control. Future combinations with emerging low-toxicity therapies may further enhance the curative potential of allogeniec hematopoietic cell transplant. New drugs can also potentially enable refractory patients to attain response as a bridge to more effective stem cell transplantation.
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Di Marco, Amerigo Mirco, Francesco Autore, Paola Lanuti, Idanna Innocenti, Giuseppe Leone, Alice Ramassone, Angelo Veronese, Renato Mariani Costantini, Luca Laurenti, and Rosa Visone. "Impact of BCR Stimulation on Mir-181b in Chronic Lymphocityc Leukemia." Blood 128, no. 22 (December 2, 2016): 2026. http://dx.doi.org/10.1182/blood.v128.22.2026.2026.

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Abstract B cell receptor (BCR) signaling plays an important pathogenic role in chronic lymphocytic leukemia (CLL) enhancing homing and homeostasis of B-CLL cells and favoring the interaction with the pro-survival stromal lymph node microenvironment. Surface expression of CD69 is required to block the cells in lymphoid compartment while Sfingosine-1-phosphate receptor-1 (S1PR1) is necessary for egress of cells to blood. BCR signaling inhibitors such as Ibrutinib and Acalabrutinib, (anti-bruton tyrosine kinase) or Idelalisib (anti-Phosphatidylinositol 3-kinases ) represent a significant therapeutic advance in CLL. At least some of these drugs are distinctive to lead to an initial lymphocitosis due to rapid release of cells from lymphoid organs to blood, where they die. Changes in microRNAs expression characterize clinical progression of CLL with a strong decrease of miR-181b associated with the more aggressive phase of the disease. In this study we demonstrate that miR-181b is part of the BCR pathway in that it influences the anatomical redistribution of CLL cells from lymph nodes into the blood by balancing the expression of CD69 and S1PR1. We co-cultured MEC_01 and pure B-CLL cells in medium supplemented or not with IgM F(ab')2, specific antibodies for BCR. We observed a significant decrease of miR-181b after 24 hrs of BCR stimulation compared with the same cells cultured in medium without IgM F(ab')2. To establish that this effect was due to the stimulation of the BCR, studies were performed on MEC_01 and in pure B-CLL cells treated separately with 1μM Ibrutinib or 1 μM Idelalisib, which are a potent BCR signaling inhibitors. After 1 hours of treatment the relative expression of miR-181b was assessed noting an increase of the transcription of miR, suggesting that the activation of BCR down regulate the expression of miR-181b. To confirm what we observed in vitro, RNA was isolated from B cells of the CLL patients at different time-point before and after treatment with a BTK inhibitor, Acalabrutinib (ACP-196). We observed a marked increase of miR-181b in the patients in therapy with this drugs compared with respective baseline. Since BTK inhibitors lead to the immediate release of CLL cells from lymphoid tissues to circulation, we evaluated whether this miRNA could be involved in this process. To test this hypothesis MEC01 cells were infected with either LV-miR-181b_coGFP or the LV-CTRL_coGFP after which migration was assessed in transwell assays. The Cells (5 × 105 cells/well) were seeded on top of the transwells and allowed to migrate for 4 h. S1P (100 nM) was added to the lower chamber as a chemo attractant. Transwell assay was performed to determine the migratory capacity of MEC-01 GFP+ cells, mimicking spleen (S1P-) vs blood (S1P+) compartments. Our data indicate that enhanced expression of miR-181b accelerate the migration of B-CLL cells. On the same cells we also evaluated the expression of S1PR1 and CD69. We observed that the restoration of miR-181b down regulated CD69 expression and increased the S1PR1. We also demonstrated that both proteins are direct targets and that the regulation on SIPR1 by the miR-181b occurs through a not canonical way. In conclusion, our findings indicate miR-181b is down regulated by BCR stimulation in CLL cells and that its enhanced expression reduced CD69 while increased S1PR1 by direct targeting. This could facilitate the egress from lymphoid tissue to blood and in turn their death. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Di Ianni, Mauro, Lorenzo Moretti, Beatrice Del Papa, Maria De Ioanni, Adelmo Terenzi, Moira Bazzucchi, Raffaella Ciurnelli, Franca Falzetti, and Antonio Tabilio. "T Cell Pathway Deficiencies in Chronic Lymphocityc Leukemia: Partial Restoration with OKT3/IL-2 Activation." Blood 110, no. 11 (November 16, 2007): 4692. http://dx.doi.org/10.1182/blood.v110.11.4692.4692.

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Abstract As Chronic Lymphocytic Leukemia (CLL) is associated with several defects in the T cell compartment, the impact of tumour burden on the autologous immune system was studied. Gene expression profiles (using Applied Biosystem Human Genome Microarray) identified 237 genes with significantly increased expression and 221 genes with significantly decreased expression (p<0.05) in CD3+ cells from CLL patients compared with healthy donors. Panther software analysis identified 34/237 upregulated genes and 26/221 downregulated genes that were involved in specific pathways, mainly cell differentiation and proliferation, survival, apoptosis, cytoskeleton formation, vesicle trafficking and T cell activation. The 26 dowregulated genes included Zap70, a member of the syk family protein tyrosine kinase, which is involved in T-cell activation. Zap-70 results were validated by mRNA quantification by RT-PCR (−1.77 fold in comparison with healthy controls) and by flow-cytometric analysis (Mean Intensity Fluorescence=33±12 vs 80±23.62 in controls, p<0.05). To test the hypothesis that activation with OKT3 /IL-2 could bypass these T cell deficiencies, activated T cells from 20 patients with CLL were tested in vitro for cytotoxicity (using the 51chromium release assay) against mutated and unmutated (according to IgVH mutational status) autologous B cells, DAUDI, K562 and P815 cell lines. After 10 days’ culture, the T cell count remained unchanged; CD8 cells expanded more than CD4; TCR spectratyping analysis indicated no differences in TCR repertoires. Activation restored the ZAP-70 mRNA (+1.67 fold). The 51chromium release cytotoxicity assay showed an index > 30% in 5/20 patients. The other 15 were partially cytotoxic against P815, K562 and Daudi. Cell line analysis in all 20 confirmed prevalently T cell-mediated cytotoxicity and poor NK/LAK activity. Cytotoxicity did not correlate with B cell mutational status. We tested the cytotoxic activity of autologous activated T cells in NOD/SCID mice co-transplanted with leukaemic B cells. Only activated T cells exerting cytotoxicity vs autologous B-cell CLL prevent CLL in human-mouse chimera, as confirmed by PCR and FACS analysis which visualised only CD3+ cells. In conclusion, in patients with CLL, activating autologous T cells with OKT3 /IL-2 bypasses, at least in part, the T cell immunological deficiencies. These in vitro and in vivo findings might serve to throw light on new mechanisms that could be exploited in immunotherapy designed to exert disease control.
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Thijssen, Rachel, Gregor van Bochove, Martin FM de Rooij, Johanna ter Burg, Marcel Spaargaren, Coumaran Egile, Marie Jose Kersten, Eric Eldering, and Arnon P. Kater. "Combined Inhibition of Phosphatidylinositol 3-Kinase (PI3K) Isoform α and δ By the Pan-Class I PI3K Inhibitor SAR245409 (XL765) in Primary Chronic Lymphocytic Leukemia Cells Blocks Survival, Adhesion and Proliferation." Blood 124, no. 21 (December 6, 2014): 4691. http://dx.doi.org/10.1182/blood.v124.21.4691.4691.

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Abstract CLL cells are highly dependent on B- cell receptor (BCR) signaling and on stimuli from the microenvironment for survival and proliferation. New drugs targeting PI3K downstream of BCR signaling have emerged as promising treatment options for patients with CLL. Among four PI3K catalytic subunits, the PI3Kd isoform is crucial for downstream BCR signaling, but the relative importance of the PI3Kα isoform in CLL is less clear. Impressive clinical activity of idelalisib in CLL and indolent NHL patients was recently reported. Idelalisib, a PI3Kd specific inhibitor, inhibits chemotaxis and adhesion of leukemia cells, resulting in rapid lymphocytosis followed by a decrease in lymphadenopathy. However, idelalisib has no direct impact on leukemic cell survival [1], raising the potential risk of residual clones responsible for the development of resistance. In this study, we evaluated the impact of a pan-class I PI3K inhibitor (SAR245409/XL765), a PI3Kα-specific inhibitor (BYL719) and a PI3Kd specific inhibitor (idelalisib) on PI3K/mTOR signaling, apoptosis, cell adhesion, CD40-induced survival and proliferation in primary patient derived leukemic cells. Phosphorylation of the downstream effector of mTOR, S6RP, was completely blocked by SAR245409 but not by BYL719 or idelalisib. SAR245409 induced apoptosis in unstimulated CLL cells (IC50= 0.86µM) in contrast to BYL719 or idelalisib (IC50 >10µM), demonstrating that targeting multiple PI3K isoforms is required to completely block the PI3K/Akt/mTOR pathway (table 1). Importantly, SAR245409 also induced apoptosis in p53 or ATM dysfunctional CLL samples. SAR245409, as well as idelalisib, and in contrast to BYL719 completely inhibited BCR-mediated adhesion to fibronectin [2]. Similarly, SAR245409 inhibited CD40L-mediated survival [3], and induced upregulation of the pro-apoptotic protein BIM. All 3 PI3K inhibitors inhibited CD40 ligation + IL-21-mediated CLL proliferation [4]. This study revealed that the pan-class I PI3K inhibitor SAR245409 is more cytotoxic to primary CLL cells than PI3Kα or PI3Kd specific inhibitors. Furthermore, combined inhibition of PI3Kα and d can block signaling pathways that are critical for CLL survival, adhesion and proliferation in the LN microenvironment (see table 1). This work provides a rationale for the evaluation of SAR245409 in CLL patients either as monotherapy or in combination therapies. [1] Hoellenriegel et al. The phospoinositide 3'-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia. Blood 2011;(118):3603-3612 [2] de Rooij et al. The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood 2012;(119):2590-2594. [3] Smit et al. Differential Noxa/Mcl-1 balance in peripheral versus lymph node chronic lymphocitic leukemia cells correlates with survival capacity. Blood 2007;(109):1660-1668. [4] Pascutti et al. IL-21 and CD40L signals from autologous T cells can induce antigen-independent proliferation of CLL cells. Blood 2013;(122):3010-3019. Table 1. The effect of the PI3Kd inhibitor idelalisib, PI3Kα inhibitor BYL719 or pan PI3K inhibitor SAR245409 on CLL cells in functional assays PI3Kd inhibitor PI3Kα inhibitor pan PI3K inhibitor Cytotoxicity (IC50)1 >10µM >10µM 0.86µM Inhibition of adhesion2 48%** 21% 43%** Activation Inhibition of CD40L-induced survival3 14% 0% 54%* Inhibition of CD40L+IL21 induced proliferation4 47%* 35%* 51%* 1 CLL cells were incubated with 0.001-10 μM idelalisib (n=18), BYL719 (n=6) or SAR245409 (n=28) for 48 hours. Viability was assessed by DiOC6/PI staining.2 CLLcells pretreated with 1 µM idelalisib, BYL719, or SAR245409 were stimulated with α-IgM and allowed to adhere to fibronectin-coated surfaces (n=5). 3 CLL cells were cultured on fibroblast expressing CD40L in the absence or presence of 1 µM of idelalisib, BYL719, or SAR245409 for 3 days. Apoptosis was assessed by DiOC6/PI staining (n=8).4 CFSE labelledCLL cells were cultured on fibroblast expressing CD40L with IL-21 and co-treated with 1 µM idelalisib, BYL719, or SAR245409. After 4 days, CFSE was measured by FACS (n=11)2-4 The one sample T test was used to determine the significance of differences between means of treated samples and normalized values of untreated samples (100%). * p <0,05;** p<0,01 Disclosures Egile: Sanofi: Employment. Kersten:Sanofi: Research Funding. Kater:Sanofi: Research Funding.
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Thijssen, Rachel, Gregor van Bochove, Ingrid AM Derks, Johanna ter Burg, Martin FM de Rooij, Marcel Spaargaren, Marie Jose Kersten, Eric Eldering, and Arnon P. Kater. "Combined Inhibition of mTOR and DNA-PK Blocks Survival, Adhesion, Proliferation and Chemoresistance in Primary Chronic Lymphocytic Leukemia (CLL) Cells." Blood 124, no. 21 (December 6, 2014): 1981. http://dx.doi.org/10.1182/blood.v124.21.1981.1981.

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Abstract CLL progression and chemoresistance can result from signals from the lymph node (LN) microenvironment and from acquired aberrations in the DNA damage repair (DDR) pathway. Clinical targeting of kinases upstream in the B cell receptor (BCR) activation pathway, such as Btk or PI3Kδ results in egress of cells from the LN microenvironment [1,2]. Such prolonged lymphocytosis during kinase-inhibitor treatment appears to pose no clinical disadvantage [3]. However, it enhances the chance of accumulating resistance-inducing mutations, and therefore drugs that combine LN egress with direct cytoxicity could provide an improved therapeutic strategy for CLL. The mTOR complex, consisting of mTOR1 and 2, is the main downstream kinase of the PI3K/Akt pathway and contributes to proliferation and survival. DNA-PK is a kinase required for non-homologous end joining (NHEJ) of the DNA repair pathway. Inhibitors of crucial components of the DDR pathway might be active in CLL, especially in patients harboring mutations in DNA repair molecules such as Ataxia telangiectasia mutated (ATM). In this study the potency of a novel dual mTOR1,2 and DNA-PK inhibitor (CC-115) was studied in primary CLL samples of different prognostic subgroups with respect to induction of cytotoxicity, and inhibition of adhesion, CD40-mediated chemoresistance and proliferation. In vitro, CC-115 inhibited mTOR1 and 2 and also affected the DDR reflected by inhibition of irradiation-induced γH2AX, not only in ATM-mutated but also in ATM-wild type CLL cells. CC-115 showed induction of caspase-dependent cell killing (IC50=0.625µM) which was more robust than selective kinase inhibitors (table 1), irrespective of p53 or ATM status. This cytotoxic effect was not observed in the T cells from CLL patients. BCR-mediated adhesion to fibronectin [4] was inhibited by CC-115 to a similar extent as PI3Kδ inhibitor (idelalisib) (table 1). CD40-mediated chemoresistance [5] could be reverted completely by CC-115 while more specific inhibitors had only modest effects. CLL proliferation induced by CD40L+IL-21 treatment [6] was completely blocked by both CC-115 and a dual mTOR1,2 inhibitor but not by inhibitor of the more upstream kinase PI3Kδ (table 1). In conclusion, these data show that CC-115 induces direct cytotoxicity and inhibits several clinically relevant biological features of CLL, and provide a rationale for clinical trials with CC-115 in CLL patients. [1] Hoellenriegel J, Meadows SA, Sivina M et al. The phospoinositide 3’-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia. Blood 2011;(118):3603-3612 [2] Burger JA. Bruton’s Tyrosine Kinase (BTK) Inhibitors in Clinical Trials. Curr Hematol Malig Rep (2014) 9:44–49 [3] Herman SE, et al. Ibrutinib-induced lymphocytosis in patients with chronic lymphocytic leukemia: correlative analyses from a phase II study. Leukemia. 2014 Apr 4. doi: 10.1038/leu.2014.122. [Epub ahead of print] [4] de Rooij MF, Kuil A, Geest CR et al. The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood 2012;(119):2590-2594. [5] Differential Noxa/Mcl-1 balance in peripheral versus lymph node chronic lymphocitic leukemia cells correlates with survival capacity. Blood 2007;(109):1660-1668. [6] Pascutti MF, Jak M, Tromp JM et al. IL-21 and CD40L signals from autologous T cells can induce antigen-independent proliferation of CLL cells. Blood 2013;(122):3010-3019.Smit LA, Hallaert DY, Spijker R et al. Table 1. The effect of the mTOR1,2 + DNA-PK inhibitor (CC-115), mTOR1,2 inhibitor (CC-214), DNA-PK inhibitor (NU7441) and PI3Kδ inhibitor (idelalisib) on CLL cells in functional assays. CC-115 CC-214 NU7441 Idelalisib (CAL-101) Target mTOR1,2 DNA-PK mTOR1,2 DNA-PK PI3Kδ Cytotoxicity (IC50) 0.625 µ M >10µM >10µM >10µM Inhibition of adhesion 40%** 0% 22% 48%** Activation Inhibition of CD40-mediated resistance to fludarabine (6.25 µ M) 92%** 42%* n.d. 21% Inhibition of CD40L+IL21 induced proliferation 98%** 98%* 28% 51%** n.d. = not done The one sample T test was used to determine the significance of differences between means of treated samples and normalized values of untreated samples (100%). * p <0,05;** p<0,01 Disclosures Kersten: Celgene: Research Funding. Kater:Celgene: Research Funding.
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Brajuskovic, Goran, Slobodan Marjanovic, and Andjelija Skaro-Milic. "Chlorambucil effect on B lymphocites in the peripheral blood of patients with chronic lymphocytic leukemia: Cell ultrastructure investigation." Vojnosanitetski pregled 60, no. 2 (2003): 175–80. http://dx.doi.org/10.2298/vsp0302175b.

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B type Chronic Lymphocytic Leukemia (B-CLL) is a malignant disease characterized by the progressive accumulation of morphologically mature, but immunologically dysphunctional CD 5+ lymphocytes in the blood, bone marrow and lymphatic organs in the early phase of the cell cycle. B-CLL is an example of human malignancy caused by alternations in the pathways of programmed cell death - apoptosis. Recent investigations showed a probable role of apoptosis as a prognostic parameter in B-CLL patients. Since the introduction of chlorambucil in the therapy in 1952, besides all the achievements in modern oncology, chlorambucil remained the most common antineoplastic agent in the treatment of CLL. Numerous experimental studies both in vitro and in vivo, showed the capability of antineoplastic agents to induce the process of apoptosis of neoplastically transformed cells. In this study the effect of chlorambucil on B lymphocites was monitored in 16 samples of peripheral blood tarlen from B-CLL diagnosed patients. According to the investigations performed in this study by ultrastructure analysis of B-CLL cells, it was concluded that chlorambucil either induced apoptosis in B-CLL cells, or activated cell response to the stress.
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Thijssen, Rachel, Christian R. Geest, Martin FM de Rooij, Nora Liu, Bogdan I. Florea, Katinka Weller, Hermen S. Overkleeft, et al. "Possible Mechanisms Of Resistance To The Novel BH3-Mimetic ABT-199 In In Vitro Lymph Node Models Of CLL – The Role Of Abl and Btk." Blood 122, no. 21 (November 15, 2013): 4188. http://dx.doi.org/10.1182/blood.v122.21.4188.4188.

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Abstract The new BH3-mimetic ABT-199 antagonizes Bcl-2 and avoids the thrombocytopenia associated with clinical application of its predecessor ABT-263 (navitoclax). Chronic lymphocytic leukemia (CLL) cells are highly sensitive to ABT-199 and the first clinical results show clear reductions in peripheral and bone marrow CLL cells and in lymph node size. In the lymph node, CLL cells receive pro-survival signals that upregulate Bcl-XL, Mcl-1 and Bfl-11. These Bcl-2 family members are not targeted by ABT-199, which poses the potential risk of remaining clones with residual viability. Here, we aimed to define the signals that determine sensitivity for ABT-199 and ABT-737 in an in vitro lymph node model of CLL. We applied CD40 and cytokine stimulation in combination with kinase inhibitors that are known to change microenviroenmental signals and increase drug resistance in CLL. Stimulation via CD40 plus IL-4 or IL-21 differentially affected the expression of Mcl-1, Bcl-XL, Bfl-1 and Noxa and this correlated with strong alterations in sensitivity to ABT-737 and ABT-199 (see table 1 for LC 50 values). As reported before2, in vitro CD40 stimulation reduced sensitivity to ABT-737 by 100-fold, and this was further decreased by IL-4. Strikingly, CD40+IL-4 stimulation in primary CLL cells resulted in full resistance to 10 μM ABT-199, probably due to very high levels of Bcl-XL.Table 1The LC50 of ABT-737 or ABT-199 for CLL cells stimulated with CD40L and IL-21 or IL-4 (averaged values n=8)StimulationLC50 (μM)ABT-737ABT-1993T3 (control)0.0050.0013T40L0.781> 103T40L + IL-210.1950.210 3T40L + IL-46.772> 103T40L + IL-21 + IL-40.4269.121 We next sought ways to circumvent resistance against ABT-199 induced in our in vitro model. We showed previously that the broad spectrum kinase inhibitor dasatinib prevented CD40-mediated resistance to various drugs, including ABT-7373. We therefore first characterized the targets of dasatinib in primary CLL by solid-phase pull-down, mass-spectrometry and competition binding. Abl and Btk were identified as dominant and specific interactors of dasatinib. Importantly, resistance for BH3-mimetics could be overcome by dasatinib (see table 2) and the Abl inhibitor imatinib, but not by the more selective Btk inhibitor ibrutinib. Conversely, BCR- and chemokine-controlled adhesion could be abolished by dasatinib and ibrutinib, but not by imatinib. Thus, Abl and Btk function in two key pro-survival arms; chemoresistance and localization in the protective environment.Table 2The LC50 of ABT-737 or ABT-199 for CLL cells stimulated with CD40L in combination with Dasatinib (averaged values n=4)StimulationLC50 (μM)ABT-737ABT-1993T30.0050.0013T40L0.781> 103T40L + 100 nM Dasatinib0.0810.066 3T40L + 1000 nM Dasatinib0.0370.020 The observed resistance to ABT-199 induced in our in vitro a co-culture system designed to simulate the CLL microenvironment does not reflect the observations from clinical trials in patients. Nevertheless, long-term clinical application of ABT-199 in CLL might select for resistant clones at protective niches. Our data suggest that this may be overcome by combination treatment with kinase inhibitors that either directly abrogate anti-apoptotic signals or cause egress from lymph node sites and prevent the resistance mechanism from coming into play. 1. Smit LA, Hallaert DY, Spijker R et al. Differential Noxa/Mcl-1 balance in peripheral versus lymph node chronic lymphocitic leukemia cells correlates with survival capacity. Blood 2007;109:1660-1668. 2. Vogler M, Butterworth M, Majid A et al. Concurrent up-regulation of BCL-XL and BCL2A1 induces approximately 1000-fold resistance to ABT-737 in chronic lymphocytic leukemia. Blood 2009;113:4403-4413. 3. Hallaert DY, Jaspers A, van Noesel CJ et al. c-Abl kinase inhibitors overcome CD40-mediated drug resistance in CLL; Implications for therapeutic targeting of chemoresistant niches. Blood 2008;112:5141-5149. Disclosures: No relevant conflicts of interest to declare.
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Cesana, Clara, Barbara Scarpati, Bruno Brando, Claudia Barba, Ursula Ferri, Linda Scampini, Pierluigi Oreste, et al. "Flow Cytometric Examination of Non-Hematic Body Fluids in Hematologic Malignancies: A Comparison with Cytology." Blood 110, no. 11 (November 16, 2007): 4237. http://dx.doi.org/10.1182/blood.v110.11.4237.4237.

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Abstract Introduction: Flow cytometry is well known to detect malignant cells in peripheral blood and bone marrow of patients with hematologic malignancies. However, its role in evaluating non-hematic body fluid contamination by tumor cells is largely unexplored. Patients and Methods: Data detected by flow cytometry in non-hematic body fluid samples drawn between 2002 and 2007 from patients with hematologic neoplasms were retrospectively compared with morphological findings obtained from cytospin slides. Immunophenotyping was carried out by using disease-specific multicolor panels of quadruple monoclonal antibodies, conjugated with the fluorochromes FITC, PE, PerCP, and APC, respectively. Acquisition of information on 1x104 to 1x105 stained cells depending on the whole sample cellularity was assessed on a dual-laser FACSCalibur flow cytometer using the CellQUEST software (Becton Dickinson, San José, CA, USA). Results: Fourty-five samples (bronchoalveolar fluid, n=5; ascites, n=2; hydrocele, n=2; pleural effusion, n=8; and cerebrospinal fluid, n=28) from 32 patients were available for comparison. Diagnoses were as follows: chronic myelomonocitic leukemia (n=1), acute promyelocytic leukaemia (n=2), acute myelomonocytic leukaemia (n=1), B-chronic lymphocitic leukemia (n=4), follicular lymphoma (n=1), acute lymphoblastic leukaemia (n=6), lymphoblastic lymphoma (n=1), high grade non-Hodgkin’s lymphoma (NHL), Burkitt-like (n=3), diffuse large B-cell NHL (n=6), peripheral T-cell NHL (n=3), and NHL, unspecified (n=4). Flow cytometry detected neoplastic cells in 24 cases. Of these cases, only 17 were positive also by morphology. In 7 cases, in which tumor cells were detected by flow cytometry but not by morphology, clinical data confirmed the presence of the disease. Flow cytometry did not show neoplastic cells in 21 cases. Of these cases, only 18 were negative also by morphology. In the remaining 3, the suggestion of diffuse large B-cell NHL contamination by morphology was not confirmed by flow cytometry, demonstrating T-reactive lymphocytes that were clearly negative for disease-specific markers. Conclusions: Our data suggest that flow cytometry is a useful tool complementary to morphology for the screening of non-hematic body fluid contamination in patients with hematologic neoplasms.
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Ferrero, Simone, Daniela Capello, Mirija Svaldi, Daniela Drandi, Michela Boi, Sara Barbiero, Daniela Gatti, et al. "IGH Repertoire Analysis In Multiple Myeloma (MM): Lack of Intra-Disease Homology and Occasional Clustering with Sequences of Other B-Cell Neoplasms Sharing Identical Geographical Origin." Blood 116, no. 21 (November 19, 2010): 2951. http://dx.doi.org/10.1182/blood.v116.21.2951.2951.

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Abstract Abstract 2951 Background: The identification of stereotyped immunoglobulin (IG) receptors has improved our knowledge on the pathogenesis of several B-cell malignancies, suggesting the role of antigen-driven stimulation in chronic lymphocitic leukemia (CLL), marginal-zone lymphoma (MZL) and mantle-cell lymphoma (MCL). Multiple myeloma (MM) is a terminally-differentiated neoplasm no longer expressing surface IG; however some reports suggest the existence of early B-lymphocyte precursors which could be susceptible to antigen-driven stimulation. IG heavy chain (IGH) repertoire has not been extensively investigated in MM, with the largest available reports containing less than 80 complete sequences. Aims: To address this issue we created a database of MM IGH sequences including our institutional records (mostly derived from minimal residual disease studies) and sequences available from the literature. We planned a two-step analysis: a) first we characterized the MM repertoire and performed intra-MM clustering analysis; b) then we compared our MM series to a large public database of IGH sequences from neoplastic and non-neoplastic B-cells in search of similarities between MM sequences and other normal or neoplastic IGH repertoires. Patients and methods: 131 MM IGH genes were amplified and sequenced at our Institutions and belonged to Italian patients, while 214 MM IGH sequences from non-Italian patients were derived from published databases (NCBI-EMBL-IMGT/LIGM-DB) for a total of 345 fully interpretable MM sequences (out of 396). 28590 IGH sequences from other malignant and non-malignant B-cells were retrieved from the same public databases, including approximately 4500 CLL/Non-Hodgkin lymphoma (NHL) sequences and comprising 500 sequences from Italian patients. All sequences were analyzed using the IMGT database and tools (Lefranc et al., Nucleic Acid Res. 2005; http://imgt.cines.fr/) to identify IGHV-D-J gene usage, to assess the somatic hypermutation (SHM) rate and to identify HCDR3. HCDR3 aminoacidic sequences were aligned together using the ClustalX 2.0 software (Larkin et al., Bioinformatics, 2007; http://www.clustal.org/). Subsets of stereotyped IGH receptors were defined according to Stamatopoulos et al. (Blood, 2007). Result: IGHV analysis in MM was almost in keeping with the normal B-cell repertoire, showing a less remarkably biased IGH usage compared to CLL, MCL and MZL (with seven genes accounting for 40% of cases, compared to respectively five, three and two genes). However, a modest but significant over-representation of IGHV1-69, 2–5, 2–70, 3–21, 3–30-3, 3–43, 5–51 and 6-1 genes and under-representation of the IGHV1-18, 1–8, 3–30, 3–53 and 4–34 was noticed. The rate of somatic hypermutation in MM followed a Gaussian distribution with a median value of 7.8%. Intra-MM search for HCDR3 similarities never met minimal requirements for stereotyped receptors. When MM sequences were compared to non-MM database, only a minority of MM sequences (2.6%, n=9) clustered with sequences from lymphoid tumors and normal B-cells (figure 1A). In particular two non-Italian MM sequences clustered with previously characterized, uncommon CLL subsets (n.37 and n.71 according to Murray et al., Blood 2008). Moreover, novel provisional clusters were observed including three MM-CLL subsets, one MM-NHL subset, and three MM-normal B-cell subsets. While the MM-normal B-cell clusters involved non-Italian patients, we unexpectedly noticed that the four MM-CLL/MM-NHL clusters were composed exclusively of Italian patients, as shown in figure 1B, although Italian subjects represented less than 12% of the entire CLL-NHL database. Conclusion: The analysis of the largest currently available database of MM IGH sequences indicates the following: 1) MM IGH repertoire is closer to physiological distribution than that of CLL, MCL and MZL; 2) MM specific clusters do not occur to a frequency detectable with currently available databases; 3) 98% of MM sequences are not related to other “highly-clustered” lymphoproliferative disorders; 4) Uncommon clustering phenomena may follow a geographical rather than a disease-related pattern. Disclosures: No relevant conflicts of interest to declare.
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Vanazzi, Anna, Alessandra Alietti, Alberto Agazzi, Mara Negri, Maria Teresa Lionetti, Aleksandra Babic, Davide Radice, et al. "90 y-Ibritumomab Tiuxetan or Purine Analogues Severely Affect Peripheral Blood Stem Cell Mobilization: An Analysis On 248 Patients." Blood 114, no. 22 (November 20, 2009): 3210. http://dx.doi.org/10.1182/blood.v114.22.3210.3210.

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Abstract Abstract 3210 Poster Board III-147 BACKGROUND High-dose chemotherapy followed by autologous Peripheral Blood Stem Cell (PBSC) transplantation represents an effective option in relapsing/refractory malignant lymphoma as well as in selected solid tumors. Collection of a sufficient amount of stem cells (CD34+ ≥ 2.0×106/kg) by apheresis is mandatory for the procedure. However many factors could influence the mobilization of PBSC and about 30% of patients eligible for this therapeutic option fail stem cell mobilization. Peripheral CD34+ counts of 20/μL is conventionally considered the cut-off for a successful collection. METHODS With the aim to identify those factors affecting PBSC mobilization, we retrospectively reviewed data about our experience at European Institute of Oncology from 01/2005 to 05/2009. By evaluating the number of CD34+cells after mobilization, patients were considered as good mobilizers (peripheral CD34+ ≥ 20/μL, group A), relative poor mobilizers (peripheral CD34+ counts <20 and ≥8/ μL, group B) and absolute poor mobilizers (peripheral CD34+ counts <8/μL, group C). A total of 248 patients were enrolled into a mobilizing PBSC program; apheresis was performed when the CD34+ cell count was >5/μL. Patients characteristics were: 140 male, 108 female; median age was 51 yrs; diagnosis included: 124 Non Hodgkin Lymphoma (NHL), 50 Hodgkin Lymphoma (HL), 35 Multiple Myeloma (MM), 5 Acute Leukemia (AL) and 33 solid tumors, 1 Chronic Lymphocitic Leukemia (CLL); mean number of previous chemotherapy lines was 1 (0-9). The main mobilization regimens in hematological patients were cyclophosphamide 4g/mq (n=118) and ESHAP either followed by G-CSF (n=27) or pegylated G-CSF (n=48); the majority of patients affected by solid tumors received ICE regimen plus G-CSF (n=26). RESULTS By evaluating the number of CD34+cells after mobilization, 163 (65.7%) patients resulted good mobilizers, 43 (17.3%) patients relative poor mobilizers and 42 (17%) patients absolute poor mobilizers. All patients in group A, 31 patients in group B (72%) and 8 patients in group C (19%) collected >2.0×106 CD34+cells/kg. According the Two-sided Fisher's exact test, more than 3 previous chemotherapy lines before mobilization (p<0.001), pretreatment with purine analogues (p=0.007) or 90Y-Ibritumomab Tiuxetan (p=0.002) were found to be independent factors able to affect PBSC mobilization. In a multivariate analysis, these factors were confirmed as detrimental (purine analogs p=0.019, 90Y-Ibritumomab Tiuxetan p=0.003). CONCLUSIONS These results could help to identify those factors affecting PBSC mobilization. To reduce poor mobilizers we suggest to anticipate mobilization program and to evaluate the opportunity to reserve purine analogs or radioimmunotherapy after collection. About 20% of patients defined as absolute poor mobilizers might successfully mobilize PBSC by lowering the CD34+ cut-off before apheresis. Disclosures No relevant conflicts of interest to declare.
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Dissertations / Theses on the topic "Chronic lymphocitic leukemia (CLL)"

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Baliakas, Panagiotis. "Reappraising prognosis in chronic lymphocytic leukemia." Doctoral thesis, Uppsala universitet, Institutionen för immunologi, genetik och patologi, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-280943.

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Chronic lymphocytic leukemia (CLL) exhibits remarkable clinical heterogeneity likely reflecting the underlying biological heterogeneity. The genetic landscape of CLL has been recently enriched with mutations within a number of genes proposed as novel prognostic markers. Mounting evidence also supports the pivotal role of the clonotypic B-cell receptor immunoglobulin (BcR IG) in the natural history of CLL. Interestingly, almost 30% of all CLL patients can be assigned to different patient subsets, each defined by expression of a distinct stereotyped BcR IG. Whether stereotyped subsets exhibit distinct clinical behavior is still an issue of debate. The aim of this thesis was to evaluate the prognostic relevance of recurrent gene mutations and to assess the clinicobiological associations and clinical impact of BcR IG stereotypy in CLL. In a cohort of 3490 patients, NOTCH1, SF3B1 and TP53 mutations were enriched within clinically aggressive cases carrying unmutated IGHV genes (U-CLL), frequently co-occurring with trisomy 12, del(11q) and del(17p), respectively. Of note, SF3B1 mutations increased in parallel with increasing timespan between diagnosis and mutational screening. NOTCH1 mutations, SF3B1 mutations and TP53 abnormalities (TP53abs, deletions and/or mutations) correlated with shorter time-to-first-treatment among early stage cases, while in multivariate analysis, only SF3B1 mutations and TP53abs retained independent significance. In a series of 8593 CLL patients, stereotyped subsets showed marked differences in demographics, clinical presentation, cytogenetic aberrations and gene mutational spectrum. Patients within a specific subset generally followed similar clinical courses, whereas patients in different stereotyped subsets—even when displaying similar IG somatic hypermutation status— experienced significantly different clinical outcome. In particular, subset #2 (IGHV3-21/IGLV3-21), the largest overall, was found to exhibit (i) a remarkably high incidence of SF3B1 mutations (44%), alluding to subset-biased acquisition of genomic aberrations, in the context of particular antigenic stimulation; and, (ii) a dismal clinical outcome, distinct from the remaining IGHV3-21 CLL. Our findings strongly support the adverse clinical impact of SF3B1 mutations in CLL in addition to TP53abs. BcR IG stereotypy also emerges as prognostically relevant, further highlighting that an immunogenetic sub-classification of CLL based on BcR IG configuration could refine patient risk stratification.
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Shen, Yandong. "The Chronic Lymphocytic Leukemia (CLL) Microenvironment and Novel Targeted Therapies." Thesis, The University of Sydney, 2019. http://hdl.handle.net/2123/20805.

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Activation of the B-cell receptor (BCR), and subsequent signalling via the Bruton's tyrosine kinase (BTK), phosphoinositide-3 kinase (PI3K) and mitogen-activated protein kinase (MAPK), plays a significant role in the pathogenesis of CLL. This thesis aimed to better understand the role of the CLL microenvironment and to investigate novel treatment strategies for targeting CLL cells in the lymph nodes or bone marrow. We demonstrated using the DotScan cluster of differentiation (CD) antibody microarray, that immunophenotypic changes induced on CLL cells by co-culture with fibroblasts expressing the CD40 ligand can be blocked by ibrutinib or idelalisib. These data provide insight on the mechanisms underlying the lymphocytosis observed in patients treated with these agents. We demonstrated that as a single agent the MEK1/2 inhibitor, binimetinib was effective against CLL cells under certain in vitro conditions and that the drug was effective and synergistic with the AKT inhibitor, MK2206, but not idelalisib. These data suggest that this combination of drugs may represent a novel therapeutic option for CLL effective against CLL cells in the tumour microenvironment. Next, we demonstrated efficacy of the dual PI3K/PIM inhibitor, IBL-202 and showed high synergy with the Bcl-2 inhibitor, venetoclax against CLL cells under conditions that mimic the tumour microenvironment and against a TP53 knock-out cell line we derived from the OSU-CLL cell line using the CRISPR-Cas9 system. This combination was synergistic in terms of apoptosis and inhibition of both the proliferative and migratory capacities of CLL cells. These data suggest that IBL-202 in combination with venetoclax may be an effective treatment option for high risk CLL disease. Collectively, the data presented highlight several pathways and novel drugs that may contribute to the development of therapeutic strategies for CLL patients.
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Beckwith, Kyle Addison. "Novel Immunotherapeutic Strategies for Chronic Lymphocytic Leukemia." The Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1461203257.

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Imam, Hasan. "Effects of protein kinase inhibitors on chronic lymphocytic leukemia (CLL) cells." Thesis, Linköpings universitet, Institutionen för klinisk och experimentell medicin, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-73883.

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B cell Chronic lymphocytic leukemia (B-CLL) is a neoplastic disorder characterized by accumulation of B lymphocytes due to uncontrolled growth and resistance to apoptosis. Src family kinases (SFKs) are non receptor tyrosine kinases present in the cytosol, which couple with downstream B cell receptor signaling and thus mediate growth, survival, proliferation and antiapoptosis. In CLL cells SFKs are remarkably overexpressed, especially Lyn kinase. This gives the rational to use SFKs inhibitor to treat CLL. Addition of the specific pharmacological inhibitors of SFKs, bosutinib and saracatinib, inhibited the global tyrosine phosphorylation as well as the basal auto-phosphorylation of SFKs. Mechanistically, inhibition of SFKs is coupled to apoptosis induction via decreased protein levels of the anti-apoptotic proteins Bcl-2, Mcl-1 and survivin, which were demonstrated by Western blotting. To assess apoptosis induction, annexin V binding to freshly isolated CLL cells with or without treatment with kinase inhibitors was measured flow cytometrically. Using the inhibitors at a concentration of 10 μM the average percentages of annexin V-positive, apoptotic cells in 11 CLL samples increased from 24 % in untreated controls to 55 %, 45 % and 37 % after treatment with bosutinib, saracatinib and dasatinib, respectively. The response to each of the inhibitors showed a high but comparable degree of variation among the investigated CLL samples. On the average bosutinib induced apoptosis with significantly higher efficiency than dasatinib, which calls for further investigation of its pre-clinical potential for treatment of CLL.
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Ljungström, Viktor. "Exploring next-generation sequencing in chronic lymphocytic leukemia." Doctoral thesis, Uppsala universitet, Experimentell och klinisk onkologi, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-302026.

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Next-generation sequencing (NGS) techniques have led to major breakthroughs in the characterization of the chronic lymphocytic leukemia (CLL) genome with discovery of recurrent mutations of potential prognostic and/or predictive relevance. However, before NGS can be introduced into clinical practice, the precision of the techniques needs to be studied in better detail. Furthermore, much remains unknown about the genetic mechanisms leading to aggressive disease and resistance to treatment. Hence, in Paper I, the technical performance of a targeted deep sequencing panel including 9 genes was evaluated in 188 CLL patients. We were able to validate 143/155 (92%) selected mutations through Sanger sequencing and 77/82 mutations were concordant in a second targeted sequencing run, indicating that the technique can be introduced in clinical practice. In Paper II we screened 18 NF-κB pathway genes in 315 CLL patients through targeted deep sequencing which revealed a recurrent 4 base-pair deletion in the NFKBIE gene. Screening of NFKBIE in 377 additional cases identified the mutation in ~6% of all CLL patients. We demonstrate that the lesion lead to aberrant NF-κB signaling through impaired interaction with p65 and is associated with unfavorable clinical outcome. In Paper III we sought to delineate the genetic lesions that leads to relapse after fludarabine, cyclophosphamide, and rituximab treatment. Through whole-exome sequencing of pre-treatment and relapse samples from 41 cases we found evidence of frequent selection of subclones harboring driver mutations and subsequent clonal evolution following treatment. We also detected mutations in the ribosomal protein RPS15 in 8 cases (19.5%) and characterization of the mutations through functional assays point to impaired p53 regulation in cells with mutated RPS15. Paper IV aimed at characterizing 70 patients assigned to three major subsets (#1, #2, and #4) through whole-genome sequencing. Besides recurrent exonic driver mutations, we report non-coding regions significantly enriched for mutations in subset #1 and #2 that may facilitate future molecular studies. Collectively, this thesis supports the potential of targeted sequencing for mutational screening of CLL in clinical practice, provides novel insight into the pathobiology of aggressive CLL, and demonstrates the clinical outcome and cellular effects of NFKBIE and RPS15 mutations.
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Browning, Rebekah L. "Combination Therapies with Interleukin-21 in Chronic Lymphocytic Leukemia." The Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1429719855.

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Mohamed, Ahmed. "Deciphering the ontogeny of unmutated and mutated subsets of Chronic Lymphocytic Leukemia." Thesis, Högskolan i Skövde, Institutionen för biovetenskap, 2019. http://urn.kb.se/resolve?urn=urn:nbn:se:his:diva-17286.

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Chronic Lymphocytic Leukemia (CLL) is a type of cancer that affects the B cells of the immune system causing problems in the process of producing antibodies. It can be sorted into mutated and unmutated CLL based on the percentage of somatic mutations in the Immunoglobulin Heavy chain Variable region (IgHV). The B cells of healthy individuals can be sorted into three groups; CD27dull memory B cells (MBCs), CD27bright MBCs and naïve B cells. The hypothesis for the project was that the unmutated CLL subset originates from CD27dull MBCs and the mutated CLL subset originates from CD27bright MBCs. RNA-sequencing data from healthy individuals were acquired from a collaboration partner in Rome and CLL-patients were collected from public datasets available online. Several bioinformatic tools were used to analyze the data. First, the quality of the data files was checked, then adapter sequence from the sequencing process and low-quality bases were removed (trimming). Good quality of the files was confirmed after the trimming. Secondly, these files were mapped against the human reference genome (GRCh38/hg38) for alignment, then the resulted data was used to check for genes that showed differential expression between the different groups. Results were analyzed and visualized using Venn diagrams, Principal Component Analysis (PCA) and heatmap plots and random forest. A list of 85 genes was generated based on the different comparisons and was used in one PCA plot that showed clear separation between the different groups. The SWAP70 gene was analyzed for single nucleotide polymorphisms (SNPs). The study concluded five genes that could be used as biomarkers for CLL and the diagnosis of its subtypes where some of them were discussed in previous studies. Also, the mutated CLL subset showed a similar behavior to the healthy individuals and this could validate the original hypothesis and justifies the better disease prognosis for this subtype.
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Lanemo, Myhrinder Anna. "Restricted antigen recognition in B cell chronic lymphocytic leukemia." Licentiate thesis, Linköping University, Linköping University, Faculty of Health Sciences, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-16355.

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Chronic lymphocytic leukemia (CLL) cells are considered to be derived from antigen-exposed B cells. To further explore the antigen-driven selection behind the leukemogenesis of CLL, we performed immunoglobulin (Ig) specificity screening of 7 CLL cell lines and 23 primary CLL clones from patient peripheral blood. We also included a recombinant monovalent monoclonal antibody (mAb) belonging to a subset of CLL cases with identical or semiidentical heavy chain complementarity determining region 3 (HCDR3) of the IGHV3-21 gene rearrangement. We found CLL mAb specificities against vimentin, filamin B, cofilin-1, proline-rich acidic protein 1, cardiolipin, oxidized low density lipoprotein and Streptococcus pneumoniae polysaccarides. These molecules are functionally associated with microbial infection and/or apoptotic cell removal. An antigen-driven selection would therefore imply that CLL B cell precursors are involved in the elimination and scavenging of pathogens and apoptotic cells, which could trigger the development of the disease.

The limited in vitro survival of CLL cells makes Epstein-Barr virus (EBV) immortalization of CLL cells a useful experimental model for studies on antibody-specificity screening. Considering the intricate procedure of EBV transformation of CLL cells and the many false cell lines used worldwide, we also wanted to characterize and evaluate the authentic origin of several previously established CLL cell lines and their normal lymphoblastoid counterparts. Three of the CLL cell lines tested were truly authentic (I83-E95, CLL-HG3 and CII), two had features of a biclonal Ig expression (232B4 and WaC3CD5+), one was only tentatively verified (PGA-1), whereas one cell line could not be verified (EHEB) due to lack of original patient cells for comparison. Two of the presumed normal lymphoblastoid cell lines tested were shown to be a neoplastic CLL clone. This study emphasizes the importance of proper cell line authentication and we will continue to verify additional cell lines not yet proven authentic.

In conclusion, we provide evidence for natural Ab production by CLL cells and suggest that these cells might be derived from B cell precursors involved in the innate immunity and, thus, providing a first-line-defence against pathogens and in elimination of apoptotic cells.

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Niu, Suli. "Quantitative Determination of Surface Markers on B-cell Chronic Lymphocytic Leukemia (CLL) Cells." Thèse, Université d'Ottawa / University of Ottawa, 2014. http://hdl.handle.net/10393/30982.

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To supplement and modify the diagnosis and clinical research of B-cell Chronic Lymphocytic Leukemia (B-CLL), a new method based on cell imaging and image processing was developed and applied to the B-CLL patient samples. The fluorophore-labelled leukemia cells were clearly visualized, reflecting the positive/negative expression of the corresponding surface markers and their distribution. Computer algorithms were devised and used to analyze a large number of images. The fluorescence intensity of the labelled antibodies on a given cell directly reflects the expression of the corresponding surface markers. The morphology and size of leukemia cells were not identical even in the same patient’s sample and the size variation does not correlate with the number of surface markers. The amount of each surface marker was approximately fixed for each patient, but there were some relationships, for instance, the number of CD19 and CD38 markers were correlated to each other. The heterogeneous expression of surface markers confirmed an assumption that surface markers have their preferred membrane positions. One of the most important results is that the cell imaging and our image processing method has provided an alternative and reliable way to diagnose B-CLL and new insights in the prognosis of subtype of B-CLL.
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Beiggi, Sara. "Epidemiological study of chronic lymphocytic leukemia (CLL) in the province of Manitoba, Canada." British Journal of Cancer (Nature Group), 2013. http://hdl.handle.net/1993/23508.

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A previous population-based study of survival in Chronic Lymphocytic Leukemia (CLL) patients in the province of Manitoba demonstrated a lower five-year relative survival among CLL patients compared with the age- and gender-adjusted general population. This decreased relative survival was most pronounced among elderly male CLL patients. In this study, we have demonstrated that the reduced five-year relative survival observed in CLL patients compared to the general population of Manitoba may partially be attributed to increased risk of second cancers and non-referral to specialized CLL clinics. The increased risk of second cancers in CLL patients compared to Follicular Lymphoma (FL), a similar indolent B cell malignancy, was only observed after CLL diagnosis indicating that a CLL-specific factor may be responsible for the increased risk of second cancers in these patients. The risk of second cancers is independent of treatment and surveillance bias but is further increased with chemotherapy. A superior outcome in CLL patients who have been referred to the CancerCare Manitoba (CCMB) specialized CLL clinic was observed that was independent of age, gender, treatment and history of previous cancers. This superior outcome was most pronounced in the elderly CLL patients. We propose that CLL patients should be referred to CLL-specific hematologists and, where not possible, that guidelines created by such experts be followed. Appropriate screening for second cancers should be performed during routine follow up of CLL patients.
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Books on the topic "Chronic lymphocitic leukemia (CLL)"

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National Cancer Institute (U.S.). Division of Cancer Epidemiology and Genetics. CLL family registry, news. [Bethesda, MD]: U.S. Dept. of Health and Human Services, Public Health Service, National Institutes of Health, 2001.

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CLL family registry update form. [Bethesda, MD: National Cancer Institute, 2002.

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Bisoyi, Minati. Chronic Lymphocytic Leukemia (CLL) Signs, Symptoms, Causes, Prevent & Treatment. Independently Published, 2019.

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Steensma, David P. Malignant Hematology. Oxford University Press, 2012. http://dx.doi.org/10.1093/med/9780199755691.003.0296.

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The hematologic neoplasms include lymphoproliferative disorders (eg, chronic lymphocytic leukemia [CLL]/small lymphocytic lymphoma [SLL], large granular lymphocyte leukemia, hairy cell leukemia [HCL], Hodgkin lymphoma, non-Hodgkin lymphoma), plasma cell disorders (multiple myeloma, light chain amyloidosis, Waldenström macroglobulinemia, POEMS syndrome, heavy chain disease, plasmacytoma), chronic myeloid neoplasms (chronic myeloid leukemia, the BCR/ABL-negative myeloproliferative neoplasms, myelodysplastic syndromes), and acute leukemia (acute myeloid leukemia, acute lymphocytic leukemia). In addition, clonal but not overtly malignant conditions are common in the general population, including monoclonal gammopathy of undetermined significance (MGUS) and monoclonal B lymphocytosis (MBL).
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Faitschuk, Elena. ˜Aœ novel dual chain-based design of a chimeric antigen receptor (CAR) for adoptive cell therapy and an FcR-specific CAR for improved targeting of chronic lymphocytic Leukemia (CLL). Köln, 2016.

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Book chapters on the topic "Chronic lymphocitic leukemia (CLL)"

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Gutman, Jonathan A., Kelly M. Smith, John M. Pagel, and John M. Pagel. "Chronic Lymphocytic Leukemia (CLL)." In Leukemia and Related Disorders, 67–96. New York, NY: Springer New York, 2011. http://dx.doi.org/10.1007/978-1-60761-565-1_3.

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Goede, Valentin, and Michael Hallek. "Chronic Lymphocytic Leukemia (CLL)." In Management of Hematological Cancer in Older People, 113–28. London: Springer London, 2014. http://dx.doi.org/10.1007/978-1-4471-2837-3_7.

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Marti, Gerald E., and Vincent Zenger. "The Natural History of CLL." In Chronic Lymphocytic Leukemia, 3–54. Totowa, NJ: Humana Press, 2004. http://dx.doi.org/10.1007/978-1-59259-412-2_1.

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Dighiero, Guillaume. "Guidelines for Clinical Management of CLL." In Chronic Lymphocytic Leukemia, 219–40. Totowa, NJ: Humana Press, 2004. http://dx.doi.org/10.1007/978-1-59259-412-2_12.

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Orsini, Enrica, and Robin Foa. "Cytokines and Soluble Molecules in CLL." In Chronic Lymphocytic Leukemia, 123–42. Totowa, NJ: Humana Press, 2004. http://dx.doi.org/10.1007/978-1-59259-412-2_6.

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Faguet, Guy B. "Clonal Evolution and Second Malignancies in B-CLL." In Chronic Lymphocytic Leukemia, 377–86. Totowa, NJ: Humana Press, 2004. http://dx.doi.org/10.1007/978-1-59259-412-2_21.

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Hamblin, Terry. "The Heterogeneous Origin of the B-CLL Cell." In Chronic Lymphocytic Leukemia, 95–107. Totowa, NJ: Humana Press, 2004. http://dx.doi.org/10.1007/978-1-59259-412-2_4.

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Johnston, Patrick B., and Neil E. Kay. "Pathogenesis of Impaired Cellular Immune Function in CLL." In Chronic Lymphocytic Leukemia, 109–21. Totowa, NJ: Humana Press, 2004. http://dx.doi.org/10.1007/978-1-59259-412-2_5.

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Siddiqi, Tanya. "Chronic Lymphocytic Leukemia (CLL): Biology and Therapy." In Cancer Treatment and Research, 133–49. Cham: Springer International Publishing, 2021. http://dx.doi.org/10.1007/978-3-030-78311-2_8.

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Okkenhaug, Klaus, and Jan A. Burger. "PI3K Signaling in Normal B Cells and Chronic Lymphocytic Leukemia (CLL)." In Current Topics in Microbiology and Immunology, 123–42. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/82_2015_484.

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Conference papers on the topic "Chronic lymphocitic leukemia (CLL)"

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Clay-Gilmour, Alyssa I., Daniel R. O'Brien, Sara J. Achenbach, Celine M. Vachon, Kari G. Chaffee, Timothy G. Call, Jose F. Leis, et al. "Abstract 1226: Rare germline variants segregating in chronic lymphocytic leukemia (CLL) families." In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-1226.

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Yan, Huihuang, Zhiquan Wang, Shulan Tian, Geffen Kleinstern, Nicholas Boddicker, Xing Li, Susan Slager, and Esteban Braggio. "Abstract 1256: Widespread alterations of chromatin accessibility in chronic lymphocytic leukemia (CLL)." In Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-1256.

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Kleinstern, Geffen, Daniel R. O’Brien, Brian F. Kabat, Kari G. Chaffee, Aaron D. Norman, Timothy G. Call, Sameer A. Parikh, et al. "Abstract 4466: Somatic mutations within chronic lymphocytic leukemia (CLL) putative driver genes are associated with outcomes beyond the CLL international prognostic index (CLL-IPI)." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-4466.

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Kleinstern, Geffen, Daniel R. O’Brien, Brian F. Kabat, Kari G. Chaffee, Aaron D. Norman, Timothy G. Call, Sameer A. Parikh, et al. "Abstract 4466: Somatic mutations within chronic lymphocytic leukemia (CLL) putative driver genes are associated with outcomes beyond the CLL international prognostic index (CLL-IPI)." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.am2019-4466.

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Sahakian, Eva, Kamira Maharaj, John Powers, Renee M. Fonesca, Susan Deng, Javier Pinilla-Ibraz, Steven N. Quayle, and Simon S. Jones. "Abstract 4485: Regulation of chronic lymphocytic leukemia (CLL) immunobiology by histone deacetylase 6 (HDAC6)." In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-4485.

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Strati, Paolo, Kari Chaffe, Sara Achenbach, Timothy Call, Neil Kay, James Cerhan, Susan Slager, and Tait Shanafelt. "Abstract 5267: Comorbidity and cause of death in patients with chronic lymphocytic leukemia (CLL)." In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-5267.

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Murali, Ishwarya, Justin Cha, Ignaty Leshchiner, Yanan Kuang, Kevin Vasquez, Jasneet Khalsa, Stacey M. Fernandes, et al. "Abstract 1097: Mechanisms of primary and acquired resistance to venetoclax in chronic lymphocytic leukemia (CLL)." In Proceedings: AACR Annual Meeting 2021; April 10-15, 2021 and May 17-21, 2021; Philadelphia, PA. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/1538-7445.am2021-1097.

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Ahmad, Waqar, Madiha Hameed, Muhammad Bilal, and Abdul Majid. "ML-Pred-CLL: Machine Learning based prediction of Chronic Lymphocytic Leukemia using protein sequential data." In 2022 International Conference on Recent Advances in Electrical Engineering & Computer Sciences (RAEE & CS). IEEE, 2022. http://dx.doi.org/10.1109/raeecs56511.2022.9954510.

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Bhattacharya, Nupur, Maiwen Caudron-Herger, Hauke Busch, Karsten Rippe, Hartmut Doehner, Stephan Stilgenbauer, and Daniel Mertens. "Abstract 2284: Dissecting signaling networks involved in the tumor-microenvironment crosstalk in chronic lymphocytic leukemia (CLL)." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-2284.

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Vishwakarma, Bandana Ajay, and Amy Wesa. "Abstract 2990: In vitro drug sensitivity screening platform for primary chronic lymphocytic leukemia (CLL) patient samples." In Proceedings: AACR Annual Meeting 2021; April 10-15, 2021 and May 17-21, 2021; Philadelphia, PA. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/1538-7445.am2021-2990.

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Reports on the topic "Chronic lymphocitic leukemia (CLL)"

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Report of public meeting to seek input on gaps in chronic lymphocytic leukemia (CLL) radiogenicity research held July 21, 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, October 2005. http://dx.doi.org/10.26616/nioshpub2006100.

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You might also be interested in the extended bibliographies on the topic 'Chronic lymphocitic leukemia (CLL)' for particular source types:
Journal articles Dissertations / Theses
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