Статті в журналах: "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 та 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, № 21 (6 грудня 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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Sorasio, R., L. Giaccone, A. M. Carella, S. Guidi, B. Allione, E. Benedetti, F. Carnevale-Schianca, et al. "Disease and Comorbidity Status Predict Outcome after Nonmyeloablative Allografting for Advanced Haematological Malignancies." Blood 110, no. 11 (November 16, 2007): 4930. http://dx.doi.org/10.1182/blood.v110.11.4930.4930.

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Abstract Nonmyeloablative (NM) regimens extended the application of allogeneic transplantation (AT) to older and/or medically unfit patients ineligible for high-dose conditionings. Moreover, several patients are offered AT after failure of prior lines of therapy. We retrospectively evaluated 108 patients, median age 51 (16–67), with advanced or heavily pre-treated hematological cancers [19 acute myeloblastic (AML) and 1 lymphoblastic leukemia (ALL); 8 myelodysplastic syndrome (MDS); 9 chronic myeloid (CML) and 9 chronic lymphocitic leukemia; 3 myelofibrosis (MF); 48 myeloma beyond first line treatment; 8 Hodgkin’s and 8 non-Hodgkin’s lymphoma) who underwent NM-AT at 12 Italian transplant Centres. Median time between diagnosis and transplant was 20 months. Sixty-one% of patients had failed at least one prior line of therapy, including 36 refractory or relapsed patients after 1 or more autologous transplants. At allografting, 15 patients had disease at lower risk of relapse (AML and ALL in first complete remission (CR), MDS without blast excess, CML in first chronic phase, untreated MF). Forty-two patients had active disease. The comorbidity score was evaluated with an AT-specific comorbidity index (CI) as described by Sorror et al: 51 patients had CI=0, 42 CI=1–2 and 15 CI≥3. Patients were conditioned with fludarabine 90 mg/m2 and 2 Gy total body irradiation. GVHD prophylaxis consisted of cyclosporine and mycophenolate mophetile. Graft failure was observed in 1 patient and rejection after disease recurrence in 4. After a median follow-up of 28 months post-allografting, 58 (54%) had refractory/progressive disease and 36 (33%) were in CR, including 23 who were not in CR at transplant (p<0,001). Cumulative incidences of grade II–IV acute GVHD and extensive chronic GVHD were 35% and 60% respectively. Fourteen patients (13%) died of transplant-related causes (TRM) and 36 (33%) of disease progression (DRM). Two-year TRM was 12% and was higher in patients with CI≥3 (HR 2.84, p=0.08) whereas DRM was 31% and was significantly influenced by disease status at transplant (HR 0.37 for patients in partial (PR) or CR, p=0.003). Median event-free (EFS) and overall survivals (OS) were 11 (95% Cl: 8–15) and 35 months (95% Cl: 21–42) respectively. OS was significantly better in patients in remission (HR 0.44, p=0.004) and a trend for better OS was also observed in patients with CI<3 (HR 0.73, p=n.s.). By multivariate analysis, disease remission at transplant was associated with better OS and EFS (HR 0.39, p=0.001 and HR 0.41, p<0.001 respectively) and there was a trend for worse EFS in patients with CI≥3 (HR 1.88, p=0.08). Age, number of prior therapies and time between diagnosis and AT did not affect OS and EFS. In summary, though retrospective, this report confirms that disease-status and comorbidity scores predict transplant outcome. The use of AT specific comorbidity scores in prospective studies is imperative to select patients who most benefit from this procedure.

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Pastano, Rocco, Giovanna Andreola, Patrizia Mancuso, Federica Gigli, Angelo Gardellini, Sarah Jayne Liptrott, Davide Radice, Giovanni Martinelli, and Francesco Bertolini. "Mature Circulating Endothelial Cells and Progenitors in Patients with Chronic Gvhd." Blood 118, no. 21 (November 18, 2011): 4700. http://dx.doi.org/10.1182/blood.v118.21.4700.4700.

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Abstract Abstract 4700 Acute and chronic graft-versus-host disease are a common complication of allogeneic stem cell transplantation. In animal models acute GVHD (aGVHD) is associated with increased neovascularization and number of circulating endothelial cells (CECs), while patients with sclerodermatous chronic GVHD (cGVHD) show a significant decrease in the number of circulating endothelial progenitor cells (EPCs) in peripheral blood as compared to patients with non sclerodermatous cGVHD or controls. In an attempt to evaluate the role of CECs and EPCs in patients with cGVHD, we analysed a total of 15 patients affected by hematological malignancies (3 Non-Hodgkin Lymphoma, 4 Hodgkin Disease, 4 Multiple Myeloma, 2 Myelodisplastic Syndrome, 2 Chronic Lymphocitic Leukemia) having undergone allogeneic stem cell transplantation following reduced intensity conditioning. Donors were HLA identical in 14 patients (12 sibling and 2 matched unrelated donors) and HLA aploidentical in 1. Acute GVHD and cGVHD were defined on the basis of time of manifestation, ≤100 days for aGVHD and >100 days for cGVHD. At the time of the blood sample collection, 8 patients, median age 42 years (28-51), with a median time after transplant of 177 days (21-1373), had no evidence of GVHD; of those 5/8 were evaluable for aGVHD and cGVHD, 2 only for aGVHD; 4/8 were on post-transplant calcineurin inhibitors immunosuppressive therapy; 7 other patients, median age 51 years (38-64), with a median time after transplant of 844 days (314-1779), were all evaluable for acute and cGVHD and had evidence of cGVHD as follows: sclerodermatous in 3 patients requiring systemic immunosuppressive therapy, oral mucosa lichen in 1 patient taking oral corticosteroid and cutaneous erythematous and dischromic cGVHD in the other 3 patients, with only 1 patient on systemic immunosuppressive therapy. Viable and apoptotic CECs and EPCs were evaluated by six color flow cytometry (Mancuso et al, Clin Cancer Res, 2009). Briefly, CECs were defined as DNA+CD45-CD31+ CD146+, EPCs as CD45- CD34+. The combination of Syto16 and 7-AAD was used to discriminate between viable (syto16bright/7-AAD-) and apoptotic (syto16weakly pos/7-AAD+) endothelial cells, and to exclude from analysis, platelets and endothelial macroparticles. The results, expressed as median of cells/mL, are summarized in the following table:Total CECsViable CECsApoptotic CECsEPCsHealthy Subject103 (33–322)21 (3–67)77* (28–303)31 (0–56)Patients with cGVHD46 (29–94)41 (25–68)5* (3–26)30 (0–213)Patients without GVHD138 (30–179)39 (10–153)68* (5–136)49 (0–355)*p<0.017 These preliminary data indicate a significant reduction in apoptotic circulating mature endothelial cells, likely reflecting a poor vascularization of multiple organs and tissues targeted by cGVHD and a trend towards a decreased number of EPCs in patients with cGVHD. A multicentric study is now planned to confirm these hypotheses and investigate a possible predictive/prognostic role of CEC and EPC counts in cGVHD. Disclosures: No relevant conflicts of interest to declare.

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Milone, Jorge, Virginia Prates, Zoppegno Lucia, Basquiera Ana, Yantorno Sebastian, Gelemur Marta, and Garcia Juan. "Rapid Infusion of Rituximab (RIR) Is Well Tolerated and Can Safely Be Delivered in Patients with Lymphoproliferative Diseases." Blood 110, no. 11 (November 16, 2007): 4503. http://dx.doi.org/10.1182/blood.v110.11.4503.4503.

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Abstract It has been proved that Rituximab is a useful drug for the treatment of patients with lymphoma. Being a humanized antibody, it presents high specificity. Rituximab is a well tolerated medicine, although a slow infusion rate given in many hours is recommended to avoid reactions derived from the liberation of cytokines. As a consequence, patients need admissions for a treatment that can take hours. The recent demostration of its usefulness in the maintenance of the response of patients with follicular lymphomas has concluded in the revision of hospitalization time, proposing a faster infusion. We are presenting our experience with RIR, on a group of patients with lymphoproliferative diseases. We used RIR with the aim to observe the toxicity and to reduce the time of hospitalization in patients with lymphoma. We evaluated the adverse events and tested the feasibility of a 90 minutes infusion schedule for rituximab (20% of the dose administered in the first 30 minutes, remaining administered over 60 minutes). Premedication included oral paracetamol and intravenous hidrocortisone and diphenhydramine. Sixty seven RIR were used to treated 31 patients (27 non-Hodgkin Lymphoma and 4 Chronic Lymphocitic Leukemia). All of them had previously received one or more rituximab conventional infusion without grade 3 or 4 toxicity. Twenty nine patients received also CHOP or CHOP-like chemotherapy and the other two Rituximab alone as maintenance therapy. Overall RIR was well tolerated. There were 5 adverse events. Four patients developed grade one adverse events: one patient had an hypotension episode, one presented chest pain and the other two had abdominal pain. Only one patient developed a grade 3 adverse event (abdominal pain) and withdrew the RIR schedule. We conclude that rapid infusion rituximab is safe and well tolerated. The adoption of this schedule in clinical practice reduces in many hours the time of hospitalization for patients with lymphoma and may be a cost-effective strategy.

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Terruzzi, Elisabetta, Chiara Scollo, Fausto Rossini, Matteo Parma, Pietro Pioltelli, and Enrico Maria Pogliani. "Early and Late Complications in 247 Adult Autologous Stem Cell Transplant Recipients." Blood 108, no. 11 (November 16, 2006): 5242. http://dx.doi.org/10.1182/blood.v108.11.5242.5242.

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Abstract High-dose therapy supported by autologous stem cell transplantation (ASCT) has became a widely applied therapy in many haematological malignancies during two decades. ASCT may be curative and even more commonly leads to prolonged survival. Along with the use of mobilised blood progenitor cells and improved supportive care after ASCT, the early treatment-related mortality (<100 d) has declined and is now in the order of 2–3%. Although relapse or progression of underlying malignancy is the most common cause of death in ASCT recipient, also late (>100 d) non-relapse mortality (NRM) occurs. We have analysed a cohort of 191 patients (108 male and 83 female) who received ASCT (247 transplant) in 1994–2005 in Bone Marrow Transplant Unit of San Gerardo Hospital. The median age was 49 years (16–70). The most common diagnoses included lymphoma (88), multiple myeloma (67), acute leukemia (32), chronic lymphocitic leukemia (2) and myelodysplastic syndrome (2). At the time of transplant (247 transplant) 93 patients was in complete remission, 67 patients in partial remission and 86 patients in persistent/progression malignancies. The most common conditioning treatment ASCT included: Melphalan (200 mg/m2 or 140 mg/m2) in 55% of case, BEAM in 30%, Busulfan-Cyclophosphamide in 4%, others in 11% (Thiotepa- Cyclophosphamide, Busulfan-melpalan, Mitoxantrone-melphalan, TBI- Cyclophosphamide). The median dose of CD34+ reinfused was 5.21 × 10^6/kg (1.2–15 × 10^6/kg). The median time to achieve an absolute neutrophil count >0.5 × 10^9/l was 12 days (range 0–49) and to achieve a platelet count > 20 × 10^9/l was 19 (range 0–36). The median time of hospitalisation was 22 days (range 10–93). During hospitalisation 158 patients (63%) developed oral mucositis: 100 (53%) of them developed mucosites of grade 1–2, 58 (37%) of grade 3–4. High dose chemotherapy with BEAM was more toxic on the oral mucose than high dose of Melphalan alone. In 41% of patients total parenteral nutrition support was necessary. During hospitalisation 180 patients (73%) developed sepsis: possible infection 61%, Gram + 20%, Gram − 12%, miscellaneous 3%, fungi 2%, viral 1%, Pneumocistis Carinii 1%. Regimens including cyclophosphamide was responsible for most sepsis. 44 patients presented a positive antigenemia of Cytomegalovirus; all of them were seropositive for CMV before ASCT; only one case of primary infection was seen and this patient died after 55 days after ASCT. At 100 days from ASCT 173 patients were in complete remission, 53 of them had a relapse of hematologic malignancies in a median time of 1 year (range 51 days-6 year), 32 patients in partial remission and 35 patients in persistent/progression malignancies. The late complications were: cardiac (30%), hepatic (16%), renal (3%), gastrointestinal (12%), CNS (8%), other (MGUS, cataract, aseptic necrosis of bone, diabete)(31%). The most important cardiac complications were: atrial fibrillation, sinusal tachycardia, arrhythmia, pericarditis. 61 patients (32%) died after ASCT. Death was due to complications related to disease progression in 62% of patients. 25% of patients died from infections. Secondary malignancies (acute myeloid leukemia) were the cause of late non relapse mortality in 2 patients. Fatal cardiovascular complications were observed in 4 patients (acute myocardial infarction or cardiomyopatia most probably due to previous anthracycline therapy).

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Byrd, John C., Stephan Stilgenbauer, and Ian W. Flinn. "Chronic Lymphocytic Leukemia." Hematology 2004, no. 1 (January 1, 2004): 163–83. http://dx.doi.org/10.1182/asheducation-2004.1.163.

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Abstract Chronic lymphocytic leukemia (CLL) is one of the most commonly diagnosed leukemias managed by practicing hematologists. For many years patients with CLL have been viewed as similar, with a long natural history and only marginally effective therapies that rarely yielded complete responses. Recently, several important observations related to the biologic significance of VH mutational status and associated ZAP-70 overexpression, disrupted p53 function, and chromosomal aberrations have led to the ability to identify patients at high risk for early disease progression and inferior survival. Concurrent with these investigations, several treatments including the nucleoside analogues, monoclonal antibodies rituximab and alemtuzumab have been introduced. Combination of these therapies in clinical trials has led to high complete and overall response rates when applied as initial therapy for symptomatic CLL. Thus, the complexity of initial risk stratification of CLL and treatment has increased significantly. Furthermore, when these initial therapies do not work, approach of the CLL patient with fludarabine-refractory disease can be quite challenging. This session will describe the natural history of a CLL patient with emphasis on important decision junctures at different time points in the disease. In Section I, Dr. Stephan Stilgenbauer focuses on the discussion that occurs with CLL patients at their initial evaluation. This includes a review of the diagnostic criteria for CLL and prognostic factors utilized to predict the natural history of the disease. The later discussion of risk stratification focuses on molecular and genomic aberrations that predict rapid progression, poor response to therapy, and inferior survival. Ongoing and future efforts examining early intervention strategies in high risk CLL are reviewed. In Section II, Drs. Ian Flinn and Jesus G. Berdeja focus on the discussion of CLL patients when symptomatic disease has developed. This includes an updated review of monotherapy trials with nucleoside analogs and recent trials that have combined these with monoclonal antibodies and/or alternative chemotherapy agents. Appropriate application of more aggressive therapies such as autologous and allogeneic immunotherapy and less aggressive treatments for appropriate CLL patient candidates are discussed. In Section III, Dr. John Byrd focuses on the discussion that occurs with CLL patients whose disease is refractory to fludarabine. The application of genetic risk stratification in choosing therapy for this subset of patients is reviewed. Available data with conventional combination based therapies and monoclonal antibodies are discussed. Finally, alternative promising investigational therapies including new antibodies, kinase inhibitors (CDK, PDK1/AKT, PKC) and alternative targeted therapies (DNA methyltransferase inhibitors, histone deacetylase inhibitors, etc.) are reviewed with an emphasis on the most promising agents for this patient population.

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Rocchi, Miriana. "A case of double leukemia: chronic myeloid leukemia intolerant to imatinib and chronic lymphocytic leukemia." Clinical Management Issues 4, no. 2S (October 13, 2015): 13–16. http://dx.doi.org/10.7175/cmi.v4i2s.1071.

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Chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML) are the most common leukemias of the elderly. However, the sequential occurrence of CML followed by CLL in the same patient is extremely rare. We present a report of a 70-year-old man who developed CLL six years after the diagnosis of CML in molecular, cytogenetic and morphologic remission. The diagnosis of CLL is confirmed by peripheral lymphocytosis. The first line therapy in CML in chronic phase is still imatinib, but in the present case the patient was intolerant to imatinib, therefore he switched to nilotinib after few months.

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Mongeau-Marceau, Zoe, Sandra Cohen, Luigina Mollica, Richard LeBlanc, Bernard Fortin, Rafik Terra, and Isabelle Fleury. "Atypical Chronic Lymphocytic Leukemia with CD200 Expression Shares Similar Outcomes to Classical Chronic Lymphocytic Leukemia." Blood 128, no. 22 (December 2, 2016): 5572. http://dx.doi.org/10.1182/blood.v128.22.5572.5572.

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Abstract Introduction Chronic lymphocytic leukemia (CLL) diagnosis relies on a characteristic immunophenotype of B-cell lymphocytes. The modified Matutes scoring system is based on five key membrane markers: CD5, CD23, CD79b, FMC7 and surface membrane immunoglobulin (smIg) (Matutes et al., Leukemia 1994; modified by Moreau et al., Am J Clin Pathol 1997). CLL typically demonstrates dim staining for smIg, low or absent expression of CD22, CD79b and FMC7 and strong expression of CD5 and CD23. However, up to 7% of B-cell clonal lymphoproliferative disorder (CLPD) cannot be classified as CLL, nor as any other well described CLPD, namely: mantle cell lymphoma, marginal zone lymphoma, follicular lymphoma, hairy cell leukemia, diffuse large B-cell lymphoma, B-cell prolymphocytic leukemia or Waldenstrom's macroglobulinemia and are classified as atypical CLL (A-CLL) (Boucher et al., ASH 2013). Furthermore, leukemic phase of mantle cell lymphoma may mimic CLL (Nelson et al., Mod Pathol 2002), leading to suboptimal management. The expression of CD200 emerged as a powerful marker to distinguish MCL from CLL and therefore better recognize A-CLL (Spacek et al., ASH 2014). Clinical outcomes of patients with A-CLL with CD200 expression have not been compared to patients with classical CLL. Methods Patients diagnosed with CLL or A-CLL expressing CD200 on flow cytometry analysis performed at Maisonneuve-Rosemont Hospital (Montreal, Canada) between July 2014 and July 2015 were reviewed. Multiparameter flow cytometric immunophenotyping (8 colors) was performed on 1 x 106cells using the Euroflow panel of CLPD (van Dongen et al., Leukemia 2012). Data were acquired using FACS CantoII flow cytometer and FACSDiva software program (Becton Dickinson Bioscience, San Jose, CA) and were analysed with Infinicyt software (Cytognos SL, Salamanca, Spain). Diagnostic criteria for A-CLL were negative or ≤ intermediate expression of CD23, ≤ intermediate expression of CD5 or strong expression of CD20. We retrospectively collected data on clinical presentation, flow cytometry and cytogenetics analysis, therapies and outcomes. Treatment response was evaluated according to Hallek (Blood 2008). Comparison between outcomes were evaluated through time to first line therapy (TT1T), time to second line therapy (TT2T) and overall survival (OS) with Kaplan-Meier curves and log-rank tests and response to first line therapy (R1T) was compared with Fisher's test. Treatment was according to physician choice. Our study was approved by local research and ethic committees. Results We retrieved 25 CLL and 10 A-CLL patients with a median age of 67 (46-93) and 67 (51-81) respectively at diagnosis. All these 35 CLL expressed CD200 as per inclusion criteria. Among the 10 A-CLL: 4 did not express CD23 (2 were negative for t(11;14) by FISH analysis and 2 had negative immunohistochemistry staining for cyclin D1 on bone marrow biopsy), 4 had intermediate expression of CD23, 1 had intermediate expression of CD5 and CD23 and 1 had intermediate expression of CD5. One of the A-CLL not expressing CD23 had strong expression of CD20. At diagnosis, 3/25 (12%) CLL presented with Rai 3-4 stage compared to 1/9 (11%) of A-CLL. Deletion 17p was detected in none of the 7 CLL and 8 A-CLL patients tested and deletion 11q was detected in 2/9 (22%) CLL and 1/8 (13%) A-CLL patients tested. At time of analysis, 7 patients with CLL and 4 patients with A-CLL received treatment. Chlorambucil was administered to 4 CLL and 2 A-CLL patients, fludarabine, cyclophosphamide and rituximab to 2 CLL and 2 A-CLL patients and rituximab only to 1 CLL patient for refractory immune thrombocytopenia. After a median follow up of 18 months, no significant difference in outcomes was observed. Median TT1T was 26 months (m) for CLL and not reached (NR) for A-CLL (p=0.53). Complete remission was achieved for 2 CLL and 2 A-CLL and partial remission for 5 CLL and 2 A-CLL patients respectively (p=0.58). During follow up, 3 CLL and 3 A-CLL patients required second-line therapy. Median TT2T was 111 m for CLL and NR for A-CLL. No Richter transformation was observed and no difference in OS could be detected (only one death in the entire cohort). Conclusion Outcomes of atypical CLL expressing CD200 appear similar to CLL using CLL management strategies in this cohort. A longer follow-up of a larger cohort may allow us to confirm the value of this marker in guiding A-CLL management. Disclosures Fleury: Lundbeck: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau.

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Kay, Neil E., Terry J. Hamblin, Diane F. Jelinek, Gordon W. Dewald, John C. Byrd, Sherif Farag, Margaret Lucas, and Thomas Lin. "Chronic Lymphocytic Leukemia." Hematology 2002, no. 1 (January 1, 2002): 193–213. http://dx.doi.org/10.1182/asheducation-2002.1.193.

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Abstract This update of early stage B-cell chronic lymphocytic leukemia (B-CLL) embraces current information on the diagnosis, biology, and intervention required to more fully develop algorithms for management of this disease. Emphasis on early stage is based on the rapid advancement in our understanding of the disease parameters and our increasing ability to predict for a given early stage patient whether there is a need for more aggressive management. In Section I, Dr. Terry Hamblin addresses the nature of the disease, accurate diagnostic procedures, evidence for an early “preclinical” phase, the use of newer prognostic features to distinguish who will be likely to progress or not, and whether it is best to watch or treat early stage disease. In Section II, Dr. Neil Kay and colleagues address the biologic aspects of the disease and how they may relate to disease progression. Review of the newer insights into gene expression, recurring genetic defects, role of cytokines/autocrine pathways, and the interaction of the CLL B cell with the microenvironment are emphasized. The relationship of these events to both trigger disease progression and as opportunities for future therapeutic intervention even in early stage disease is also considered. In Section III, Dr. John Byrd and colleagues review the historical and now current approaches to management of the previously untreated progressive B-CLL patient. They discuss what decision tree could be used in the initial decision to treat a given patient. The use of single agents versus newer combination approaches such as chemoimmunotherapy are discussed here. In addition, the place of marrow transplant and some of the newer antibodies available for treatment of B-CLL are considered. Finally, a challenge to utilize our growing knowledge of the biology of B-CLL in the early stage B-CLL is proffered.

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Darawshy, Fares, Arieh Ben-Yehuda, Karine Atlan, and Deborah Rund. "Chronic Lymphocytic Leukemia and Myelofibrosis." Case Reports in Hematology 2018 (August 8, 2018): 1–5. http://dx.doi.org/10.1155/2018/7426739.

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Background. Chronic lymphocytic lymphoma (CLL) can be associated with several malignancies, but rarely with myelofibrosis. Only isolated case reports in the literature described the association between CLL and primary myelofibrosis (PMF) in the same patient. Objectives. We describe a case of CLL characterized by the development of PMF and a review of literature. Methods. We describe an 86-year-old female diagnosed as having CLL and followed by the development of splenomegaly and progressively rising LDH levels 27 months later. A bone marrow biopsy was consistent with the diagnosis of PMF, with positive JAK-2 V617F mutation. We also review the clinical and molecular characteristics of patients with CLL and PMF. Results. Patients with CLL and PMF are usually older. A lead diagnosis of CLL harbored by PMF is the most common clinical course, although concomitant diseases may occur in 31.7% of patients. JAK-2 V617F mutation can be found in 48.7% of patients. Conclusion. This case reported here constitutes an unusual situation of CLL characterized by the development of PMF. Etiologic and pathogenic associations—the role of t (1; 6) and JAK-2 V617F mutation—are discussed.

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20

Fricke, William. "CD11b Is Useful in the Diagnosis of Chronic Lymphocytic Leukemia/Prolymphocytic Leukemia, Mixed Chronic Lymphocytic Leukemia, and Prolymphocytic Leukemia." Blood 104, no. 11 (November 16, 2004): 4806. http://dx.doi.org/10.1182/blood.v104.11.4806.4806.

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Abstract CD11b is well known as an integrin, Mac-1, is often complexed with CD18, and is found on monocytes, granulocytes, and natural killer cells. It also serves as a receptor for iC3b. However, its occurrence in B cell chronic lymphoproliferative disorders is not generally recognized and has not been fully evaluated. To address this issue, a series of B cell leukemias and lymphomas referred for primary diagnosis was evaluated for the presence of CD11b. The purpose was to determine the frequency of its expression on these tumors and to evaluate its diagnostic value. Consecutive cases referred for flow cytometry as possible lymphoproliferative disease were analyzed. Included were bone marrow, peripheral blood, and lymph nodes. All cases were diagnosed according to the WHO classification based on immunophenotypic, morphologic, and clinical findings. The morphologic criteria of Melo (1986) and Bennett (1989) were used for classification of chronic lymphocytic leukemia (CLL), CLL/prolymphocytic leukemia (CLL/PLL), mixed CLL, and PLL. Cases identified as not related to chronic lymphocytic leukemia or prolymphocytic leukemia were recorded but not further analyzed. Similarly, lymph node and spleen-based tumors were excluded from the final analysis. CD11b was present on cells from 32 of 123 cases, including occasional follicular lymphoma, (5/35); mantle cell lymphoma, (1/8); diffuse large B cell lymphoma, (3/9); hairy cell leukemia, (3/5); multiple myeloma, (1/2); lymphoplasmacytic lymphoma, (2/2); nodal marginal zone lymphoma, 0/1); and splenic marginal zone lymphoma, (1/1). However, it was most consistently expressed on CLL that contained increased numbers of prolymphocytes or large cells and on PLL. A total of 16 such cases were found. Morphologic assessment showed them to include 8 CLL/PLL, 3 mixed CLL, 4 PLL, and 1 typical CLL. The typical CLL case included both large cells and prolymphocytes but did not have more than 10% PLs. Five of the 16 cases (31%) were negative for CD5, CD23, and CD38 but were positive for FMC-7. In contrast, the other 11 cases were all CD5(+) and CD23(+); 3/11 were positive for CD38; and 5/11 were positive for FMC-7. Forty-five CLLs also were identified during the study, of which 27 had sufficient data for comparison. Twenty-six of the 27 CLLs were morphologically typical. The remaining case was mixed CLL. All of the CLLs were CD11b(−), CD5(+) and CD23(+); 15/43 were CD38(+), and 6/43 were FMC-7(+). The findings show that CD11b is expressed on chronic B cell lymphoproliferative disorders. In particular, it is expressed on almost all CLL cases that contain large cells or prolymphocytes and on PLL. Inclusion of CD11b in routine screening panels of possible chronic B cell leukemiaa will improve diagnosis of these disorders.

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21

Dreger, Peter. "Allotransplantation for chronic lymphocytic leukemia." Hematology 2009, no. 1 (January 1, 2009): 602–9. http://dx.doi.org/10.1182/asheducation-2009.1.602.

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AbstractEfforts to develop curative treatment strategies for chronic lymphocytic leukemia (CLL) in recent years have focused on allogeneic stem cell transplantation (alloSCT). The crucial anti-leukemic principle of alloSCT in CLL appears to be the immune-mediated anti-host activities conferred with the graft (graft-versus-leukemia effects, GVL). Evidence for GVL in CLL is provided by studies analyzing the kinetics of minimal residual disease on response to immune modulation after transplantation, suggesting that GVL can result in complete and durable suppression of the leukemic clone. AlloSCT from matched related or unrelated donors can overcome the treatment resistance of poor-risk CLL, ie, purine analogue refractory disease and CLL with del 17p-. Even with reduced-intensity conditioning, alloSCT in CLL is associated with significant mortality and morbidity due to graft-versus-host disease, which has to be weighed against the risk of the disease when defining the indication for transplantation. Therefore, it can be regarded as a reasonable treatment option only for eligible patients who fulfill accepted criteria for poor-risk disease. If alloSCT is considered, it should be performed before CLL has advanced to a status of complete refractoriness to assure an optimum chance for a successful outcome. Prospective trials are underway to prove whether allo-SCT can indeed change the natural history of poor-risk CLL.

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Allard, David, Pavel Chrobak, Yacine Bareche, Bertrand Allard, Priscilla Tessier, Marjorie A. Bergeron, Nathalie A. Johnson, and John Stagg. "CD73 Promotes Chronic Lymphocytic Leukemia." Cancers 14, no. 13 (June 26, 2022): 3130. http://dx.doi.org/10.3390/cancers14133130.

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The ecto-nucleotidase CD73 is an important immune checkpoint in tumor immunity that cooperates with CD39 to hydrolyze pro-inflammatory extracellular ATP into immunosuppressive adenosine. While the role of CD73 in immune evasion of solid cancers is well established, its role in leukemia remains unclear. To investigate the role of CD73 in the pathogenesis of chronic lymphocytic leukemia (CLL), Eµ-TCL1 transgenic mice that spontaneously develop CLL were crossed with CD73−/− mice. Disease progression in peripheral blood and spleen, and CLL markers were evaluated by flow cytometry and survival was compared to CD73-proficient Eµ-TCL1 transgenic mice. We observed that CD73 deficiency significantly delayed CLL progression and prolonged survival in Eµ-TCL1 transgenic mice, and was associated with increased accumulation of IFN-γ+ T cells and effector-memory CD8+ T cells. Neutralizing IFN-γ abrogated the survival advantage of CD73-deficient Eµ-TCL1 mice. Intriguingly, the beneficial effects of CD73 deletion were restricted to male mice. In females, CD73 deficiency was uniquely associated with the upregulation of CD39 in normal lymphocytes and sustained high PD-L1 expression on CLL cells. In vitro studies revealed that adenosine signaling via the A2a receptor enhanced PD-L1 expression on Eµ-TCL1-derived CLL cells, and a genomic analysis of human CLL samples found that PD-L1 correlated with adenosine signaling. Our study, thus, identified CD73 as a pro-leukemic immune checkpoint in CLL and uncovered a previously unknown sex bias for the CD73-adenosine pathway.

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23

Viswanathan, Kartik, Gail Roboz, Amy Chadburn, and Susan Mathew. "Chronic Myelogenous Leukemia Diagnosed in the Setting of Untreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma." International Journal of Surgical Pathology 28, no. 2 (September 22, 2019): 216–24. http://dx.doi.org/10.1177/1066896919876704.

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Chronic myeloid leukemia (CML) is rarely reported to occur in treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). In this article, we report a woman in her 70s, diagnosed with CLL/SLL in 2000, untreated, who subsequently presented 12 years later with de novo CML, BCR-ABL1+. Her IGHV mutated CLL/SLL based on the initial sample in our laboratory showed homozygous and heterozygous 13q14.3 deletions, whereas her CML, at presentation, showed a 46,XX,t(9;22)(q34;q11.2)[7]/46,XX[18] karyotype with a p190 BCR-ABL1 transcript. The tumor burden of each clone varied with treatment, including when treated with dasatinib, used to target both clones. In addition, the cytogenetic abnormalities evolved over time and treatments and included acquisition of an extra chromosome 8 in the CML clone and a novel K1992T ATM missense mutation (47% allele frequency) in the CLL/SLL clone. The patient’s last bone marrow biopsy, 5 years after her CML diagnosis and 17 years after the CLL/SLL diagnosis, showed residual CML with extensive involvement by CLL/SLL (80%). Cytogenetic studies showed a 46,XX karyotype, while FISH identified 13q14.3 deletion and the BCR-ABL1 translocation in the CLL/SLL and CML clones, respectively. To date, this is the fourth case of concurrent CML, BCR-ABL1+ arising in untreated CLL/SLL. Here we show dynamic variation in the size of the 2 clonal processes reflecting the variable responsiveness to specific therapies. In addition to the unusual BCR-ABL1+ p190 transcript in the patient’s CML, a novel ATM K1992T mutation was identified in the CLL/SLL population.

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Wan, Youzhong, and Catherine J. Wu. "SF3B1 mutations in chronic lymphocytic leukemia." Blood 121, no. 23 (June 6, 2013): 4627–34. http://dx.doi.org/10.1182/blood-2013-02-427641.

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Abstract SF3B1 is a critical component of the splicing machinery, which catalyzes the removal of introns from precursor messenger RNA (mRNA). Next-generation sequencing studies have identified mutations in SF3B1 in chronic lymphocytic leukemia (CLL) at high frequency. In CLL, SF3B1 mutation is associated with more aggressive disease and shorter survival, and recent studies suggest that it can be incorporated into prognostic schema to improve the prediction of disease progression. Mutations in SF3B1 are predominantly subclonal genetic events in CLL, and hence are likely later events in the progression of CLL. Evidence of altered pre-mRNA splicing has been detected in CLL cases with SF3B1 mutations. Although the causative link between SF3B1 mutation and CLL pathogenesis remains unclear, several lines of evidence suggest SF3B1 mutation might be linked to genomic stability and epigenetic modification.

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25

Vaisitti, Tiziana, Francesca Arruga, and Alessandra Ferrajoli. "Chronic Lymphocytic Leukemia." Cancers 12, no. 9 (September 3, 2020): 2504. http://dx.doi.org/10.3390/cancers12092504.

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26

Stilgenbauer, Stephan, Richard R. Furman, and Clive S. Zent. "Management of Chronic Lymphocytic Leukemia." American Society of Clinical Oncology Educational Book, no. 35 (May 2015): 164–75. http://dx.doi.org/10.14694/edbook_am.2015.35.164.

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Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) is usually diagnosed in asymptomatic patients with early-stage disease. The standard management approach is careful observation, irrespective of risk factors unless patients meet the International Workshop on CLL (IWCLL) criteria for “active disease,” which requires treatment. The initial standard therapy for most patients combines an anti-CD20 antibody (such as rituximab, ofatumumab, or obinutuzumab) with chemotherapy (fludarabine/cyclophosphamide [FC], bendamustine, or chlorambucil) depending on multiple factors including the physical fitness of the patient. However, patients with very high-risk CLL because of a 17p13 deletion (17p-) with or without mutation of TP53 (17p-/ TP53mut) have poor responses to chemoimmunotherapy and require alternative treatment regimens containing B-cell receptor (BCR) signaling pathway inhibitors. The BCR signaling pathway inhibitors (ibrutinib targeting Bruton's tyrosine kinase [BTK] and idelalisib targeting phosphatidyl-inositol 3-kinase delta [PI3K-delta], respectively) are currently approved for the treatment of relapsed/refractory CLL and all patients with 17p- (ibrutinib), and in combination with rituximab for relapsed/refractory patients (idelalisib). These agents offer great efficacy, even in chemotherapy refractory CLL, with increased tolerability, safety, and survival. Ongoing studies aim to determine the best therapy combinations with the goal of achieving long-term disease control and the possibility of developing a curative regimen for some patients. CLL is associated with a wide range of infectious, autoimmune, and malignant complications. These complications result in considerable morbidity and mortality that can be minimized by early detection and aggressive management. This active monitoring requires ongoing patient education, provider vigilance, and a team approach to patient care.

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27

Wirths, Stefan, and Antonio Lanzavecchia. "Homeostatic Proliferation of Chronic Lymphocytic Leukemia." Blood 106, no. 11 (November 16, 2005): 2954. http://dx.doi.org/10.1182/blood.v106.11.2954.2954.

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Abstract Slow accumulation of chronic lymphocytic leukemia cells in vivo was considered due to defective apoptosis rather than proliferation. However, recent data, based on isotope incorporation studies, suggested significant continuous proliferation of CLL cells in vivo and similar observations has been made for human memory B cells. As previous gene expression studies revealed close relation of CLL cells to memory B cells we asked, whether the mechanisms driving homeostatic proliferation of human memory B cells were stimulating CLL cells as well. Comparison of CLL samples (n=20) and memory B cells of healthy donors showed high expression levels of Toll-like receptor (TLR) 7 and TLR9 and of IL2 and IL15 cytokine receptors compared to naive B cells. Proliferation of CLL cells compared to their normal counterparts was analyzed after FACS sorting and CFSE-labeling.Naive B cells did neither respond to TLR7 ligand resiquimod, TLR9 ligand CpG2006, IL2 and IL15 nor to their combination. In contrast, CLL cells and memory B cells showed comparable patterns of proliferation. Remarkably, under these conditions, terminal differentiation to plasma cells was observed for memory B cells only, while proliferation of CLL ceased after the 4th division without differentiation into Ig-secreting cells. To estimate in vivo turnover rates, B cells of healthy donors and CLL cells were stained for intracellular Ki67, that identifies recently divided cells, and were analyzed by flow cytometry. Memory B cells showed high in vivo turnover rates (2–5% Ki67+) while naive B cells where largely quiescent - results that are in line with previous isotope incorporation studies with healthy donors. Turnover rates of CLL ex vivo ranged from 0.025–1.4% Ki67+ cells, which in absolute numbers (per mL of blood) was comparable to memory B cells. These results are consistent with a concept of homeostatic proliferation of both memory B cells and CLL cells, the latter being arrested without terminal differentiation, which might account for their accumulation in vivo.

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28

Laurenti, Luca, Michela Tarnani, Patrizia Chiusolo, Federica Sorà, and Simona Sica. "ALLOGENEIC TRANSPLANTATION FOR CHRONIC LYMPHOCYTIC LEUKEMIA." Mediterranean Journal of Hematology and Infectious Diseases 2, no. 2 (August 31, 2010): e2010026. http://dx.doi.org/10.4084/mjhid.2010.026.

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Even if Chronic lymphocytic leukemia (CLL) often has an indolent behavior with good responsiveness to cytoreductive treatment, about 20% of the patients, so called "poor-risk" patients, show an aggressive course and die within a few years despite early intensive therapies. Criteria for poor-risk disease according to the European Bone Marrow Transplantation (EBMT) CLL Transplant Consensus are: purine analogue refractoriness, early relapse after purine analogue combination therapy, CLL with p53 lesion requiring treatment.Allogeneic transplant has potential curative role in CLL, however burden with very high transplant related mortality (TRM) rates of 38-50%:A major advance in reducing the short-term morbidity and mortality of allogeneic stem cell transplantation (SCT) has been the introduction of non-myeloablative or reduced intensity conditioning (RIC) regimens to allow engraftment of allogeneic stem cells. There is no doubt that the crucial therapeutic principle of allo-SCT in CLL is graft versus leukemia (GVL) activity.The major complications of allogeneic SCT in CLL are: chronic graft-versus-host-disease (GVHD) affecting quality of life, high graft rejection and infection rates rates correlated with preexisting immunosuppression. Disease relapse remains the major cause of failure after RIC allo-HCT in CLL patients.Sensitive minimal residual disease (MRD) quantification has strong prognostic impact after transplant.

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Malek, Sami, Kamlai Saiya-Cork, Erlene Seymour, Cheng Li, Kerby Shedden, and Peter Ouillette. "Clonal Evolution in Chronic Lymphocytic Leukemia." Blood 120, no. 21 (November 16, 2012): 3870. http://dx.doi.org/10.1182/blood.v120.21.3870.3870.

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Abstract Abstract 3870 Introduction: The phenotypic characterization of dominant CLL clones at various disease stages using multiple experimental approaches has deepened our understanding of CLL biology and clinical behavior. However, much less is known about the phenotype and phenotypic changes that occur in CLL over time and with disease progression when measured longitudinally. Analysis of large CLL cohorts at various disease time points is needed to better capture the dynamics of this disease. Methods: A total of 143 CLL cases were surveyed at trial enrollment and longitudinally for changes in acquired genomic copy number aberrations (aCNA), acquired uniparental disomy (aUPD), and somatically acquired mutations in the genes TP53, SF3B1, and NOTCH1. On an unselected basis, longitudinal samples were studied at a minimum of 24 months after initial sample procurement in the case of no therapeutic intervention or at the time of relapse after chemotherapy. The median time span between enrollment and longitudinal samples was 40.5 months for samples without intervening therapy (range 9–79 mos.) and 42 months for relapsed cases (range 7–74 mos.). One hundred eight cases did not receive therapeutic interventions in-between sample procurements, while 35 were relapsed from therapy. In 13 cases, time spans less than 24 months were allowed if the patient carried a high-risk CLL genomic feature or if limited follow-up samples were available. Cells were purified by flow cytometry sorting of viable CD19+ and CD3+ cells. DNA samples isolated from paired tumor and normal samples were studied for aCNA using Affymetrix SNP 6.0 arrays and the software program dChip. Samples were also analyzed for LOH/aUPD via internally-developed software. aCNA were scored through visual interpretations of the dChip display of paired samples and corroborated through an algorithmic lesion calling method. Finally, the genes TP53 exons 2–10, SF3B1 exons 13–17, and NOTCH1 exons 34 were resequenced in all samples. Results: The dominant phenomenon observed in this large CLL cohort was genomic stability for aCNA and gene mutations, which was detected in 116 (81%) of cases analyzed. Importantly however, 27 (19%) of CLL cases differed between enrollment and longitudinal follow-up. Within this subgroup of cases, 21 cases harbored changes in aCNA/LOH/aUPD, while 7 cases carried a change in the mutation status of TP53, NOTCH1 or SF3B1 (one case had both aCNA and mutation changes). Specifically, 19 cases with aCNA/LOH/aUPD changes added lesions at longitudinal analysis and lost none: clear examples of clonal evolution. Four cases added TP53 mutations and two cases added a NOTCH1 mutation. Conversely, TP53 mutations were never lost, while one case with a novel TP53 mutation lost a pre-existing NOTCH1 mutation and one case lost a SF3B1 mutation. No case gained a SF3B1 mutation. Only one CLL case at relapse demonstrated an aCNA/LOH/aUPD pattern that was completely unrelated to the dominant CLL clone at enrollment. Conclusion: In this report, we describe genomic changes in a cohort of 143 CLL cases analyzed longitudinally. This study constitutes the largest analysis of such changes reported to date. Our overall estimates of genomic instability in CLL are likely underestimates of the true frequency, given the observed natural selection against aggressive CLL inherent in this type of analysis. From this data several conclusions can be reached that have implications for our understanding of CLL clonal dynamics and the effects of therapy on clonal evolution/emergence: i) the vast majority of genomic changes are acquisitions of new lesions/mutations combined with the retention of pre-existing lesions–therefore persistence of antecedent clones underlies CLL relapse and disease persistence; ii) CLL cases demonstrating clonal evolution were enriched for cases that received intervening chemotherapy (∼50% in this cohort); iii) the acquisition of TP53 mutations followed intervening chemotherapy, providing further impetus to carefully select patients for chemotherapy; iv) NOTCH1 mutations were rarely acquired over time and in one case lost; v) no SF3B1 mutations were acquired over time and in one case lost; vi) the latter two observations argue against a strong driver role for these mutations in CLL progression/relapse; vii) the acquisition of aCNA/LOH/aUPD and gene mutation was non-overlapping, indicative of distinct roles for each aberration type in CLL evolution. Disclosures: No relevant conflicts of interest to declare.

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Keating, Michael J., Nicholas Chiorazzi, Bradley Messmer, Rajendra N. Damle, Steven L. Allen, Kanti R. Rai, Manlio Ferrarini, and Thomas J. Kipps. "Biology and Treatment of Chronic Lymphocytic Leukemia." Hematology 2003, no. 1 (January 1, 2003): 153–75. http://dx.doi.org/10.1182/asheducation-2003.1.153.

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Abstract Major advances have occurred in our understanding of the biology, immunology, and opportunities for treatment of chronic lymphocytic leukemia (CLL) in recent times. Surface antigen analysis has helped us define classical CLL and differentiate it from variants such as marginal zone leukemia, mantle cell leukemia, and prolymphocytic leukemia. An important observation has been that the B-cells in indolent types of CLL, which do not require therapy, have undergone somatic hypermutation and function as memory B-lymphocytes whereas those more likely to progress have not undergone this process. Section I by Dr. Nicholas Chiorazzi encompasses emerging elements of the new biology of CLL and will address the types of somatic hypermutation that occur in CLL cells and their correlation with other parameters such as telomere length and ZAP70 status. In addition he addresses the concept of which cells are proliferating in CLL and how we can quantitate the proliferative thrust using novel methods. The interaction between these parameters is also explored. Section II by Dr. Thomas Kipps focuses on immune biology and immunotherapy of CLL and discusses new animal models in CLL, which can be exploited to increase understanding of the disease and create new opportunities for testing the interaction of the CLL cells with a variety of elements of the immune system. It is obvious that immunotherapy is emerging as a major therapeutic modality in chronic lymphocytic leukemia. Dr. Kipps addresses the present understanding of the immune status of CLL and the role of passive immunotherapy with monoclonal antibodies such as rituximab, alemtuzumab, and emerging new antibodies. In addition the interaction between the CLL cells and the immune system, which has been exploited in gene therapy with transfection of CLL cells by CD40 ligand, is discussed. In Section III, Dr. Michael Keating examines the question “Do we have the tools to cure CLL?” and focuses on the fact that we now have three distinct modalities, which are able to achieve high quality remissions with polymerase chain reaction (PCR) negativity for the immunoglobulin heavy chain in CLL. These modalities include initial chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab, the use of alemtuzumab for marrow cytoreduction in minimal residual disease and allogeneic bone marrow transplants. The emergence of non-ablative marrow transplants in CLL has led to the broadening of the range of opportunities to treat older patients. The addition of rituximab to the chemotherapy preparative regimens appears to be a significant advance. The combination of our increased understanding of the biology, immune status, and therapy of CLL provides for the first time the opportunity for curative strategies.

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Stevenson, Freda K., Francesco Forconi, and Thomas J. Kipps. "Exploring the pathways to chronic lymphocytic leukemia." Blood 138, no. 10 (June 1, 2021): 827–35. http://dx.doi.org/10.1182/blood.2020010029.

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Abstract In chronic lymphocytic leukemia (CLL), increasing knowledge of the biology of the tumor cells has led to transformative improvements in our capacity to assess and treat patients. The dependence of tumor cells on surface immunoglobulin receptor signaling, survival pathways, and accessory cells within the microenvironment has led to a successful double-barreled attack with designer drugs. Studies have revealed that CLL should be classified based on the mutational status of the expressed IGHV sequences into 2 diseases, either unmutated (U) or mutated (M) CLL, each with a distinctive cellular origin, biology, epigenetics/genetics, and clinical behavior. The origin of U-CLL lies among the natural antibody repertoire, and dominance of IGHV1-69 reveals a superantigenic driver. In both U-CLL and M-CLL, a calibrated stimulation of tumor cells by self-antigens apparently generates a dynamic reiterative cycle as cells, protected from apoptosis, transit between blood and tissue sites. But there are differences in outcome, with the balance between proliferation and anergy favoring anergy in M-CLL. Responses are modulated by an array of microenvironmental interactions. Availability of T-cell help is a likely determinant of cell fate, the dependency on which varies between U-CLL and M-CLL, reflecting the different cells of origin, and affecting clinical behavior. Despite such advances, cell-escape strategies, Richter transformation, and immunosuppression remain as challenges, which only may be met by continued research into the biology of CLL.

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Vincent, AM, JC Cawley, and J. Burthem. "Integrin function in chronic lymphocytic leukemia." Blood 87, no. 11 (June 1, 1996): 4780–88. http://dx.doi.org/10.1182/blood.v87.11.4780.bloodjournal87114780.

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Integrins are central to many aspects of the tissue localization of normal and malignant lymphocytes. We examined how integrin function, rather than simple expression, might determine disease behavior in chronic lymphocyte leukemia (CLL). Using fluorescence-activated cell sorting (FACS) and immunoprecipitation, we first established the precise integrin heterodimer expression of a representative group of CLL patients (beta1 consistently present, with variable alpha 3, alpha 4, and alpha 5; alpha 4 beta 7 often expressed; alpha L beta 2 high; alpha V beta 3 absent). Regarding function, we initially examined the ability of CLL cells to interact with endothelium, because such interaction is the initial event determining the entry of CLL lymphocytes into tissues. The abnormal lymphocytes were shown to bind at low levels to unstimulated endothelium via beta 2/intercellular adhesion molecule (ICAM). However, when the endothelium was stimulated, markedly enhanced interaction with endothelium was observed in approximately half the cases; in these patients, the neoplastic population expressed alpha 4 beta 1, which conferred the ability to adhere strongly to stimulated endothelium via the alpha 4 beta 1 ligand, vascular cellular adhesion molecule-1 (VCAM-1). In relation to the migration of CLL cells within tissues, the abnormal lymphocytes showed differential binding to various adhesive proteins; they did not attach to basement membrane components, but displayed variable adhesion to fibronectin (FN). Finally, we examined the role of cell activation in these processes, and showed that activated CLL lymphocyte populations showed an increased capacity to adhere to both endothelium and matrix. Moreover, ex vivo CLL cells showed no capacity to migrate through endothelium/stroma, but were able to do so after cytokine stimulation. These studies show how the constitutive integrin expression/function, the intrinsic activation state of the cell, and the capacity of cytokines to modify integrin-mediated function all combine to determine the different patterns of clinical disease observed in CLL.

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González-Rodríguez, Ana Pilar, Angel R. Payer, Andrea Acebes-Huerta, Leticia Huergo-Zapico, Monica Villa-Alvarez, Esther Gonzalez-García, and Segundo Gonzalez. "Lenalidomide and Chronic Lymphocytic Leukemia." BioMed Research International 2013 (2013): 1–9. http://dx.doi.org/10.1155/2013/932010.

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Lenalidomide is an oral immunomodulatory drug used in multiple myeloma and myelodysplastic syndrome and most recently it has shown to be effective in the treatment of various lymphoproliferative disorders such as chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma. The mechanism of action of lenalidomide varies depending on the pathology, and in the case of CLL, it appears to primarily act by restoring the damaged mechanisms of tumour immunosurveillance. This review discusses the potential mechanism of action and efficacy of lenalidomide, alone or in combination, in treatment of CLL and its toxic effects such as tumor lysis syndrome (TLS) and tumor flare reaction (TFR), that make its management different from other hematologic malignancies.

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Heitmann, Jonas S., Melanie Maerklin, Alexandra Poljak, Bettina Hackl, Juliane Stickel, Lothar Kanz, Hans-Georg Kopp, Stefan Wirths, and Martin Rudolf Mueller. "Aberrant NFAT2 signaling in chronic lymphocytic leukemia." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 7019. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.7019.

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7019 Background: CLL is a malignancy of mature B cells and constiututes the most common leukemia in adults. It is characterized by a progressive accumulation of clonal B cells, which coexpress CD19, CD23 and CD5. NFAT is a family of highly phosphorylated transcription factors residing in the cytoplasm of resting cells. Upon dephosphorylation by calcineurin, NFAT proteins translocate to the nucleus where they orchestrate developmental and activation programs in diverse cell types. In this study, we investigated the significance of NFAT signaling in B-CLL. Methods: NFAT2 expression and aberrant nuclear translocation in CLL cells (n=30) was assessed by Western Blotting and immunofluorescence. In addition, NFAT2 mRNA levels were measured by qRT-PCR and its DNA binding capacity was assessed using an electrophoretic mobility shift assay. Transcriptional activity of NFAT2 proteins in CLL cells was further analyzed by determining the expression of several well characterized NFAT target genes. Results: We detected a profound overexpression of NFAT2 mRNA and protein in all CLL samples. Using qRT-PCR we found that CD19+CD5+ CLL cells exhibited a significant overexpression of NFAT2 as compared to CD19+ B cells isolated from healthy donors (8-200fold). This overexpression of NFAT2 in CLL cells could also be confirmed on the protein level. We could further demonstrate that even under resting conditions significant amounts of NFAT2 protein had translocated to the nucleus in CLL cells, whereas virtually all NFAT2 was in the cytoplasm in non-malignant B cells. Nuclear NFAT2 in CLL cells was able to bind DNA but its transcriptional activity with respect to several apoptosis-regulating genes (i.e. Spp1, Pdcd1) was severely compromised. Conclusions: These results provide strong evidence that the Ca2+/NFAT signalling axis is constitutively activated in CD5+CD19+ CLL cells. Reduced expression of several apoptosis regulators which are known target genes of NFAT2 links deregulation of this signaling cascade to CLL progression. Further investigation is warranted to investigate the therapeutic potential of modulating Ca2+/Calcineurin/ NFAT signaling in CLL.

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Schlette, Ellen, L. Jeffrey Medeiros, Michael Keating, and Raymond Lai. "CD79b Expression in Chronic Lymphocytic Leukemia." Archives of Pathology & Laboratory Medicine 127, no. 5 (May 1, 2003): 561–66. http://dx.doi.org/10.5858/2003-127-0561-ceicll.

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Abstract Context.—CD79b is a relatively newly characterized B-cell marker that is expressed in a minority of chronic lymphocytic leukemia (CLL) cases. Objective.—To systematically correlate CD79b expression with specific morphologic and immunophenotypic findings and trisomy 12. Design.—We assessed CD79b expression in 100 consecutively accrued CLL cases that were also analyzed by conventional cytogenetics. Based on the association between trisomy 12 and CD79b expression, we then assessed 43 additional CLL cases with trisomy 12. CD79b expression was correlated with morphology and expression of other immunophenotypic markers. Results.—Eighteen (18%) of 100 consecutively accrued cases were CD79b positive. No significant association was found between CD79b expression and atypical morphology. CD79b expression correlated with CD22 and FMC7 positivity. Eight (8%) cases had trisomy 12; 4 (50%) of these were CD79b positive, suggesting an association with trisomy 12. Examination of a second group of 51 CLL cases with trisomy 12 (including 8 cases from the initial study group) showed that CD79b was positive in 26 cases (49%), a frequency significantly higher than that of the consecutively accrued CLL cases without trisomy 12 (P < .05). Conclusions.—We conclude that CD79b immunoreactivity is positive in approximately 20% of CLL cases and that expression correlates with trisomy 12 and atypical immunophenotypic findings.

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Alhourani, Eyad, Martina Rincic, Joana B. Melo, Isabel M. Carreira, Anita Glaser, Beate Pohle, Cordula Schlie, and Thomas Liehr. "Isochromosome 17q in Chronic Lymphocytic Leukemia." Leukemia Research and Treatment 2015 (November 30, 2015): 1–6. http://dx.doi.org/10.1155/2015/489592.

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In chronic lymphocytic leukemia (CLL), presence of acquired cytogenetic abnormalities may help to estimate prognosis. However, deletion of TP53 gene, which is associated with an aggressive course of the disease and poor prognosis along with a lack of response to treatment, is one of the alterations which may escape cytogenetic diagnoses in CLL. Thus, other techniques have emerged such as interphase fluorescence in situ hybridization (iFISH). Deletion of TP53 may but must not go together with the formation of an isochromosome i(17q); surprisingly this subgroup of patients was not in the focus of CLL studies yet. This study was about if presence of i(17q) could be indicative for a new subgroup in CLL with more adverse prognosis. As a result, TP53 deletion was detected in 18 out of 150 (12%) here studied CLL cases. Six of those cases (~33%) had the TP53 deletion accompanied by an i(17q). Interestingly, the cases with i(17q) showed a tendency towards more associated chromosomal aberrations. These findings may be the bases for follow-up studies in CLL patients with TP53 deletion with and without i(17q); it may be suggested that the i(17q) presents an even more adverse prognostic marker than TP53 deletion alone.

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37

Silber, R., CM Farber, E. Papadopoulos, D. Nevrla, L. Liebes, M. Bruck, R. Brown, and ZN Canellakis. "Glutathione depletion in chronic lymphocytic leukemia B lymphocytes." Blood 80, no. 8 (October 15, 1992): 2038–43. http://dx.doi.org/10.1182/blood.v80.8.2038.2038.

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Abstract Glutathione (GSH) content may be the major determinant of a cell's sensitivity to cytotoxic alkylating agents. In the present study, the GSH concentration was determined in lymphocytes isolated from the blood of normal subjects and patients with chronic lymphocytic leukemia (CLL). Comparable levels were found in both types of cells. Incubation for 20 hours led to a decrease in GSH to 51% of baseline values in CLL B cells. Under the same conditions, normal B- or T-lymphocyte GSH content remained constant. GSH depletion was shown to be a characteristic of the B-CLL B lymphocyte. It was not found in the T cells of patients with B-CLL or in cells from patients with T-CLL. Chlorambucil (CLB) contributes to the decrease in GSH in B-CLL lymphocytes; after incubation with the drug, lower levels of GSH were found than in the normal B or T lymphocytes, B-CLL T cells, or T-CLL (CD4 or CD8) cells. GSH depletion of CLL B lymphocytes may be related to the greater therapeutic efficacy of CLB in B-CLL than in T-CLL.

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38

Silber, R., CM Farber, E. Papadopoulos, D. Nevrla, L. Liebes, M. Bruck, R. Brown, and ZN Canellakis. "Glutathione depletion in chronic lymphocytic leukemia B lymphocytes." Blood 80, no. 8 (October 15, 1992): 2038–43. http://dx.doi.org/10.1182/blood.v80.8.2038.bloodjournal8082038.

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Glutathione (GSH) content may be the major determinant of a cell's sensitivity to cytotoxic alkylating agents. In the present study, the GSH concentration was determined in lymphocytes isolated from the blood of normal subjects and patients with chronic lymphocytic leukemia (CLL). Comparable levels were found in both types of cells. Incubation for 20 hours led to a decrease in GSH to 51% of baseline values in CLL B cells. Under the same conditions, normal B- or T-lymphocyte GSH content remained constant. GSH depletion was shown to be a characteristic of the B-CLL B lymphocyte. It was not found in the T cells of patients with B-CLL or in cells from patients with T-CLL. Chlorambucil (CLB) contributes to the decrease in GSH in B-CLL lymphocytes; after incubation with the drug, lower levels of GSH were found than in the normal B or T lymphocytes, B-CLL T cells, or T-CLL (CD4 or CD8) cells. GSH depletion of CLL B lymphocytes may be related to the greater therapeutic efficacy of CLB in B-CLL than in T-CLL.

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39

Rai, Kanti R., Hartmut Döhner, Michael J. Keating, and Emili Montserrat. "Chronic Lymphocytic Leukemia: Case-Based Session." Hematology 2001, no. 1 (January 1, 2001): 140–56. http://dx.doi.org/10.1182/asheducation-2001.1.140.

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Abstract Drs. Hartmut Döhner, Michael J. Keating, Kanti R. Rai and Emili Montserrat form the panel to review chronic lymphocytic leukemia (CLL) while focusing on the clinical features of a particular patient. The pace of progress in CLL has accelerated in the past decade. The pathophysiological nature of this disease, as had been known in the past, was based largely on the intuitive and empiric notions of two leaders in hematology, William Dameshek and David Galton. Now the works of a new generation of leaders are providing us with the scientific explanations of why CLL is a heterogeneous disease, perhaps consisting of at least two separate entities. In one form of CLL, the leukemic lymphocytes have a surface immunoglobulin (Ig) variable region gene that has undergone somatic mutations, with tell-tale markers suggesting that these cells had previously traversed the germinal centers. Such patients have a distinctly superior prognosis than their counterparts whose leukemic lymphocytes IgV genes have no mutations (these are indeed immunologically naive cells), who have a worse prognosis. The introduction of fluorescence in situ hybridization (FISH) technique has provided us with new insights into the diverse chromosomal abnormalities that can occur in CLL, and which have significant impact on the clinical behavior and prognosis of patients with this disease. Major advances in therapeutics of CLL also have occurred during the past decade. Two monoclonal antibodies, Campath-1H (anti-CD52) and rituximab (anti-CD20), and one nucleoside analogue, fludarabine, have emerged as three agents of most promise in the front-line treatment of this disease. Studies currently in progress reflect our attempts to find the most effective manner of combining these agents to improve the overall survival statistics for CLL patients. As in many other hematological malignancies, high dose chemotherapy followed by autologous or HLA-compatible allogeneic stem cells rescue strategies are under study as a salvage treatment for a relatively younger age group of CLL patients with poor prognosis characteristics.

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Strati, Paolo, Joon Uhm, Timothy Kaufmann, Sameer A. Parikh, Curtis A. Hanson, Kari Chaffee, Sara Achenbach, Timothy G. Call, and Tait D. Shanafelt. "Central Nervous System Involvement By Chronic Lymphocytic Leukemia." Blood 126, no. 23 (December 3, 2015): 2919. http://dx.doi.org/10.1182/blood.v126.23.2919.2919.

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Abstract INTRODUCTION. Although uncommon, involvement of the central nervous system (CNS) is the most common extramedullary manifestation of Chronic Lymphocytic Leukemia (CLL). Nonetheless, a broad array of conditions can lead to neurologic symptoms in CLL patients and distinguishing between clinically significant CLL involvement of the CNS and other etiologies can be challenging. The actual prevalence of CNS involvement by CLL is unknown, the only available data being case reports and small case series. METHODS. Between 01/1995 and 11/2014, 186 of the 4317 (4%) patients with CLL followed at our center underwent an MRI of the CNS (e.g. brain, spine) and/or a lumbar puncture (LP) with cerebral spinal fluid (CSF) analysis to evaluate neurologic symptoms. As the mere presence of CLL cells in the CSF is not diagnostic of clinically significant CNS disease, a final diagnosis of clinically significant CNS involvement by CLL was established by the collaborative review of the pathologist, neurologist and treating hematologist based on comprehensive work-up and multi-disciplinary evaluation. RESULTS. After evaluation, the etiology of neurologic symptoms was clinically significant involvement of the CNS by CLL in 19 (10%) patients, CNS Richter Syndrome (RS) in 15 (8%), infection in 42 (23%), autoimmune conditions in 31 (17%), other cancer in 9 (5%), and another etiology in 70 (37%). The sensitivity of LP to detect clinically significant CNS involvement by CLL was 89%, however its specificity was only 42% where CLL cells were also frequently observed in the CSF in concomitance with inflammatory processes, such as infections and autoimmune disease. Factors associated with clinically significant CNS involvement by CLL/RS were mutated IGHV (p=0.04), low CSF glucose (p=0.02), elevated CSF total nucleated cells (TNC)(p=0.004), lymphocytes (p=0.02) and CLL cells, both as absolute count (p=0.05) and percentage of TNC (p=0.02). Median OS among patients with clinically significant CNS involvement by CLL or RS were 21 and 11 months, respectively. Median OS for patients with neurological symptoms secondary to infection was 6 months, to autoimmune process was 63 months, to other cancers was 19 months, and to other non-CLL related etiologies was 37 months. CONCLUSIONS. Clinically significant CNS involvement by CLL and RS are rare conditions. Neurologic symptoms in patients with CLL are attributable to non-CLL-related etiologies in the majority of cases, even when CLL B-cells are present in the CSF. Analysis of the CSF has high sensitivity but limited specificity to distinguish clinically significant CNS involvement by CLL from other etiologies. Comprehensive evaluation is required before attributing neurologic symptoms to CLL. Disclosures No relevant conflicts of interest to declare.

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41

Almasri, Mohammad, Marah Amer, Joseph Ghanej, Abdurraouf Mokhtar Mahmoud, Gianluca Gaidano, and Riccardo Moia. "Druggable Molecular Pathways in Chronic Lymphocytic Leukemia." Life 12, no. 2 (February 14, 2022): 283. http://dx.doi.org/10.3390/life12020283.

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Chronic lymphocytic leukemia (CLL), the most common type of leukemia in adults, is characterized by a high degree of clinical heterogeneity that is influenced by the disease’s molecular complexity. The genes most frequently affected in CLL cluster into specific biological pathways, including B-cell receptor (BCR) signaling, apoptosis, NF-κB, and NOTCH1 signaling. BCR signaling and the apoptosis pathway have been exploited to design targeted medicines for CLL therapy. Consistently, molecules that selectively inhibit specific BCR components, namely Bruton tyrosine kinase (BTK) and phosphoinositide 3-kinase (PI3K) as well as inhibitors of BCL2, have revolutionized the therapeutic management of CLL patients. Several BTK inhibitors and PI3K inhibitors with different modes of action are currently used or are in development in advanced stage clinical trials. Moreover, the restoration of apoptosis by the BCL2 inhibitor venetoclax offers meaningful clinical activity with a fixed-duration scheme. Inhibitors of the BCR and of BCL2 are able to overcome the chemorefractoriness associated with high-risk genetic features, including TP53 disruption. Other signaling cascades involved in CLL pathogenesis, in particular NOTCH signaling and NF-kB signaling, already provide biomarkers for a precision medicine approach to CLL and may represent potential druggable targets for the future. The aim of the present review is to discuss the druggable pathways of CLL and to provide the biological background of the high efficacy of targeted biological drugs in CLL.

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42

Fabbri, Giulia, Vladimir Trifonov, Davide Rossi, Oliver T. Elliot, Joseph M. Chan, Andrea Rinaldi, Ivo Kwee, et al. "The Genome of Chronic Lymphocytic Leukemia." Blood 116, no. 21 (November 19, 2010): 51. http://dx.doi.org/10.1182/blood.v116.21.51.51.

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Abstract Abstract 51 Chronic lymphocytic leukemia (CLL) is a malignancy of CD5+ mature B cells that includes two distinct subtypes marked by the differential presence of immunoglobulin gene mutations and a distinct clinical course. The pathogenesis of CLL is largely unknown: in contrast to other types of B cell malignancies, CLL is not associated with recurrent, balanced chromosomal translocations, nor genes have been found that are specifically targeted by somatic mutations, with the exception of ATM and p53 in 6–12% of cases. Instead, more than 80% of CLL patients carry genomic deletions of chromosomal regions 13q14, 11q22–23, and 17p13, or trisomy 12. Of these, the 13q14.3 deletion, encompassing the DLEU2/miR-15a/miR-16-1 cluster (Calin and Croce, Nat Rev Cancer 2006), has been recently shown to promote the development of CLL in mice (Klein et al., Cancer Cell 2010), suggesting its pathogenetic role in the human disease. To determine the extent of somatic genetic lesions (mutations and gene copy number changes) that are present in the CLL genome, we have integrated next generation whole-exome sequencing analysis (Nimblegen/Roche FLX454) and genome-wide high-density single nucleotide polymorphism array analysis (Affymetrix SNP 6.0) in 5 cases representative of the two CLL immunogenetic subgroups and their paired normal DNAs. Candidate tumor-specific nonsynonymous mutations were verified by Sanger sequencing in the same tumor/normal pairs, and all genes validated as mutated were then screened in an independent panel of 48 CLL DNAs by PCR amplification/direct sequencing of their entire coding region. The whole-exome sequencing approach revealed a total of 36 mutations, corresponding to 36 distinct genes at an average of 7 mutations/case (range, 5–9 mutations/case). The majority of these events were represented by single base pair substitutions (N=34, of which 30 missense mutations and 4 nonsense mutations), while frameshift insertion/deletions were rare (N=2 deletions of 4 and 32 base pairs, respectively; 5.5%). Analysis of the mutation features showed a prevalence of transitions versus transversions (64% vs 36%) and an elevated G+C over A+T ratio (66% vs 44%), analogous to the mutation spectrum observed in the genome of epithelial tumors such as colorectal, pancreatic and brain cancer. SNP array analysis in 4 of the 5 “discovery” cases confirmed the presence of the 13q14 deletion in 2 samples and identified 25 additional regions of copy number changes, corresponding to ∼7 lesions/case (range: 3 to 10) and mostly represented by deletions (N=16/27, ∼60%). When screened in the extended CLL panel, several of the 36 genes identified through the whole exome sequencing approach appeared to be mutated in at least one additional patient. Overall, these data indicate that the coding genome of CLL contains on average ∼14 somatic gene alterations per case. When classified based on functional annotation, most of these lesions appeared to converge on discrete signaling pathways, which likely represent important pathogenetic and possibly therapeutic targets in CLL. Disclosures: No relevant conflicts of interest to declare.

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43

Seifert, Marc, Ludger Sellmann, Johannes Bloehdorn, Frederik Wein, Stephan Stilgenbauer, Jan Dürig, and Ralf Küppers. "Cellular origin and pathophysiology of chronic lymphocytic leukemia." Journal of Experimental Medicine 209, no. 12 (October 22, 2012): 2183–98. http://dx.doi.org/10.1084/jem.20120833.

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The cellular origin of chronic lymphocytic leukemia (CLL) is still debated, although this information is critical to understanding its pathogenesis. Transcriptome analyses of CLL and the main normal B cell subsets from human blood and spleen revealed that immunoglobulin variable region (IgV) gene unmutated CLL derives from unmutated mature CD5+ B cells and mutated CLL derives from a distinct, previously unrecognized CD5+CD27+ post–germinal center B cell subset. Stereotyped V gene rearrangements are enriched among CD5+ B cells, providing independent evidence for a CD5+ B cell derivation of CLL. Notably, these CD5+ B cell populations include oligoclonal expansions already found in young healthy adults, putatively representing an early phase in CLL development before the CLL precursor lesion monoclonal B cell lymphocytosis. Finally, we identified deregulated proteins, including EBF1 and KLF transcription factors, that were not detected in previous comparisons of CLL and conventional B cells.

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44

Trepel, Martin, Fabian Muller, Mareike Frick, Janina Rahlff, Claudia Wehr, Frederic Simon, Bernd Leistler, Hendrik Veelken, Roland H. Mertelsmann, and Mascha Binder. "Evidence for Autostimulatory Mechanisms in Chronic Lymphocytic Leukemia." Blood 120, no. 21 (November 16, 2012): 2880. http://dx.doi.org/10.1182/blood.v120.21.2880.2880.

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Abstract Abstract 2880 Background: The development and / or course of chronic lymphocytic leukemia (CLL) may be driven by the recognition of antigens through the B cell receptor (BCR). While it has been recognized that the diversity of epitope recognition may be astonishingly confined in CLL, knowledge on antigens recognized by CLL BCRs is still limited. Here, we identified and characterized an epitope recognized by a defined CLL BCR which may broaden our view on potential mechanisms of antigenic drive in CLL. Methods: The B- cell receptor of a random CLL-patient was cloned and expressed as Fab fragment in E.coli. Random phage display reptile litanies we skeletal on the immobilized Fab and landed peptides were tested for specific binding. Specific clones we sequenced and sequences were analyzed for homology to known proteins. Recognition of candidate proteins was verified in brooding assays or recombinant proteins. Results: Screening random phage display peptide libraries, we identified a CLL BCR epitope mimic that displayed a high degree of homology to a conserved peptide string in the variable region of immunoglobulin heavy and light chains. CLL BCR binding to this epitope as well as binding to full length heavy and light immunoglobulin chains was verified by binding assays and a protein array screening. Interestingly, the CLL BCR also interacted with itself, as the identified epitope was also present in its own primary amino acid sequence. Conclusions: These findings suggest the possibility of self-recognition of BCRs within the CLL cell membrane or BCR interactions between neighboring CLL cells. This may potentially result in autostimulation of the leukemic cell independent of “exogenous” antigens and may account for self-sufficient signaling of some CLL-BCRs in driving disease progression. As the peptide mimicking this immunoglobulin epitope is known to be recognized by BCRs of other CLL cases in addition to the index case investigated here, such autostimulatory mechanisms may be relevant to a large number of CLL patients. Disclosures: No relevant conflicts of interest to declare.

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Markovtseva, Mariya Vladimirovna, and Ekaterina Nikolaevna Zgural'skaya. "CHRONIC KIDNEY DISEASE IN PATIENTS WITH CHRONIC LYMPHATIC LEUKEMIA AND THEIR SURVIVABILITY." Ulyanovsk Medico-biological Journal, no. 3 (September 26, 2022): 43–48. http://dx.doi.org/10.34014/2227-1848-2022-3-43-48.

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Chronic lymphocytic leukemia (CLL) is one of the most common lymphoproliferative diseases in the European population with an increase in the incidence in the elderly and senile age. However, it is among the elderly that a decrease in glomerular filtration rate (GFR) and concomitant chronic kidney disease (CKD) are associated with the severity in long-term prognosis. The aim of the study was to analyze CKD incidence and prognostic value in patients with CLL. Materials and Methods. CLL retrospective analysis was performed in 132 patients (60 men and 72 women). CKD was diagnosed according to the 2021-Guidelines of Russian Scientific Society of Nephrologists. Results. Among the examined patients, 64 (48.5 %) were diagnosed with CKD: stage C2 – in 23 patients. (17.4 %), stage C3a – in 41 patients. (31.1 %). CKD incidence in patients with CLL was higher than in the similar population without CLL. The authors revealed that there was no correlation between CLL stage and CKD severity. Survival analysis showed that only 43 patients (32.5 %) overcame the estimated Binet median survival. C3a in patients with CLL at the time of CKD diagnosis is strongly correlated with survival. Conclusion. CKD occurs in 48.5 % of patients with CLL. It has been established that C3a CKD worsens CLL patient survivability.

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46

Nosari, AnnaMaria. "INFECTIOUS COMPLICATIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA." Mediterranean Journal of Hematology and Infectious Diseases 4, no. 1 (November 5, 2012): e2012070. http://dx.doi.org/10.4084/mjhid.2012.070.

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Infectious complications have been known to be a major cause of morbidity and mortality in CLL patients who are predisposed to infections because of both the humoral immunodepression inherent to hematologic disease, which is related to stage and duration of CLL, and to further immunosuppression related to therapy. The majority of infections in CLL patients treated with alkilating agents is of bacterial origin. The immunodeficiency and natural infectious history of alkylator-resistant, corticosteroid-treated patients appears to have changed with the administration of purine analogs, which has been complicated by very severe and unusual infections and also more viral infections due to sustained reduction of CD4-positive T lymphocytes. The following introduction of monoclonal antibody therapies, in particular alemtuzumab, further increased the immunodepression, increasing also infections which appeared more often in patients with recurrent neutropenia due to chemotherapy cycles.Epidemiological data regarding fungal infections in lymphoproliferative disorders are scarce. Italian SEIFEM group in a retrospective multicentre study regarding CLL patients reported an incidence of mycoses 0.5%; however, chronic lymphoproliferative disorders emerged as second haematological underlying disease after acute leukemia in a French study on aspergillosis; in particular CLL with aspergillosis accounted for a third of these chronic lymphoproliferative diseases presenting mould infection.

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47

Friedman, Daphne R., Eross Guadeloupe, Alicia Volkheimer, and J. Brice Weinberg. "Surface CD5 Protein Risk Stratifies Chronic Lymphocytic Leukemia." Blood 128, no. 22 (December 2, 2016): 3212. http://dx.doi.org/10.1182/blood.v128.22.3212.3212.

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Abstract Introduction: Chronic Lymphocytic Leukemia (CLL) is a malignancy characterized by B-lymphocytes with aberrant expression of CD5. In normal T-lymphocytes, CD5 is an important regulator of T-cell receptor signaling. In CLL, CD5 acts as a repressor of B-cell receptor (BCR) signaling, whereby phosphorylated CD5 anchors SHP-1 at the cell membrane, resulting in inhibition of BCR-mediated second messenger signaling. The significance of CD5 on outcomes of CLL patients has not been evaluated. Because BCR signaling is an oncogenic stimulus in CLL, we hypothesized that higher levels of CD5 may be associated with superior clinical outcomes. Methods: Median fluorescence intensity (MFI) of CD5 on CLL cells was determined by flow cytometry. CLL samples and clinical data were obtained from patients enrolled in IRB-approved protocols at the Duke University and Durham VA Medical Centers. Molecular prognostic markers were measured as described previously. Descriptive and time to event (Cox proportional hazard and Kaplan-Meier) statistical analyses were performed in the statistical environment, R. Results: Between March 2011 and April 2015, 961 CLL samples were evaluated from 352 unique CLL patients. One to 10 samples were evaluated per CLL patient. The mean CD5 MFI was calculated for each unique patient, with a median of 206.59 (range 0.50 - 768.31) and median standard deviation of 33.02 (range 0.09 - 315.46) for CLL patients with multiple samples collected. 150 patients received therapy (44%), and there was no significant difference in CD5 MFI mean or standard deviation between patients who received and did not receive therapy. CD5 MFI values did not significantly differ among CLL demographic or prognostic groups. Cox proportional hazard ratio analyses showed that higher CD5 MFI is associated with longer time to therapy (TTT, p = 0.037), but not overall survival. Based on the distribution of CD5 MFI, we divided the CLL cohort into thirds, with low CD5 defined as MFI < 137, high CD5 defined as MFI > 283.5, and medium CD5 with MFI between these values. Kaplan-Meier analyses demonstrated a significant difference in TTT between these three groups (p = 0.004), with higher CD5 MFI associated with longer TTT. Moreover, CD5 MFI added to established molecular prognostic markers to risk stratify CLL patients (p < 0.0001 for CD38 and IGHV, p = 0.0003 for FISH, and p = 0.004 for ZAP70). Importantly, for those with good prognostic markers such as IGHV mutation or low CD38 expression, lower CD5 identified patients with shorter TTT (p = 0.01 for IGHV mutated; p = 0.0009 for CD38 negative). However, TTT was not significantly different in unmutated IGHV CLL patients or CD38 positive CLL patients with varying degrees of CD5 expression. Conclusions: Surface CD5 expression varies among CLL patients. For most individual patients, there appears to be a low level of variability in CD5 expression, regardless of CLL-directed therapy. Higher CD5 expression is associated with superior clinical outcomes in CLL, consistent with prior in vitro determination of CD5 as a negative regulator of BCR signaling. The relevance of CD5 in risk-stratifying IGHV mutated and CD38 negative CLL patients is of particular relevance, since these subgroups of CLL are particularly dependent on BCR-signaling as an oncogenic process. These findings are important both for prognostication and for development of therapies for this group of CLL patients. Disclosures No relevant conflicts of interest to declare.

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48

Jain, Preetesh, and Kanti R. Rai. "Overview of recent developments in chronic lymphocytic leukemia." South Asian Journal of Cancer 01, no. 02 (October 2012): 84–89. http://dx.doi.org/10.4103/2278-330x.103721.

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AbstractMultiple advances have been made in our understanding of pathobiology of chronic lymphocytic leukemia (CLL). These developments in the laboratory include new prognostic markers, risk stratification of the disease and newer therapeutic agents in CLL. These advances in CLL have come a long way in the past three decades since the development of Rai and Binet clinical staging systems. Important strides in the pathobiology, from defining mutational status of IGHV, to B-cell receptor (BCR) signaling pathways and CLL microenvironment have made a major difference in our understanding of this disease. Mutational status of immunoglobulin heavy chain genes (IGHV), CD38 and Zap-70, chromosomal aberrations and newer mutations, are the most clinically relevant prognostic markers. Chemoimmunotherapy (CIT) has become the treatment of choice for young and fit CLL patients. Various inhibitors of BCR signaling pathways and immunomodulatory drugs have shown efficacy in clinical trials. The most recent advance is the use of chimeric antigen receptor therapy (CAR) based on autologous T-lymphocytes. Nevertheless, CLL remains an incurable disease today. Coordinated developments between laboratory and clinic will hopefully translate into a cure for CLL. This short review focuses on advances in prognostication and therapy in CLL.

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49

Robak, Tadeusz, Jarosław D. Kasprzak, Dorota Jesionek-Kupnicka, Cezary Chudobiński, and Paweł Robak. "Cardiac Involvement in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma." Journal of Clinical Medicine 11, no. 23 (November 26, 2022): 6983. http://dx.doi.org/10.3390/jcm11236983.

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Cardiac involvement of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is recognized extremely rarely. In addition, most CLL/SLL patients with heart infiltration are asymptomatic. In this review, we present the results of a literature search for English language articles concerning CLL/SLL or Richter transformation with symptomatic cardiac involvement. In total, 18 well-described cases with CLL/SLL and heart infiltration were identified. Only three patients were not diagnosed with CLL/SLL before the cardiac manifestation. In other patients, cardiac CLL/SLL was diagnosed between 5 months and 20 years from CLL/SLL diagnosis. All patients in these series had a diagnosis of secondary cardiac CLL/SLL. In addition, we identified four reported cases with Richter transformation in the heart. The treatment of patients with CLL/SLL and cardiac infiltration is variable and depends on the previous history and clinical characteristics of heart infiltration. In addition, no recommendations exist on how to treat patients with CLL/SLL and cardiac involvement.

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50

Wang, Zhiquan, Justin C. Boysen, Huihuang Yan, Charla R. Secreto, Sameer A. Parikh, Saad S. Kenderian, Wei Ding, Esteban Braggio, Susan L. Slager, and Neil E. Kay. "Targeting Aberrant Chromatin in Chronic Lymphocytic Leukemia." Blood 136, Supplement 1 (November 5, 2020): 1. http://dx.doi.org/10.1182/blood-2020-140309.

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Introduction: Chronic Lymphocytic Leukemia (CLL) is characterized by the accumulation of mature-appearing malignant lymphocytes (CLL B-cells) in the blood, marrow, lymph nodes, and spleen. Despite improved outcome with the introduction of novel BCR and BCL-2 inhibitors, disease progression is still a therapeutic challenge from either differential responses or acquired drug resistance. Recent studies in CLL reported alterations of the epigenetic landscape as well as mutations of genes encoding key chromatin machineries. These aberrant chromatin structures may provide novel therapeutic targets for CLL. Here, we identify aberrant chromatin features in CLL B-cells as novel therapeutic targets. Methods: Histones were extracted by acid from B cells derived from 10 random selected CLL patients and 10 normal donors and histone modifications were checked by western blot. For ChIP-seq study, published H3K27me3 ChIP-seq data (GSE113336) were downloaded from and analyzed (Control samples, n= 6; CLL samples, n=16). Gene ontology analysis used the Panther Classification System. Cell Survival was determined by CellTiter 96® AQueous Assay (Promega). Results: While most histone modifications do not vary between CLL and controls, H3K27me3 and H3.3S31ph are increased and decreased respectively, albeit variably, in CLL B-cells (Fig1. A and B). Notably, the low level of H3.3S31ph was observed in a subset of samples (7 of 10 CLL samples tested). To further investigate the biology and role of H3K27me3 in CLL, we analyzed its genome-wide distribution by chromatin immunoprecipitation followed by sequencing (ChIP-seq). Our analysis showed that the genes with increased H3K27me3 occupancy were mostly enriched in tumor suppression pathways (e.g., negative regulation of PI3K-Akt pathway) or down-regulated genes in CLL such as genes involved in the pro-apoptotic pathway (FAS) (Fig1. C and D). These results suggested that high enrichment of H3K27me3 may regulate the expression of these genes, contributing to CLL survival. H3K27 methylation, an important suppressive histone modification that is associated with transcription repression, is catalyzed by Polycomb Repressive Complex 2 (PRC2). Therefore, inhibition of Enhancer of Zeste Homolog 2 (EZH2), the catalytic subunit of PRC2, could be explored as a therapy approach in CLL. However, feedback activation of H3K27 acetylation (H3K27ac) can promote expression of pro-survival genes that confers EZH2 inhibitor (EZH2i) resistance, which limits its use in human malignancy. Thus, the epigenetic determinants that reliably overcome EZH2i resistance or sensitize cells to EZH2 inhibition have yet to be identified. As we observed that the CLL B-cells in a subset of CLL patients have low levels of H3.3S31ph, and a recent study showed the importance of H3.3S31ph for the enzymatic activity of p300 to acetylate H3 at lysine 27(Martire S et al., Nat Genet. 2019), we assessed the role of H3.3S31ph in the process of EZH2 inhibitor-mediated H3K27ac. Our results showed that inhibition of H3.3S31ph by CHK1 inhibitor MK-8776 abolished the activation of H3K27ac by EZH2i in MEC1 cells, which represents the patients who have CLL cells with relatively high level H3.3S31ph. However, we did not see a major increase of H3K27ac and H3.3S31ph in primary CLL B-cells with EZH2 inhibition (Fig. 1E), consistent with the relatively low expression of CHK1 protein in these cells (Fig. 1F). Because our data shows the requirement of H3.3S31ph in H3K27ac activation by EZH2 inhibition, we next tested if H3.3S31ph inhibition could overcome H3K27ac induced EZH2 inhibition resistance. We found that suppression of H3.3S31ph by CHK1 inhibitor MK-8776 sensitizes the CLL-like line MEC1 to EZH1/2 inhibition (Fig. 1 G). We then showed that an EZH2 inhibitor, Valemetostat, reduce the survival of the primary CLL B-cells (Fig. 1 H). These results suggest that the low level of H3.3S31ph may provide a therapeutic opportunity for CLL treatment with EZH inhibition. Conclusion: In summary, we have elucidated how epigenetic features in leukemic CLL B-cells (H3K27me3 and H3.3S31ph), can provide novel treatment targets for CLL (Fig. 1 I). Moreover, this study may provide a proof of concept to develop new treatment strategies based on epigenetic vulnerabilities in other hematological malignancies. Disclosures Parikh: GlaxoSmithKline: Honoraria; MorphoSys: Research Funding; Genentech: Honoraria; Ascentage Pharma: Research Funding; AbbVie: Honoraria, Research Funding; TG Therapeutics: Research Funding; Janssen: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Verastem Oncology: Honoraria; Merck: Research Funding. Kenderian:Kite: Research Funding; MorphoSys: Research Funding; Tolero: Research Funding; Humanigen: Consultancy, Patents & Royalties, Research Funding; BMS: Research Funding; Gilead: Research Funding; Juno: Research Funding; Lentigen: Research Funding; Mettaforge: Patents & Royalties; Novartis: Patents & Royalties, Research Funding; Torque: Consultancy; Sunesis: Research Funding. Ding:Beigene: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Membership on an entity's Board of Directors or advisory committees; alexion: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Research Funding; DTRM: Research Funding; Abbvie: Research Funding. Braggio:DASA: Consultancy; Bayer: Other: Stock Owner; Acerta Pharma: Research Funding. Kay:Oncotracker: Membership on an entity's Board of Directors or advisory committees; Juno Theraputics: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Cytomx: Membership on an entity's Board of Directors or advisory committees; Agios Pharma: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; MEI Pharma: Research Funding; Abbvie: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Research Funding.

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