Editorial

4 pages, 163 KiB

Open AccessEditorial

by Tiziana Vaisitti, Francesca Arruga and Alessandra Ferrajoli

Cancers 2020, 12(9), 2504; https://doi.org/10.3390/cancers12092504 - 03 Sep 2020

Cited by 4 | Viewed by 1621

This Special Issue of Cancers, made up of nine articles (four original papers, four reviews, and a brief report), is dedicated to chronic lymphocytic leukemia (CLL) [...] Full article

(This article belongs to the Special Issue Chronic Lymphocytic Leukemia)

Research

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11 pages, 922 KiB

Open AccessArticle

Prognostic Significance of PET/CT in Patients with Chronic Lymphocytic Leukemia (CLL) Treated with Frontline Chemoimmunotherapy

by Marika Porrazzo, Emanuele Nicolai, Mara Riminucci, Candida Vitale, Marta Coscia, Lorenzo De Paoli, Angela Rago, Giulia Buscicchio, Giacomo Maestrini, Silvio Ligia, Alessio Di Prima, Alessandro Corsi, Roberto Caronna, Gianluca Gaidano and Francesca Romana Mauro

Cancers 2020, 12(7), 1773; https://doi.org/10.3390/cancers12071773 - 03 Jul 2020

Cited by 4 | Viewed by 2332

Abstract

The role of positron emission tomography/computed tomography (PET/CT) in identifying Richter Syndrome (RS) is well established, while its impact on the survival of patients with chronic lymphocytic leukemia (CLL) has been less explored. The clinical characteristics and PET/CT data of 40 patients with [...] Read more.

The role of positron emission tomography/computed tomography (PET/CT) in identifying Richter Syndrome (RS) is well established, while its impact on the survival of patients with chronic lymphocytic leukemia (CLL) has been less explored. The clinical characteristics and PET/CT data of 40 patients with a biopsy-proven CLL who required frontline chemoimmunotherapy, FCR (fludarabine, cyclophosphamide, rituximab) in 20 patients, BR (bendamustine, rituximab) in 20, were retrospectively analyzed. Standardized uptake volume (SUV_max) values ≥ 5 were observed more frequently in patients with deletion 11q (p = 0.006) and biopsies characterized by a rate of Ki67 positive cells ≥ 30% (p = 0.02). In the multivariate analysis, the presence of large and confluent PCs emerged as the only factor with a negative impact on progression-free survival (PFS), and overall survival (OS). Deletion 11q also revealed a significant and independent effect on PFS. SUV_max values ≥ 5 showed no statistical impact on PFS while in multivariate analysis, they revealed a significant adverse impact on OS (median survival probability not reached vs. 56 months; p = 0.002). Moreover, patients with higher SUV_max values more frequently developed Richter Syndrome (p = 0.015). Our results show that higher SUV_max values identify CLL patients with a pronounced rate of proliferating cells in the lymph-node compartment, inferior survival, and an increased risk of developing RS. Full article

(This article belongs to the Special Issue Chronic Lymphocytic Leukemia)

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19 pages, 3179 KiB

Open AccessArticle

Mitochondrial Respiration Correlates with Prognostic Markers in Chronic Lymphocytic Leukemia and Is Normalized by Ibrutinib Treatment

by Subir Roy Chowdhury, Eric D. J. Bouchard, Ryan Saleh, Zoann Nugent, Cheryl Peltier, Edgard Mejia, Sen Hou, Carly McFall, Mandy Squires, Donna Hewitt, Linda Davidson, Garry X. Shen, James B. Johnston, Christine Doucette, Grant M. Hatch, Paul Fernyhough, Aaron Marshall, Spencer B. Gibson, David E. Dawe and Versha Banerji

Cancers 2020, 12(3), 650; https://doi.org/10.3390/cancers12030650 - 11 Mar 2020

Cited by 17 | Viewed by 4212

Abstract

Mitochondrial bioenergetics profiling, a measure of oxygen consumption rates, correlates with prognostic markers and can be used to assess response to therapy in chronic lymphocytic leukemia (CLL) cells. In this study, we measured mitochondrial respiration rates in primary CLL cells using respirometry to [...] Read more.

Mitochondrial bioenergetics profiling, a measure of oxygen consumption rates, correlates with prognostic markers and can be used to assess response to therapy in chronic lymphocytic leukemia (CLL) cells. In this study, we measured mitochondrial respiration rates in primary CLL cells using respirometry to evaluate mitochondrial function. We found significant increases in mitochondrial respiration rates in CLL versus control B lymphocytes. We also observed amongst CLL patients that advanced age, female sex, zeta-chain-associated protein of 70 kD (ZAP-70⁺), cluster of differentiation 38 (CD38⁺), and elevated β2-microglobulin (β2-M) predicted increased maximal respiration rates. ZAP-70⁺ CLL cells exhibited significantly higher bioenergetics than B lymphocytes or ZAP-70⁻ CLL cells and were more sensitive to the uncoupler, carbonyl cyanide-p-trifluoro-methoxyphenylhydrazone (FCCP). Univariable and multivariable linear regression analysis demonstrated that ZAP-70⁺ predicted increased maximal respiration. ZAP-70⁺ is a surrogate for B cell receptor (BCR) activation and can be targeted by ibrutinib, which is a clinically approved Bruton’s tyrosine kinase (BTK) inhibitor. Therefore, we evaluated the oxygen consumption rates (OCR) of CLL cells and plasma chemokine (C-C motif) ligands 3 and 4 (CCL3/CCL4) levels from ibrutinib-treated patients and demonstrated decreased OCR similar to control B lymphocytes, suggesting that ibrutinib treatment resets the mitochondrial bioenergetics, while diminished CCL3/CCL4 levels indicate the down regulation of the BCR signaling pathway in CLL. Our data support evaluation of mitochondrial respiration as a preclinical tool for the response assessment of CLL cells. Full article

(This article belongs to the Special Issue Chronic Lymphocytic Leukemia)

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18 pages, 3963 KiB

Open AccessArticle

Transcriptional Modulation by Idelalisib Synergizes with Bendamustine in Chronic Lymphocytic Leukemia

by Sara E. F. Kost, Ali Saleh, Edgard M. Mejia, Marina Mostafizar, Eric D. J. Bouchard, Versha Banerji, Aaron J. Marshall, Spencer B. Gibson, James B. Johnston and Sachin Katyal

Cancers 2019, 11(10), 1519; https://doi.org/10.3390/cancers11101519 - 09 Oct 2019

Cited by 5 | Viewed by 3552

Abstract

The phosphatidyl-inositol 3 kinase (PI3K) δ inhibitor, idelalisib (IDE), is a potent inhibitor of the B-cell receptor pathway and a novel and highly effective agent for the treatment of chronic lymphocytic leukemia (CLL). We evaluated the activities of IDE in comparison to bendamusine [...] Read more.

The phosphatidyl-inositol 3 kinase (PI3K) δ inhibitor, idelalisib (IDE), is a potent inhibitor of the B-cell receptor pathway and a novel and highly effective agent for the treatment of chronic lymphocytic leukemia (CLL). We evaluated the activities of IDE in comparison to bendamusine (BEN), a commonly used alkylating agent, in primary CLL cells ex vivo. In contrast to BEN, IDE was cytotoxic to cells from extensively-treated patients, including those with a deletion (del)17p. Cross-resistance was not observed between BEN and IDE, confirming their different modes of cytotoxicity. Marked synergy was seen between BEN and IDE, even in cases that were resistant to BEN or IDE individually, and those with deletion (del) 17p. CD40L/interleukin 4 (IL4) co-treatment mimicking the CLL microenvironment increased resistance to IDE, but synergy was retained. PI3Kδ-deficient murine splenic B cells were more resistant to IDE and showed reduced synergy with BEN, thus confirming the importance of functional PI3Kδ protein. Although IDE was observed to induce γH2AX, IDE did not enhance activation of the DNA damage response nor DNA repair activity. Interestingly, IDE decreased global RNA synthesis and was antagonistic with 5,6-Dichlorobenzimidazole 1-b-D-ribofuranoside (DRB), an inhibitor of transcription. These findings add to the increasingly complex cellular effects of IDE, and B cell receptor (BCR) inhibitors in general, in CLL. Full article

(This article belongs to the Special Issue Chronic Lymphocytic Leukemia)

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12 pages, 1704 KiB

Open AccessArticle

Elevated Lactate Dehydrogenase Has Prognostic Relevance in Treatment-Naïve Patients Affected by Chronic Lymphocytic Leukemia with Trisomy 12

by Francesco Autore, Paolo Strati, Idanna Innocenti, Francesco Corrente, Livio Trentin, Agostino Cortelezzi, Carlo Visco, Marta Coscia, Antonio Cuneo, Alessandro Gozzetti, Francesca Romana Mauro, Anna Maria Frustaci, Massimo Gentile, Fortunato Morabito, Stefano Molica, Paolo Falcucci, Giovanni D’Arena, Roberta Murru, Donatella Vincelli, Dimitar G Efremov, Antonietta Ferretti, Gian Matteo Rigolin, Candida Vitale, Maria Chiara Tisi, Gianluigi Reda, Andrea Visentin, Simona Sica, Robin Foà, Alessandra Ferrajoli and Luca Laurenti Show full author list Hide full author list

Cancers 2019, 11(7), 896; https://doi.org/10.3390/cancers11070896 - 26 Jun 2019

Cited by 13 | Viewed by 4610

Abstract

Chronic Lymphocytic Leukemia (CLL) patients with +12 have been reported to have specific clinical and biologic features. We performed an analysis of the association between demographic; clinical; laboratory; biologic features and outcome in CLL patients with +12 to identify parameters predictive of disease [...] Read more.

Chronic Lymphocytic Leukemia (CLL) patients with +12 have been reported to have specific clinical and biologic features. We performed an analysis of the association between demographic; clinical; laboratory; biologic features and outcome in CLL patients with +12 to identify parameters predictive of disease progression; time to treatment; and survival. The study included 487 treatment-naive CLL patients with +12 from 15 academic centers; diagnosed between January 2000 and July 2016; and 816 treatment-naïve patients with absence of Fluorescence In Situ Hybridization (FISH) abnormalities. A cohort of 250 patients with +12 CLL followed at a single US institution was used for external validation. In patients with +12; parameters associated with worse prognosis in the multivariate model were high Lactate DeHydrogenase (LDH) and β-2-microglobulin and unmutated immunoglobulin heavy-chain variable region gene (IGHV). CLL patients with +12 and high LDH levels showed a shorter Progression-Free-Survival (PFS) (30 months vs. 65 months; p < 0.001), Treatment-Free-Survival (TFS) (33 months vs. 69 months; p < 0.001), Overall Survival (OS) (131 months vs. 181 months; p < 0.001) and greater CLL-related mortality (29% vs. 11% at 10 years; p < 0.001) when compared with +12 CLL patients with normal LDH levels. The same differences were observed in the validation cohort. These data suggest that serum LDH levels can predict PFS; TFS; OS and CLL-specific survival in CLL patients with +12. Full article

(This article belongs to the Special Issue Chronic Lymphocytic Leukemia)

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Review

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33 pages, 2348 KiB

Open AccessFeature PaperReview

Mechanisms of B Cell Receptor Activation and Responses to B Cell Receptor Inhibitors in B Cell Malignancies

by Dimitar G. Efremov, Sven Turkalj and Luca Laurenti

Cancers 2020, 12(6), 1396; https://doi.org/10.3390/cancers12061396 - 28 May 2020

Cited by 38 | Viewed by 11929

Abstract

The B cell receptor (BCR) pathway has been identified as a potential therapeutic target in a number of common B cell malignancies, including chronic lymphocytic leukemia, diffuse large B cell lymphoma, Burkitt lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone B cell lymphoma, [...] Read more.

The B cell receptor (BCR) pathway has been identified as a potential therapeutic target in a number of common B cell malignancies, including chronic lymphocytic leukemia, diffuse large B cell lymphoma, Burkitt lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone B cell lymphoma, and Waldenstrom’s macroglobulinemia. This finding has resulted in the development of numerous drugs that target this pathway, including various inhibitors of the kinases BTK, PI3K, and SYK. Several of these drugs have been approved in recent years for clinical use, resulting in a profound change in the way these diseases are currently being treated. However, the response rates and durability of responses vary largely across the different disease entities, suggesting a different proportion of patients with an activated BCR pathway and different mechanisms of BCR pathway activation. Indeed, several antigen-dependent and antigen-independent mechanisms have recently been described and shown to result in the activation of distinct downstream signaling pathways. The purpose of this review is to provide an overview of the mechanisms responsible for the activation of the BCR pathway in different B cell malignancies and to correlate these mechanisms with clinical responses to treatment with BCR inhibitors. Full article

(This article belongs to the Special Issue Chronic Lymphocytic Leukemia)

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15 pages, 751 KiB

Open AccessReview

P66Shc: A Pleiotropic Regulator of B Cell Trafficking and a Gatekeeper in Chronic Lymphocytic Leukemia

by Laura Patrussi, Nagaja Capitani and Cosima T. Baldari

Cancers 2020, 12(4), 1006; https://doi.org/10.3390/cancers12041006 - 19 Apr 2020

Cited by 9 | Viewed by 3083

Abstract

Neoplastic B cells from chronic lymphocytic leukemia patients (CLL) have a profound deficiency in the expression of p66Shc, an adaptor protein with pro-apoptotic and pro-oxidant activities. This defect results in leukemic B cell resistance to apoptosis and additionally impinges on the balance between [...] Read more.

Neoplastic B cells from chronic lymphocytic leukemia patients (CLL) have a profound deficiency in the expression of p66Shc, an adaptor protein with pro-apoptotic and pro-oxidant activities. This defect results in leukemic B cell resistance to apoptosis and additionally impinges on the balance between chemokine receptors that control B cell homing to secondary lymphoid organs and the sphingosine phosphate receptor S1PR1 that controls their egress therefrom, thereby favoring leukemic B cell accumulation in the pro-survival lymphoid niche. Ablation of the gene encoding p66Shc in the Eµ-TCL1 mouse model of human CLL enhances leukemogenesis and promotes leukemic cell invasiveness in both nodal and extranodal organs, providing in vivo evidence of the pathogenic role of the p66Shc defect in CLL pathogenesis. Here we present an overview of the functions of p66Shc in B lymphocytes, with a specific focus on the multiple mechanisms exploited by p66Shc to control B cell trafficking and the abnormalities in this process caused by p66Shc deficiency in CLL. Full article

(This article belongs to the Special Issue Chronic Lymphocytic Leukemia)

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17 pages, 642 KiB

Open AccessReview

An Updated Perspective on Current Prognostic and Predictive Biomarkers in Chronic Lymphocytic Leukemia in the Context of Chemoimmunotherapy and Novel Targeted Therapy

by Jared A. Cohen, Riccardo Bomben, Federico Pozzo, Erika Tissino, Andrea Härzschel, Tanja Nicole Hartmann, Antonella Zucchetto and Valter Gattei

Cancers 2020, 12(4), 894; https://doi.org/10.3390/cancers12040894 - 07 Apr 2020

Cited by 20 | Viewed by 4066

Abstract

Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with a variable clinical course. Novel biomarkers discovered over the past 20 years have revolutionized the way clinicians approach prognostication and treatment especially in the chemotherapy-free era. Herein, we review the best established prognostic and [...] Read more.

Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with a variable clinical course. Novel biomarkers discovered over the past 20 years have revolutionized the way clinicians approach prognostication and treatment especially in the chemotherapy-free era. Herein, we review the best established prognostic and predictive biomarkers in the setting of chemoimmunotherapy (CIT) and novel targeted therapy. We propose that TP53 disruption (defined as either TP53 mutation or chromosome 17p deletion), unmutated immunoglobulin heavy chain variable region gene status (UM IGHV), NOTCH1 mutation, and CD49d expression are the strongest prognosticators of disease progression and overall survival in the field of novel biomarkers including recurrent gene mutations. We also highlight the predictive role of TP53 disruption, UM IGHV, and NOTCH1 mutation in the setting of CIT and TP53 disruption and CD49d expression in the setting of novel targeted therapy employing B-cell receptor (BCR) and B-cell lymphoma-2 (BCL2) inhibition. Finally, we discuss future directions in the field of biomarker development to identify those with relapsed/refractory disease at risk for progression despite treatment with novel therapies. Full article

(This article belongs to the Special Issue Chronic Lymphocytic Leukemia)

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16 pages, 2195 KiB

Open AccessReview

Tumor Suppressors in Chronic Lymphocytic Leukemia: From Lost Partners to Active Targets

by Giacomo Andreani, Giovanna Carrà, Marcello Francesco Lingua, Beatrice Maffeo, Mara Brancaccio, Riccardo Taulli and Alessandro Morotti

Cancers 2020, 12(3), 629; https://doi.org/10.3390/cancers12030629 - 09 Mar 2020

Cited by 6 | Viewed by 3630

Abstract

Tumor suppressors play an important role in cancer pathogenesis and in the modulation of resistance to treatments. Loss of function of the proteins encoded by tumor suppressors, through genomic inactivation of the gene, disable all the controls that balance growth, survival, and apoptosis, [...] Read more.

Tumor suppressors play an important role in cancer pathogenesis and in the modulation of resistance to treatments. Loss of function of the proteins encoded by tumor suppressors, through genomic inactivation of the gene, disable all the controls that balance growth, survival, and apoptosis, promoting cancer transformation. Parallel to genetic impairments, tumor suppressor products may also be functionally inactivated in the absence of mutations/deletions upon post-transcriptional and post-translational modifications. Because restoring tumor suppressor functions remains the most effective and selective approach to induce apoptosis in cancer, the dissection of mechanisms of tumor suppressor inactivation is advisable in order to further augment targeted strategies. This review will summarize the role of tumor suppressors in chronic lymphocytic leukemia and attempt to describe how tumor suppressors can represent new hopes in our arsenal against chronic lymphocytic leukemia (CLL). Full article

(This article belongs to the Special Issue Chronic Lymphocytic Leukemia)

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Other

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11 pages, 923 KiB

Open AccessBrief Report

Meta-Analysis Reveals Significant Sex Differences in Chronic Lymphocytic Leukemia Progression in the Eµ-TCL1 Transgenic Mouse Model

by Maximilian Koch, Sebastian Reinartz, Julia Saggau, Gero Knittel, Natascha Rosen, Oleg Fedorchenko, Lisa Thelen, Romy Barthel, Nina Reinart, Tamina Seeger-Nukpezah, Hans Christian Reinhardt, Michael Hallek and Phuong-Hien Nguyen

Cancers 2020, 12(7), 1980; https://doi.org/10.3390/cancers12071980 - 20 Jul 2020

Cited by 5 | Viewed by 4078

Abstract

The Eµ-TCL1 transgenic mouse model represents the most widely and extensively used animal model for chronic lymphocytic leukemia (CLL). In this report, we performed a meta-analysis of leukemia progression in over 300 individual Eµ-TCL1 transgenic mice and discovered a significantly accelerated disease progression [...] Read more.

The Eµ-TCL1 transgenic mouse model represents the most widely and extensively used animal model for chronic lymphocytic leukemia (CLL). In this report, we performed a meta-analysis of leukemia progression in over 300 individual Eµ-TCL1 transgenic mice and discovered a significantly accelerated disease progression in females compared to males. This difference is also reflected in an aggressive CLL mouse model with additional deletion of Tp53 besides the TCL1 transgene. Moreover, after serial adoptive transplantation of murine CLL cells, female recipients also succumbed to CLL earlier than male recipients. This sex-related disparity in the murine models is markedly contradictory to the human CLL condition. Thus, due to our observation we urge both careful consideration in the experimental design and accurate description of the Eµ-TCL1 transgenic cohorts in future studies. Full article

(This article belongs to the Special Issue Chronic Lymphocytic Leukemia)

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