Review
Oncology
Andrew H. Lipsky, Nicole Lamanna
Summary: Targeted therapies have revolutionized the frontline treatment for CLL, reducing reliance on chemoimmunotherapy. Drugs such as ibrutinib, acalabrutinib, and venetoclax have shown efficacy in oral therapy. This review explores novel therapeutic strategies using these agents in combination, highlighting the importance of patient characteristics and study methodology.
Article
Biochemistry & Molecular Biology
Andrea Rizzuto, Angelo Pirrera, Emilia Gigliotta, Salvatrice Mancuso, Candida Vullo, Giulia Maria Camarda, Cristina Rotolo, Arianna Roppolo, Corinne Spoto, Massimo Gentile, Cirino Botta, Sergio Siragusa
Summary: The current treatment for chronic lymphocytic leukemia (CLL) relies on chemotherapy, immunotherapy, and targeted inhibitors. However, the multitude of choices and lack of direct comparisons make treatment selection challenging. To address this, a systematic review and meta-analysis of clinical trials in CLL were performed. The results showed that a combination of obinutuzumab with acalabrutinib was the most effective treatment, especially in the absence of del17/P53 mutations. Additionally, chemotherapy is becoming less relevant in the first-line treatment of CLL.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Immunology
Tina YuXuan Luo, Yonghong Shi, Guizhi Wang, David E. Spaner
Summary: This study investigates the role of autocrine IFN in human chronic lymphocytic leukemia (CLL) cells and finds that autocrine IFN can protect CLL cells from stressful environments and therapeutic drugs. Hypersensitivity to IFN may be associated with aggressive clinical behavior. Specific blockade of IFN signaling may improve outcomes for CLL patients with higher-risk disease.
JOURNAL OF IMMUNOLOGY
(2022)
Review
Oncology
Krish Patel, John M. Pagel
Summary: Treatment decisions for patients with chronic lymphocytic leukemia (CLL) are based on symptoms and risk classifications. New therapies targeting specific genetic aberrations have shown promising results, improving outcomes and prolonging progression-free survival. Novel targeted oral therapies have largely replaced chemoimmunotherapy in the treatment of CLL.
JOURNAL OF HEMATOLOGY & ONCOLOGY
(2021)
Review
Cell & Tissue Engineering
Hanieh Mojtahedi, Niloufar Yazdanpanah, Nima Rezaei
Summary: CML is driven by the BCR-ABL1 oncoprotein, and TKI therapy has been successful. However, mechanisms leading to resistance and disease progression in CML LSCs call for targeted therapies to eradicate them.
STEM CELL RESEARCH & THERAPY
(2021)
Review
Biochemistry & Molecular Biology
Nawar Maher, Samir Mouhssine, Bassam Francis Matti, Alaa Fadhil Alwan, Gianluca Gaidano
Summary: Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. Chemoimmunotherapy (CIT) was the commonest option for CLL treatment, but resistance to CIT has led to the use of targeted pathway inhibitors such as BTK and BCL2 inhibitors. However, acquired genetic lesions can cause resistance to these inhibitors.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Biochemistry & Molecular Biology
Paolo Sportoletti, Filomena De Falco, Beatrice Del Papa, Stefano Baldoni, Valerio Guarente, Andrea Marra, Erica Dorillo, Chiara Rompietti, Francesco Maria Adamo, Loredana Ruggeri, Mauro Di Ianni, Emanuela Rosati
Summary: Key features of CLL include immune system defects and leukemic cells’ ability to evade immune defenses, leading to increased susceptibility to infections and disease progression. The role of NK cells in CLL is less understood, but evidence suggests that NK cell dysfunctions in CLL mainly depend on escape mechanisms employed by leukemic cells. NK cells, with their preserved ADCC function and reversible dysfunctions, are an attractive source for novel immunotherapeutic strategies in CLL.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Oncology
Jing Zhang, Xueying Lu, Jianyong Li, Yi Miao
Summary: The combination of BTK inhibitors and BCL2 inhibitors in the treatment of CLL and MCL is of great clinical significance.
BIOMARKER RESEARCH
(2022)
Article
Cell & Tissue Engineering
Franziska von Heydebrand, Maximilian Fuchs, Meik Kunz, Simon Voelkl, Anita N. Kremer, Robert A. J. Oostendorp, Jochen Wilke, Michael Leitges, Alexander Egle, Andreas Mackensen, Gloria Lutzny-Geier
Summary: PKC beta plays a significant role in influencing glucose metabolism in CLL cells upon contact with BMSC, by stimulating glucose uptake to alleviate stress and apoptosis in CLL cells, and could potentially be targeted as a therapeutic strategy to overcome drug resistance mediated by the stromal microenvironment.
Review
Immunology
Marzia Palma, Tom A. Mulder, Anders Osterborg
Summary: BTK inhibitors have revolutionized the treatment of B-cell malignancies, especially chronic lymphocytic leukemia, with three FDA-approved inhibitors and many more in development. While these inhibitors have shown promising anti-tumor effects, their off-target effects on other kinases and impact on the immune system need to be further investigated for potential clinical implications.
FRONTIERS IN IMMUNOLOGY
(2021)
Review
Oncology
Yilin Chen, Jing Zou, Fanjun Cheng, Weiming Li
Summary: The therapeutic landscape for chronic myeloid leukemia has improved significantly with the approval of tyrosine kinase inhibitors. Most patients experience normal life expectancy with optimal responses to TKIs, but relapse after discontinuation hinders attempts at treatment-free remission. New monitoring methods and strategies targeting leukemic stem cells are being explored to address this challenge.
FRONTIERS IN ONCOLOGY
(2021)
Review
Hematology
Bita Fakhri, Charalambos Andreadis
Summary: The treatment landscape of chronic lymphocytic leukemia (CLL) has significantly changed in the past decade due to the introduction of novel agents, including BTK and BCL2 inhibitors. Acalabrutinib, as a second generation BTK inhibitor, demonstrated efficacy and tolerability advantages in two major phase III trials.
THERAPEUTIC ADVANCES IN HEMATOLOGY
(2021)
Review
Oncology
Cooper Quartermaine, Sanam M. Ghazi, Aneeq Yasin, Farrukh T. Awan, Michael Fradley, Tracy Wiczer, Sujay Kalathoor, Mussammat Ferdousi, Satyam Krishan, Alma Habib, Adnan Shaaban, Onaopepo Kola-Kehinde, Adam S. Kittai, Kerry A. Rogers, Michael Grever, Patrick Ruz, Seema Bhat, Tyler Dickerson, John C. Byrd, Jennifer Woyach, Daniel Addison
Summary: Over the past decade, the treatment landscape of chronic lymphocytic leukemia (CLL) has undergone significant changes, shifting towards targeted therapies. However, the use of Bruton's tyrosine kinase (BTK) inhibitors, which have revolutionized CLL treatment, is associated with serious cardiovascular toxicities. Newer BTK inhibitors are also linked to cardiotoxic risks. This review examines the current evidence, including incidence rates, risk factors, mechanisms, and management strategies related to cardiovascular toxicities in patients receiving BTK inhibitors and other CLL therapies. The review also discusses emerging BTK therapies and identifies key unanswered questions and future research directions.
JACC: CARDIOONCOLOGY
(2023)
Article
Oncology
Iwona Hus, Bartosz Pula, Tadeusz Robak
Summary: The development of small agents targeting the B-cell receptor (BCR) pathway has greatly improved the treatment of chronic lymphocytic leukemia (CLL). Selective inhibitors of PI3K delta, such as idelalisib and duvelisib, have been approved for CLL treatment. Umbralisib, a selective inhibitor of PI3K delta and CK1 epsilon, has shown promising results in combination regimens in clinical trials for CLL treatment.
Review
Hematology
Sigrid S. Skanland, Anthony R. Mato
Summary: Insight into the mechanisms of resistance to targeted therapies in chronic lymphocytic leukemia (CLL) has led to the development of strategies to prevent and overcome resistance, including combination therapies targeting bypass mechanisms, temporally sequencing of therapies, improved clinical trial designs, and real-time monitoring of patient response. These approaches aim to secure effective treatment options at the relapsed setting and overcome acquired resistance to existing therapies.
Article
Immunology
Laura Quotti Tubi, Elisa Mandato, Sara Canovas Nunes, Arash Arjomand, Fortunato Zaffino, Sabrina Manni, Alessandro Casellato, Paolo Macaccaro, Nicola Vitulo, Sara Zumerle, Odile Filhol, Brigitte Boldyreff, Christian W. Siebel, Antonella Viola, Giorgio Valle, Federica Mainoldi, Stefano Casola, Valeria Cancila, Alessandro Gulino, Claudio Tripodo, Marco Pizzi, Angelo Paolo Dei Tos, Livio Trentin, Gianpietro Semenzato, Francesco Piazza
Summary: The role of CK2 in B-cell development and activation is not well understood. Using a CK2 beta(KO) mouse model, we found that CK2 beta(KO) mice exhibit increased marginal zone (MZ) B cells and reduced follicular B cells, suggesting a role for CK2 in the regulation of BCR and NOTCH2 signaling pathways. Further analysis revealed enhanced activation of the NOTCH2 pathway in CK2 beta(KO) mice, supporting MZ B-cell development. Additionally, CK2 beta(KO) mice showed alterations in immune response and B-cell activation processes. In vitro assays demonstrated impaired signaling downstream of BCR, Toll-like receptor, CD40, and IL-4R in B cells lacking CK2 beta.
FRONTIERS IN IMMUNOLOGY
(2023)
Letter
Hematology
Ilaria Del Giudice, Luca Vincenzo Cappelli, Julio Delgado, Carsten Utoft Niemann, Michael Asger Andersen, Emelie Hamotal Curovic Rotbain, Kathrine Aarup, Renata Walewska, Andrea Visentin, Marina Deodato, Anna Maria Frustaci, Chiara Cavalloni, Massimo Gentile, Mohamed A. Yassin, Deepesh Lad, Lydia Scarfo, Max Flogegard, Mattias Mattsson, Sara Raponi, Caterina Ilari, Irene Della Starza, Ester M. Orlandi, Alessandra Tedeschi, Livio Trentin, Gianpietro Semenzato, Anna Guarini, Paolo Ghia, Emili Montserrat, Robin Foa
BRITISH JOURNAL OF HAEMATOLOGY
(2023)
Letter
Hematology
Francesca R. Mauro, Andrea Visentin, Diana Giannarelli, Maria C. Molinari, Giulia Proietti, Marco Petrella, Francesco Angotzi, Sara Pepe, Livio Trentin, Silvia Baroncelli, Emanuela Giombini, Silvia Meschi, Fabrizio Maggi, Daniele Focosi
BRITISH JOURNAL OF HAEMATOLOGY
(2023)
Article
Oncology
John N. Allan, Ian W. Flinn, Tanya Siddiqi, Paolo Ghia, Constantine S. Tam, Thomas J. Kipps, Paul M. Barr, Anna Elinder Camburn, Alessandra Tedeschi, Xavier C. Badoux, Ryan Jacobs, Bryone J. Kuss, Livio Trentin, Cathy Zhou, Anita Szoke, Christopher Abbazio, William G. Wierda
Summary: The CAPTIVATE study demonstrates that fixed-duration ibrutinib plus venetoclax is effective in controlling chronic lymphocytic leukemia, including patients with high-risk genomic features. This treatment provides durable progression-free survival and similar overall survival rates.
CLINICAL CANCER RESEARCH
(2023)
Review
Oncology
Alessandro Cellini, Federico Scarmozzino, Francesco Angotzi, Edoardo Ruggeri, Angelo Paolo Dei Tos, Livio Trentin, Marco Pizzi, Andrea Visentin
Summary: Immune evasion through overexpression of PD-L1 and PD-L2 proteins and the role of the microenvironment are key factors in classical Hodgkin Lymphoma. This review discusses the strategies used by cHL to create an immunosuppressive microenvironment and achieve optimal immune evasion, as well as the success and resistance mechanisms of checkpoint inhibitors in cHL immunotherapy.
FRONTIERS IN ONCOLOGY
(2023)
Article
Oncology
Francesco Angotzi, Marco Petrella, Tamara Berno, Gianni Binotto, Giorgia Bonetto, Antonio Branca, Marco Carraro, Chiara Adele Cavaretta, Alessandro Cellini, Fabio D'Amore, Laura Forlani, Ilaria Gianesello, Carmela Gurrieri, Silvia Imbergamo, Federica Lessi, Antonio Maroccia, Federica Mazzetto, Laura Pavan, Sara Pezone, Francesco Piazza, Stefano Pravato, Valeria Ruocco, Greta Scapinello, Fabrizio Vianello, Renato Zambello, Ivan Zatta, Simone Zoletto, Andrea Padoan, Livio Trentin, Andrea Visentin
Summary: The combination of Tixagevimab/Cilgavimab has been approved to decrease symptomatic SARS-CoV-2 infection in high-risk patients. However, its effectiveness in patients with hematological malignancies remains uncertain. This study prospectively evaluated the rate of infection in seronegative patients receiving Tixagevimab/Cilgavimab compared to seropositive patients observed or given a fourth vaccine dose. The findings showed no significant difference in the incidence of infection between the two groups.
FRONTIERS IN ONCOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Nayla Mouawad, Guido Capasso, Edoardo Ruggeri, Leonardo Martinello, Filippo Severin, Andrea Visentin, Monica Facco, Livio Trentin, Federica Frezzato
Summary: The ongoing search for molecules involved in apoptosis resistance and pathogenesis of onco-hematological malignancies has identified Heat Shock Protein of 70kDa (HSP70) as a potential therapeutic target. HSP70, a highly cytoprotective protein, is induced in response to various insults and is associated with poor prognosis and therapy resistance in onco-hematological diseases. This review provides an overview of HSP70's potential as a therapeutic target and explores its partners and inhibitors.
Article
Hematology
Filippo Severin, Nayla Mouawad, Edoardo Ruggeri, Andrea Visentin, Leonardo Martinello, Elisa Pagnin, Valentina Trimarco, Stefano Pravato, Francesco Angotzi, Monica Facco, Livio Trentin, Federica Frezzato
Summary: Signalling events downstream the B-cell receptor (BCR) are crucial for survival and progression of chronic lymphocytic leukemia (CLL) cells. Focal adhesion kinase (FAK), regulated by calpain, interacts with molecules involved in BCR signalling and disease progression, such as Src/Lyn, cortactin, and HS1. The down-modulation of FAK and its cleavage due to calpain activity were observed upon BCR stimulation. Additionally, FAK inhibitor treatment induced apoptosis in CLL cells, suggesting a potential druggable pathway involving FAK, cortactin, and HS1 in CLL pathogenesis.
BRITISH JOURNAL OF HAEMATOLOGY
(2023)
Article
Oncology
Francesco Autore, Idanna Innocenti, Gianluigi Reda, Andrea Visentin, Candida Vitale, Alfonso Piciocchi, Alberto Fresa, Monica M. A. Leone, Lucia Farina, Giulia Quaresmini, Claudia Barate, Annamaria Giordano, Angela Ferrari, Ilaria Angeletti, Maria Rosaria De Paolis, Lara Malerba, Federico Chiurazzi, Giacomo Loseto, Gioacchino Catania, Paolo Sportoletti, Ilaria Scortechini, Riccardo Moia, Massimo Gentile, Gian Matteo Rigolin, Veronica Mattiello, Valter Gattei, Marta Coscia, Livio Trentin, Robin Foa, Antonio Cuneo, Luca Laurenti
Summary: The usefulness of clinical or biological parameters in predicting progression during treatment with ibrutinib, idelalisib, and venetoclax in CLL patients is still controversial. A multi-center retrospective study found no significant clinical or biological differences among patients who switched from ibrutinib or idelalisib to venetoclax. Lymph node diameter before starting treatment was identified as an independent risk factor for progression during venetoclax treatment.
HEMATOLOGICAL ONCOLOGY
(2023)
Letter
Oncology
Annalisa Martines, Angela Grassi, Andrea Visentin, Monica Facco, Silvia Nalio, Valeria Sacchetto, Elisa Pagnin, Alessandro Cellini, Roberta Bertorelle, Livio Trentin, Laura Bonaldi
HEMATOLOGICAL ONCOLOGY
(2023)
Letter
Hematology
Nicolo Danesin, Mariella Lo Schirico, Greta Scapinello, Angela Grassi, Marcello Riva, Tamara Berno, Antonio Branca, Andrea Visentin, Marco Carraro, Laura Pavan, Sabrina Manni, Laura Bonaldi, Annalisa Martines, Roberta Bertorelle, Fabrizio Vianello, Carmela Gurrieri, Chiara Briani, Renato Zambello, Livio Trentin, Francesco Piazza
