Article
Multidisciplinary Sciences
Veronika Ecker, Martina Stumpf, Lisa Brandmeier, Tanja Neumayer, Lisa Pfeuffer, Thomas Engleitner, Ingo Ringshausen, Nina Nelson, Manfred Juecker, Stefan Wanninger, Thorsten Zenz, Clemens Wendtner, Katrin Manske, Katja Steiger, Roland Rad, Markus Mueschen, Juergen Ruland, Maike Buchner
Summary: Current therapeutic approaches in CLL focus on suppressing the PI3K/AKT signaling pathway, but research shows that CLL cells are vulnerable to hyperactivation of this pathway, which may be a promising concept for CLL therapy.
NATURE COMMUNICATIONS
(2021)
Article
Oncology
Deepti Gadi, Alec Griffith, Svitlana Tyekucheva, Zixu Wang, Vanessa Rai, Alexander Vartanov, Emily Thrash, Stacey M. Fernandes, Timothy Z. Lehmberg, Brandon Lee, Stephen P. Martindale, John-Hanson Machado, Oreofe Odejide, Philippe Armand, David C. Fisher, Jon Arnason, Matthew S. Davids, James A. Lederer, Jennifer R. Brown
Summary: Combination therapy with the PI3K delta gamma inhibitor duvelisib and chemoimmunotherapy shows promising efficacy in treating CLL patients, but approximately one-third of patients develop autoimmune toxicity. The treatment modulates CD4 and CD8 T cell subsets as well as pro-inflammatory cytokines, resulting in an increase in activated CD8 T cells and Th17 T cells.
Article
Hematology
Ishwarya Murali, Siddha Kasar, Aishath Naeem, Svitlana Tyekucheva, Jasneet K. Khalsa, Emily M. Thrash, Gilad Itchaki, Dimitri Livitz, Ignaty Leshchiner, Shuai Dong, Stacey M. Fernandes, Gad Getz, Amy Johnson, Jennifer R. Brown
Summary: Resistance to PI3K delta inhibitors in CLL is associated with baseline activating mutations and activation of the MAPK/ERK pathway, suggesting a rationale for combination therapy with PI3K delta and ERK inhibitors.
Article
Hematology
Martin Spacek, Lukas Smolej, Martin Simkovic, Lucie Nekvindova, Zlatuse Kristkova, Yvona Brychtova, Anna Panovska, Stanislava Maslejova, Lucie Bezdekova, Dominika Ecsiova, Pavel Vodarek, Jana Zuchnicka, Jana Mihalyova, Renata Urbanova, Peter Turcsanyi, Daniel Lysak, Jan Novak, Martin Brejcha, Tereza Likarova, Prokop Vodicka, Jana Baranova, Marek Trneny, Michael Doubek
Summary: Idelalisib plus rituximab showed inferior efficacy and tolerability compared to ibrutinib in patients with relapsed/refractory CLL, but may still be considered in select cases.
BRITISH JOURNAL OF HAEMATOLOGY
(2023)
Article
Hematology
Chiara Cavallini, Marilisa Galasso, Elisa Dalla Pozza, Roberto Chignola, Ornella Lovato, Ilaria Dando, Maria G. Romanelli, Mauro Krampera, Giovanni Pizzolo, Massimo Donadelli, Maria T. Scupoli
Summary: The study revealed the negative regulatory effects of CD20 monoclonal antibodies and their combination with BAKi on BCR signaling and cell survival in CLL. Additionally, the combination of CD20 mAbs and BAKi significantly enhanced leukemia cell death, indicating the potential of combined therapies in CLL patients.
BRITISH JOURNAL OF HAEMATOLOGY
(2021)
Article
Hematology
Max J. Gordon, Julie Huang, Rebecca J. Chan, Pankaj Bhargava, Alexey V. Danilov
Summary: Comorbidities do not significantly impact outcomes in CLL patients treated with idelalisib. In patients with high comorbidities or severe comorbidities, idelalisib + anti-CD20 combination therapy is associated with superior PFS and ORR compared to anti-CD20 monotherapy.
BRITISH JOURNAL OF HAEMATOLOGY
(2021)
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.
Article
Hematology
Chaitra Ujjani, Mazyar Shadman, Ryan C. Lynch, Brian Tu, Philip A. Stevenson, Caitlin Grainger, Haiying Zhu, Joshua A. Hill, Meei-Li Huang, Leslie Nielsen, Christina Poh, Tyler Sorensen, Ajay K. Gopal, Edus H. Warren, Brian G. Till, Sydney Lee, Daria Gausman, Stephen D. Smith, Ted Gooley, Alex Greninger
Summary: This study found that SARS-CoV-2 vaccine efficacy was lower in chronic lymphocytic leukemia (CLL) patients, with decreased rates of seroconversion and lower antibody levels compared to healthy controls. The results from the Roche anti-S assay and neutralization activity were similar. Durable immune responses were observed up to six months, and booster shots were effective in improving the immune response in patients who had a response. The absence of normal B cells, commonly seen in CLL patients receiving certain treatments, was a strong predictor of lack of seroconversion.
BRITISH JOURNAL OF HAEMATOLOGY
(2022)
Review
Hematology
Shazia Nakhoda, Aldana Vistarop, Y. Lynn Wang
Summary: Bruton tyrosine kinase inhibitors (BTKi) have had a significant impact on the treatment of chronic lymphocytic leukaemia (CLL) and non-Hodgkin lymphoma. However, resistance to BTKi remains a challenge, and this review article provides an update on the key clinical data, mechanisms of resistance, and ongoing clinical investigations in CLL, mantle cell lymphoma, and diffuse large B-cell lymphoma (DLBCL).
BRITISH JOURNAL OF HAEMATOLOGY
(2023)
Review
Hematology
Sigrid S. Skanland, Jennifer R. Brown
Summary: Phosphatidylinositol 3-kinase (PI3K) inhibitors have shown efficacy in CLL, but their use is limited due to severe toxicity and availability of more tolerable agents. Optimizing the administration of current PI3K inhibitors and developing next-generation agents is important to improve tolerability. Strategies to overcome limitations include intermittent dosing and combination with other agents, as well as identifying biomarkers to personalize treatment decisions.
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
Hematology
Agnes Mattsson, Sandra Eketorp Sylvan, Per Axelsson, Fredrik Ellin, Christian Kjellander, Karin Larsson, Birgitta Lauri, Catharina Lewerin, Christian Scharenberg, Love Tatting, Hemming Johansson, Anders Osterborg, Lotta Hansson
Summary: We evaluated the effectiveness and safety of idelalisib in combination with rituximab for CLL patients in Sweden. Results showed an overall response rate of 65% and a median progression-free survival of 16.4 months. The most common adverse events were colitis and infection.
EUROPEAN JOURNAL OF HAEMATOLOGY
(2023)
Article
Genetics & Heredity
Qiuyi Zhang, Ying Gao, Shuchun Lin, Lynn R. Goldin, Yonghong Wang, Holly Stevenson, Daniel C. Edelman, Keith Killian, Gerald Marti, Paul S. Meltzer, Song Xiang, Neil E. Caporaso
Summary: This study investigated the DNA methylation aberrations in malignant B lymphocytes of CLL patients and identified differentially methylated positions (DMPs) and differentially methylated and expressed genes (DMEGs) associated with CLL by integrating public databases. The direction of each DMEG in CLL was observed based on DMPs in the promoter and the body region, and the methylation heterogeneity of CLL subgroups and the effect of B cell maturation on CLL were explored. The findings suggest the importance of DNA methylation in the pathogenesis of CLL and provide potential markers for diagnostic and therapeutic purposes.
FRONTIERS IN GENETICS
(2023)
Article
Hematology
Dale Jobson, Christopher J. McCormack, Victoria Mar, Constantine Tam, Michael A. Henderson
Summary: This retrospective case-controlled study examined the impact of CLL on melanoma-specific survival and recurrence. The results showed that CLL was associated with significantly worse melanoma outcomes, and prior CLL treatment did not affect the melanoma outcomes.
BRITISH JOURNAL OF HAEMATOLOGY
(2022)
Article
Oncology
Paul J. Hampel, Kari G. Rabe, Timothy G. Call, Wei Ding, Jose F. Leis, Asher A. Chanan-Khan, Saad S. Kenderian, Eli Muchtar, Yucai Wang, Sikander Ailawadhi, Amber B. Koehler, Ricardo Parrondo, Susan M. Schwager, Taimur Sher, Curtis A. Hanson, Min Shi, Daniel L. Van Dyke, Esteban Braggio, Susan L. Slager, Neil E. Kay, Sameer A. Parikh
Summary: Patients with chronic lymphocytic leukemia (CLL) who have disease progression on ibrutinib have worse outcomes compared to those who stop ibrutinib due to toxicity. A study evaluated the outcomes of CLL patients with disease progression on ibrutinib and found that overall survival (OS) was longer for patients who received ibrutinib as a frontline treatment and next-line treatments such as chimeric antigen receptor T-cell therapy and venetoclax-based treatment showed better outcomes compared to other approved treatments. These findings suggest a need for better treatment options for CLL patients with disease progression on ibrutinib.
BLOOD CANCER JOURNAL
(2022)