A History of Targeted Therapy Development and Progress in Novel-Novel Combinations for Chronic Lymphocytic Leukemia (CLL)

被引:8
作者
Karr, Matthew [1 ]
Roeker, Lindsey [2 ]
机构
[1] Univ Calif San Francisco, Heme BMT Hospitalist Div, San Francisco, CA 94720 USA
[2] Mem Sloan Kettering Canc Ctr, Div Hematol Oncol, New York, NY 10065 USA
基金
美国国家卫生研究院;
关键词
chronic lymphocytic leukemia (CLL); targeted therapy; precision therapy; minimal residual disease; BTK inhibitors; BCL-2; inhibitors; OPEN-LABEL; VENETOCLAX; IBRUTINIB; RITUXIMAB; OBINUTUZUMAB; CHEMOIMMUNOTHERAPY; CYCLOPHOSPHAMIDE; MULTICENTER; FLUDARABINE; PHASE-3;
D O I
10.3390/cancers15041018
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Simple Summary The treatment landscape for CLL has changed dramatically since the advent of targeted therapies. Studies have shown clear progression-free survival (PFS) benefit of these agents, as well as overall survival (OS) benefit in some instances, when compared with chemoimmunotherapy (CIT). Building on these successes, novel-novel combinations, including doublets and triplets, are under development with study designs exploring fixed and depth-of-response-driven durations. Further studies will be needed to elucidate the relative contributions of agents more clearly in these combinations and the optimal approach when using novel-novel combinations. Over the last 10 years, the traditional treatment paradigms for CLL have been upended as the use of traditional chemoimmunotherapy regimens has declined in favor of novel targeted therapies. Targeted therapies have become the new standard of care in CLL given their superior progression-free survival (and overall survival, in some cases) when compared with chemoimmunotherapy, as well as their improved toxicity profiles. Targeted agents are FDA approved for the treatment of CLL including ibrutinib, acalabrutinib, zanubrutinib, and venetoclax. Importantly, as opposed to traditional chemotherapy regimens, the benefits of these targeted therapies appear to be consistent regardless of high-risk mutational status. In this review, we discuss the pivotal CLL studies of the last decade and the data supporting doublet and triplet novel-novel combinations. We explore the use of new surrogate end points for PFS/OS in targeted therapies such as undetectable minimal residual disease (uMRD) and their potential role in minimizing toxicity by permitting earlier treatment discontinuation. We also highlight areas that warrant further exploration and future studies that may help address some of these key questions.
引用
收藏
页数:13
相关论文
共 46 条
[1]  
Al-Sawaf O, 2022, HEMASPHERE, V6, P49
[2]   Treatment Outcomes after Undetectable MRD with First-Line Ibrutinib (Ibr) Plus Venetoclax (Ven): Fixed Duration Treatment (Placebo) Versus Continued Ibr with up to 5 Years Median Follow-up in the CAPTIVATE Study [J].
Allan, John N. ;
Siddiqi, Tanya ;
Kipps, Thomas J. ;
Kuss, Bryone J. ;
Badoux, Xavier C. ;
Barrientos, Jacqueline C. ;
Tedeschi, Alessandra ;
Opat, Stephen ;
Flinn, Ian W. ;
Barca, Eva Gonzalez ;
Jacobs, Ryan ;
Szafer-Glusman, Edith ;
Zhou, Cathy ;
Szoke, Anita ;
Wierda, William G. ;
Ghia, Paolo ;
Tam, Constantine S. .
BLOOD, 2022, 140
[3]  
Awan Farrukh T, 2020, Am Soc Clin Oncol Educ Book, V40, P1, DOI 10.1200/EDBK_279099
[4]   Up to 8-year follow-up from RESONATE-2: first-line ibrutinib treatment for patients with chronic lymphocytic leukemia [J].
Barr, Paul M. ;
Owen, Carolyn ;
Robak, Tadeusz ;
Tedeschi, Alessandra ;
Bairey, Osnat ;
Burger, Jan A. ;
Hillmen, Peter ;
Coutre, Steve E. ;
Dearden, Claire ;
Grosicki, Sebastian ;
McCarthy, Helen ;
Li, Jian-Yong ;
Offner, Fritz ;
Moreno, Carol ;
Zhou, Cathy ;
Hsu, Emily ;
Szoke, Anita ;
Kipps, Thomas J. ;
Ghia, Paolo .
BLOOD ADVANCES, 2022, 6 (11) :3440-3450
[5]   Minimal Residual Disease Quantification Is an Independent Predictor of Progression-Free and Overall Survival in Chronic Lymphocytic Leukemia: A Multivariate Analysis From the Randomized GCLLSG CLL8 Trial [J].
Boettcher, Sebastian ;
Ritgen, Matthias ;
Fischer, Kirsten ;
Stilgenbauer, Stephan ;
Busch, Raymonde M. ;
Fingerle-Rowson, Guenter ;
Fink, Anna Maria ;
Buehler, Andreas ;
Zenz, Thorsten ;
Wenger, Michael Karl ;
Mendila, Myriam ;
Wendtner, Clemens-Martin ;
Eichhorst, Barbara F. ;
Doehner, Hartmut ;
Hallek, Michael J. ;
Kneba, Michael .
JOURNAL OF CLINICAL ONCOLOGY, 2012, 30 (09) :980-988
[6]   Zanubrutinib Demonstrates Superior Progression-Free Survival (PFS) Compared with Ibrutinib for Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma (R/R CLL/SLL): Results from Final Analysis of ALPINE Randomized Phase 3 Study [J].
Brown, Jennifer R. ;
Eichhorst, Barbara ;
Hillmen, Peter ;
Lamanna, Nicole ;
O'Brien, Susan M. ;
Tam, Constantine S. ;
Qiu, Lugui ;
Kazmierczak, Maciej ;
Jurczak, Wojciech ;
Zhou, Keshu ;
Simkovic, Martin ;
Mayer, Jiri ;
Gillespie-Twardy, Amanda L. ;
Ferrajoli, Alessandra ;
Ganly, Peter S. ;
Weinkove, Robert ;
Grosicki, Sebastian ;
Mital, Andrzej ;
Robak, Tadeusz ;
Osterborg, Anders ;
Yimer, Habte A. ;
Salmi, Tommi ;
Wang, Megan ;
Fu, Lina ;
Li, Jessica ;
Wu, Kenneth ;
Cohen, Aileen ;
Shadman, Mazyar .
BLOOD, 2022, 140 :19-23
[7]   Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia [J].
Burger, J. A. ;
Tedeschi, A. ;
Barr, P. M. ;
Robak, T. ;
Owen, C. ;
Ghia, P. ;
Bairey, O. ;
Hillmen, P. ;
Bartlett, N. L. ;
Li, J. ;
Simpson, D. ;
Grosicki, S. ;
Devereux, S. ;
McCarthy, H. ;
Coutre, S. ;
Quach, H. ;
Gaidano, G. ;
Maslyak, Z. ;
Stevens, D. A. ;
Janssens, A. ;
Offner, F. ;
Mayer, J. ;
O'Dwyer, M. ;
Hellmann, A. ;
Schuh, A. ;
Siddiqi, T. ;
Polliack, A. ;
Tam, C. S. ;
Suri, D. ;
Cheng, M. ;
Clow, F. ;
Styles, L. ;
James, D. F. ;
Kipps, T. J. ;
Keating, Michael ;
Jen, Jie ;
Jindra, Pavel ;
Simkovic, Martin ;
Braester, Andrei ;
Ruchlemer, Rosa ;
Foa, Roberto ;
Semenzato, Gianpietro ;
Hawkins, Timothy ;
Atanasio, Carolina Moreno ;
Demirkan, Fatih ;
Kaynar, Leylagul ;
Pylypenko, Halyna ;
Fox, Christopher ;
Thirman, Michael ;
Campbell, Philip .
NEW ENGLAND JOURNAL OF MEDICINE, 2015, 373 (25) :2425-2437
[8]   Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia: Results of the First Randomized Phase III Trial [J].
Byrd, John C. ;
Hillmen, Peter ;
Ghia, Paolo ;
Kater, Arnon P. ;
Chanan-Khan, Asher ;
Furman, Richard R. ;
O'Brien, Susan ;
Yenerel, Mustafa Nuri ;
Illes, Arpad ;
Kay, Neil ;
Garcia-Marco, Jose A. ;
Mato, Anthony ;
Pinilla-Ibarz, Javier ;
Seymour, John F. ;
Lepretre, Stephane ;
Stilgenbauer, Stephan ;
Robak, Tadeusz ;
Rothbaum, Wayne ;
Izumi, Raquel ;
Hamdy, Ahmed ;
Patel, Priti ;
Higgins, Kara ;
Sohoni, Sophia ;
Jurczak, Wojciech .
JOURNAL OF CLINICAL ONCOLOGY, 2021, 39 (31) :3441-+
[9]   Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia [J].
Byrd, John C. ;
Furman, Richard R. ;
Coutre, Steven E. ;
Flinn, Ian W. ;
Burger, Jan A. ;
Blum, Kristie A. ;
Grant, Barbara ;
Sharman, Jeff P. ;
Coleman, Morton ;
Wierda, William G. ;
Jones, Jeffrey A. ;
Zhao, Weiqiang ;
Heerema, Nyla A. ;
Johnson, Amy J. ;
Sukbuntherng, Juthamas ;
Chang, Betty Y. ;
Clow, Fong ;
Hedrick, Eric ;
Buggy, Joseph J. ;
James, Danelle F. ;
O'Brien, Susan .
NEW ENGLAND JOURNAL OF MEDICINE, 2013, 369 (01) :32-42
[10]   Ascorbic acid (vitamin C) synergistically enhances the therapeutic effect of targeted therapy in chronic lymphocytic leukemia [J].
Darwiche, Walaa ;
Gomila, Cathy ;
Ouled-Haddou, Hakim ;
Naudot, Marie ;
Doualle, Cecile ;
Morel, Pierre ;
Nguyen-Khac, Florence ;
Garcon, Loic ;
Marolleau, Jean-Pierre ;
Ghamlouch, Hussein .
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH, 2020, 39 (01)