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Ferrata Storti Foundation
Haematologica 2019 Volume 104(11):2144-2154
Sequential and combination treatments with novel agents in chronic lymphocytic leukemia
Moritz Fürstenau,1 Michael Hallek1,2 and Barbara Eichhorst1
1University of Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, German CLL Study Group, University Hospital Cologne and 2Cologne Cluster of Excellence in Cellular Stress Responses in Aging-associated Disease (CECAD), University of Cologne, Cologne, Germany
ABSTRACT
Chemoimmunotherapy has been the standard of care for patients with chronic lymphocytic leukemia for a long time. However, over the last few years, novel agents have produced unprecedented out- comes in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia. With the advent of these targeted agents, treatment options have diversified very considerably and new questions have emerged. For exam- ple, it is unclear whether these novel agents should be used as sequential monotherapies until disease progression or whether they should preferably be combined in time-limited treatment regimens aimed at achieving deep and durable remissions. While both approaches yield high response rates and long progression-free and overall survival, it remains challenging to identify patients individually for the optimal concept. This review provides guidance in this decision process by presenting evidence on sequential and combined use of novel agents and discussing the advantages and draw- backs of these two approaches.
Introduction
Chemoimmunotherapy has been the standard first-line treatment of choice for patients with chronic lymphocytic leukemia (CLL) for many years.1,2 However, with the advent of novel, targeted agents, the survival of CLL patients has improved markedly and treatment options have diversified, especially for patients with high-risk CLL.3-7 Recently published studies directly comparing standard chemoimmunotherapy against novel agents have demonstrated the superiority of the latter in various groups of patients.8-10 Chemoimmunotherapy still plays a role in the treatment of patients with mutated IGHV genes, in whom the combination of fludarabine, cyclophosphamide and rituximab produces a remarkably long pro- gression-free survival (PFS) in nearly half of the patients, with the possibility of cure in those who have not relapsed beyond 10 years.11,12
With ibrutinib pushing into first-line treatment algorithms and other novel agents such as venetoclax and idelalisib proving their efficacy as monotherapy as well as in various combinations, new challenges are emerging. Information is needed to determine whether novel agents should be used in combination or as sequential monotherapies. Another burning issue is how to manage patients who are refrac- tory to or relapse after treatment with novel agents.
In this review, we discuss currently approved treatment options as well as new approaches using novel agents and address optimal sequencing of single agents and the most promising combination treatments. Furthermore, we debate the concepts of time-limited versus indefinite treatment and offer guidance for treatment deci- sions in routine care of patients.
Approved targeted agents in chronic lymphocytic leukemia
BTK inhibitors
Ibrutinib is an inhibitor of Bruton tyrosine kinase (BTK), which is an intracellular protein downstream of the B-cell receptor. Ibrutinib has been approved for and implemented in the treatment of previously untreated and relapsed/refractory (r/r)
Correspondence:
BARBARA EICHHORST
barbara.eichhorst@uk-koeln.de
Received: April 15, 2019. Accepted: May 22, 2019. Pre-published: October 4, 2019.
doi:10.3324/haematol.2018.208603
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/11/2144
©2019 Ferrata Storti Foundation
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haematologica | 2019; 104(11)
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