Fine-tuning front-line therapy in chronic lymphocytic leukemia
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memo https://doi.org/10.1007/s12254-020-00615-y
Fine-tuning front-line therapy in chronic lymphocytic leukemia News from ASH 2019 Jan-Paul Bohn
· Dominik Wolf
Received: 1 April 2020 / Accepted: 28 April 2020 © The Author(s) 2020
Summary A deeper understanding of disease biology and the advent of targeted drugs have implemented chemotherapy-free treatment options in chronic lymphocytic leukemia (CLL). With consistently superior outcome data and good tolerability, the Bruton’s kinase inhibitor ibrutinib as well as the B-cell lymphoma 2 inhibitor venetoclax +/– CD20 antibody have recently been licensed for first-line treatment independently of TP53 status and are currently recommended as therapy of choice in most patient subgroups according to international management guidelines. Survival curves, however, have not reached a plateau and relapse due to acquired resistance or drug intolerance remain major hurdles in CLL treatment. Clinical trials currently focus on the most promising combinations and sequences of highly effective targeted drugs aimed at avoiding drug resistance by further enhancing eradication of minimal residual disease and optimizing drug tolerability. This brief review provides an update on the recently presented clinical trial data in first-line CLL at ASH 2019 and discusses clinically relevant obstacles to overcome. Keywords First-line · Ibrutinib · Acalabrutinib · Venetoclax · Obinutuzumab
Introduction Novel scientific insights into disease biology have facilitated introduction of targeted therapies to the treatment landscape of chronic lymphocytic leukemia J.-P. Bohn, MD, PhD () · Prof. D. Wolf, MD Department of Internal Medicine V, Hematology and Oncology, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria [email protected]
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(CLL). In particular, the Bruton’s kinase (BTK) inhibitor ibrutinib and the B-cell lymphoma 2 (BCL2) inhibitor venetoclax +/– CD20 antibody have become front-line treatment of choice in vast parts of the CLL patient spectrum based on consistently superior outcome and tolerability data when compared to chemoimmunotherapy (CIT) [1–4]. Nonetheless, relapse due to acquired resistance and drug intolerance remain major hurdles in patient management [5]. Current clinical trials focus on the most promising sequences and combinations of targeted drugs to prevent resistance formation by enhancing eradication of minimal residual disease (MRD) and optimize drug tolerability. This short review provides an update on currently ongoing first-line clinical trials in CLL presented at ASH (American Society of Hematology) 2019 and discusses clinically relevant obstacles to overcome.
Targeting Bruton’s tyrosine kinase Aberrant B-cell receptor (BCR) signaling plays a key pathogenetic role in CLL by regulating several pathways essential for B-cell proliferation and apoptosis [6]. BTK functioning downstream of BCR can be selectively targeted and has provided the framework for the striking efficacy seen with the BTK inhibitor ibrutinib in CLL treatment [7]. At
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