Chronic lymphocytic leukemia therapy: new targeted therapies on the way

ABSTRACT

Introduction: The critical role of the tissue microenvironment and B-cell receptor (BCR) signaling in chronic lymphocytic leukemia (CLL) pathogenesis, and the clinical success of targeted agents that disrupt BCR signaling are currently changing the CLL landscape. Three new drugs were recently approved for CLL therapy, and other agents are in late development.

Areas covered: In this review, we summarize data on promising new targeted drugs for CLL. The heterogeneous mechanisms of actions of these molecules are described, such as the inhibition of BCR signaling, direct targeting of CD20 molecules on the CLL cell surface, and BCL-2 inhibition. We present preclinical and clinical data from phase I to III studies in order to describe efficacy and side effect profile of these new drugs. Data are derived from peer-reviewed articles indexed in PubMed and from abstracts presented at major international meetings.

Expert opinion: Ibrutinib and idelalisib are challenging the role of chemo-immunotherapy in CLL therapy in the frontline and relapsed disease settings. High-risk CLL patients particularly benefit from these new agents. Venetoclax and obinutuzumab are other effective agents added to our therapeutic armamentarium. Studies to better define the optimal use of these drugs, alone, or rather in combination or sequenced are underway.

KEYWORDS:

• Chronic lymphocytic leukemia
• anti-CD20 mAb
• BCL-2 antagonist
• BTK inhibitor
• ibrutinib
• obinutuzumab
• PI3Kδ inhibitor
• venetoclax

Article highlights

• Several new targeted agents were recently approved and are challenging established CLL treatment regimens

• The BTK inhibitor ibrutinib and PI3Kδ inhibitor idelalisib induce high overall response rates and durable remissions, mostly partial remissions

• The BCL-2 inhibitor venetoclax induces more complete remissions, but response durability is not yet well established

• At the approved dose, the anti-CD20 mAb obinutuzumab has higher efficacy than rituximab

• Disease eradication may become possible with combination therapy approaches of novel agents and/or with chemo-immunotherapy in low-risk CLL

• Longer follow-up is needed to fully characterize the spectrum of side effects of the novel agents

This box summarizes key points contained in the article.

Declaration of interest

This work was supported in part by a Leukemia & Lymphoma Society Scholar Award in Clinical Research (to JAB), the MD Anderson Cancer Center Moon Shot Program in CLL, and the MD Anderson Cancer Center Support Grant CA016672. JAB has received research funding from Pharmacyclics, Gilead and Portola. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.