Pharmacotherapy of relapsed/refractory chronic lymphocytic leukemia

ABSTRACT

Introduction: The treatment of relapsed/refractory (RR) CLL has been revolutionized by the advent of the new oral inhibitors of B-cell receptor (BCR) signaling and the pro-survival protein, B-cell lymphoma 2 (BCL2). Additionally, new and more potent monoclonal antibodies against CD20 have replaced/may replace rituximab in many settings.

Areas covered: Herein, we review the entire therapeutic landscape of RR CLL, with particular attention to the new small-molecule kinase inhibitors and BH3-mimetics. We discuss preclinical data with these agents in CLL, cover available efficacy and safety information, and examine potential resistance mechanisms and possible rational combinations to circumvent them.

Expert opinion: The availability of potent and selective inhibitors of BCR signaling and of the anti-apoptotic functions of BCL2 has enormously enhanced our therapeutic armamentarium, with unprecedented efficacy now observed in patients who historically had poor outcomes with chemoimmunotherapy (CIT), e.g., those with deletion 17p/11q and/or IGHV-unmutated disease. The next challenge is to optimally sequence these agents and develop rational combinations that will hopefully lead to deeper and more durable remissions than ever seen before. Indeed, long term relapse free survival, already achievable with CIT in patients with genetically favorable-risk disease, now appears to be a realistic possibility for most patients with CLL.

KEYWORDS:

• CLL
• ibrutinib
• idelalisib
• venetoclax
• BCL2
• B-cell receptor
• BTK
• PI3K
• chemoimmunotherapy
• rational combinations

Article highlights

• The treatment of CLL has been revolutionized by the advent of the new small-molecule targeted therapies, which have unique mechanisms of action.

• Optimally sequencing and combining novel targeted agents such as BTK inhibitors, BCL-2 antagonists and newer, more potent CD20 monoclonal antibodies will be key to therapeutic success.

• Minimal residual disease status is a major determinant of long-term outcomes in CLL and MRD eradication has emerged as a key endpoint in contemporary clinical trials.

• Other novel strategies such as targeting CD37 and immune checkpoints are being explored, and early data suggesting efficacy of an anti-PD1 monoclonal antibody in Richter's syndrome are exciting.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

The authors were supported in part by a MD Anderson cancer centre support grant from the National Cancer Institute P30 CA016672.