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.

• Authors: Abdallah Abou Zahr, Prithviraj Bose, Michael J Keating
• Journal: Expert opinion on pharmacotherapy (Expert Opin Pharmacother) Vol. 18 Issue 9 Pg. 857-873 (Jun 2017) ISSN: 1744-7666 [Electronic] England
• PMID: 28446054 (Publication Type: Journal Article, Review)

Chemical References

• Antibodies, Monoclonal
• BCL2 protein, human
• CD28 Antigens
• Proto-Oncogene Proteins c-bcl-2
• Rituximab
• Protein-Tyrosine Kinases
• Agammaglobulinaemia Tyrosine Kinase
• BTK protein, human

Topics

• Adult
• Agammaglobulinaemia Tyrosine Kinase
• Antibodies, Monoclonal (administration & dosage, adverse effects, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects, therapeutic use)
• CD28 Antigens (antagonists & inhibitors, immunology)
• Clinical Trials as Topic
• Drug Interactions
• Humans
• Immunotherapy (methods)
• Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy, enzymology, immunology)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors)
• Recurrence
• Rituximab (administration & dosage, adverse effects, therapeutic use)
• Treatment Outcome