Recent therapeutic advances in chronic lymphocytic leukemia.

Prithviraj Bose,Varsha Gandhi

doi:10.12688/f1000research.11618.1

Abstract

The last several years have witnessed a paradigm shift in the management of patients with chronic lymphocytic leukemia (CLL). The course of this very heterogeneous disease, traditionally treated with chemotherapeutic agents usually in combination with rituximab, typically has been characterized by remissions and relapses, and survival times vary greatly, depending on intrinsic biological attributes of the leukemia. The developments of the last few years have been transformative, ushering in an era of novel, molecularly targeted therapies, made possible by extensive efforts to elucidate the biology of the disease that predated the new targeted drugs. Thus, successful therapeutic targeting of the B-cell receptor signaling pathway and of the Bcl-2 anti-apoptotic protein with small molecules has now made chemotherapy-free approaches possible, hopefully mitigating the risk of development of therapy-related myeloid neoplasms and making eventual cure of CLL with the use of optimal drug combinations a realistic goal. Most importantly, these therapies have demonstrated unprecedented efficacy in patients with deletion 17p/TP53 mutation, a subset that historically has been very difficult to treat. However, as we gain more experience with the newer agents, unique safety concerns and resistance mechanisms have emerged, as has the issue of cost, as these expensive drugs are currently administered indefinitely. Accordingly, novel laboratory-based strategies and clinical trial designs are being explored to address these issues. The availability of whole exome/genome sequencing has given us profound insights into the mutational landscape of CLL. In this article, we highlight some of the most impactful advances since this topic was last reviewed in this journal.

Highlights

The pace of discovery, with respect to both biology and therapeutic targets, as well as that of drug approval, in chronic lymphocytic leukemia (CLL) has been rapid in recent years, so much so that therapeutic advances made in the treatment of CLL were named the “advance of the year” in 2015 by the American Society of Clinical Oncology
We review more recent developments, focusing on new genomic information, novel targeted therapies, and emerging targets and drugs/drug combinations as well as new information that has accumulated on agents that had just been approved or whose approval was imminent when the last review was written, namely ibrutinib and idelalisib
We have recently shown that in mantle cell lymphoma cell lines and patient-derived samples, idelalisib inhibits protein synthesis, which correlates with reductions in AKT and mitogenactivated protein kinase kinase (MEK) phosphorylation[85]

Summary

Introduction

The pace of discovery, with respect to both biology and therapeutic targets, as well as that of drug approval, in chronic lymphocytic leukemia (CLL) has been rapid in recent years, so much so that therapeutic advances made in the treatment of CLL were named the “advance of the year” in 2015 by the American Society of Clinical Oncology. Emerging drug targets Single-agent immune checkpoint blockade with pembrolizumab (Keytruda®), a monoclonal antibody directed against programmed death 1 (PD-1), was recently shown to have substantial clinical activity in patients with RT, a difficult-to-treat, poor-prognosis entity, but not in CLL117 As noted above, this agent is being studied in combination with ublituximab plus TGR-1202 in patients with R/R CLL or RT (NCT02535286). Therapy with BCR axis inhibitors such as ibrutinib[111], acalabrutinib[69], idelalisib[124], and duvelisib[116] results in a decline in MCL-1 protein levels in CLL cells, providing a mechanism-based rationale to combine them with venetoclax Another strategy involves downregulating this shortlived anti-apoptotic protein through transcriptional repression, achievable by inhibition of cyclin-dependent kinase 9 (CDK9)[125]. Both small-molecule kinase inhibitors (for example, pexidartinib[130] and BLZ945131) and monoclonal antibodies targeting CSF1R are in development for various tumor types

Conclusions

Findings

19. International CLL-IPI working group