Recent therapeutic advances in chronic lymphocytic leukemia

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.

From Biology to Therapy: The CLL Success Story

“…128,129 Resistance to venetoclax is also largely driven by MCL-1, thus this antiapoptotic protein is a promising target in CLL. 76 Inhibitors of BCR signaling tend to decrease MCL-1 levels in CLL cells, thus providing a rationale for simultaneous use with venetoclax. 130,131 More specific approaches to antagonize MCL-1 function are by using the novel MCL-1 selective BH3-mimetics (A-1210477 and S63845) that are at preclinical stage of development, 132,133 or by transcriptional repression via inhibition of cyclin-dependent kinase 9 (CDK9).…”

Silencing of HDAC6 as a therapeutic target in chronic lymphocytic leukemia

“…2 Targeted therapies, such as ibrutinib, idelalisib, and venetoclax, have been developed to counter the effects of aberrant signaling in CLL B cells; however, patients may relapse, experience toxicities, develop resistant disease, or respond only partially. 3 In these cases, rational combinations or novel therapeutic approaches are desirable.…”

Resistance-Associated Mutations in Chronic Lymphocytic Leukemia Patients Treated With Novel Agents

“…Very promising is the combination of ibrutinib with anti-CD20 antibodies (28). In addition, the combination of ibrutinib with venetoclax represents a great potential in the treatment of CLL, as there is increasing evidence that CLL cells previously treated with BCR inhibitors show an increased dependence on BCL-2 expression (45,46). This is further supported by the observation of the changes in BCL-2 family protein levels in CLL cells when treated with ibrutinib (45) and acalabrutinib (47).…”

“…Additionally, venetoclax complements ibrutinib and acalabrutinib-mediated apoptosis in CLL cells (45,47). The synergic effect of both drugs acting by different mechanisms has led to a deep therapeutic effect in CLL (45,46,48); however, the exact mechanism of their interaction in CLL should be further elucidated.…”