From Biology to Therapy: The CLL Success Story

Abstract

Chemoimmunotherapy has been the standard of care for patients with chronic lymphocytic leukemia (CLL) over the last decade. Advances in monoclonal antibody technology have resulted in the development of newer generations of anti-CD20 antibodies with improved therapeutic effectiveness. In parallel, our knowledge about the distinctive biological characteristics of CLL has progressively deepened and has revealed the importance of B-cell receptor (BCR) signaling and upregulated antiapoptotic proteins for survival and expansion of malignant cell clones. This knowledge provided the basis for development of novel targeted agents that revolutionized treatment of CLL. Ibrutinib and idelalisib inhibit the Bruton tyrosine kinase (BTK) and phosphoinositide 3-kinase (PI3K) delta, respectively, thus interfering with supportive signals coming from the microenvironment via the BCR. These drugs induce egress of CLL cells from secondary lymphoid organs and remarkably improve clinical outcomes, especially for patients with unmutated immunoglobulin heavy-chain genes or with p53 abnormalities that do not benefit from classical treatment schemes. Latest clinical trial results have established ibrutinib with or without anti-CD20 antibodies as the preferred first-line treatment for most CLL patients, which will reduce the use of chemoimmunotherapy in the imminent future. Further advances are achieved with venetoclax, a BH3-mimetic that specifically inhibits the antiapoptotic B-cell lymphoma 2 protein and thus causes rapid apoptosis of CLL cells, which translates into deep and prolonged clinical responses including high rates of minimal residual disease negativity. This review summarizes recent advances in the development of targeted CLL therapies, including new combination schemes, novel BTK and PI3K inhibitors, spleen tyrosine kinase inhibitors, immunomodulatory drugs, and cellular immunotherapy.

TBET‐expressing Th1 CD4+T cells accumulate in chronic lymphocytic leukaemia without affecting disease progression in Eµ‐TCL1 mice

“…Chronic lymphocytic leukaemia (CLL) is a common leukaemia, which results in the accumulation of mature CD5 + B cells in peripheral blood (PB) and lymphoid organs, such as bone marrow (BM) and lymph nodes (Yosifov et al , ). Recently, novel, targeted therapeutic approaches including ibrutinib, venetoclax and idelalisib have dramatically changed treatment regimens (Yosifov et al , ).…”

“…Chronic lymphocytic leukaemia (CLL) is a common leukaemia, which results in the accumulation of mature CD5 + B cells in peripheral blood (PB) and lymphoid organs, such as bone marrow (BM) and lymph nodes (Yosifov et al , ). Recently, novel, targeted therapeutic approaches including ibrutinib, venetoclax and idelalisib have dramatically changed treatment regimens (Yosifov et al , ). In addition to targeting the malignant cells directly, an impact of these inhibitors on non‐malignant immune cells, including T cells, was reported (Dubovsky et al , ; Kohrt et al , ; Hanna et al , ).…”

Effects of CD20 antibodies and kinase inhibitors on B‐cell receptor signalling and survival of chronic lymphocytic leukaemia cells

“…Moreover, combined administration of CD20 mAbs and BAKi augments apoptosis induced by the single agents in primary CLL cells. These findings are of clinical relevance since these agents are currently used in combination in several clinical trials 41,42 . The key advances of this study are identifying the ability of CD20 therapeutic antibodies to perturb BCR signalling and gaining insights into the effects of the combination of CD20 mAbs and BAKi on BCR signalling and cell death in CLL.…”

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

“…So far, most information about resistance-associated mutations has been described for patients treated with ibrutinib, an oral agent inactivating Bruton's tyrosine kinase (BTK). This antiproliferative and proapoptotic agent, acting via formation of an irreversible covalent bond at the C481 position of BTK, inhibits both B-cell receptor (BCR) and NF-κB pathways [ Figure 1; (5,6)]. Ibrutinib has been shown to be highly effective not only in R/R CLL patients with del(17p) and/or TP53 mutation or complex karyotype (1,2) but also in previously untreated patients with/without poor-risk features (3,4).…”