Emerging role of kinase-targeted strategies in chronic lymphocytic leukemia

Abstract

IntroductionOncogenic mutations in kinases have been identified in multiple cancers often leading to successful targeted therapy with kinase inhibitors. The paradigm in hematologic malignancies has been the discovery of the BCR-ABL fusion kinase in chronic myeloid leukemia and its successful targeting by tyrosine kinase inhibitors that changed the natural history of the disease. In contrast, possible disease-relevant mutations in kinases have been a rare finding in chronic lymphocytic leukemia (CLL). The most commonly mutated kinase in CLL is BRAF, with Ͻ 2% of patients affected. 1 However, kinase inhibitors that target signaling pathways that are essential for B-cell development, in particular, those targeting the B-cell receptor (BCR) have induced striking clinical responses. Here I briefly review these signaling pathways and discuss the ongoing clinical development of kinase inhibitors for the targeted therapy of CLL. Signaling pathways and their kinases in the pathogenesis of CLL Biology of CLLCLL is a malignancy of mature B cells involving blood, bone marrow, and lymphoid tissues. 2 CLL is the most common leukemia in Western countries and currently is most often diagnosed from an incidental blood count showing lymphocytosis. The median survival with early-stage disease is 10.7 years, but the clinical course is heterogeneous. 3 Two major CLL subtypes are distinguished by the presence or absence of somatic mutations in the immunoglobulin heavy chain variable region gene (IGHV), which encodes part of the antigen-binding domain of the BCR. Patients whose CLL cells express an unmutated IGHV gene (U-CLL) have a more rapidly progressive clinical course than patients whose CLL cells express a mutated IGHV gene (M-CLL). ZAP70, a nonreceptor tyrosine kinase essential for T-cell receptor signal transduction, is expressed in most cases of U-CLL and less frequently in M-CLL. ZAP70 expression correlates with more rapid disease progression in both subtypes defined by IGHV gene mutation status. 4The role of the microenvironment in CLL pathogenesis CLL cells in the blood are resting cells with a gene expression profile similar to memory B cells. 2 However, CLL cells in the lymph node and bone marrow show characteristics of activated B cells and demonstrate increased proliferation. 5 In the tissue sites, CLL proliferation is often highest in anatomic structures labeled as "proliferation centers" where CLL cells can interact with other cells, in particular T cells and stromal cells. 6 Thus, the biology of CLL cells in vivo depends on their anatomic location and is influenced by extrinsic signals from the tissue-microenvironment. In vitro, CLL cells undergo apoptosis unless appropriate microenvironmental factors are provided. This dependence of CLL cells on pathways that also promote normal B-cell development, expansion, and survival, [5][6][7][8][9] indicates that this tumor is "addicted to the host," constituting an example of a novel concept termed "non-oncogene addiction." 10 The term "microenvironment" collectively descri...

Chronic lymphocytic leukemia: Time to go past genomics?

“…BCR signaling has long been recognized as a major player in CLL development, based on structural restrictions of the BCR, and BCRdependent survival and growth of the malignant B cells [65][66][67][68]. As compared with normal B cells, CLL has distinct BCR-related features that include low-level IgM expression, variable response to antigen stimulation, and activation of anti-apoptotic signaling pathways [65][66][67][68][69].…”

“…As compared with normal B cells, CLL has distinct BCR-related features that include low-level IgM expression, variable response to antigen stimulation, and activation of anti-apoptotic signaling pathways [65][66][67][68][69]. Recent work suggests a ligand-independent signaling arising from such CLL BCR [70].…”

A krónikus lymphocytás leukaemia korszerű molekuláris diagnosztikája és kezelése az új célzott terápiák korszakában

“…Az ibrutinib egy orálisan alkalmazható kis molekula, amely irreverzibilisen gátolja a BTK-t, ezáltal gátolva a sejtjelátviteli útvonalakat. A BTK a BCR-jelát-viteli komplex nélkülözhetetlen molekulája, amely kulcsfontosságú szerepet játszik a malignus B-sejtek túl-élésében és cirkulációjában [2]. Az ibrutinibet első vonalban a RESONATE 2 klinikai vizsgálat eredményei alapján törzskönyvezték, amelyben a másik kar chlorambucil-monoterápia volt.…”

“…Ezen jellemzők integrálása a prognosztikus rendszerekbe további alcsoportok meghatározásához vezetett. A CLL patogenezisében fontos szerepet betöltő mikrokörnyezet és jelátvi-teli utak feltérképezése hozzájárult az új molekulák kifejlesztéséhez, amelyek a célzott terápia nélkülözhetet-len elemeivé váltak [2,3]. A célzott kezelések rutinszerű alkalmazásával növekedett a betegek teljes túlélése (overall survival -OS) és a progressziómentes túlélése (progression-free survival -PFS), még a nagy rizikójú betegcsoportban is.…”

Management of chronic lymphocytic leukemia

“…The phenomenon of increasing lymphocytosis in these kinase inhibitors is probably due to a compartment shift of CLL cells. To address this problem, most of these drugs are currently in combination with rituximab and/or bendamustine to resolve the lymphocytosis, 72,73 achieving a higher number of responses. 72 In this respect, a phase III study testing idelalisib in combination with rituximab versus rituximab plus placebo has been stopped early on the recommendation of the Data Safety Monitoring Board due to overwhelming efficacy in unfit, comorbid relapsed patients, with improved progressionfree survival, response rate, and overall survival.…”