Abstract
Chemo immunotherapies for chronic lymphocytic leukemia (CLL) showed a positive impact on clinical outcome, but many patients relapsed or become refractory to the available treatments. The main goal of the researchers in CLL is the identification of specific targets in order to develop new therapeutic strategies to cure the disease. The Bcell receptor-signalling pathway is necessary for survival of malignant B cells and its related molecules recently become new targets for therapy. Moreover, leukemic microenvironment delivers survival signals to neoplastic cells also overcoming the apoptotic effect induced by traditional drugs. In this context, the investigation of Bruton’s tyrosine kinase (Btk) is useful in: i) dissecting CLL pathogenesis; ii) finding new therapeutic approaches striking simultaneously intrinsic as well as extrinsic pro-survival signals in CLL. This paper will review these main topics.
Highlights
Introduction to Chronic Lymphocytic LeukemiaChronic lymphocytic leukemia (CLL) is a lymphoproliferative disease characterized by a progressive accumulation of CD19+/CD5+/ CD23+ B cells in the blood, bone marrow and lymphatic tissues
Baldari’s group and we demonstrated that Ibrutinib was able to restore the expression of the cytokine receptor S1P1, which plays a pivotal role in lymph node egress [63]
Data so far collected from clinical studies involving the use of Ibrutinib or other molecules inhibiting BtkKnown Physiological FunctionsBruton’s tyrosine kinase (Btk), alone or in combination with traditional therapies, reported a good safety profile and a high activity of the Btk inhibitors in CLL
Summary
Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disease characterized by a progressive accumulation of CD19+/CD5+/ CD23+ B cells in the blood, bone marrow and lymphatic tissues. Researches on the molecular pathogenesis of CLL allowed the identification of differences in morphology, immunophenotype, specific chromosomal abnormalities, aberrations in the B-cell receptor (BCR) signalling and mutations of cancer related genes [5] This biological heterogeneity reflects the wide spectrum of clinical behaviours of the disease, ranging from patients with a slow accumulation of leukemic cells to subjects with rapidly increasing lymph nodes. Taking into account the importance of cell-cell contact, it was demonstrated that Ibrutinib inhibits pseudoemperipolesis in CLL B cells co-cultured with MSCs, a process that involves the down-modulation of the integrin CD49d expression [59] This evidence suggests that Ibrutinib is able to reduce CLL B cell viability by blocking key molecules for cell survival, but it interferes with leukemic B clone-microenvironment interaction; this aspect finds confirmation by the typical transient lymphocytosis during Ibrutinib treatment due to the egress from the lymph nodes. PCI-32765 PCI-32765 + SEL PCI-32765 + R + LENA PCI-32765 + OBI + GDC-0199 PCI-32765 + scF ACP196 + ACP319 DUV + OBI PCI-32765 + RFC ACP-196 + PEM PCI-32765 and OFA + BMT or consolidation PCI-32765 vs. ACP-196
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