Clinical Perspectives About the Molecular Management of B-Lymphoproliferative Neoplasms

tic disorders may have a stable disease with only clini-cal watch and wait approach, or a slowly progressive disease requiring therapy in due course when needed, or a progressive bulky tumor and/or cytopenias repre-senting urgency for chemo-immunotherapy. Therefore, disease presentations in B-lymphoproliferative diseases are heterogeneous and treatment decisions are reached based on the individual patient together with the diverse clinicopathological correlations, staging, risk profile and prognostication. From the clinical point of view, the chemotherapy should not be worse than the disease in B-lymphomas since usually those disorders are indo-lent and incurable. From the biological point of view, the genesis of the malignant B-cell lymphoproliferative neoplastic disorders is significantly complicated with multi-hit targets. Among the numerous pathobiological pathways, B-cell receptor (BCR) signaling is implicated as a pivotal pathway in tumorigenesis in B-cell malig-nancies. Moreover, the mechanisms of the BCR activa-tion are quite diverse and range from chronic antigenic drive by microbial or viral antigens to auto-stimulation of B-cells by self-antigens to activating mutations in intracellular components of the BCR pathway.1 Signal-ing activation via the BCR could drive neoplastic cell proliferation and survival via the cascade of involved and upregulated protein kinases. Thus, understanding the biology of the BCR-signaling pathway has led to identification of novel molecular targets and the devel-opment of drugs capable of targeting pathways down-stream of the BCR. Particularly the inhibitors of Bru-ton’s tyrosine kinase (BTK) and phosphatidylinositide 3-kinase-delta have included into the clinical studies and demonstrated high response rates in B-cell lym-phoproliferative neoplastic disorders such as chronic lymphocytic leukemia (CLL).2 Registered clinical trials of Ibrutinib, a small molecule that irreversibly inhibit