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  Indian J Med Microbiol
 

Figure 1: Various therapeutic targets and newer agents in CLL.[18] CLL B cell, B-cell receptor (BCR) and its intracellular signaling pathways, interactions of T cells and Nurse-like cells (NLC) are shown. Lightening bolt symbol indicates therapeutic targets. (a) DNA-damaging agents – Most commonly used chemotherapeutic agents in CLL (alkylating agents with purine analogs e.g., fludarabine with cyclophosphamide; FC). (b) Monoclonal Antibodies (mAb) – Common surface epitopes exploited for therapy are (CD20, CD52, CD19, CD37 and CD23). Rituximab and ofatumumab (anti-CD20) and alemtuzumab (anti-CD52) these are most commonly used agents. (c) ImID (Immunomodulatory agents) – Lenalidomide acts by multiple mechanisms by altering the cytokines, inhibiting TNF-alpha, angiogenesis and affects the microenvironmental interactions (T cells and NLC) which are not known. Other agents active in microenvironment are inhibitors of CD40L (SGN-40), CXCR4 antagonists (plerixafor). (d) Inhibitors of BCR signaling - BCR is composed of two immunoglobulin (Ig) heavy and light chains (variable and constant regions) and C79a and CD79b which has an intracellular activation motif that transmits signals to intracellular tyrosine kinases (for example, SYK and LYN). Activation of these kinases differs among CLL patients (Unmutated CLL and high ZAP-70 and high CD38 status, have higher degree of activation and calcium phosphorylation). SYK inhibitors (fostamatinib), BTK inhibitor (PCI-32765), PI3K&948; inhibitor (CAL-101), Akt inhibitor (perifosine) are under evaluation. (e) Inhibitors of cell cycle (CDK inhibitors) – Flavopiridol is a pan-CDK inhibitors agent under trial. (f) Agents affecting apoptotic pathways - Small molecule BH3 mimetics agents inhibit the activation of antiapoptotic proteins (Mcl-1 and Bcl2) and promote apoptosis. Antisense oligonucleotides (ASO) such as oblimersen are under exploration

Figure 1: Various therapeutic targets and newer agents in CLL.[18] CLL B cell, B-cell receptor (BCR) and its intracellular signaling pathways, interactions of T cells and Nurse-like cells (NLC) are shown. Lightening bolt symbol indicates therapeutic targets. (a) DNA-damaging agents – Most commonly used chemotherapeutic agents in CLL (alkylating agents with purine analogs e.g., fludarabine with cyclophosphamide; FC). (b) Monoclonal Antibodies (mAb) – Common surface epitopes exploited for therapy are (CD20, CD52, CD19, CD37 and CD23). Rituximab and ofatumumab (anti-CD20) and alemtuzumab (anti-CD52) these are most commonly used agents. (c) ImID (Immunomodulatory agents) – Lenalidomide acts by multiple mechanisms by altering the cytokines, inhibiting TNF-alpha, angiogenesis and affects the microenvironmental interactions (T cells and NLC) which are not known. Other agents active in microenvironment are inhibitors of CD40L (SGN-40), CXCR4 antagonists (plerixafor). (d) Inhibitors of BCR signaling - BCR is composed of two immunoglobulin (Ig) heavy and light chains (variable and constant regions) and C79a and CD79b which has an intracellular activation motif that transmits signals to intracellular tyrosine kinases (for example, SYK and LYN). Activation of these kinases differs among CLL patients (Unmutated CLL and high ZAP-70 and high CD38 status, have higher degree of activation and calcium phosphorylation). SYK inhibitors (fostamatinib), BTK inhibitor (<i>PCI-32765</i>), PI3K&948; inhibitor (CAL-101), Akt inhibitor (perifosine) are under evaluation. (e) Inhibitors of cell cycle (CDK inhibitors) – Flavopiridol is a pan-CDK inhibitors agent under trial. (f) Agents affecting apoptotic pathways - Small molecule BH3 mimetics agents inhibit the activation of antiapoptotic proteins (Mcl-1 and Bcl2) and promote apoptosis. Antisense oligonucleotides (ASO) such as oblimersen are under exploration