title: Targeting neoplastic B cells and harnessing microenvironment: the "double face" of ibrutinib and idelalisib.
abstract: Tyrosine kinase inhibitors (TKIs) targeting signaling molecules downstream B cell receptor (BCR) are powerfully spreading in the therapeutic landscape of B cell lymphoproliferative disease, due to a manageable toxicity profile and encouraging clinical effectiveness. In particular, ibrutinib, previously called PCI-32765, is a potent inhibitor of Bruton tyrosine kinase (Btk), recently approved for the treatment of relapsed mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). Moreover, idelalisib (formerly GS-1101 and CAL-101) is a selective reversible inhibitor of the p110δ isoform of phosphoinositol 3 kinase (PI3K) approved for the treatment of patients with relapsed follicular lymphoma (FL) and CLL. These agents directly affect the neoplastic clone, disrupting the supportive platform provided by BCR signaling cascade and by other microenvironmental mutualistic interactions, and also interfering with chemokine gradients and adhesive properties of neoplastic B cells. In the present review, we describe the clinical efficacy of ibrutinib and idelalisib in CLL and B cell non-Hodgkin lymphoma (B-NHL), then focusing on the mode of action (MOA) of these TKIs towards the neoplastic B cell compartment. At last, the review would further expand the view on potential additional targets of ibrutinib and idelalisib belonging to other microenvironmental cellular elements.
authors.affiliation: Hematology Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Via Del Pozzo 71, 41124, Modena, Italy. rossana.maffei@unimore.it.
authors.forename: Rossana
authors.initials: R
authors.lastname: Maffei
authors.affiliation: Hematology Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Via Del Pozzo 71, 41124, Modena, Italy. stefania.fiorcari@unimore.it.
authors.forename: Stefania
authors.initials: S
authors.lastname: Fiorcari
authors.affiliation: Hematology Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Via Del Pozzo 71, 41124, Modena, Italy. silmar78@libero.it.
authors.forename: Silvia
authors.initials: S
authors.lastname: Martinelli
authors.affiliation: Hematology Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Via Del Pozzo 71, 41124, Modena, Italy. leonardo.potenza@unimore.it.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Potenza
authors.affiliation: Hematology Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Via Del Pozzo 71, 41124, Modena, Italy. mario.luppi@unimore.it.
authors.forename: Mario
authors.initials: M
authors.lastname: Luppi
authors.affiliation: Hematology Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Via Del Pozzo 71, 41124, Modena, Italy. roberto.marasca@unimore.it.
authors.forename: Roberto
authors.initials: R
authors.lastname: Marasca
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D007694:Killer Cells, Natural; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011687:Purines / Q000008:administration & dosage / Q000627:therapeutic use*; D011720:Pyrazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use*; D052999:Quinazolinones / Q000008:administration & dosage / Q000627:therapeutic use*; D015398:Signal Transduction; D059016:Tumor Microenvironment
chemical_list: D000970:Antineoplastic Agents; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011687:Purines; D011720:Pyrazoles; D011743:Pyrimidines; D052999:Quinazolinones; C551803:ibrutinib; D000225:Adenine; C552946:idelalisib