title: Targeting of B-cell receptor signalling in B-cell malignancies.
abstract: Pharmacological agents that inhibit enzymes of the B-cell receptor (BCR) pathway are of increasing importance in the treatment of B-cell malignancies. These include inhibitors of Bruton tyrosine kinase (BTK), phosphatidylinositol 3-kinase (PI3K), splenic tyrosine kinase and protein kinase Cβ. Two agents are already approved in the USA and Europe: ibrutinib, a BTK inhibitor, for the treatment of chronic lymphatic leukaemia (CLL), mantle cell lymphoma (MCL) and Waldenström's macroglobulinemia; and idelalisib, a PI3Kδ inhibitor, for the treatment of CLL and follicular lymphoma. In addition, the role of these drugs in diffuse large B-cell lymphoma and marginal zone lymphoma is under investigation, as single agents and in combination with chemotherapy. In CLL, both ibrutinib and idelalisib have an established role as first-line therapy in patients with del(17p), and in MCL, ibrutinib is a standard option for patients relapsing after chemoimmunotherapy. Unexpected toxicities have been encountered when combining these potent new agents with other drugs, including chemotherapy and lenalidomide, and based on this experience the risks and benefits of novel combinations must be evaluated carefully. In this review, we summarize the efficacy and safety results with these inhibitors and discuss novel combinations that are under study and the future role of BCR inhibitors in these disorders.
authors.affiliation: Department of Oncology, Lund University, Lund, Sweden.
authors.forename: M
authors.identifier: 0000-0003-4509-6707
authors.initials: M
authors.lastname: Jerkeman
authors.affiliation: Department of Internal Medicine I, Cologne University Hospital, Cologne, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Hallek
authors.affiliation: Department of Medicine III, University of Munich, Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Dreyling
authors.affiliation: Hemato-Oncology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Thieblemont
authors.affiliation: Hematology Center, Department of Medicine, Karolinska Institute, Stockholm, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Kimby
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: L
authors.initials: L
authors.lastname: Staudt
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects; D006801:Humans; D015448:Leukemia, B-Cell / Q000188:drug therapy*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy; D010880:Piperidines; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; 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*; D011947:Receptors, Antigen, B-Cell / Q000187:drug effects*; D008258:Waldenstrom Macroglobulinemia / Q000188:drug therapy
chemical_list: D010880:Piperidines; D011687:Purines; D011720:Pyrazoles; D011743:Pyrimidines; D052999:Quinazolinones; D011947:Receptors, Antigen, B-Cell; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D000225:Adenine; C552946:idelalisib
keywords: B-cell receptor; leukaemia; lymphoma