Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma
| Autor: | Thomas M. Habermann, Chih Jian Lih, Ranjana H. Advani, Davina Moussa, Andre Goy, Paul M. Barr, Rebecca Elstrom, Nathan Fowler, Fong Clow, Betty Y. Chang, Maria Fardis, Darrin M. Beaupre, Brian Munneke, John F. Gerecitano, Ryan M. Young, Wyndham H. Wilson, Louis M. Staudt, Roland Schmitz, Stefania Pittaluga, Vaishalee P. Kenkre, Yandan Yang, P. Mickey Williams, George E. Wright, Andrei R. Shustov, Julie M. Vose, Jacqueline C. Barrientos, Jesse McGreivy, Sven de Vos, Arthur L. Shaffer, Kristie A. Blum |
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| Rok vydání: | 2015 |
| Předmět: |
Adult
Male Molecular Sequence Data B-cell receptor Receptors Antigen B-Cell Biology Article General Biochemistry Genetics and Molecular Biology chemistry.chemical_compound Piperidines hemic and lymphatic diseases medicine Humans Protein Kinase Inhibitors Aged Base Sequence Adenine breakpoint cluster region Germinal center General Medicine Middle Aged CD79B medicine.disease Lymphoma Pyrimidines chemistry Ibrutinib Mutation Myeloid Differentiation Factor 88 Immunology Cancer research Pyrazoles Female Lymphoma Large B-Cell Diffuse Diffuse large B-cell lymphoma CD79 Antigens Signal Transduction |
| Zdroj: | Nat Med |
| ISSN: | 1546-170X 1078-8956 |
| Popis: | The two major subtypes of diffuse large B cell lymphoma (DLBCL)—activated B cell–like (ABC) and germinal center B cell–like (GCB)—arise by distinct mechanisms, with ABC selectively acquiring mutations that target the B cell receptor (BCR), fostering chronic active BCR signaling(1). The ABC subtype has a ∼40% cure rate with currently available therapies, which is worse than the rate for GCB DLBCL, and highlights the need for ABC subtype-specific treatment strategies(2). We hypothesized that ABC, but not GCB, DLBCL tumors would respond to ibrutinib, an inhibitor of BCR signaling. In a phase 1/2 clinical trial that involved 80 subjects with relapsed or refractory DLBCL, ibrutinib produced complete or partial responses in 37% (14/38) of those with ABC DLBCL, but in only 5% (1/20) of subjects with GCB DLBCL (P = 0.0106). ABC tumors with BCR mutations responded to ibrutinib frequently (5/9; 55.5%), especially those with concomitant myeloid differentiation primary response 88 (MYD88) mutations (4/5; 80%), a result that is consistent with in vitro cooperation between the BCR and MYD88 pathways. However, the highest number of responses occurred in ABC tumors that lacked BCR mutations (9/29; 31%), suggesting that oncogenic BCR signaling in ABC does not require BCR mutations and might be initiated by non-genetic mechanisms. These results support the selective development of ibrutinib for the treatment of ABC DLBCL. |
| Databáze: | OpenAIRE |
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