Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma

• Published in: Nature medicine Vol. 21; no. 8; pp. 922 - 926
• Main Authors: Wilson, Wyndham H, Young, Ryan M, Schmitz, Roland, Yang, Yandan, Pittaluga, Stefania, Wright, George, Lih, Chih-Jian, Williams, P Mickey, Shaffer, Arthur L, Gerecitano, John, de Vos, Sven, Goy, Andre, Kenkre, Vaishalee P, Barr, Paul M, Blum, Kristie A, Shustov, Andrei, Advani, Ranjana, Fowler, Nathan H, Vose, Julie M, Elstrom, Rebecca L, Habermann, Thomas M, Barrientos, Jacqueline C, McGreivy, Jesse, Fardis, Maria, Chang, Betty Y, Clow, Fong, Munneke, Brian, Moussa, Davina, Beaupre, Darrin M, Staudt, Louis M
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2015; Nature Publishing Group
• Subjects: 13/44; 14/1; 38/39; 45/41; 45/77; 631/67/1990/291/1621/1915; 692/699/67/1990/291/1621/1915; 82/80; Adenine - analogs & derivatives; Adult; Aged; Base Sequence; Biomedicine; Cancer Research; CD79 Antigens - genetics; Chemotherapy; Female; Humans; Infectious Diseases; letter; Lymphocytes; Lymphoma; Lymphoma, Large B-Cell, Diffuse - drug therapy; Lymphoma, Large B-Cell, Diffuse - genetics; Lymphoma, Large B-Cell, Diffuse - mortality; Male; Metabolic Diseases; Middle Aged; Molecular Medicine; Molecular Sequence Data; Mutation; Myeloid Differentiation Factor 88 - genetics; Neurosciences; Pharmacology; Piperidines; Protein Kinase Inhibitors - pharmacology; Pyrazoles - pharmacology; Pyrimidines - pharmacology; Receptors, Antigen, B-Cell - physiology; Signal transduction; Signal Transduction - drug effects; Tumors
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.3884

Clinical testing of BCR inhibition on DLBCL reveals determinants of response. 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.