• Wyndham H Wilson, Ryan M Young, Roland Schmitz, Yandan Yang, Stefania Pittaluga, George Wright, Chih-Jian Lih, P Mickey Williams, Arthur L Shaffer, John Gerecitano, Sven de Vos, Andre Goy, Vaishalee P Kenkre, Paul M Barr, Kristie A Blum, Andrei Shustov, Ranjana Advani, Nathan H Fowler, Julie M Vose, Rebecca L Elstrom, Thomas M Habermann, Jacqueline C Barrientos, Jesse McGreivy, Maria Fardis, Betty Y Chang, Fong Clow, Brian Munneke, Davina Moussa, Darrin M Beaupre, and Louis M Staudt.
• Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA.
• Nat. Med. 2015 Aug 1; 21 (8): 922-6.

AbstractThe 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. 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. 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.

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