Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma Journal Article
| Authors: | Wilson, W. H.; Young, R. M.; Schmitz, R.; Yang, Y.; Pittaluga, S.; Wright, G.; Lih, C. J.; Williams, P. M.; Shaffer, A. L.; Gerecitano, J.; de Vos, S.; Goy, A.; Kenkre, V. P.; Barr, P. M.; Blum, K. A.; Shustov, A.; Advani, R.; Fowler, N. H.; Vose, J. M.; Elstrom, R. L.; Habermann, T. M.; Barrientos, J. C.; McGreivy, J.; Fardis, M.; Chang, B. Y.; Clow, F.; Munneke, B.; Moussa, D.; Beaupre, D. M.; Staudt, L. M. |
| Article Title: | Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma |
| Abstract: | 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. 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. © 2015 Nature America, Inc. All rights reserved. |
| Keywords: | signal transduction; adult; cancer chemotherapy; clinical article; controlled study; protein phosphorylation; aged; overall survival; disease course; drug tolerability; pathogenesis; treatment duration; cancer patient; follow up; prospective study; progression free survival; phase 2 clinical trial; gene expression; gene expression profiling; gene frequency; cell differentiation; in vitro study; b lymphocyte; germinal center; large cell lymphoma; phase 1 clinical trial; b lymphocyte receptor; gain of function mutation; ibrutinib; human; male; priority journal; article |
| Journal Title: | Nature Medicine |
| Volume: | 21 |
| Issue: | 8 |
| ISSN: | 1078-8956 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2015-08-01 |
| Start Page: | 922 |
| End Page: | 926 |
| Language: | English |
| DOI: | 10.1038/nm.3884 |
| PROVIDER: | scopus |
| PUBMED: | 26193343 |
| DOI/URL: | |
| Notes: | Export Date: 2 September 2015 -- Source: Scopus |
