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 signaling1. 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 strategies2. 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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Acknowledgements
This research was supported in part by the Intramural Research Program of the United States National Institutes of Health, National Cancer Institute, Center for Cancer Research. Research grant was provided by the Dr. Mildred Scheel Stiftung für Krebsforschung (Deutsche Krebshilfe; R.S.). Medical writing and editorial support were provided by M. Gersh and funded by Janssen Pharmaceuticals, Titusville, New Jersey. These studies, NCT00849654 and NCT01325701, were sponsored by Pharmacyclics, Inc., Sunnyvale, California.
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L.M.S. and W.H.W. conceived of this study, led the clinical trial, analyzed data and wrote the manuscript with D.M.B., R.M.Y., R.S., Y.Y., G.W., S.P., C.-J.L., and P.M.W. A.L.S. performed experiments and analyses. J.G., S.d.V., A.G., V.P.K., P.M.B., K.A.B., A.S., R.A., N.H.F., J.M.V., R.L.E., T.M.H. and J.C.B. enrolled subjects in the clinical trials and reviewed data. J.M., B.Y.C., M.F., F.C., B. M., D.M. and D.M.B. analyzed and reviewed data and provided logistical support for the trial. All authors provided critical review of the manuscript draft and provided final approval for submission.
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L.M.S. and J.C.B. have received institutional research funding from Pharmacyclics. L.M.S. and W.H.W. are inventors on a patent application regarding the use of ibrutinib in ABC DLBCL. A.G. has served on advisory boards for Pharmacyclics and Johnson & Johnson and on the speaker's bureau for Johnson & Johnson. N.H.F. has served on advisory board and has received research grants from Pharmacyclics. R.A. has received research grants from Pharmacyclics and Janssen. P.M.B. and J.M.V. have received research grants from Pharmacyclics. R.L.E. is currently an employee of Genentech, Inc. J.M., M.F., B.Y.C., F.C. B.M., D.M., and D.M.B. are employees of Pharmacyclics, Inc. and own stock options. R.M.Y., R.S., Y.Y., S.P., G.W., C.-J.L., P.M.W., A.L.S., J.G., S.d.V., V.P.K., K.A.B., A.S. and T.M.H. declare no competing financial interests.
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Wilson, W., Young, R., Schmitz, R. et al. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat Med 21, 922–926 (2015). https://doi.org/10.1038/nm.3884
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DOI: https://doi.org/10.1038/nm.3884
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