Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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



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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

Figure 1: Tumor response to ibrutinib therapy.
Figure 2: Influence of B cell receptor mutations on ibrutinib response in ABC DLBCL.
Figure 3: Influence of recurrent genetic alterations on ibrutinib response in ABC DLBCL.


  1. Shaffer, A.L. III, Young, R.M. & Staudt, L.M. Pathogenesis of human B cell lymphomas. Annu. Rev. Immunol. 30, 565–610 (2012).

    Article  CAS  Google Scholar 

  2. Lenz, G. et al. Stromal gene signatures in large-B-cell lymphomas. N. Engl. J. Med. 359, 2313–2323 (2008).

    Article  CAS  Google Scholar 

  3. Davis, R.E., Brown, K.D., Siebenlist, U. & Staudt, L.M. Constitutive nuclear factor kappa B activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells. J. Exp. Med. 194, 1861–1874 (2001).

    Article  CAS  Google Scholar 

  4. Davis, R.E. et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 463, 88–92 (2010).

    Article  CAS  Google Scholar 

  5. Ngo, V.N. et al. Oncogenically active MYD88 mutations in human lymphoma. Nature 470, 115–119 (2011).

    Article  CAS  Google Scholar 

  6. Lenz, G. et al. Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science 319, 1676–1679 (2008).

    Article  CAS  Google Scholar 

  7. Compagno, M. et al. Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma. Nature 459, 717–721 (2009).

    Article  CAS  Google Scholar 

  8. Yang, Y. et al. Exploiting synthetic lethality for the therapy of ABC diffuse large B cell lymphoma. Cancer Cell 21, 723–737 (2012).

    Article  CAS  Google Scholar 

  9. Sehn, L.H. et al. The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood 109, 1857–1861 (2007).

    Article  CAS  Google Scholar 

  10. Loiarro, M. et al. Peptide-mediated interference of TIR domain dimerization in MyD88 inhibits interleukin-1-dependent activation of NF-κB. J. Biol. Chem. 280, 15809–15814 (2005).

    Article  CAS  Google Scholar 

  11. Young, R.M. & Staudt, L.M. Targeting pathological B cell receptor signalling in lymphoid malignancies. Nat. Rev. Drug Discov. 12, 229–243 (2013).

    Article  CAS  Google Scholar 

  12. Schmitz, R. et al. Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics. Nature 490, 116–120 (2012).

    Article  CAS  Google Scholar 

  13. Byrd, J.C. et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 369, 32–42 (2013).

    Article  CAS  Google Scholar 

  14. Wang, M.L. et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N. Engl. J. Med. 369, 507–516 (2013).

    Article  CAS  Google Scholar 

  15. Quesada, V. et al. Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Nat. Genet. 44, 47–52 (2012).

    Article  CAS  Google Scholar 

  16. Beà, S. et al. Landscape of somatic mutations and clonal evolution in mantle cell lymphoma. Proc. Natl. Acad. Sci. USA 110, 18250–18255 (2013).

    Article  Google Scholar 

  17. Wang, L. et al. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N. Engl. J. Med. 365, 2497–2506 (2011).

    Article  CAS  Google Scholar 

  18. Cheson, B.D. et al. Revised response criteria for malignant lymphoma. J. Clin. Oncol. 25, 579–586 (2007).

    Article  Google Scholar 

Download references


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.

Author information

Authors and Affiliations



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.

Corresponding author

Correspondence to Louis M Staudt.

Ethics declarations

Competing interests

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.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1 and 2, Supplementary Table 1 and Supplementary Notes 1–5 (PDF 663 kb)

Source data

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing