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

Nature Medicine volume 21, pages 922–926 (2015)Cite this article

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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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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.

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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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Authors and Affiliations

  1. Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA

    Wyndham H Wilson, Ryan M Young, Roland Schmitz, Yandan Yang, Arthur L Shaffer & Louis M Staudt

  2. Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, Maryland, USA

    Stefania Pittaluga

  3. Division of Cancer Treatment and Diagnosis, Biometric Research Branch, National Cancer Institute, NIH, Bethesda, Maryland, USA

    George Wright

  4. Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA

    Chih-Jian Lih & P Mickey Williams

  5. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA

    John Gerecitano

  6. Department of Medicine, Weill Cornell Medical College, New York, New York, USA

    John Gerecitano

  7. Division of Hematology and Oncology, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California, USA

    Sven de Vos

  8. John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey, USA

    Andre Goy

  9. Division of Hematology and Medical Oncology, University of Wisconsin, Madison, Wisconsin, USA

    Vaishalee P Kenkre

  10. James P. Wilmot Cancer Center, University of Rochester, Rochester, New York, USA

    Paul M Barr

  11. Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA

    Kristie A Blum

  12. Department of Medicine, Hematology, University of Washington School of Medicine, Seattle, Washington, USA

    Andrei Shustov

  13. Medical Oncology, Stanford University Medical Center, Stanford, California, USA

    Ranjana Advani

  14. Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Nathan H Fowler

  15. Division of Hematology & Oncology, Department of Internal Medicine, University of Nebraska, Omaha, Nebraska, USA

    Julie M Vose

  16. Clinical Development, Genentech, Inc., South San Francisco, California, USA

    Rebecca L Elstrom

  17. Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA

    Thomas M Habermann

  18. Division of Hematology and Medical Oncology, Department of Medicine, Hofstra North Shore–Long Island Jewish School of Medicine, Hempstead, New York, USA

    Jacqueline C Barrientos

  19. Pharmacyclics, Inc., Sunnyvale, California, USA

    Jesse McGreivy, Maria Fardis, Betty Y Chang, Fong Clow, Brian Munneke, Davina Moussa & Darrin M Beaupre

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  1. Wyndham H Wilson
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Contributions

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.

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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.

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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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