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

Clinical testing of BCR inhibition on DLBCL reveals determinants of response. 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 cel...

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Veröffentlicht in:	Nature medicine Jg. 21; H. 8; S. 922 - 926
Hauptverfasser:	Wilson, Wyndham H, Young, Ryan M, Schmitz, Roland, Yang, Yandan, Pittaluga, Stefania, Wright, George, Lih, Chih-Jian, Williams, P Mickey, Shaffer, Arthur L, Gerecitano, John, de Vos, Sven, Goy, Andre, Kenkre, Vaishalee P, Barr, Paul M, Blum, Kristie A, Shustov, Andrei, Advani, Ranjana, Fowler, Nathan H, Vose, Julie M, Elstrom, Rebecca L, Habermann, Thomas M, Barrientos, Jacqueline C, McGreivy, Jesse, Fardis, Maria, Chang, Betty Y, Clow, Fong, Munneke, Brian, Moussa, Davina, Beaupre, Darrin M, Staudt, Louis M
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	New York Nature Publishing Group US 01.08.2015 Nature Publishing Group
Schlagworte:	13/44 14/1 38/39 45/41 45/77 631/67/1990/291/1621/1915 692/699/67/1990/291/1621/1915 82/80 Adenine - analogs & derivatives Adult Aged Base Sequence Biomedicine Cancer Research CD79 Antigens - genetics Chemotherapy Female Humans Infectious Diseases letter Lymphocytes Lymphoma Lymphoma, Large B-Cell, Diffuse - drug therapy Lymphoma, Large B-Cell, Diffuse - genetics Lymphoma, Large B-Cell, Diffuse - mortality Male Metabolic Diseases Middle Aged Molecular Medicine Molecular Sequence Data Mutation Myeloid Differentiation Factor 88 - genetics Neurosciences Pharmacology Piperidines Protein Kinase Inhibitors - pharmacology Pyrazoles - pharmacology Pyrimidines - pharmacology Receptors, Antigen, B-Cell - physiology Signal transduction Signal Transduction - drug effects Tumors
ISSN:	1078-8956, 1546-170X
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Zusammenfassung:	Clinical testing of BCR inhibition on DLBCL reveals determinants of response. 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 1 . 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 2 . 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.
Bibliographie:	SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-1 ObjectType-Feature-2 content type line 23 AUTHOR 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.
ISSN:	1078-8956 1546-170X
DOI:	10.1038/nm.3884