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.
authors.affiliation: Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Wyndham H
authors.initials: WH
authors.lastname: Wilson
authors.affiliation: Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Young
authors.affiliation: Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Roland
authors.initials: R
authors.lastname: Schmitz
authors.affiliation: Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Yandan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, Maryland, USA.
authors.forename: Stefania
authors.initials: S
authors.lastname: Pittaluga
authors.affiliation: Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, Maryland, USA.
authors.forename: George
authors.initials: G
authors.lastname: Wright
authors.affiliation: Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Chih-Jian
authors.initials: CJ
authors.lastname: Lih
authors.affiliation: Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: P Mickey
authors.initials: PM
authors.lastname: Williams
authors.affiliation: Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Shaffer
authors.affiliation: 1] Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA. [2] Department of Medicine, Weill Cornell Medical College, New York, New York, USA.
authors.forename: John
authors.initials: J
authors.lastname: Gerecitano
authors.affiliation: Division of Hematology and Oncology, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Sven
authors.initials: S
authors.lastname: de Vos
authors.affiliation: John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey, USA.
authors.forename: Andre
authors.initials: A
authors.lastname: Goy
authors.affiliation: Division of Hematology and Medical Oncology, University of Wisconsin, Madison, Wisconsin, USA.
authors.forename: Vaishalee P
authors.initials: VP
authors.lastname: Kenkre
authors.affiliation: James P. Wilmot Cancer Center, University of Rochester, Rochester, New York, USA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Barr
authors.affiliation: Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA.
authors.forename: Kristie A
authors.initials: KA
authors.lastname: Blum
authors.affiliation: Department of Medicine, Hematology, University of Washington School of Medicine, Seattle, Washington, USA.
authors.forename: Andrei
authors.initials: A
authors.lastname: Shustov
authors.affiliation: Medical Oncology, Stanford University Medical Center, Stanford, California, USA.
authors.forename: Ranjana
authors.initials: R
authors.lastname: Advani
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Nathan H
authors.initials: NH
authors.lastname: Fowler
authors.affiliation: Division of Hematology &Oncology, Department of Internal Medicine, University of Nebraska, Omaha, Nebraska, USA.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Vose
authors.affiliation: Clinical Development, Genentech, Inc., South San Francisco, California, USA.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Elstrom
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Habermann
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, Hofstra North Shore-Long Island Jewish School of Medicine, Hempstead, New York, USA.
authors.forename: Jacqueline C
authors.identifier: 0000000160185535
authors.initials: JC
authors.lastname: Barrientos
authors.affiliation: Pharmacyclics, Inc., Sunnyvale, California, USA.
authors.forename: Jesse
authors.initials: J
authors.lastname: McGreivy
authors.affiliation: Pharmacyclics, Inc., Sunnyvale, California, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Fardis
authors.affiliation: Pharmacyclics, Inc., Sunnyvale, California, USA.
authors.forename: Betty Y
authors.initials: BY
authors.lastname: Chang
authors.affiliation: Pharmacyclics, Inc., Sunnyvale, California, USA.
authors.forename: Fong
authors.initials: F
authors.lastname: Clow
authors.affiliation: Pharmacyclics, Inc., Sunnyvale, California, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Munneke
authors.affiliation: Pharmacyclics, Inc., Sunnyvale, California, USA.
authors.forename: Davina
authors.initials: D
authors.lastname: Moussa
authors.affiliation: Pharmacyclics, Inc., Sunnyvale, California, USA.
authors.forename: Darrin M
authors.initials: DM
authors.lastname: Beaupre
authors.affiliation: Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Staudt
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000328:Adult; D000368:Aged; D001483:Base Sequence; D051925:CD79 Antigens / Q000235:genetics; D005260:Female; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D051925:CD79 Antigens; C497881:CD79A protein, human; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D011947:Receptors, Antigen, B-Cell; C551803:ibrutinib; D000225:Adenine