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Nat Med. 2015 Aug;21(8):922-6. doi: 10.1038/nm.3884. Epub 2015 Jul 20.

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

Author information

1
Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA.
2
Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, Maryland, USA.
3
Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, Maryland, USA.
4
Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
5
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.
6
Division of Hematology and Oncology, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California, USA.
7
John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey, USA.
8
Division of Hematology and Medical Oncology, University of Wisconsin, Madison, Wisconsin, USA.
9
James P. Wilmot Cancer Center, University of Rochester, Rochester, New York, USA.
10
Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA.
11
Department of Medicine, Hematology, University of Washington School of Medicine, Seattle, Washington, USA.
12
Medical Oncology, Stanford University Medical Center, Stanford, California, USA.
13
Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
14
Division of Hematology &Oncology, Department of Internal Medicine, University of Nebraska, Omaha, Nebraska, USA.
15
Clinical Development, Genentech, Inc., South San Francisco, California, USA.
16
Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA.
17
Division of Hematology and Medical Oncology, Department of Medicine, Hofstra North Shore-Long Island Jewish School of Medicine, Hempstead, New York, USA.
18
Pharmacyclics, Inc., Sunnyvale, California, USA.

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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00849654 NCT01325701.

PMID:
26193343
DOI:
10.1038/nm.3884
[Indexed for MEDLINE]

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