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

Publication Date

2015

Journal Title

Nat Med

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(1). The ABC subtype has a similar to 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.

Volume Number

21

Issue Number

8

Pages

922-926

Document Type

Article

Status

Faculty

Facility

School of Medicine

Primary Department

Hematology/Medical Oncology

PMID

26193343

DOI

10.1038/nm.3884

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