Abstract
In early results of a phase II clinical trial of the BTK inhibitor ibrutinib for the treatment of diffuse large B-cell lymphoma, multiple previously treated patients are responding to the drug.
Some patients with diffuse large B-cell lymphoma respond to BTK inhibitor
In early results of a phase II clinical trial of the targeted therapy ibrutinib for the treatment of diffuse large B-cell lymphoma (DLBCL), multiple previously treated patients are responding to the drug. Some patients with activated B cell-like (ABC) lymphoma, a subtype of DLBCL that produces the poorest outcomes with existing therapies, have shown complete remission.
“It's remarkable,” says Louis Staudt, MD, PhD, deputy chief, metabolism branch at the National Cancer Institute (NCI), who is scheduled to present these findings as part of the opening plenary session at the American Association for Cancer Research (AACR) Annual Meeting 2012 in Chicago on April 1. “In patients who have extensive tumors, the disease melts away.”
DLBCL accounts for 30% to 40% of newly diagnosed lymphomas. There have been no significant advances in its treatment for more than a decade.
Earlier research from Staudt's lab used structural and functional genomics to characterize subtypes of DLBCL. They found that B-cell receptors (BCR), which normally help B cells recognize infections, have a chronically active form in ABC lymphoma that keeps cancer cells alive. Knocking down an enzyme called Bruton's tyrosine kinase (BTK), a downstream effector of BCR signaling, kills these tumor cells.
In a “happy circumstance,” says Staudt, he presented these findings at an earlier AACR meeting and subsequently met attendees from Pharmacyclics, Inc. (Sunnyvale, CA), who had fashioned ibrutinib, a potent BTK inhibitor.
Staudt and clinical collaborator Wyndham Wilson, MD, also of NCI, recruited 10 patients with refractory ABC lymphoma to participate in a pilot clinical trial of ibrutinib. The study yielded two complete responses, one partial response, and one stabilization of disease. Sixteen months later, one patient is still taking ibrutinib as a once-daily pill and remains in complete remission with no side effects.
The phase II clinical trial, now ongoing at 15 sites in the United States, has recruited 47 of a planned 60 patients with relapsing or refractory DLBCL. Early results include some complete responses in ABC lymphomas as well as partial responses in patients with other forms of DLBCL, suggesting that B-cell signaling may also be involved in other subtypes. Reported side-effects are mild and include diarrhea, nausea, and fatigue. Final results are expected later this year or early in 2013.
