Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell Lymphoma

Posted by Carla Rothaus • August 7th, 2013

Travel back in time to 2003. The oncologist is about to confer with Mr. P., a patient previously treated for mantle cell lymphoma (MCL) who had recently complained of fatigue, and whose subsequent CT scan showed evidence of relapsed disease. The doctor will have to tell Mr. P. that the tools at hand for relapsed MCL have a response rate of only 6 to 10%.

Now flash forward to 2013, and discover that the outlook is changing. A new treatment is so promising that it has been given breakthrough therapy designation by the FDA. What accounts for the new landscape? Progress in understanding the biology of mantle cell lymphoma has led to the design of experimental drugs that target specific molecular abnormalities involved in the pathogenesis of MCL.

Mantle cell lymphoma is a rare B-cell non-Hodgkin’s lymphoma characterized by the overexpression of cyclin D1 and dysregulation of cell cycle control. It typically has an aggressive clinical course, and poor prognosis. While initial treatments often produce a good response, most patients relapse, and in the absence of effective salvage treatments, die from their disease.

Prior studies have shown that B-cell receptor signaling has an essential role in the survival and proliferation of malignant B cells, and multiple kinases involved in this signaling pathway have been identified as possible targets for therapeutic agents. Bruton’s tyrosine kinase (BTK), a vital component of B-cell receptor signaling, is the target of ibrutinib (PCI-32765), an oral covalent inhibitor of BTK which has shown anti-tumor activity in B-cell lymphomas in early stage clinical trials.

In this week’s NEJM, Michael L. Wang and colleagues report on their phase 2, open-label study of the efficacy and safety of ibrutinib in patients with relapsed or refractory mantle cell lymphoma. Their results show ibrutinib to be a highly active agent, with a significant response rate and favorable safety profile.

The study enrolled 111 patients who met eligibility requirements. All patients received oral ibrutinib at a daily dose of 560 mg until their disease progressed, or until they experienced adverse events requiring withdrawal from the trial. The primary end point of the study was response rate; secondary end points were response duration, progression-free survival, overall survival, and safety.

The results showed a 68 % response rate (75 patients), including a complete response rate of 21%. With an estimated median follow up of 15.3 months, the estimated median response duration was 17.5 months, and the estimated median progression-free survival was 13.9 months. The estimated overall survival rate was 58% at 18 months. Safety data showed that with continuous ibrutinib treatment, the majority of adverse events were Grade 1 or 2. The most common treatment related adverse effects were mild or moderate diarrhea (in 50%), fatigue (in 41%), and nausea (in 31%).

NEJM Deputy Editor Dr. Dan Longo says the results are startling, and will intensify interest in ibrutinib’s potential use for other types of lymphoma. “The high response rate that includes complete responses using a single agent provides encouragement that the treatment for this difficult-to-treat lymphoma will improve even further when ibrutinib is incorporated into multiagent treatment programs.”

In an accompanying editorial, Dr. Emanuele Zucca and Dr. Francesco Bertoni emphasize that ibrutinib cannot be expected to single-handedly cure mantle cell lymphoma, but will most likely be part of next-generation combination therapies.  Ongoing and future studies, they note, “will clarify the proper place of this compound in the management of mantle cell lymphoma, a disease whose refractoriness to treatment may be yielding to new agents.”

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