The US Food and Drug Administration (FDA) has approved ibrutinib (Imbruvica, Pharmacyclics and Janssen Biotech) to treat patients with mantle cell lymphoma (MCL), a non-Hodgkin lymphoma, who have received at least one prior therapy. The approval was based on the overall response rate observed in a phase 2 trial.1

“Mantle cell lymphoma is a rare, aggressive type of B-cell lymphoma,” said Michael Wang, MD, of the Department of Lymphoma/Myeloma at The University of Texas M.D. Anderson Cancer Center, Houston, TX, and lead investigator for the pivotal trial. “With ibrutinib, we now have a once-daily oral therapy that has a very good side-effect profile and achieves more than chemotherapy could.”

In the United States, approximately 2,900 new cases of MCL are diagnosed each year. Patients treated with combination chemotherapies or intensive chemoimmunotherapy followed by stem cell transplantation have high initial response rates, but most relapse and eventually die of the disease.

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High Response Rate, But No Overall Survival Results Yet

Ibrutinib, an inhibitor of Bruton’s tyrosine kinase—an essential component of the B-cell–receptor signaling pathway—was studied in an open-label trial of 111 patients with relapsed or refractory MCL. It was administered as single-agent therapy (560 mg once daily) until progression of disease or until the drug was no longer tolerated. Patients were followed for a median of 15.3 months.

The overall response rate to ibrutinib therapy was 68%, with 47% of patients having a partial response and 21% achieving a complete response. “No single agent has ever achieved such a high response rate in mantle cell lymphoma,” Dr. Wang said. “This degree of response usually requires three or four drugs given in combination. In this case, we have excellent results from a drug that does not require patients to be hospitalized or undergo IV administration.”

For the 75 patients who responded to ibrutinib, the estimated median response duration was 17.5 months.The median overall survival for this study was not reached, but the estimated overall survival rate at 18 months was 58%.

Of the 43 patients who had lymph nodes 5 cm or larger, 27 (63%) had a favorable response to ibrutinib. “Usually, the larger the tumor, the more resistant it is to treatment,” Dr. Wang said. “The fact that patients with advanced disease had such a good response demonstrates that the biological pathway targeted by this drug must be very critical to tumor growth.”

For Most, a Well-tolerated Therapy

In the pivotal trial, after 15.3 months (range, 1.9-22.3 months), 46 patients were still receiving treatment with ibrutinib and 65 had discontinued it. Fifty patients discontinued because of disease progression and eight because of adverse events (AEs), including subdural hematoma, pneumonia, elevated bilirubin level, sepsis, metastatic adenocarcinoma, respiratory failure, and cardiac arrest.

Most AEs experienced during ibrutinib therapy were mild to moderate. Diarrhea was reported in 50% of patients and fatigue in 41%. Nausea, peripheral edema, dyspnea, constipation, upper respiratory tract infection, vomiting, and decreased appetite all occurred in at least 20% of patients.

Serious hematologic AEs included neutropenia, which occurred in 16% of patients, followed by thrombocytopenia (11%), and anemia (10%). Five patients had bleeding events.

Ibrutinib is only the second drug approved via the FDA’s Breakthrough Therapy Designation pathway, which allows the agency to designate a drug as a breakthrough therapy if clinical evidence indicates that it may offer a substantial improvement over available therapies for patients with serious or life-threatening diseases.


  1. Wang ML, Rule S, Martin P et al. “Targeting BTK with ibrutinib in relapsed for refractory mantle cell lymphoma.” N Engl J Med. 2013;369(6):507-516.