Most patients with mantle cell lymphoma (MCL) will experience a recurrence, states Brad S. Kahl, MD. A next-line treatment option for relapsed disease is ibrutinib, an oral Bruton’s tyrosine kinase (BTK) inhibitor, which is well tolerated and has response rates of more than 70%. However, most patients will progress while on ibrutinib and may be given lenalidomide plus rituximab, which has response rates closer to 60% after recurrence. Another option is bortezomib, which has shown response rates of 33%.

When MCL evolves from a low-grade lymphoma to a blastic variant, the disease becomes difficult to control and requires different therapies, says Richard R. Furman, MD. Low-grade variants respond well to therapies like ibrutinib, lenalidomide, and bortezomib, but the efficacy of these agents is limited by the development of resistance and transformation.

Ibrutinib is dosed at 560 mg daily and is typically given until disease progression or intolerance. While patients tend to experience a benefit within days of starting therapy, it may take months to achieve maximal remission, says Kahl. Toxicities include diarrhea, muscle ache, arthralgia, fatigue, and a small risk of bleeding.

Mechanisms of resistance to ibrutinib include those that prevent ibrutinib from binding to BTK. In these patients, ibrutinib is converted from an irreversible inhibitor to a reversible inhibitor and loses efficacy, explains Furman. Moving ibrutinib to an earlier line of therapy before patients are exposed to chemotherapy may help, says Furman, as it increases the likelihood of using ibrutinib before the development of blastic disease.