Ibrutinib in Patients with Bortezomib-Refractory Mantle-Cell Lymphoma

Conference Correspondent - ASH 2014 - Castleman's Disease


Despite recent advances, mantle-cell lymphoma (MCL) remains difficult to treat, with frequent chemoresistance in the relapsed or refractory setting. Ibrutinib, a first-in-class, oral inhibitor of Bruton’s tyrosine kinase (BTK), demonstrated durable single-agent efficacy in a previous phase 2 study of patients with MCL who had received 1 to 5 previous therapies, with an overall response rate (ORR) of 68% (complete response rate, 21%; Wang ML, et al. N Engl J Med. 2013;369:507-516). At ASH 2014, Wang and colleagues reported on the efficacy and safety of single-agent ibrutinib in patients with MCL who had received a rituximab (RTX)-containing regimen and had progressed after at least 2 cycles of bortezomib (Blood. 2014;124. Abstract 4471).

In this phase 2, multicenter, single-arm study, 120 patients with a median of 2 previous lines of therapy (33% with previous stem-cell transplantation) received ibrutinib 560 mg daily continuously until progressive disease or unacceptable toxicity. The primary end point was the ORR, and the secondary end points included duration of response, progression-free survival (PFS), overall survival (OS), and safety.

After a median follow-up of 14.9 months, the ORR was 63% with a complete response rate of 21%. The subgroup analysis suggested that the ORR was independent of age, sex, geographic region, number of previous lines of therapies, baseline extranodal disease, bulky disease, and stage of MCL. The median duration of response was 14.9 months, and the median time to first response was 2.1 months. The median PFS was 10.5 months, and 47% of the patients remained progression free at 1 year. The OS rate at 18 months was 61%.

The most common adverse events (AEs) were fatigue and diarrhea. The most common grade ?3 AEs were neutropenia, thrombocytopenia, and pneumonia. Any-grade hemorrhagic events were reported in 45 (37.5%) patients, including 3 (2.5%) patients with major hemorrhagic events. Atrial fibrillation was reported in 13 (10.8%) patients, which was grade 3 or 4 in 6 (5%) patients.

This study demonstrated that single-agent ibrutinib is effective and well-tolerated, with an acceptable toxicity profile in patients with MCL who progressed after receiving RTX-containing chemotherapy and bortezomib.