Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma

Abstract

Background: Bruton's tyrosine kinase (BTK) is a mediator of the B-cell-receptor signaling pathway implicated in the pathogenesis of B-cell cancers. In a phase 1 study, ibrutinib, a BTK inhibitor, showed antitumor activity in several types of non-Hodgkin's lymphoma, including mantle-cell lymphoma.

Methods: In this phase 2 study, we investigated oral ibrutinib, at a daily dose of 560 mg, in 111 patients with relapsed or refractory mantle-cell lymphoma. Patients were enrolled into two groups: those who had previously received at least 2 cycles of bortezomib therapy and those who had received less than 2 complete cycles of bortezomib or had received no prior bortezomib therapy. The primary end point was the overall response rate. Secondary end points were duration of response, progression-free survival, overall survival, and safety.

Results: The median age was 68 years, and 86% of patients had intermediate-risk or high-risk mantle-cell lymphoma according to clinical prognostic factors. Patients had received a median of three prior therapies. The most common treatment-related adverse events were mild or moderate diarrhea, fatigue, and nausea. Grade 3 or higher hematologic events were infrequent and included neutropenia (in 16% of patients), thrombocytopenia (in 11%), and anemia (in 10%). A response rate of 68% (75 patients) was observed, with a complete response rate of 21% and a partial response rate of 47%; prior treatment with bortezomib had no effect on the response rate. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months (95% confidence interval [CI], 15.8 to not reached), the estimated median progression-free survival was 13.9 months (95% CI, 7.0 to not reached), and the median overall survival was not reached. The estimated rate of overall survival was 58% at 18 months.

Conclusions: Ibrutinib shows durable single-agent efficacy in relapsed or refractory mantle-cell lymphoma. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01236391.)

Figure 1. Overall Response Rates According to Subgroup

This forest plot of data for all treated patients shows the overall response rate according to demographic and clinical characteristics and risk factors. The 95% confidence intervals (CIs) are based on normal approximation to the binomial distribution. The simplified Mantle-Cell Lymphoma International Prognostic Index (MIPI) score ranges from 0 to 11 and was derived with the use of the four prognostic factors of age, Eastern Cooperative Oncology Group (ECOG) performance-status score, lactate dehydrogenase level, and white-cell count at baseline. The index classifies patients as having low-, intermediate-, or high-risk disease, as defined by scores of 0 to 3, 4 or 5, and 6 to 11, respectively. ECOG performance-status scores range from 0 to 5, with 0 indicating asymptomatic, 1 symptomatic but ambulatory, and 2 symptomatic and in bed less than half the day; a score of more than 2 indicates only limited self-care and in bed more than half the day (3), completely disabled and confined to bed or chair (4), or dead (5). Advanced disease was defined as involvement of bone marrow, extranodal sites, or both; and refractory disease as a lack of at least a partial response to the last therapy before study entry. High-intensity therapy was defined as stem-cell transplantation; treatment with hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD); or treatment with a hyper-CVAD–like regimen.

Figure 2. Duration of Response, Progression-free Survival, and Overall Survival

Panel A shows the duration of the response (shown as the percentage of patients alive without progression of disease) for the 75 patients who had a response; the estimated median duration was 17.5 months. For the 43 patients in the cohort without prior bortezomib treatment who had a response, the estimated median duration was 15.8 months. For the 32 patients in the cohort with prior bortezomib treatment who had a response, the median duration was not reached. Panel B shows progression-free survival for all 111 treated patients, according to cohort. In this analysis, data from the 1 patient who received subsequent anticancer therapy before progression of disease were censored at the time of the start of that therapy. For all patients, the estimated median progression-free survival was 13.9 months; for the 63 patients without prior borte zomib treatment and for the 48 with prior bortezomib treatment, the estimated median progression-free survival was 7.4 and 16.6 months, respectively. Panel C shows the results of the overall-survival analysis performed at the time of the primary analysis of progression-free survival, when 70 patients (63%) were alive. The median overall survival was not reached.