Targeting Bruton tyrosine kinase with ibrutinib in relapsed/refractory marginal zone lymphoma

Abstract

Marginal zone lymphoma (MZL) is a heterogeneous B-cell malignancy for which no standard treatment exists. MZL is frequently linked to chronic infection, which may induce B-cell receptor (BCR) signaling, resulting in aberrant B-cell survival and proliferation. We conducted a multicenter, open-label, phase 2 study to evaluate the efficacy and safety of ibrutinib in previously treated MZL. Patients with histologically confirmed MZL of all subtypes who received ≥1 prior therapy with an anti-CD20 antibody-containing regimen were treated with 560 mg ibrutinib orally once daily until progression or unacceptable toxicity. The primary end point was independent review committee-assessed overall response rate (ORR) by 2007 International Working Group criteria. Among 63 enrolled patients, median age was 66 years (range, 30-92). Median number of prior systemic therapies was 2 (range, 1-9), and 63% received ≥1 prior chemoimmunotherapy. In 60 evaluable patients, ORR was 48% (95% confidence interval [CI], 35-62). With median follow-up of 19.4 months, median duration of response was not reached (95% CI, 16.7 to not estimable), and median progression-free survival was 14.2 months (95% CI, 8.3 to not estimable). Grade ≥3 adverse events (AEs; >5%) included anemia, pneumonia, and fatigue. Serious AEs of any grade occurred in 44%, with grade 3-4 pneumonia being the most common (8%). Rates of discontinuation and dose reductions due to AEs were 17% and 10%, respectively. Single-agent ibrutinib induced durable responses with a favorable benefit-risk profile in patients with previously treated MZL, confirming the role of BCR signaling in this malignancy. As the only approved therapy, ibrutinib provides a treatment option without chemotherapy for MZL. This study is registered at www.clinicaltrials.gov as #NCT01980628.

Figure 1.

ORRs and waterfall plot for reductions in lymph node sum of the products of longest diameters (SPD). (A) ORRs as assessed by the independent review committee and by investigators. (B) Waterfall plot for maximum percentage decrease in lymph node SPD by investigator assessment. *Data based on investigator assessment for 59 patients; 4 patients who discontinued treatment prior to first response assessment were not evaluable. Investigator-assessed data were used given that IRC assessment included 2 separate sets of SPD data due to readings by 2 radiologists.

Figure 2.

ORRs according to subgroup. Forest plot representing subgroup analyses of ORRs as assessed by the independent review committee in the efficacy population (N = 60). The sizes of the circles are proportional to the sizes of the subgroups; error bars indicate 95% CIs. The dashed vertical line represents the overall treatment effect for all patients. *Results of bone marrow assessment were considered indeterminate in 4 patients.

Figure 3.

DOR, PFS, and OS with ibrutinib. (A) DOR as assessed by the IRC. (B) PFS in the efficacy population (N = 60) as assessed by the IRC. (C) OS in the efficacy population (N = 60). The median PFS was 14.2 months (95% CI, 8.3 to NE), and the median OS has not been reached. The tick marks indicate patients with censored data.