Patients

Eligible patients had a confirmed diagnosis of mantle-cell lymphoma with cyclin D1 overexpression or translocation breakpoints at t(11;14) and measurable disease (lymph-node diameter, ≥2 cm). Patients had received at least one but no more than five previous lines of treatment, with no partial or better response to the most recent treatment regimen or with disease progression after the most recent regimen.

Other eligibility criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less (scores range from 0 to 5, with 0 indicating asymptomatic and higher numbers indicating increasing disability) and adequate organ function. An absolute neutrophil count of at least 0.75×109 per liter and a platelet count of at least 50×109 per liter were required unless the patient had bone marrow involvement by lymphoma.

Study Design and Treatment

This international open-label, phase 2 study was conducted at 18 sites. Patients with mantle-cell lymphoma were enrolled without randomization and were classified as either having received treatment with bortezomib (≥2 cycles) or not having received such treatment (<2 complete cycles or no prior bortezomib therapy). Single-agent bortezomib is a treatment approved by the Food and Drug Administration for patients with mantle-cell lymphoma that has progressed after at least one initial treatment. Therefore, a defined cohort of patients with prior bortezomib treatment was included in this study, and the combination of the two cohorts was representative of a broad population of patients with relapsed or refractory mantle-cell lymphoma. Patients received single-agent ibrutinib administered orally at a daily dose of 560 mg until progression of disease or until unacceptable levels of adverse events occurred. All the patients provided written informed consent.

The institutional review board at each site approved the study protocol, which was conducted according to the principles of the Declaration of Helsinki and the International Conference on Harmonisation Guidelines for Good Clinical Practice. The protocol, including the statistical analysis plan, is available with the full text of this article at NEJM.org.

Study Oversight

The academic authors were responsible for designing the study protocol and statistical analysis plan together with the sponsor, Pharmacyclics. The investigators and their respective research teams collected all the data, and the sponsor confirmed the accuracy of the data and compiled them for summation and analysis. Statistical analyses were performed by the biometrics group at Janssen Research and Development and were independently confirmed and validated by a separate statistical group at Pharmacyclics. The investigators had full access to the data and analyses for the compilation of this report. Manuscript drafts were prepared by all the authors, with editorial assistance from a professional medical writer paid by the sponsor. All the authors vouch for the accuracy and completeness of the data reported and for the adherence of the study to the protocol, and all the authors made the decision to submit the manuscript for publication.

Assessments

The primary end point was the rate of overall response, defined as either a partial response or a complete response according to the Revised International Working Group Criteria for non-Hodgkin's lymphoma.16 In addition, a response evaluation based on computed tomographic (CT) and positron-emission tomographic (PET) scans, bone marrow–biopsy specimens, gastrointestinal biopsy specimens (if a gastrointestinal biopsy was performed), and clinical data was conducted by an independent central review vendor (BioClinica). Tumor assessment was performed during screening with the use of CT scans of the chest, abdomen, pelvis, and any other disease sites (e.g., neck); PET scans; and bone marrow biopsy. CT scanning was repeated at cycles 3, 5, and 7 and then every three cycles until disease progression. A PET scan was mandatory for confirmation of a complete response.

The secondary end points included response duration, measured from the time when the criteria for a response were met until the first date on which recurrent or progressive disease was objectively documented; progression-free survival, measured as the time from the first administration of the study drug until lymphoma progression or death from any cause; overall survival, measured from the time of the first administration of the study drug until the date of death; and safety. Safety was assessed on the basis of the frequency and severity of adverse events. Adverse events were graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0.17 The safety assessment was based on reported adverse events, clinical laboratory tests (hematologic testing, serum chemical testing, and urinalysis), measurements of weight and vital signs, physical examinations, and ECOG performance status.

Peripheral-Blood Lymphocyte Counts

In chronic lymphocytic leukemia, ibrutinib causes a transient increase in blood lymphocytes that is concurrent with a reduction in lymph-node size.15 Whether a similar phenomenon occurs in patients with mantle-cell lymphoma was investigated by counting and characterizing peripheral-blood lymphocytes after treatment with ibrutinib (see the Supplementary Appendix, available at NEJM.org). The effect of ibrutinib on cytokine expression was also evaluated in a subset of patients (see the Supplementary Appendix).

Statistical Analysis

The sample for this study was 115 patients; we planned to include 65 patients with no prior treatment with bortezomib and 50 with prior bortezomib treatment. With the use of Simon's two-stage design18 (see the study protocol), the study was designed to check the efficacy of the drug in a small group of patients before enrolling the entire planned study population. If an appropriate number of patients had a response in the first stage (see below), then we would continue enrollment; if the level of response did not meet our success criteria for clinical benefit, the study would be terminated for that group.

For the cohort of patients without prior treatment with bortezomib, a two-stage design was planned to test the null hypothesis that the response rate would be 20% or less (i.e., before the investigators could proceed to stage 2 of the study, at least 6 of 25 patients had to have a response). We calculated that a sample of 65 patients would provide 91% power to test a difference in the response rate of 20% versus 40% at a one-sided alpha level of 0.01. For the cohort of patients with prior bortezomib treatment, a two-stage design was planned to test the null hypothesis that the response rate would be 15% or less (i.e., before the investigators could proceed to stage 2 of the study, at least 5 of 25 patients had to have a response). We calculated that a sample of 50 patients would provide 80% power to test a difference in the response rate of 15% versus 35% at a one-sided alpha level of 0.01.

In each cohort, an interim analysis for futility was conducted on the basis of the stopping rules for Simon's two-stage design.18 On the basis of this interim analysis, enrollment in both study cohorts was allowed to continue, per protocol.

The final analysis was planned to be performed approximately 8 months after the last patient was enrolled in the study. Frequency tables were used to summarize categorical variables. The distribution of time-to-event end points, including response duration, progression-free survival, and overall survival, were estimated with the use of the Kaplan–Meier method.19 All statistical tests were based on a two-sided alpha level of 0.05.