Ibrutinib in combination with rituximab in relapsed or refractory mantle cell lymphoma: a single-centre, open-label, phase 2 trial

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• 作者：Prof Michael L Wang ; MD^a ; ^b ; ^{miwang@mdanderson.org" class="auth_mail" title="E-mail the corresponding author} ; Hun Lee ; MD^a ; Hubert Chuang ; MD^c ; Nicolaus Wagner-Bartak ; MD^d ; Prof Frederick Hagemeister ; MD^a ; Jason Westin ; MD^a ; Luis Fayad ; MD^a ; Felipe Samaniego ; MD^a ; Prof Francesco Turturro ; MD^a ; Yasuhiro Oki ; MD^a ; Wendy Chen ; PA^a ; Maria Badillo ; MSN^a ; Krystle Nomie ; PhD^a ; Maria DeLa Rosa ; BS^a ; Donglu Zhao ; MD^a ; Laura Lam ; PhD^a ; Alicia Addison ; MS^a ; Hui Zhang ; BSN^a ; Ken H Young ; MD^e ; Shaoying Li ; MD^e ; David Santos ; MD^f ; Prof L Jeffrey Medeiros ; MD^e ; Prof Richard Champlin ; MD^b ; Prof Jorge Romaguera ; MD^a ; Leo Zhang ; MD^a
• 刊名：The Lancet Oncology
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：17
• 期：1
• 页码：48-56
• 全文大小：342 K

文摘

Ibrutinib is approved in the EU, USA, and other countries for patients with mantle cell lymphoma who received one previous therapy. In a previous phase 2 study with single-agent ibrutinib, the proportion of patients who achieved an objective response was 68%; 38 (34%) of 111 patients had transient lymphocytosis. We hypothesised that adding rituximab could target mantle cell lymphoma cells associated with redistribution lymphocytosis, leading to more potent antitumour activity.

Methods

Patients with a confirmed mantle cell lymphoma diagnosis (based on CD20-positive and cyclin D1-positive cells in tissue biopsy specimens), no upper limit on the number of previous treatments received, and an Eastern Cooperative Oncology Group performance status score of 2 or less were enrolled in this single-centre, open-label, phase 2 study. Patients received continuous oral ibrutinib (560 mg) daily until progessive disease or unacceptable toxic effects. Rituximab 375 mg/m² was given intravenously once per week for 4 weeks during cycle 1, then on day 1 of cycles 3–8, and thereafter once every other cycle up to 2 years. The primary endpoint was the proportion of patients who achieved an objective response in the intention-to-treat population and safety assessed in the as-treated population. The study is registered with gov">ClinicalTrials.gov, number gov" data-locatorKey="NCT01880567">NCT01880567, and is still ongoing, but no longer accruing patients.

Findings

Between July 15, 2013, and June 30, 2014, 50 patients were enrolled. Median age was 67 years (range 45–86), and the median number of previous regimens was three (range 1–9). At a median follow-up of 16·5 months (IQR 12·09–19·28), 44 (88%, 95% CI 75·7–95·5) patients achieved an objective response, with 22 (44%, 30·0–58·7) patients achieving a complete response, and 22 (44%, 30·0–58·7) a partial response. The only grade 3 adverse event in >=10% of patients was atrial fibrillation, which was noted in six (12%) patients. Grade 4 diarrhoea and neutropenia occurred in one patient each. Adverse events led to discontinuation of therapy in five (10%) patients (atrial fibrillation in three [6%] patients, liver infection in one [2%], and bleeding in one [2%]). Two patients died while on-study from cardiac arrest and septic shock; the latter was deemed possibly related to treatment.

Interpretation

Ibrutinib combined with rituximab is active and well tolerated in patients with relapsed or refractory mantle cell lymphoma. Our results provide preliminary evidence for the activity of this combination in clinical practice. A phase 3 trial is warranted for more definitive data.

Funding

Pharmacyclics LLC, an AbbVie Company.