Michael L Wang1, Hun Lee2, Hubert Chuang3, Nicolaus Wagner-Bartak4, Frederick Hagemeister2, Jason Westin2, Luis Fayad2, Felipe Samaniego2, Francesco Turturro2, Yasuhiro Oki2, Wendy Chen2, Maria Badillo2, Krystle Nomie2, Maria DeLa Rosa2, Donglu Zhao2, Laura Lam2, Alicia Addison2, Hui Zhang2, Ken H Young5, Shaoying Li5, David Santos6, L Jeffrey Medeiros5, Richard Champlin7, Jorge Romaguera2, Leo Zhang2. 1. Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: miwang@mdanderson.org. 2. Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 3. Department of Nuclear Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 4. Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 5. Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 6. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 7. Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Abstract
BACKGROUND: 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 progressive disease or unacceptable toxic effects. Rituximab 375 mg/m(2) 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 ClinicalTrials.gov, number 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.
BACKGROUND: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 progressive disease or unacceptable toxic effects. Rituximab 375 mg/m(2) 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 ClinicalTrials.gov, number 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.
Authors: Leo Zhang; Krystle Nomie; Hui Zhang; Taylor Bell; Lan Pham; Sabah Kadri; Jeremy Segal; Shaoying Li; Shouhao Zhou; David Santos; Shawana Richard; Shruti Sharma; Wendy Chen; Onyekachukwu Oriabure; Yang Liu; Shengjian Huang; Hui Guo; Zhihong Chen; Wenjing Tao; Carrie Li; Jack Wang; Bingliang Fang; Jacqueline Wang; Lei Li; Maria Badillo; Makhdum Ahmed; Selvi Thirumurthi; Steven Y Huang; Yiping Shao; Laura Lam; Qing Yi; Y Lynn Wang; Michael Wang Journal: Clin Cancer Res Date: 2017-03-27 Impact factor: 12.531
Authors: Michael Wang; Javier Munoz; Andre Goy; Frederick L Locke; Caron A Jacobson; Brian T Hill; John M Timmerman; Houston Holmes; Samantha Jaglowski; Ian W Flinn; Peter A McSweeney; David B Miklos; John M Pagel; Marie-Jose Kersten; Noel Milpied; Henry Fung; Max S Topp; Roch Houot; Amer Beitinjaneh; Weimin Peng; Lianqing Zheng; John M Rossi; Rajul K Jain; Arati V Rao; Patrick M Reagan Journal: N Engl J Med Date: 2020-04-02 Impact factor: 91.245