In a major international study led by researchers at The University of Texas MD Anderson Cancer Center, the targeted therapy ibrutinib continues to show remarkable promise for the treatment of relapsed or refractory mantle cell lymphoma (MCL).
The most recent interim findings of the 18-center Phase 2 study were published today in the New England Journal of Medicine. Previous interim findings were presented in December 2012 at the 54th American Society of Hematology Annual Meeting and Exposition.
Unprecedented results, fewer side effects
"This oral inhibitor of the Bruton's tyrosine kinase in the B-cell receptor pathway is the most important breakthrough to date in the treatment of mantle cell lymphoma," said Michael Wang, M.D., associate professor in MD Anderson's Departments of Lymphoma and Myeloma and Stem Cell Transplantation and Cellular Therapy. Wang is lead author of the trial.
"It is an oral drug, taken once a day, and its side effects are not severe. Yet it can achieve more than previous combination chemotherapy approaches. Our results constitute excellent news for our patients and patients around the world."
The ongoing trial of oral ibrutinib in patients with heavily treated relapsed or refractory MCL has maintained a response rate as high as 70 percent - better than any other single agent ever tested in the challenging disease – with milder side effects than other treatments.
Targeted approach to dangerous disease
MCL is a rare and aggressive B-cell subtype of non-Hodgkin lymphoma that, according to the Leukemia and Lymphoma Society, accounts for 6 percent of non-Hodgkin cases. Despite high response rates to initial highly toxic combination-drug chemotherapy, patients often relapse.The B-cell receptor pathway is critical in B-cell lymphoma, and Bruton's tyrosine kinase (BTK) is an essential component of this pathway. Ibrutinib targets the BTK molecule, causing cell death and decreasing cellular migration and adhesion in malignant B-cells.
Seventy-seven percent had stage 4 disease, and the median number of prior treatments was three.
Ongoing results continue to show promise
In the past six months, ibrutinib has continued to show excellent results. With a median follow-up period of 15 months:Overall response rate was 68 percent
Wang believes further investigation of ibrutinib as a first line therapy and in combination with other targeted therapies and traditional cytotoxic agents is essential.
"This drug, which is the safest option we have for MCL, shows unprecedented durable single agent activity," he said. "The favorable toxicity profile also implies that ibrutinib provides the opportunity for less intense and more effective regimens. The long-term impact of ibrutinib definitely warrants further clinical testing."
Pharmacyclics, Inc., which developed ibrutinib, sponsored the clinical trial.
Wang's co-authors at MD Anderson include Jorge E. Romaguera, M.D., Liang Zhang, M.D., Ph.D., Kate Newberry, Ph.D., and Zhishuo Ou, M.D., Department of Lymphoma and Myeloma; Lei Li, Ph.D., Department of Experimental Radiation Oncology; and Bingliang Fang, Ph.D., Department of Thoracic and Cardiovascular Surgery.
Other members of the research team include Simon Rule, M.D., Derriford Hospital, Plymouth, United Kingdom; Peter Martin, M.D., Weill Cornell Medical College, New York, New York; Andre Goy, M.D., John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ; Rebecca Auer, M.D., Ph.D., Barts Health NHS Trust, London, United Kingdom; Brad S. Kahl, M.D., University of Wisconsin, Madison; Wojciech Jurczak, M.D., Ph.D., Jagiellonian University, Krakow, Poland; Ranjana Advani, M.D., Stanford University Medical Center, Stanford, California; Michael E. Williams M.D., University of Virginia School of Medicine, Charlottesville, Virginia; Jacqueline Barrientos, M.D., Department of Medicine, Hofstra North Shore-LIJ, New Hyde Park, New York; Ewa Chmielowska, M.D., Oddzial Kliniczny Onkologii Centrum Onkologii, Bydgoszcz, Poland; John Radford, M.D., The Christie NHS Foundation Trust and the University of Manchester, Manchester, United Kingdom; Stephan Stilgenbauer, M.D., Universitatsklinikum Ulm, Klinik fur Innere Medizin II, Ulm, Germany; Martin Dreyling, M.D., Klinikum der Universitat Munchen – Campus Grosshadern, Munich, Germany; Wieslaw Wiktor Jedrzejczak, M.D., Medical University of Warsaw, Poland; Peter Johnson, M.D., Cancer Research UK Centre, University of Southampton, United Kingdom; Stephen E. Spurgeon, M.D., Oregon Health and Science University, Portland, Oregon; Nancy Cheng, M.S., Baylor College of Medicine, Houston, Texas; Jesse McGreivy, M.D., Fong Clow, Sc.D., Joseph Buggy, Ph.D., Betty Chang, Ph.D., Darrin Beaupre, M.D., Ph.D. and Lori A. Kunkel, M.D., Pharmacyclics, Inc., Sunnyvale, CA; and Kristie Blum, M.D., Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
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