Nearly all of the high-risk chronic lymphocytic leukemia patients in a phase II clinical trial responded to treatment with the targeted therapy ibrutinib and the antibody rituximab, researchers reported today, at the 55th Annual Meeting of the American Society of Hematology.
“This combination improves on the already excellent response rate from ibrutinib alone, which is usually around 70-80 percent. It’s also well-tolerated with manageable side effects and significantly improves patients’ quality of life,” said Jan Burger, M.D., Ph.D., associate professor of Leukemia at The University of Texas MD Anderson Cancer Center.
The combination produced complete or partial responses in 38 of 40 (95 percent) high-risk CLL patients. At a median follow-up of 18 months, 31 patients (78 percent) remained on the drug with no sign of progression, with overall survival at 84 percent.
Ten percent of responses were complete, but partial responses are substantial, Burger said. “You can still detect a few CLL cells in the blood or bone marrow, but they don’t’ cause any symptoms.”
CLL is a malignancy of immune system B cells, white blood cells that normally produce antibodies against infection. Ibrutinib blocks Bruton’s tyrosine kinase (BTK), a vital component of B cell receptor signaling.
Patients report major quality of life improvement
Among a subgroup of 20 patients with either mutated versions of the cancer-suppressing gene TP53 or chromosome 17p deletions, both known indicators of poor prognosis, the combination sparked a 90 percent response rate (16 partial and two complete responses).
Patients reported significant improvement in overall health and quality of life at six months, which coincided with weight gain at three and six months. The proportion of patients reporting high quality of life using EORTC-QOLv.3 questionnaires increased from 46 percent before treatment to 89 percent after six months of ibrutinib treatment.
The faster, improved response rate, Burger said, is most likely due to rituximab addressing an early effect of ibrutinib treatment – temporarily higher counts of white blood cells and leukemia cells during the first months of treatment.
Burger’s earlier research showed that this effect occurs because ibrutinib breaks ties that allow leukemia cells to hide out in the bone marrow and in lymph nodes, pushing them out into the bloodstream. Rituximab picks off these now more vulnerable CLL cells.
Low-grade diarrhea, bruising and rashes, joint pain, nausea, fatigue and upper respiratory infections were the most common toxicities during treatment. Grade 3 toxicities, significant events that require treatment but aren’t life-threatening, included four lung infections, one case of mucositis, inflammation of the lining of the digestive tract, and two of peripheral neuropathy, pain and numbness in the hands and feet.
Nine patients withdrew from the study, two due to progressive disease and one from mucositis possibly caused by ibrutinib; two with pneumonia, one due to ear and pulmonary infections, one with Richter’s transformation to an aggressive lymphoma, and one with unrelated progressive respiratory disease and heart failure. One patient died of unknown causes while in remission.
New combination clinical trial under MD Anderson CLL moon shot
Burger leads a new combination trial launched at MD Anderson last week which will compare ibrutinib to ibrutinib plus rituximab in 208 previously treated CLL patients. Genomic analyses of patients’ CLL cells will be done before and during treatment and at the point of disease resistance to help researchers understand how the disease changes during treatment.
The clinical trial is part of MD Anderson’s Moon Shots Program to accelerate the pace of converting scientific discoveries into clinical advances that reduce cancer deaths.
The U.S. Food and Drug Administration approved the drug, known commercially as IMBRUVICA, for treatment of mantle cell lymphoma last month under its breakthrough therapy designation. A similar application for CLL by Pharmacyclics, Inc., the drug’s developer, is pending at the FDA.
Burger receives research funding from Pharmacyclics and serves on an unpaid advisory board for another clinical trial, senior author Susan O’Brien, M.D., professor of Leukemia, also receives research funding.
Other co-authors are Michael Keating, M.D., William Wierda, M.D., Ph.D., Julia Hoellenriegel, Ghayathri Jeyakumar, M.D., Alessandra Ferrajoli, M.D, Stefan Faderl, M.D., Marylou Cardenas-Turanzas, M.D., Dr.PH, Susan Lerner, Gracy Zacharian, and Hagop Kantarjian, M.D., of MD Anderson’s Department of Leukemia; and Xuelin Huang, Ph.D., of the Department of Biostatistics.