Even as the targeted therapy ibrutinib makes its way through clinical trials as a single treatment for chronic lymphocytic leukemia (CLL), researchers are studying the new drug in combinations and identifying genomic changes that allow malignant cells to resist treatment.
Jan Burger, M.D., Ph.D., associate professor of Leukemia at The University of Texas MD Anderson Cancer Center, presented two such studies at the 55th Annual Meeting of the American Society of Hematology this month.
- Combining ibrutinib with the targeted antibody rituximab resulted in complete or partial responses in 37 of 39 (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.
- Genomic analysis of CLL before treatment and after resistance so far point to mutations inside and outside the B cell receptor pathway targeted by ibrutinib as promoting resistance.
"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," Burger said.
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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. CLL is the most common adult leukemia. The American Cancer Society estimates about 15,680 new cases will be diagnosed in 2013 and about 4,580 people will die of the disease.
Patients reported significant improvement in overall health and quality of life at six months, which coincided with weight gain. The proportion of patients reporting high quality of life on a questionnaire rose from 46% before treatment to 89% after six months.
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.
New clinical trial under MD Anderson CLL moon shot
Burger leads a new combination trial launched at MD Anderson in December that compares 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 reveal 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.
CLL resistance to ibrutinib arises outside BTK mutations
To better understand how CLL develops resistance to ibrutinib, Burger and colleagues from MD Anderson and the Broad Institute in Boston analyzed the genetics of CLL cells before treatment and after drug resistance in three patients with advanced disease who achieved partial remissions on the drug.
"We were surprised to find no mutations in BTK itself, but we found mutations in other components of the B cell receptor pathway," Burger said. "We also found new mutations that developed during treatment in separate pathways."
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All of the mutations identified arise in a background of pre-existing 17p and 11q deletions, the study found.
"This is a small study, but it shows that CLL cells, under pressure from ibrutinib, can adapt to bypass BTK-related signaling crucial to their survival." he said. "We will need to identify and understand these mechanisms to develop ways to defeat resistance."
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.
ASH abstracts on combination and resistance (Agree to terms for free access)
MD Anderson news release