Combining ibrutinib and rituximab to treat aggressive chronic lymphocytic leukemia (CLL) produced profound responses with minor side effects.

CLL is the most common type of adult leukemia in the United States, according to the National Cancer Institute (NCI). An estimated 16,000 new cases will be diagnosed this year, and approximately 4,600 people will die of the disease. The median age of diagnosis is 72 years, and it is more common in men than women. Although chemotherapy has improved the cure rate for CLL, its side effects are often severe. A sizeable number of CLL deaths are from secondary cancers caused by treatment.

Ibrutinib is a tyrosine kinase inhibitor that thwarts B-cell receptor signaling. Phase I/II trials have shown that patients with high- or low-risk CLL responded to ibrutinib. However, the response often is lessened because of persistent lymphocytosis, which is an increase in leukemia cells in the blood due to release of CLL cells from the lymph glands into the blood stream. Rituximab was added to capture the CLL cells in the blood and thereby accelerate and improve response.

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This phase II study enrolled 40 patients with high-risk CLL, who received daily oral doses of 420 mg ibrutinib throughout treatment, weekly infusions of 375 mg/m2 rituximab during weeks 1 through 4, and monthly rituximab infusions for the next 5 months.

At a median follow-up of 4 months, 38 patients remained on ibrutinib therapy without disease progression. One patient died from an unrelated infectious complication, and one patient discontinued therapy due to oral ulcers.

Of the 20 patients evaluated for early response at 3 months, 17 achieved partial response for an overall response rate of 85%. Three achieved partial remission with persistent lymphocytosis. Interestingly, the lymphocytosis peaked earlier and had a shorter duration with the combination treatment than with ibrutinib alone.

The treatment was well tolerated, with 13 cases of grade 3 or 4 toxicities, which included neutropenia, fatigue, pneumonia, insomnia, and bone aches. Most side effects were unrelated and transient. Many patients reported improved overall health and quality of life after three cycles of treatment.

“Although this study has a short follow-up time, we are encouraged by the fact that the vast majority of patients are responding and are able to continue on treatment,” said Jan Burger, MD, of the University of Texas M.D. Anderson Cancer Center.

A phase III study is proceeding with Pharmacyclics, the company that is developing ibrutinib. Also, M.D. Anderson will conduct a follow-up study on their research in high-risk CLL patients.

This study was presented at the annual meeting of the American Society of Hematology, held in Atlanta, Georgia, December 8-11, 2012.