NEW YORK (Reuters Health) - The new drug ibrutinib has been well tolerated and highly effective in patients with untreated, relapsed and unresponsive chronic lymphocytic leukemia (CLL) in an ongoing phase II trial, researchers said today at the annual meeting of the American Association for Cancer Research (AACR) in Washington, D.C.
Ibrutinib (formerly PCI-32765) is a selective inhibitor of Bruton's tyrosine kinase, a component of the B-cell receptor signaling pathway that plays a key role in the development and progression of CLL, explained lead author Dr. Adrian Wiestner, head of the Lymphoid Malignancies Section in the Hematology Branch at the National Heart, Lung, and Blood Institute at the National Institutes of Health in Bethesda, Maryland.
"It's a smart drug that inhibits a specific pathway within the cancer cell and as such is more focused and has a smarter way of attacking the tumor," Dr. Wiestner told Reuters Health.
"Part of the excitement about this agent is that it is well tolerated and highly active for patients who otherwise have run out of options, such as those who are refractory or resistant to normal chemotherapy and patients who have less good treatment options, either because they are elderly and would not be able to tolerate the standard chemotherapy approaches or because they have deletion of chromosome 17p," he said.
Dr. Wiestner and his team enrolled 53 patients with CLL in two cohorts. The first consisted of 29 patients with del 17p, and the second consisted of 24 patients without del 17p who were at least 65 years old.
All patients received 420 mg of ibrutinib orally once a day. The response to the drug was evaluated at six months and every six months thereafter, until disease progression.
Most adverse events were mild or moderate and included diarrhea, fatigue and rash. Severe events occurred in less than 13% of patients.
At six months, 95% of patients showed at least a 50% reduction in lymph node disease, and all showed reduction in spleen enlargement, with a median reduction of 55%.
In 26 patients who had a bone marrow biopsy, tumor infiltration had decreased by 82%.
In addition, absolute lymphocyte count decreased by a median of 62%.
Using standard CLL response criteria, 52% of patients had a partial response. At 12 months, the estimated event-free survival rate was 94%, Dr. Wiestner reported.
Blood and tissue samples of lymph nodes collected from 15 patients before and during ibrutinib treatment showed effective inhibition of B-cell receptor signaling and tumor proliferation, which was reduced by more than 80%, as measured by Ki67 staining.
Ibrutinib has generated a lot of excitement, and was recently given breakthrough designation by the U.S. Food and Drug Administration in recognition of its important potential for diseases that are similar to CLL, such as mantle cell lymphoma and Waldenstrom's macroglobulinemia, Dr. Wiestner said.
"Targeted therapy using these smart drugs is starting to pay off in the clinic in a big way. It's good news for patients who are currently not well served by standard treatments or who have run out of options. Looking into the future, I think these drugs will actually change how we approach patients with CLL and related B cell tumors," he said.
There are about 16,000 new cases of CLL diagnosed in the US each year, noted Dr. Christopher R. Flowers, Director of the Lymphoma Program at Winship Cancer Institute of Emory University in Atlanta, Georgia.
"It is the most common adult leukemia in Western countries, and the course of the disease is highly variable, with some patients having stable, asymptomatic disease that does not require treatment for several years, while others experience rapid disease progression," Dr. Flowers said.
Substantial progress has been made in the past decade in understanding and treating CLL, but the disease remains incurable with current conventional treatment strategies, and patients with relapsed or treatment-refractory disease have a poor prognosis, he noted.
"CLL with 17p deletion is the worst subtype of CLL and these patients very often have very short-lived responses to most therapies and are less likely to respond to the standard approaches," he said.
"These data on the activity of ibrutinib for these poor-risk patients represents a significant advance. While only 29 patients with del 17p were studied, this provides an early signal that this is a promising approach for this type of CLL."
Ibrutinib is being developed by Pharmacyclics Inc. The company said in a statement that eight other reports on the drug would also be presented at the AACR meeting this week.
The current study's clinicaltrials.gov identifier is NCT01500733.
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