(ChemotherapyAdvisor) – Ibrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase (BTK), was found to be well tolerated and highly effective in patients with chronic lymphocytic leukemia (CLL), an ongoing phase 2 trial presented at the American Association for Cancer Research (AACR) Annual Meeting 2013 in Washington, DC, has found.

“The degree of tumor reduction achieved by once-daily oral therapy was impressive,” said Adrian Wiestner, MD, PhD, investigator and head of the Lymphoid Malignancies Section in the Hematology Branch at the National Heart, Lung and Blood Institute, Bethesda, MD, and colleagues. “We have seen patients with more than 90% reduction of lymph node disease within just 2 months.”

The investigators enrolled patients with both treatment-naïve and relapsed/refractory CLL in two cohorts: 1) those with deletion of chromosome 17p and 2) those without the deletion of chromosome 17p who were older than 65 years of age. All were treated with ibrutinib 420 mg until disease progression, with response evaluated at 6 months and every 6 months thereafter.

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They reported on the first 53 patients, with a median follow-up of 9 months. In cohort 1 (n=29), 15 patients were treatment naïve and 14 had relapsed/refractory disease; in cohort 2 (n=24), eight were treatment naïve and 16 had relapsed/refractory disease. At 6 months, 95% of patients (n=44 evaluable) had a nodal response (median reduction in lymph node size of 73%) and 52% had a partial response. Estimated event-free survival at 12 months is 94%.

Most adverse events were mild; less than 13% of patients had nonhematologic toxicities that were grade 3 or higher. The two deaths were not treatment related. One patient had progressive disease that was presumed to be Richter’s transformation.

Also evaluated were the in vivo effects of ibrutinib, using blood and tissue samples collected before and during treatment. Ibrutinib effectively inhibited B-cell receptor signaling and tumor proliferation, which was reduced by more than 80%, as measured by Ki67 staining.

“All patients had a decrease in splenomegaly,” Dr. Wiestner noted; median reduction in splenic CT volume was 55%. Tumor infiltration in bone marrow biopsies (n=26) decreased by a median 82% and median absolute lymphocyte count reduction was 62%.

“Ibrutinib was highly efficacious as a single agent in patients with untreated, relapsed, and unresponsive CLL, irrespective of their del 17p status,” Dr. Wiestner said. “Responses appear to be durable, and the drug is effective against the disease in lymph nodes, spleen and bone marrow. This is important because existing therapies often fail to effectively eliminate cancer cells in these tissue sites. Targeted therapy for CLL is becoming a reality, and this new approach will greatly improve the lives of patients with this disease.”

The study was supported by the Intramural Research Program of the National Institutes of Health.

On April 8, Pharmacyclics, Inc., Sunnyvale, CA, announced that the US Food and Drug Administration (FDA) had granted Breakthrough Therapy Designation for ibrutinib as monotherapy for the treatment of patients with CLL or small lymphocytic lymphoma with deletion 17p. In February 2013, the FDA granted Breakthrough Therapy Designations for ibrutinib as monotherapy for the treatment of patients with relapsed or refractory mantle cell lymphoma and as a monotherapy for the treatment of patients with Waldenstrom’s macroglobulinemia, both of which are also B-cell malignancies. Ibrutinib is jointly being developed by Pharmacyclics and Janssen for treatment of B-cell malignancies.

Abstract #LB-141