Promising Phase II Results Continue to Support Ibrutinib in CLL  

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Results from an ongoing phase II study reported at the recent Annual Meeting of the American Association for Cancer Research (AACR) demonstrate impressive activity with the use of ibrutinib in patients with chronic lymphocytic leukemia (CLL) and 17p deletions, which are associated with a poor prognosis.1

Growing Body of Evidence

This study adds to a growing body of evidence that is highly promising for this novel Bruton’s tyrosine kinase inhibitor in the treatment of CLL. In fact, during the AACR meeting, the U.S. Food and Drug Administration announced that ibrutinib was awarded a “breakthrough designation” for CLL with 17p deletions, suggesting that it is on a fast track for approval. (See the May 1 issue of The ASCO Post, pages 1 and 24, for more on ibrutinib’s road to approval.)

Two phase II studies previously reported at the 2012 American Society of Hematology Annual Meeting demonstrated impressive results in CLL. One study included treatment-naive patients and relapsed/refractory patients, while the other focused on those with high-risk CLL.2,3

The study reported at the AACR meeting focused on CLL with 17p deletion and in a second cohort enrolled patients older than 65. Ibrutinib was well tolerated and highly effective in eradicating tumor cells in both treatment-naive and relapsed/refractory patients with CLL. Treatment with ibrutinib achieved dramatic clearance of tumor burden in the lymph nodes, blood, spleen, and bone marrow, and importantly, responses were durable. According to correlative studies, ibrutinib exerts sustained inhibition of B-cell receptor signaling and nuclear factor–kappaB signaling in both peripheral blood and lymph nodes.

Novel Approach for Challenging Patients

“Ibrutinib as a single agent is well tolerated and highly effective in CLL. Responses are durable, and high response rates are achieved irrespective of deletion of 17p. The drug achieved rapid disease control in all anatomic sites and rapid and sustained inhibition of BCR signaling. Ibrutinib should be investigated further, possibly as a single agent in CLL,” said lead author Adrian Wiestner, MD, PhD, Head of the Lymphoid Malignancies Section in the Hematology Branch at the National Heart, Lung, and Blood Institute at the NIH in Bethesda, Maryland.

The FCR regimen (fludarabine, cyclophosphamide, rituximab [Rituxan]) is a standard of care for CLL in the United States. Although FCR is effective, patients with 17p deletions have a poorer response and so do elderly and frail patients. Ibrutinib represents a novel approach for these difficult-to-treat patients, Dr. Wiestner told listeners. Ibrutinib is a selective inhibitor of Bruton’s tyrosine kinase (BTK), an element of the B-cell receptor signaling pathway implicated in the evolution of CLL.

Study Details

The phase II single-center trial included two cohorts of CLL patients who required treatment: elderly patients over age 65 (n = 24, 8 treatment-naive) and those with deletion of chromosome 17p (n = 29, 15 treatment-naive). This study continues to enroll treatment-naive patients with 17p deletion.

Patients were treated with single-agent ibrutinib at 420 mg/d in 28-day cycles, with the primary endpoint of response at 6 months. Treatment will be continued and response evaluated every 6 months.

Ibrutinib was safe and well tolerated. The most common adverse events were grade 1 or 2 diarrhea, rash, arthralgia, cramps, mouth sores and fatigue. Hematologic adverse events were rare, and no treatment-related drug discontinuations were reported. Two deaths occurred, both unrelated to the study drug.

Rapid disease control was evident at 6 months in the blood, lymph nodes, and spleen. Lymph node disease burden was reduced by at least 50% in 95% of patients; median reduction of splenomegaly was 55%.

Response Data

In 26 patients with an available bone marrow biopsy, ibrutinib reduced tumor infiltration by CLL cells by 82%. Absolute lymphocyte count was reduced by a median of 62%. According to standard response criteria for CLL, the rate of partial response was 52%. At 12 months, the estimated event-free survival was 94%. However, nodal responses were seen in 95% of patients.

Ibrutinib exhibited on-target effects by inhibiting B-cell receptor signaling in CLL cells in the lymph nodes and blood cells. However, no correlation was observed between the degree of inhibition of B-cell receptor signaling and the degree of clinical response, Dr. Wiestner commented.

“The durability of response is noteworthy. However, currently follow-up is short. Existing therapies often fail to eliminate cancer cells effectively in the blood, lymph nodes, spleen, and bone marrow. Ibrutinib is an example of targeted therapy that has the potential to greatly improve patients’ lives,” he stated. ■

Disclosure: Dr. Wiestner reported no potential conflicts of interest.


1. Wiestner A, et al: AACR Annual Meeting. Abstract LB-141. Presented April 8, 2013.

2. Byrd JC, et al: ASH Annual Meeting. Abstract 189. Presented December 9, 2012.

3. Burger JA, et al: ASH Annual Meeting. Abstract 187. Presented December 9, 2012.

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