The Emerging Role of Ibrutinib in the Treatment of Chronic Lymphocytic Leukemia

Stefano Molica


Expert Rev Hematol. 2013;6(5):543-546. 

In This Article

Five-year View

The favorable therapeutic index observed with ibrutinib led to test this BTK inhibitor in combination with different drugs active in CLL. Phase Ib/II studies evaluated the association of ibrutinib with rituximab or ofatumumab.[15,16] Results of these trials, although interesting, did not reveal any increase of ORR in comparison with ibrutinib single agent.[15,16]

The possibility of using ibrutinib in combination with bendamustine and rituximab (BR) has been explored in a Phase Ib/II clinical trial in relapsed/refractory CLL patients. This study included 30 patients with relapsed/refractory CLL who had received 1–3 prior regimens. ORR was 93%, with 13% being complete responses, and estimated 11-month PFS was 90%.[17] These results seem to be encouraging especially if compared with BR alone, for which the ORR was 59%.[18]

The HELIOS trial is a randomized, double-blind, placebo-controlled, Phase III study of ibrutinib in combination with BR in patients with relapsed or refractory CLL or SLL. Primary end point of study is PFS and recently, Pharmacyclics, Inc. (Nasdaq: PCYC) announced that the enrollment target of 350 patients was achieved.[101] We would expect to have a read out from the interim analysis during the first quarter of 2014.

RESONATE is a Phase III study of ibrutinib versus ofatumumab in patients with relapsed or refractory CLL. Primary end point is PFS and estimated study completion date is December 2015.[102]

RESONATE 2 is an open-label, Phase III study of the ibrutinib versus chlorambucil in patients 65 years or older with treatment-naive CLL or SLL. The primary end point of this study is PFS as assessed by IWCLL 2008 criteria with modification for treatment-related lymphocytosis. The study started in January 2013 and the estimated date of study completion is February 2016.[103]

The RESONATE 17 is an open-label, single arm Phase II study of the ibrutinib in patients with relapsed or refractory CLL or SLL with 17p deletion. The primary end point of study is ORR. The study was activated in January 2001 and the estimated completion date is March 2016.[104]

When available, results of these Phase III studies will contribute to define the role of ibrutinib in the treatment of elderly as well its activity in patients with 17p deletion who represent the CLL category with worst clinical outcome. Furthermore, ibrutinib should be evaluated as possible maintenance therapy for high-risk patients who have had a response to more conventional treatment.