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

Methods & Results

In the study in question, Byrd et al. evaluated safety, efficacy, pharmacokinetics and pharmacodynamics of ibrutinib (PCI-32765) in patients with relapsed or refractory CLL or SLL.[4] The trial is based on 85 patients (median age 66 years; range, 37–82) who were enrolled in a Phase Ib/II multicenter study. The authors considered eligible three different cohorts of patients: the first and second cohorts had received at least two previous therapies, including a purine analog while a third cohort consisted of patients with high-risk disease non-responsive to chemoimmunotherapy or progressing within 24 months after completion. Fifty-one received a fixed daily dose of 420 mg, and 34 received a daily dose of 840 mg, with both doses administered orally on a continuous schedule. The primary end point of study was the safety while secondary end points were the overall response rate (ORR), progression-free survival (PFS), pharmacodynamics and pharmacokinetics.

As far as patient characteristics are concerned, 65% had advanced-stage disease, 33% had 17p deletion and 36% had 11q deletion. After a median follow-up time of 20.9 months (range, 0.7–26.7) from the starting of ibrutinib, 54 patients (64%) were still on therapy while in 31 (36%) treatment with ibrutinib was stopped. Interruption of ibrutinib was due to disease progression only in 11 patients (13%).

According to the Internation Workshop on CLL (IWCLL) response criteria,[10] ORR was virtually the same in the group that received 420 or 840 mg (71% in both). Interestingly, an additional 20 and 15% of patients in the respective groups had a 'partial response (PR) with lymphocytosis'.

The response to ibrutinib was not affected by the presence of 17p deletion. In fact, it was 68% among patients with a 17p deletion and 71% among those without this deletion. Interestingly, a PR was observed in 4 of the 12 patients with a mutated IGVH gene (33%) and in 53 of the 69 patients with an unmutated IGVH gene (77%).

PFS and OS curves projected at 26 months revealed respectively 75 and 83% rate. Among the 28 patients with 17p deletion, the 26-month PFS was 57% and OS 70%.

Toxicity related to therapy with ibrutinib was mild with a prevalence of grade 1–2 adverse events. The most common side effects included diarrhea, fatigue and upper respiratory tract infection. Ibrutinib was discontinued in two patients in the 420-mg cohort (4%) and in four patients in the 840-mg cohort (12%). The grade 3–4 adverse events observed were pneumonia (in 10 patients [12%]) and dehydration (in 5 patients [6%]). Infections were generally encountered in earlier phase of therapy. IgG and IgM levels remained relatively stable throughout treatment, whereas IgA levels increased at 3, 6 and 12 months.