Grant: Project Grant

Chronic lymphocytic leukemia (CLL) is an incurable blood malignancy with a long natural history, typically characterized by multiple recurrences and repeated requirement for treatment. Ibrutinib (Imbruvica®) has emerged as an effective novel therapy for the management of CLL. The standard ibrutinib dose for CLL is 420 mg once daily (3 tablets/day in 28 day cycles), with large randomized clinical trials demonstrating superiority over standard comparators. However, use of ibrutinib in the "real world" (outside of clinical trials) has demonstrated that important toxicities do arise, including major bleeding, heart rhythm abnormalities, diarrhea, joint pains, and infections. As such, dose reductions are frequently required to reduce toxicity with ibrutinib administration. Population-based studies of ibrutinib use suggest that this practice is very common, occurring in ~30-60% of patients. In a recent such study, pre-emptive dose reduction (within the first 3 months of treatment initiation) was able to reduce the toxicity of ibrutinib without compromising the effectiveness in the treatment of CLL. Furthermore, a recent study by our group of a pre-emptive dose reduction strategy ("3-2-1" dosing with initial cycle of 420mg/d or 3 tablets, reduced to 280mg or 2 tablets/d in cycle 2, and 140mg or 1 tablet/d in cycle 3 and onwards) confirmed that, at lower doses, the biologic activity of ibrutinib was fully maintained. We propose a randomized phase III study comparing these two common dosing strategies (a pre-emptive 3-2-1 strategy vs. a full dose strategy) to ensure that the lower dose strategy is just as effective and less toxic compared to full dosing. We further anticipate that the lower dose approach will be associated with improved outcomes of importance to patients and caregivers, including reductions in patient-reported side effects, less "financial toxicity" given the high out-of-pocket costs associated with treatment, and improved quality of life.