Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia

SUMMARY: Normal B-cell activation and proliferation is dependent on B-cell receptor (BCR) signaling. This signaling is also important for initiation and progression of B-cell lymphoproliferative disorders. Bruton’s tyrosine kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. Following binding of antigen to the BCR, Syk (Spleen Tyrosine Kinase), Lyn (member of the Src family of protein tyrosine kinases) and BTK (Bruton’s Tyrosine Kinase) are activated, with subsequent propagation through PI3K/Akt, MAPK, NF-κB pathways and resulting B-cell activation and proliferation. IMBRUVICA® (Ibrutinib, PCI-32765) is an oral, irreversible inhibitor of BTK and inhibits cell proliferation and promotes programmed cell death (Apoptosis). The FDA granted accelerated approval of IMBRUVICA® for the treatment of patients with Chronic Lymphocytic Leukemia (CLL) who had received at least one prior therapy. This approval was based on the outcomes in a select group of 48 patients who were a part of a larger group of 85 patients, enrolled in a multicenter single arm phase Ib/II trial. The median age was 67 years and 71% were male. Patients had a median number of 4 prior treatments and had an ECOG PS of 0-1. Patients in this group received IMBRUVICA® 420 mg PO daily until disease progression or unacceptable toxicity. The overall response rate was 58.3% as assessed by an independent review committee. No complete responses were seen and the response duration ranged from 5.6 to over 24 months. This analysis did not include data from those patients enrolled in the trial who received IMBRUVICA® 840 mg PO daily or those with Small Lymphocytic Lymphoma (N=37). The most common toxicities included fatigue, myalgias and arthralgias, cytopenias, nausea, diarrhea, fever and rash. Transient asymptomatic increase in lymphocyte count with resolution of lymphadenopathy and splenomegaly was common but resolved with continued treatment. The confirmatory RESONATE trial is a multicenter, randomized, open-label Phase III study in which single agent IMBRUVICA® was compared to single agent ARZERRA® (Ofatumumab) in patients with relapsed or refractory CLL or Small Lymphocytic Lymphoma . This was a part of the requirement by the FDA. Enrolled patients had measurable nodal disease and were not eligible for treatment with purine analog-based therapy. In this study, 391 patients who had received at least one prior therapy, were enrolled and randomized to receive 420 mg of IMBRUVICA® orally once daily or ARZERRA® given intravenously. Treatment was given over a period of 24 weeks until disease progression or unacceptable toxicity. Patients randomized to the ARZERRA® group on disease progression were allowed to receive treatment with IMBRUVICA®. The primary endpoint of this study was progression-free survival and the secondary endpoint was overall survival. Following recommendations from the Independent Data Monitoring Committee (IDMC), the study was stopped earlier, as the primary endpoint as well as an important secondary endpoint of the study were met. At the planned interim analysis, patients in the IMBRUVICA® group showed a statistically significant improvement in progression-free survival, the primary endpoint of the study as well as a statistically significant improvement in overall survival, the secondary endpoint of the trial. This data confirmed the efficacy of IMBRUVICA® and gives patients with CLL, an important new treatment option. Byrd JC, Furman RR, Coutre SE, et al. N Engl J Med 2013; 369:32-42