Versha Banerji

Chronic lymphocytic leukemia (cll) is the most commonly diagnosed adult leukemia in Canada. Biologic heterogeneity of cll between patients results in variable disease trajectories and responses to therapy. Notably, compared with patients lacking high-risk features, those with such features—such as deletions in chromosome 17p, aberrations in the TP53 gene, or unmutated immunoglobulin heavy chain variable region genes—experience inferior outcomes and responses to standard chemoimmunotherapy. Novel agents that target the B cell receptor signalling pathway, such as Bruton tyrosine kinase (btk) inhibitors, have demonstrated clinical efficacy and safety in patients with treatment-naïve cll, particularly those with high-risk features. However, given the current lack of head-to-head trials comparing btk inhibitors, selection of the optimal btk inhibitor for patients with cll is unclear and requires consideration of multiple factors. In the present review, we focus on the efficacy, safety, and pharmacologic features of the btk inhibitors that are approved or under clinical development, and we discuss the practical considerations for the use of those agents in the Canadian treatment landscape.

Purpose: Chronic lymphocytic leukemia (CLL) remains incurable despite advances in therapy. In this study, we characterize the effect of nicotinamide phosphoribosyltransferase (NAMPT) inhibition by FK866 in primary CLL cells from patients with various clinical prognostic markers. Experimental Design: CLL cells were treated with FK866 to assess viability by Annexin V/PI staining. Functional analysis of FK866 included time- and concentration-dependent evaluation of cellular NAD, ATP, mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and apoptotic signaling. Chemosensitization potential by FK866 to fludarabine was also assessed. Prognostic markers were correlated with drug response. Results: FK866 induced CLL cell death by depleting cellular NAD content by day 1, followed by a drop in ATP on day 2. We observed loss of MMP, ROS increase, and induction of apoptotic signaling at day 3. On-target activity of FK866 was confirmed by NAD-mediated rescue of NAD and ATP loss, apoptotic signaling, and viability. The response to FK866 was independent of most prognostic markers. Higher doses were required with short lymphocyte doubling time and positive CD38 status, whereas CLL cells resistant to fludarabine in vitro and from patients with del17p13.1 were equally sensitive to FK866. FK866 did not upregulate the p53-target p21, nor did the p53 activator Nutlin improve FK866-mediated cell death. Furthermore, fludarabine and FK866 were synergistic at clinically relevant concentrations. Conclusions: NAMPT inhibition by FK866 may be a potential treatment for CLL, including patients with del17p13.1 or other high-risk features. FK866 may complement standard agents to enhance their efficacy and/or allow dose reduction for improved tolerability. Clin Cancer Res; 20(18); 4861–72. ©2014 AACR.