Novel Treatments for Chronic Lymphocytic Leukemia and Moving Forward

Abstract

The last several years have seen an explosion of novel therapies for chronic lymphocytic leukemia (CLL). These include the antibody obintutuzumab (GA-101), as well as small-molecule inhibitors of key pathways involved in the pathogenesis of CLL, specifically the B-cell receptor (BCR) pathway (especially Bruton's tyrosine kinase [BTK] and P13K), and the antiapoptotic pathway (especially BCL-2). We will consider each in turn, focusing on the molecules most advanced in clinical development. There has also been extensive development in rewiring the patient's own immune system to treat CLL. This has been done through modifying autologous T cells to express a chimeric antigen receptor (CAR). Thus far all CAR-T preparations have targeted the CD19 antigen. This is a good rational for B-cell malignancies as CD19 expression is limited to B-cell malignancies and normal B cells. The in vivo amplification of the transduced T cells relies on signaling and co-signaling domains and provides significant killing of CLL cells. As exciting as these novel agents and approaches are, they obviously beg the question, will chemotherapy as a treatment for CLL soon be obsolete? Although chemotherapy is associated with known short-term toxicities, it has the advantage of being completed in a short period of time and being relatively inexpensive in comparison to novel therapies. In addition, long-term follow-up of results with chemoimmunotherapy have now identified a group of patients whose remissions are maintained for more than 10 years. An important question that will arise going forward is how to incorporate novel agents without eliminating the long term benefits possible with chemoimmunotherapy in a subset of patients with CLL.KEY POINTSB-cell receptor inhibitors, such as ibrutinib and idelalisib, result in rapid reduction in lymphadenopathy with a simultaneous rise in the absolute lymphocyte count which should not be mistaken for progressive disease.ABT-199, a novel BCL-2 inhibitor, results in marked efficacy in patients with relapsed and refractory disease but also can result in tumor lysis.All trials with targeted oral agents have thus far been designed with continuous administration compared with the short specified number of cycles seen with chemotherapy.Chimeric antigen receptor (CAR)–modified T-cell therapy is associated with prolonged remissions in patients with refractory disease; toxicities include a cytokine release syndrome that may be abrogated by anti–interleukin-6 (IL-6) monoclonal antibodies.Fludarabine/cyclophosphamide/rituximab (FCR) can result in remissions lasting 10 years in a subset of patients with mutated IgVH genes and absence of poor cytogenetics such as 17p deletion or 11q deletion.