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Review Leukemia Current and Emerging Drug Therapies in Chronic Lymphocytic Leukemia Tarsheen K Sethi and Nishitha M Reddy Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, US U ntil recently, chemoimmunotherapy has been the mainstay of treatment approach in chronic lymphocytic leukemia (CLL) patients requiring intervention. With the emergence of targeted treatments, there has been a shift in CLL therapy. With a better understanding of disease biology and risk stratification, a tailored approach based on patient age and comorbidities has evolved over time. The development of new and potent, next generation CD20 antibodies has refined therapy options especially for elderly unfit patients. Furthermore, agents targeting important pathways involved in proliferation and survival of CLL cells including B-cell receptor (BCR) signaling have provided additional treatment options in traditionally chemo-refractory CLL. Given the rapidly expanding repertoire of drugs, current research is focused on optimizing treatment sequence, duration of treatment and assessing long-term toxicities. Several immune mediated therapies are emerging and new combinations are being tested to re-establish antitumor immune effector response in CLL. While embracing the advances in CLL therapy, a few longstanding lessons remain. There is still little role of treatment of asymptomatic individuals. This review presents an overview of current and emerging drug therapies in the rapidly changing area of CLL treatment. Keywords CLL, novel agents, targeted therapy Disclosure: Tarsheen K Sethi and Nishitha M Reddy have nothing to disclose in relation to this article. No funding was received for the publication of this article. This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors. Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit. Received: February 10, 2017 Accepted: March 9, 2017 Citation: Oncology & Hematology Review, 2017;13(1):34–40 Corresponding Author: Nishitha M Reddy, 3927 The Vanderbilt Clinic, Vanderbilt University Medical Center, Nashville, Tennessee, US. E: nishitha.reddy@vanderbilt.edu 34 Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia with an estimated 18,960 new cases diagnosed in the US in 2016. 1 The past few years have witnessed major advances in the treatment of CLL with several new drugs receiving US Food and Drug Administration (FDA) approval in both the frontline and relapsed/refractory setting leading to improvement in overall survival (OS). The availability of several active and relatively well-tolerated agents has raised questions on the optimal drug sequence, duration, and tailoring therapy based on the underlying disease biology. With effective drugs in the previously considered poor prognostic individuals, there is also a need to redefine the prognostic criteria. Several guiding principles have already been established including the management of early asymptomatic disease with observation alone. Indications for treatment of untransformed disease include at least one of the following based on The International Workshop Group on CLL (IWCLL) 2008 guidelines: 2 • • • • • • Progressive marrow failure due to CLL infiltration as evidenced by worsening cytopenias Massive (>6 cm below costal margin) splenomegaly with symptoms Bulky (>10 cm) or symptomatic lymphadenopathy Progressive lymphocytosis Autoimmune cytopenias unresponsive to immunosuppressive therapy Presence of B symptoms or significant fatigue (Eastern Cooperative Oncology Group Performance Status [ECOG PS] of 2 or more related to disease). In those that meet criteria for treatment, important considerations include: patient age, performance status, comorbidities, and presence of chromosomal aberrations. Recent advancements in the understanding of disease biology have highlighted the importance of several potentially targetable pathways contributing to disease pathogenesis such as aberrant activation of BCR signaling pathway, anti-apoptotic BCL2 pathway, and the role of the microenvironment. These novel agents have expanded the repertoire for patients ineligible for chemoimmunotherapy (CIT) due to age or comorbidities and those with poorly responsive disease (high risk genomics such as del[17p]). This review aims to outline the role of standard CIT, targeted agents and ongoing studies of novel agents defining the present landscape of CLL drug treatment. Currently approved therapies and general treatment approach in the first-line and relapsed/refractory (R/R) settings are summarized in Figure 1. TOUCH ME D ICA L ME D IA