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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.
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
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.
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