Current and Emerging Drug Therapies in Chronic Lymphocytic Leukemia

Oncology & Hematology Review, 2017;13(1):34–40 DOI:


Until 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.
Acknowledgments: 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 09, 2017
Correspondence: Nishitha M Reddy, 3927 The Vanderbilt Clinic, Vanderbilt University Medical Center, Nashville, Tennessee, US. E:
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.

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.

Chemoimmunotherapy regimens in CLL—fit patients with no major comorbidities
CIT regimens combine chemotherapeutic agents with a CD20 antibody like rituximab, ofatumumab and obinutuzumab. CIT regimens such as fludarabine, cyclophosphamide, and rituximab (FCR) have been the mainstay of frontline CLL therapy especially in the young, fit individuals. At present, there is no proven benefit to early treatment of patients with CLL. Patients who meet criteria for treatment need to be stratified further based on fitness assessment (age, organ function and performance status) and biological risk (most importantly TP53mutation and /or del[17p]) for treatment decision. Table 1 summarizes the trials comparing different CIT combinations incorporating cytotoxic chemotherapy in combination with a CD20 monoclonal antibody (mAb) that are recommended in the young and elderly fit patients.

FCR is the regimen of choice in young (<65 years), fit patients without evidence of TP53 disruption based on the FCR300 and CLL8 trials. In FCR300,3 a single arm phase II study received FCR as first line treatment. At a median follow up of 6 years, complete remission (CR) was seen in 72% with an overall response rate (ORR) of 95%. Six-year overall survival (OS) rate was 77% and progression free survival (PFS) rate was 51%. Recently updated results at a median follow up of 12.8 years show a median PFS of 6.4 years. Considering unmutated (UM) and mutated (M) immunoglobulin heavy chain variable (IGHV) gene status, IGHV-UM and IGHV-M, 12.8 year PFS was 8.7% and 53.9% respectively. Importantly, in the IGHV-M subgroup there were no relapses after 10.4 years represented by a plateau on the PFS curve.4 A larger phase III study, the CLL8 trial compared FCR with FC. FCR was associated with a superior ORR (90% versus 80%), CR (44% versus 22%), 3-year PFS (65% versus 45%), and 3-year OS (87% versus 83%). FCR was associated with a higher rate of grade 3/4 neutropenia.5 Long-term follow up studies after FCR treatment have revealed durable responses in patients with IGHV-M CLL and those without del(17p) or del(11q).4,6,7

Bendamustine and rituximab (BR) was evaluated in a phase II study with 117 patients in the front-line setting showed an ORR of 88% and a CR rate of 23%. At a median follow up of 27 months, the median (m)-PFS was 33.9 months. A quarter of the patients in this study were >70 years and their m-PFS was similar to younger patients despite a lower ORR in this age group.8 Further in the randomized phase III CLL10 trial, BR was compared with FCR in the front-line setting.9 This was a non-inferiority trial with PFS as primary endpoint and excluded patients with del(17p). The final analysis of 561 patients included 282 patients in the FCR arm and 279 in the BR arm. At a median follow up of 37.1 months, the m-PFS was 55.2 months and 41.7 months in the FCR and BR arms respectively. OS was not different between the two arms. The FCR arm was associated with more grade 3/4 neutropenia and infections especially in patients older than 65 years. There was no difference in PFS in the subgroup of patients >65 years. In addition, post-hoc analysis, favored the use of FCR in patients with IGHV-UM (p=0.017) and del(11q) (p=0.0002) CLL. Due to a lower rate of complications in older patients, BR is a reasonable front-line choice in fit CIT eligible patients >65 years of age. Several additional CIT regimens were tested in the frontline setting and are summarized in Table 1.10–14

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Keywords: CLL, novel agents, targeted therapy