Key Molecular Drivers of Chronic Lymphocytic Leukemia

Alsagaby, Suliman A.; Brennan, Paul; Pepper, Chris

doi:10.1016/j.clml.2016.08.008

Cited by 18 publications

(26 citation statements)

References 263 publications

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“…84 In addition to these drugs under study in clinical trials in CLL, preclinical studies have outlines several additional pathways that can be targeted for therapy including CD38, nuclear factor-κB and MYD88 (beyond lenalidomide and ibrutinib), surrogates of zeta chain- (NOTCH1), and Splicing factor 3B1 (SF3B1). 85 …”

Section: Immunomodulators and Other Immune Based Treatments In Cllmentioning

confidence: 99%

Current and Emerging Drug Therapies in Chronic Lymphocytic Leukemia

Sethi¹,

Reddy²

2017

Oncology &Amp; Hematology Review (US)

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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 therapyDisclosure: 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. 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 tr...

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Section: Immunomodulators and Other Immune Based Treatments In Cllmentioning

confidence: 99%

Current and Emerging Drug Therapies in Chronic Lymphocytic Leukemia

Sethi¹,

Reddy²

2017

Oncology &Amp; Hematology Review (US)

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“…The biological basis for the association between trisomy 12 and t(14;18) has yet to be elucidated. Unlike chromosomal translocations that result in hybrid fusion genes (e.g., BCR-ABL1 in chronic myeloid leukemia), the IGH-BCL2 translocation juxtaposes BCL2 , a gene transcribing an antiapoptotic protein, downstream from a highly transcribed IGH gene, resulting in BCL2 overexpression [2,13]. Interestingly, BCL2 overexpression is also observed in CLL/SLL cells without BCL2 rearrangements, thus making BCL2 an attractive therapeutic target [2,13].…”

Section: Figmentioning

confidence: 99%

“…BCL2 (18q21) rearrangements with immunoglobulin gene partners (IGK [2p11.2], IGH [14q32.33], or IGL [22q11.22]) are characteristically observed in follicular lymphoma and diffuse large B cell lymphoma (DLBCL), but have also been reported, albeit rarely, in splenic marginal zone lymphoma (SMZL) and CLL/SLL [9,10,11,12]. Nevertheless, neoplasms with juxtaposition of BCL2 with an immunoglobulin gene will result in overexpression of the antiapoptotic protein BCL2, thus contributing to oncogenesis [2,13]. To date, only 2 cases of CLL/SLL harboring double-hit translocations involving IGH and BCL2 have been reported; however, both translocations were observed within the same clone [9,11].…”

Section: Figmentioning

confidence: 99%

“…Cytogenetic aberrations observed in CLL/SLL provide valuable prognostic information including trisomy 12 and the deletions 13q14.3, 6q21, 11q22-23 ( ATM ), and 17p13 ( TP53 ) [1,2,3,4,5,6]. Importantly, CLL/ SLL can also acquire cytogenetic aberrations that result in clonal evolution and disease progression [7,8].…”

Section: Figmentioning

confidence: 99%

“…Unlike chromosomal translocations that result in hybrid fusion genes (e.g., BCR-ABL1 in chronic myeloid leukemia), the IGH-BCL2 translocation juxtaposes BCL2 , a gene transcribing an antiapoptotic protein, downstream from a highly transcribed IGH gene, resulting in BCL2 overexpression [2,13]. Interestingly, BCL2 overexpression is also observed in CLL/SLL cells without BCL2 rearrangements, thus making BCL2 an attractive therapeutic target [2,13]. BCL2 inhibitors including venetoclax have yielded impressive results in clinical trials, and appear to be a promising approach for CLL/SLL treatment in the future [2,13].…”

Section: Figmentioning

confidence: 99%

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