EHA Library - The official digital education library of European Hematology Association (EHA)

Mechanisms of resistance to targeted therapies in chronic lymphocytic leukemia
EHA Library. Sutton L. 06/15/19; 273671
Lesley-Ann Sutton
Lesley-Ann Sutton
Learning Objectives

Tadeusz Robak - Chair introduction

Chronic lymphocytic leukemia (CLL) is the most common forms of adult leukemia in the Western world, and is typically diagnosed at 70 years. This is an exciting era in CLL biology, particularly for its understanding, prognostic classification and novel treatment approaches. This educational session will review recent developments in the biology and treatment of CLL. In the first talk, Dr Philip J Law and Dr Richard S Houlston from the Institute of Cancer Research, Sutton (United Kingdom) will review the familial risks of CLL. They will discuss the genomewide association studies (GWAS) that identified the single nucleotide polymorphisms (SNPs) at 43 genetic regions influencing the risk of sporadic CLL. Therapeutic strategies are changing rapidly with the introduction of newer drugs, most of which are orally available, and which are more effective and better tolerated than previously-available therapies. Two of the leading agents now used in the treatment of CLL are ibrutinib and venetoclax. Although these newer agents have improved the prognosis of CLL, particularly in older patients and patients with high-risk genetics, especially thosewith del 17p/TP53 mutation and unmutated immunoglobulin variable region heavy chain (IGHV), resistant cases are sometimes observed and treatment is often discontinued due to disease progression. In the second lecture, Dr LA Sutton from the Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm (Sweden) will review the mechanism of resistance to novel antileukemic agents used inCLL. Finally, Dr Iris de Weerdt and Dr Arnon P Kater from the University of Amsterdam (The Netherlands) will review new treatment approaches, particularly combination therapies including chemotherapy-free regimens, in previously-untreated and refractory/relapsed patients with CLL in 2019. The results of recent trials clearly demonstrate improved progression-free survival, and sometimes overall survival, associated with the use of newtargeted drugs, as single agents or in combination with anti-CD20 monoclonal antibodies, compared with chemoimmunotherapy.

Learning goals of the article
• Get knowledge of the growing importance of molecular genetics providing evidence for inherited susceptibility to CLL and risk of sporadic disease.
• To understand the mechanisms of acquired clinical resistance in patients treated with novel targeted drugs, particular with ibrutinib, idelalisib, and venetoclax.
• To learn that many new combination therapies with targeted drugs, monoclonal anti-CD20 antibodies and chemotherapy will improve the outcome of the standard of care for CLL.

Learning goals of the presentation
After attending this lecture, the participant will be able to
• understand how next-generation sequencing technologies are helping us to explore the genetic landscape of chronic lymphocytic leukemia patients relapsing on novel therapies,
• understand resistance mechanisms to kinase inhibitors in chronic lymphocytic leukemia, and
• gain insight into the potential mechanisms leading to relapse following treatment with small-molecule inhibitors of the antiapoptotic protein BCL2.

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