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Chronic lymphocytic leukemia

Chronic lymphocytic leukemia in 2020: a surfeit of riches?

Leukemia volume 34, pages 1979–1983 (2020)Cite this article

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How did we get to these recent and dramatic advances in CLL therapy? The tidal wave resulted from substantial advances in understanding the biology of CLL, especially the reliance of CLL cells on the lymph node and bone marrow microenvironment to survive [2,3,4,5]. Small molecule inhibitors of the B-cell receptor signaling pathway such as ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor and idelalisib, a phosphoinositide 3-kinase inhibitor, were approved based on data from randomized studies comparing these drugs to previously approved therapies such as single-agent ofatumumab, chlorambucil, and rituximab [6,7,8]. However, two major North American Inter Group (NAIG) studies recently reported better PFS with ibrutinib with or without rituximab compared with CIT in previously untreated persons with CLL (FCR in adults <70 years [E1912] [9], and bendamustine and rituximab in those >65 years of age [A041202]) [10]. The E1912 trial also reported better overall survival (OS) of young persons with CLL receiving ibrutinib and rituximab compared with FCR. People typically considered having poor risk disease such as those with unmutated IGHV genes, del(17p), and complex cytogenetics also benefit from ibrutinib. Despite these excellent outcomes, ibrutinib therapy is associated with several issues: (1) non-hematologic adverse events such as hypertension, atrial fibrillation, bleeding, and others requiring stopping therapy in up to 40% of people [11]; and (2) emergence of mutations in BTK and/or PLCG2 resistant to ibrutinib and eventuating in disease progression [12]. Unfortunately, many other BTK inhibitors studied in advanced clinical trials for CLL, such as zanubrutinib and tirabrutinib, or drugs recently approved such as acalabrutinib, are inactive against these mutations.

In most cancers, drugs which are effective and safe in advanced disease work as well or better when given as initial therapy. This is not necessarily so in CLL. For example, use of idelalisib as initial therapy is associated increased risks of opportunistic infections, autoimmune complications, and deaths resulting in the stopping of several clinical trials [13]. These events are an important reminder to rigorously test new drugs in carefully conducted clinical trials before broader clinical use. Advances in our understanding of how CLL B-cells survive led to the finding of an important role for BCL2 in the pathogenesis of CLL. Consequently, it was not surprising venetoclax, a BH3 mimetic, combined with obinutuzumab improved PFS compared with chlorambucil and obinutuzumab [14]. However, this combination does not overcome the poor prognosis associated with TP53 disruption (genetic defects detected by either del(17p) by FISH or TP53 mutation by Sanger or next generation sequencing).

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Fig. 1: Timeline of US Food and Drug Administration approvals for chronic lymphocytic leukemia.

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Acknowledgements

RPG acknowledges support from the National Institute of Health Research (NIHR) Biomedical Research Centre funding scheme. NEK acknowledges support from the National Institutes of Health RO1 AG58266 and RO1 CA 193541.

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  1. Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA

    Sameer A. Parikh & Neil E. Kay

  2. Department of Immunology and Inflammation, Centre for Haematology, Imperial College London, London, UK

    Robert Peter Gale

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Correspondence to Sameer A. Parikh.

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SAP: research funding to the institution from Pharmacyclics, MorphoSys, Janssen, Astra Zeneca, TG Therapeutics, Bristol Myers Squibb, AbbVie, and Ascentage Pharma. Advisory Board compensation to the institution from: Pharmacyclics, AstraZeneca, Genentech, Gilead, GlaxoSmithKline, Verastem Oncology, and AbbVie. NEK: research funding to the institution from Acerta Pharma, Bristol Myers Squibb, Pharmacyclics, Tolero Pharmaceuticals, MEI Pharma Abbvie and Sunesis. Data Safety Monitoring Committee (DSMC) for Agios Pharm, AstraZeneca, Cytomyx Therapeutics, and Rigel. Advisory Board for Cytomx Therapy, Pharmacyclics, Juno Therapeutics, Astra Zeneca, and Oncotracker. The other author declare that he has no conflict of interest.

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Parikh, S.A., Gale, R.P. & Kay, N.E. Chronic lymphocytic leukemia in 2020: a surfeit of riches?. Leukemia 34, 1979–1983 (2020). https://doi.org/10.1038/s41375-020-0852-7

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