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Evolution of CLL treatment — from chemoimmunotherapy to targeted and individualized therapy

Abstract

During the past 5 years, a number of highly active novel agents, including kinase inhibitors targeting BTK or PI3Kδ, an antagonist of the antiapoptotic protein BCL-2, and new anti-CD20 monoclonal antibodies, have been added to the therapeutic armamentarium for patients with chronic lymphocytic leukaemia (CLL). In these exciting times, care is needed to optimally integrate these novel agents into the traditional treatment algorithm without overlooking or compromising the benefits of established treatments, especially chemoimmunotherapy. A more personalized approach to CLL therapy that takes into account individual risk factors, patient characteristics, and their treatment preferences is now possible. Herein, we discuss the biological basis for the novel therapeutic agents and outline not only the major advantages of these agents over traditional therapies but also their adverse effects and the rationale for continued use of older versus newer types of therapy for selected patients with CLL. We conclude by providing recommendations for an individualized therapy approach for different populations of patients with CLL.

Key points

  • Novel drugs enable targeting of key pathogenic pathways of chronic lymphocytic leukaemia (CLL), including BTK, SYK, and PI3Kδ inhibitors that disrupt B cell receptor signalling and venetoclax, an antagonist of the anti-apoptotic protein BCL-2.

  • The kinase inhibitors typically cause mobilization of tissue-resident CLL cells into the circulation, resulting in rapid resolution of lymphadenopathy and splenomegaly and transient redistribution lymphocytosis.

  • Kinase inhibitor monotherapy mostly induces partial remissions, which are typically maintained with long-term therapy but can be compromised by toxicities and the emergence of resistance; hence, limited-duration therapy, if effective, would be desirable.

  • Venetoclax has direct cytotoxic activity, sometimes resulting in tumour lysis; this drug has mostly been used after failure of kinase inhibitor therapy, but emerging data support its use in earlier treatment lines and/or in combination with other agents.

  • Given the expanding therapeutic armamentarium for CLL, risk-based individualized therapy is now possible, ranging from chemoimmunotherapy for low-risk (IGHV-mutated) CLL to novel molecularly targeted therapy — primarily with BTK inhibitors — for high-risk (del(17p), IGHV-unmutated) disease.

  • New anti-CD20 antibodies, immunomodulatory agents, and cellular therapies (such as chimeric antigen receptor T cells and allogeneic haematopoietic stem cell transplantation) are additional important components of CLL treatment.

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Fig. 1: Factors in the CLL microenvironment activate growth and survival pathways that can be targeted using novel therapeutic agents.
Fig. 2: Signalling by B cell receptors, chemokine receptors, and adhesion molecules.
Fig. 3: Milestones in biological and clinical CLL research that have paved the way for new targeted therapies.
Fig. 4: Characteristic response of patients with CLL to treatment with BTK or PI3Kδ inhibitors.
Fig. 5: Algorithm for management of patients with CLL.

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Acknowledgements

The work of J.A.B. is supported by a Leukemia & Lymphoma Society Scholar Award in Clinical Research, the University of Texas MD Anderson Cancer Center Chronic Lymphocytic Leukemia (CLL) Moon Shot programme, the CLL Global Research Foundation, and in part by the MD Anderson Cancer Center Support Grant CA016672.

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Nature Reviews Clinical Oncology thanks M. Hallek, T. Robak, and the other, anonymous reviewer(s) for their contribution to the peer review of this work.

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J.A.B. and S.O’B. contributed equally to all stages of preparation of this manuscript for submission.

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J.A.B. has received research support from Gilead and Pharmacyclics. S.O’B. has received research support from Acerta, Gilead, Kite, Pharmacyclics, and TG Therapeutics.

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Burger, J.A., O’Brien, S. Evolution of CLL treatment — from chemoimmunotherapy to targeted and individualized therapy. Nat Rev Clin Oncol 15, 510–527 (2018). https://doi.org/10.1038/s41571-018-0037-8

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