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The therapeutic landscape of chronic lymphocytic leukemia (CLL) underwent a paradigm shift in 2014 with the approval of ibrutinib, which binds covalently to the C481 residue of Bruton’s tyrosine kinase (BTK) and irreversibly inhibits it. A number of large, phase 3 trials conducted in both the frontline and the relapsed/refractory settings resulted in the approval of ibrutinib for all CLL. Indeed, the role of chemoimmunotherapy in CLL is fast dwindling. The limitations of ibrutinib, e.g. the development of resistance-conferring C481 BTK mutations and the toxicity issues of atrial fibrillation and bleeding, in particular, have also become apparent with longer-term follow-up. This has spurred the development of second-generation, irreversible inhibitors with greater selectivity for BTK and third-generation, reversible BTK inhibitors to address C481 site mutations. The last 3 years have also witnessed enormous growth in the therapeutic role of the B-cell lymphoma 2 (BCL-2) antagonist venetoclax, initially approved (in 2016) only for patients with relapsed, 17p-deleted CLL. Venetoclax, in combination with CD20 antibodies, is currently approved for both treatment-naïve and relapsed/refractory patients, regardless of genomic subtype. Robust results have also been reported for ibrutinib plus venetoclax, and “triple” combinations of a BTK inhibitor, venetoclax, and obinutuzumab are now being pursued. The major questions facing the field at present are how best to select patients for BTK inhibitor monotherapy versus venetoclax/obinutuzumab upfront, what to do after failure of both BTK inhibitor(s) and venetoclax, and the ideal way to integrate measurable residual disease data into decisions regarding treatment choice, duration, and discontinuation.

Managing chronic lymphocytic leukemia in 2020: an update on recent clinical advances with a focus on BTK and BCL-2 inhibitors