Research in context
Evidence before this study
We searched the PubMed database (using the terms “treatment-naive” OR “treatment naive” OR “untreated” AND “Bruton” OR “Bruton's” OR “ibrutinib” OR “acalabrutinib” OR “zanubrutinib” AND “chronic lymphocytic leukemia” OR “chronic lymphocytic leukaemia”) to find research published between Jan 1, 2000, and Oct 3, 2019. No published randomised studies have analysed the efficacy of the Bruton tyrosine-kinase (BTK) inhibitor acalabrutinib either as monotherapy or in combination with an anti-CD20 monoclonal antibody in patients with untreated chronic lymphocytic leukaemia, or compared acalabrutinib (with or without an anti-CD20 antibody) with chemoimmunotherapy. Previous randomised, controlled studies have shown the superior efficacy of the BTK inhibitor ibrutinib with or without an anti-CD20 monoclonal antibody compared with chemoimmunotherapy in chronic lymphocytic leukaemia. These studies reported that adding rituximab to ibrutinib treatment did not increase the likelihood for progression-free survival versus ibrutinib monotherapy in patients with chronic lymphocytic leukaemia. Obinutuzumab, which is a more potent and efficacious anti-CD20 monoclonal antibody compared with rituximab, used in combination with ibrutinib, has been shown to provide greater efficacy than chemoimmunotherapy.
Added value of this study
The results of this study provide new evidence for therapy in patients with treatment-naive chronic lymphocytic leukaemia by showing the efficacy of acalabrutinib used with or without obinutuzumab compared with chemoimmunotherapy. Acalabrutinib with or without obinutuzumab was associated with improved efficacy over obinutuzumab-chlorambucil with a manageable safety profile. After a median follow-up of 28·3 months, the primary endpoint was met at the interim analysis, showing significantly longer progression-free survival with acalabrutinib-obinutuzumab versus obinutuzumab-chlorambucil. Similarly, acalabrutinib monotherapy was associated with statistically improved progression-free survival versus obinutuzumab-chlorambucil therapy. Improvements in progression-free survival were consistently observed across prespecified patient subgroups, including age and high-risk genomic features such as del(17)(p13.1), unmutated immunoglobulin heavy-chain variable-region (IGHV), and complex karyotype. A post hoc analysis showed the benefit of adding obinutuzumab therapy to acalabrutinib in treatment-naive patients who have chronic lymphocytic leukaemia, which had not been previously reported in a randomised trial. Indeed, this is the first study to provide insight into the value of a third-generation anti-CD20 antibody plus a BTK inhibitor over a BTK inhibitor alone in chronic lymphocytic leukaemia.
Implications of all the available evidence
These results show the clinical potential of acalabrutinib as first-line therapy, either in combination with obinutuzumab or as monotherapy, to improve clinical outcomes in patients with chronic lymphocytic leukaemia.