Research in context
Evidence before this study
Based on preclinical data, combination therapies have the potential to enhance the activity of novel agents in the treatment of patients with relapsed or refractory chronic lymphocytic leukaemia. We searched PubMed for clinical trial reports published up to Aug 15, 2016, to identify new agents used to treat relapsed or refractory chronic lymphocytic leukaemia, using the terms “chronic lymphocytic leukemia” and “CLL”, as well as the following terms together with “CLL”: “relapsed” and “refractory”. Nearly 1450 articles were identified using these search parameters, with 279 reporting results of clinical trials. Based on recent data published within the past 5 years, several novel agents, including the B-cell receptor signalling inhibitors ibrutinib and idelalisib, and the BCL-2 inhibitor venetoclax, emerged as effective treatment options in this patient population.
Most patients treated with ibrutinib as a single agent and idelalisib in combination with rituximab (anti-CD20 antibody) achieve disease response; however, the number of complete remissions achieved is low. In addition, some patients are unable to tolerate these agents due to adverse events such as nausea, diarrhoea, colitis, elevated alanine transaminase, and elevated aspartate transaminase enzymes. Outcomes are poor for patients who must discontinue treatment due to toxicity or who progress on therapy; median overall survival after ibrutinib discontinuation ranges from 3 months for patients who have Richter's progression to 18 months for chronic lymphocytic leukaemia progression. To date, phase 2 studies of B-cell receptor signalling inhibitors in combination with other agents have not reported clearly higher complete remission rates than ibrutinib alone and indefinite therapy is still required.
BCL-2 inhibition with venetoclax monotherapy has been shown to result in a high proportion of patients with overall responses and complete remission in two recently published studies: a first-in-human study of patients with relapsed or refractory chronic lymphocytic leukaemia (79% of patients had an overall response with 20% complete remission as determined by investigators) and a phase 2 study of patients with chronic lymphocytic leukaemia that harbours chromosome 17p deletion (79% of patients had an overall response with 8% complete remission, as determined by an independent review committee). In preclinical models of B-cell malignancy, synergy was observed when venetoclax was combined with rituximab.
Added value of the study
This phase 1b study was the first to evaluate venetoclax in any combination for the treatment of patients with relapsed or refractory chronic lymphocytic leukaemia. We hypothesised that venetoclax plus rituximab would be tolerable and increase depth of response. Our results show that venetoclax plus rituximab is highly active with an acceptable safety profile in patients with relapsed or refractory chronic lymphocytic leukaemia. A high proportion of patients achieved an overall response, with 51% of patients achieving a complete remission. Systematic evaluations of serial bone marrow biopsies revealed that 57% of all patients were negative for minimal residual disease. Patients achieving such deep responses can maintain responses without ongoing therapy for periods up to 2 years, and respond to retreatment with venetoclax at progression.
Implications of all available evidence
Venetoclax administration in combination with rituximab is a tolerable and active combination for difficult-to-treat patients with relapsed or refractory chronic lymphocytic leukaemia. The data indicate that minimal residual disease-negative complete remissions are now readily achievable in patients with relapsed chronic lymphocytic leukaemia, and that patients achieving such deep responses need not continue therapy indefinitely. Abbreviated courses of treatment with venetoclax-containing combination regimens should be explored as alternatives to long-term therapy with B-cell receptor signalling inhibitors or venetoclax monotherapy in randomised trials.