Venetoclax: a chance for patients with chronic lymphocytic leukaemia previously treated with ibrutinib

Abstract

In recent years, biological and clinical research has identified several targeted agents that are changing the management of patients with chronic lymphocytic leukaemia. In clinical trials, 1 Jain N O'Brien S Targeted therapies for CLL: practical issues with the changing treatment paradigm. Blood Rev. 2016; 30: 233-244 Crossref PubMed Scopus (55) Google Scholar the B-cell receptor inhibitor ibrutinib has led to durable responses and longer survival (overall and progression-free) than chemotherapy in patients with this disease. Ibrutinib is now largely used in clinical practice in patients with chromosome 17p deletions or TP53 mutations and relapsed or refractory chronic lymphocytic leukaemia. More recently, the drug has also been approved in the USA and European Union as a front-line therapy for chronic lymphocytic leukaemia. 1 Jain N O'Brien S Targeted therapies for CLL: practical issues with the changing treatment paradigm. Blood Rev. 2016; 30: 233-244 Crossref PubMed Scopus (55) Google Scholar However, many patients discontinue ibrutinib because of adverse events such as atrial fibrillation, infections, and cytopenias. Another common reason for treatment discontinuation is disease progression, which is observed most frequently in patients with TP53 mutations or complex karyotypes. 2 Jain P Keating M Wierda W et al. Outcomes of patients with chronic lymphocytic leukemia after discontinuing ibrutinib. Blood. 2015; 125: 2062-2067 Crossref PubMed Scopus (284) Google Scholar , 3 Mato AR Nabhan C Barr PM et al. Outcomes of CLL patients treated with sequential kinase inhibitor therapy: a real world experience. Blood. 2016; 128: 2199-2205 Crossref PubMed Scopus (142) Google Scholar Mutations conferring resistance to ibrutinib are also commonly found in patients with high-risk genetic landscapes or who have disease progression during ibrutinib treatment. 4 Woyach JA Ruppert AS Guinn D et al. BTKC481S-mediated resistance to ibrutinib in chronic lymphocytic leukemia. J Clin Oncol. 2017; 35: 1437-1443 Crossref PubMed Scopus (267) Google Scholar , 5 Jones D Woyach JA Zhao W et al. PLCG2 C2 domain mutations co-occur with BTK and PLCG2 resistance mutations in chronic lymphocytic leukemia undergoing ibrutinib treatment. Leukemia. 2017; 31: 1645-1647 Crossref PubMed Scopus (40) Google Scholar Outcomes after ibrutinib discontinuation are poor, 2 Jain P Keating M Wierda W et al. Outcomes of patients with chronic lymphocytic leukemia after discontinuing ibrutinib. Blood. 2015; 125: 2062-2067 Crossref PubMed Scopus (284) Google Scholar , 3 Mato AR Nabhan C Barr PM et al. Outcomes of CLL patients treated with sequential kinase inhibitor therapy: a real world experience. Blood. 2016; 128: 2199-2205 Crossref PubMed Scopus (142) Google Scholar and few treatment options are available for such patients. Therefore, treatment options for patients with relapsed or refractory disease previously treated with ibrutinib are a primary unmet medical need in the management of chronic lymphocytic leukaemia, especially given the increasing use of this drug in clinical practice. Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trialThe results of this interim analysis show that venetoclax has durable clinical activity and favourable tolerability in patients with relapsed or refractory chronic lymphocytic leukaemia whose disease progressed during or after discontinutation of ibrutinib therapy. The durability of response to venetoclax will be assessed in the final analysis in 2019. Full-Text PDF