Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease

Munir, Talha; Cairns, David A.; Bloor, Adrian; Allsup, David; Cwynarski, Kate; Pettitt, Andrew; Paneesha, Shankara; Fox, Christopher P.; Eyre, Toby A.; Forconi, Francesco; Elmusharaf, Nagah; Kennedy, Ben; Gribben, John; Pemberton, Nicholas; Sheehy, Oonagh; Preston, Gavin; Schuh, Anna; Walewska, Renata; Duley, Lelia; Howard, Dena; Hockaday, Anna; Jackson, Sharon; Greatorex, Natasha; Girvan, Sean; Bell, Sue; Brown, Julia M.; Webster, Nichola; Dalal, Surita; de Tute, Ruth; Rawstron, Andrew; Patten, Piers E.M.; Hillmen, Peter

Abstract

BACKGROUND: The combination of ibrutinib and venetoclax has been shown to improve outcomes in patients with chronic lymphocytic leukemia (CLL) as compared with chemoimmunotherapy. Whether ibrutinib-venetoclax and personalization of treatment duration according to measurable residual disease (MRD) is more effective than fludarabine-cyclophosphamide-rituximab (FCR) is unclear. METHODS: In this phase 3, multicenter, randomized, controlled, open-label platform trial involving patients with untreated CLL, we compared ibrutinib-venetoclax and ibrutinib monotherapy with FCR. In the ibrutinib-venetoclax group, after 2 months of ibrutinib, venetoclax was added for up to 6 years of therapy. The duration of ibrutinib-venetoclax therapy was defined by MRD assessed in peripheral blood and bone marrow and was double the time taken to achieve undetectable MRD. The primary end point was progression-free survival in the ibrutinib-venetoclax group as compared with the FCR group, results that are reported here. Key secondary end points were overall survival, response, MRD, and safety. RESULTS: A total of 523 patients were randomly assigned to the ibrutinib-venetoclax group or the FCR group. At a median of 43.7 months, disease progression or death had occurred in 12 patients in the ibrutinib-venetoclax group and 75 patients in the FCR group (hazard ratio, 0.13; 95% confidence interval [CI], 0.07 to 0.24; P<0.001). Death occurred in 9 patients in the ibrutinib-venetoclax group and 25 patients in the FCR group (hazard ratio, 0.31; 95% CI, 0.15 to 0.67). At 3 years, 58.0% of the patients in the ibrutinib-venetoclax group had stopped therapy owing to undetectable MRD. After 5 years of ibrutinib-venetoclax therapy, 65.9% of the patients had undetectable MRD in the bone marrow and 92.7% had undetectable MRD in the peripheral blood. The risk of infection was similar in the ibrutinib-venetoclax group and the FCR group. The percentage of patients with cardiac serious adverse events was higher in the ibrutinib-venetoclax group than in the FCR group (10.7% vs. 0.4%). CONCLUSIONS: MRD-directed ibrutinib-venetoclax improved progression-free survival as compared with FCR, and results for overall survival also favored ibrutinib-venetoclax. (Funded by Cancer Research UK and others; FLAIR ISRCTN Registry number, ISRCTN01844152; EudraCT number, 2013-001944-76.).

• Journal Article Type: Article
• Acceptance Date: Dec 1, 2023
• Online Publication Date: Dec 10, 2023
• Publication Date: Jan 25, 2024
• Deposit Date: Feb 9, 2024
• Publicly Available Date: Feb 9, 2024
• Journal: New England Journal of Medicine
• Print ISSN: 0028-4793
• Electronic ISSN: 1533-4406
• Publisher: Massachusetts Medical Society
• Peer Reviewed: Peer Reviewed
• Volume: 390
• Issue: 4
• Pages: 326-337
• DOI: https://doi.org/10.1056/nejmoa2310063
• Public URL: https://nottingham-repository.worktribe.com/output/31157122
• Publisher URL: https://www.nejm.org/doi/10.1056/NEJMoa2310063