Munir, T., Cairns, D.A., Bloor, Adrian, Allsup, D., Cwynarski, K., Pettitt, A., Paneesha, S., Fox, C.P., Eyre, T.A., Forconi, F., Elmusharaf, N., Kennedy, B., Gribben, J., Pemberton, N., Sheehy, O., Preston, G., Schuh, A., Walewska, R., Duley, L., Howard, D., Hockaday, A., Jackson, S., Greatorex, N., Girvan, S., Bell, S., Brown, J.M., Webster, N., Dalal, S., de Tute, R., Rawston, A., Patten, P.E.M. and Hillmen, P. , (2023) Chronic lymphocytic leukemia therapy guided by measurable residual disease. New England Journal of Medicine. (doi:10.1056/NEJMoa2310063).
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 severe 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. opens in new tab; EudraCT number, 2013-001944-76. opens in new tab.)
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