Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease

Background: Ibrutinib plus venetoclax improves outcomes in chronic lymphocytic leukemia (CLL) versus chemoimmunotherapy, but whether ibrutinib–venetoclax with treatment duration individualized by measurable residual disease (MRD) is more effective than fludarabine–cyclophosphamide–rituximab (FCR) is unclear. Methods: In this phase 3, multicenter, randomized, open-label trial in previously untreated CLL, ibrutinib–venetoclax and ibrutinib monotherapy were compared with FCR. In the ibrutinib–venetoclax group, venetoclax was added after 2 months of ibrutinib and continued for up to 6 years; treatment duration was twice the time taken to achieve undetectable MRD in peripheral blood and bone marrow. The primary end point was progression-free survival (PFS) for ibrutinib–venetoclax versus FCR; key secondary end points included overall survival (OS), response, MRD, and safety. Results: Among 523 randomized patients, at a median of 43.7 months, progression or death occurred in 12 patients with ibrutinib–venetoclax and 75 with FCR (hazard ratio [HR], 0.13; 95% CI, 0.07–0.24; P<0.001). Death occurred in 9 and 25 patients, respectively (HR, 0.31; 95% CI, 0.15–0.67). At 3 years, 58.0% of patients in the ibrutinib–venetoclax group had stopped therapy due to undetectable MRD. After 5 years of ibrutinib–venetoclax, 65.9% had undetectable MRD in bone marrow and 92.7% in peripheral blood. Infection risk was similar between groups, while cardiac severe adverse events were more frequent with ibrutinib–venetoclax (10.7% vs. 0.4%). Conclusions: MRD-directed ibrutinib–venetoclax improved PFS compared with FCR, with OS also favoring ibrutinib–venetoclax. (Funded by Cancer Research UK and others; FLAIR ISRCTN01844152; EudraCT 2013-001944-76.)

T. Munir, D.A. Cairns, A. Bloor, D. Allsup, K. Cwynarski, A. Pettitt, S. Paneesha, C.P. Fox, T.A. Eyre, F. Forconi, N. Elmusharaf, B. Kennedy, J. Gribben, N. Pemberton, O. Sheehy, G. Preston, A. Schuh, R. Walewska, L. Duley, D. Howard, A. Hockaday, S. Jackson, N. Greatorex, S. Girvan, S. Bell, J.M. Brown, N. Webster, S. Dalal, R. de Tute, A. Rawstron, P.E.M. Patten, P. Hillmen