Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease
Talha Munir1, David A Cairns1, Adrian Bloor1
1From the Department of Clinical Hematology (T.M., P.H.) and the Hematological Malignancy Diagnostic Service (N.W., S.D., R.T., A.R.), Leeds Cancer Centre, and the Leeds Cancer Research UK Clinical Trials Unit (D.A.C., D.H., A.H., S.J., N.G., S.G., S.B., J.M.B.) and Leeds Institute of Medical Research (N.W., S.D., P.H.), University of Leeds, Leeds, the Christie Hospital NHS Foundation Trust and the University of Manchester, Manchester (A.B.), Hull University Teaching Hospitals NHS Trust, Hull (D.A.), University College London Hospitals NHS Foundation Trust (K.C.), the Comprehensive Cancer Centre, King's College London (P.E.M.P.), King's College Hospital NHS Foundation Trust (P.E.M.P.), and Barts Health NHS Trust (J.G.), London, the Clatterbridge Cancer Centre NHS Foundation Trust and the University of Liverpool, Liverpool (A.P.), University Hospitals Birmingham NHS Foundation Trust, Birmingham (S.P.), Nottingham University Hospitals NHS Trust, Nottingham (C.P.F), Oxford University Hospitals NHS Foundation Trust, Oxford (T.A.E., A.S.), Cancer Sciences, Faculty of Medicine, University of Southampton and the Hematology Department, Cancer Care Directorate, University Hospital Southampton NHS Foundation Trust, Southampton (F.F.), University Hospital of Wales, Cardiff (N.E.), University Hospitals of Leicester NHS Trust, Leicester (B.K.), Worcestershire Acute Hospitals NHS Trust, Worcester (N.P.), Belfast City Hospital, Belfast (O.S.), Aberdeen Royal Infirmary, Aberdeen (G.P.), University Hospitals Dorset NHS Foundation Trust, Bournemouth (R.W.), and CLL Support, Chippenham (L.D.) - all in the United Kingdom.
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.).
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