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N Engl J Med. 2018 Dec 27;379(26):2517-2528. doi: 10.1056/NEJMoa1812836. Epub 2018 Dec 1.

Ibrutinib Regimens versus Chemoimmunotherapy in Older Patients with Untreated CLL.

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From Ohio State University Comprehensive Cancer Center, Columbus (J.A.W., A.S.R., N.A.H., W.Z., K.A.R., G.L., J.S.B., H.G.O., J.C.B.); the Alliance Statistics and Data Center (A.S.R., A.M.B., B.M.-E., B.F., S.J.M.), Mayo Clinic (W.D., S.A.P., M.L.), Rochester, MN; Washington University School of Medicine, St. Louis (N.L.B.); Duke Cancer Institute, Duke University Medical Center, Durham (D.M.B., H.E.), and First Health of the Carolinas Cancer Center, Pinehurst (C.K.) - both in North Carolina; the University of Rochester Medical Center, Rochester, NY (P.M.B.); Stanford University School of Medicine, Stanford (S.C.), and the City of Hope Comprehensive Cancer Center, Duarte (A.H.) - both in California; Dana-Farber Partners CancerCare (J.R.B., R.M.S.) and the Massachusetts General Hospital Cancer Center (J.S.A.) - both in Boston; Fort Wayne Medical Oncology and Hematology, Fort Wayne, IN (S.N.); University of Chicago Comprehensive Cancer Center (R.A.L.) and Loyola University Chicago (S.E.S.) - both in Chicago; the University of Calgary, Tom Baker Cancer Centre, Calgary, AB, Canada (C.O.); and the Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD (R.F.L.).



Ibrutinib has been approved by the Food and Drug Administration for the treatment of patients with untreated chronic lymphocytic leukemia (CLL) since 2016 but has not been compared with chemoimmunotherapy. We conducted a phase 3 trial to evaluate the efficacy of ibrutinib, either alone or in combination with rituximab, relative to chemoimmunotherapy.


Patients 65 years of age or older who had untreated CLL were randomly assigned to receive bendamustine plus rituximab, ibrutinib, or ibrutinib plus rituximab. The primary end point was progression-free survival. The Alliance Data and Safety Monitoring Board made the decision to release the data after the protocol-specified efficacy threshold had been met.


A total of 183 patients were assigned to receive bendamustine plus rituximab, 182 to receive ibrutinib, and 182 to receive ibrutinib plus rituximab. Median progression-free survival was reached only with bendamustine plus rituximab. The estimated percentage of patients with progression-free survival at 2 years was 74% with bendamustine plus rituximab and was higher with ibrutinib alone (87%; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.26 to 0.58; P<0.001) and with ibrutinib plus rituximab (88%; hazard ratio, 0.38; 95% CI, 0.25 to 0.59; P<0.001). There was no significant difference between the ibrutinib-plus-rituximab group and the ibrutinib group with regard to progression-free survival (hazard ratio, 1.00; 95% CI, 0.62 to 1.62; P=0.49). With a median follow-up of 38 months, there was no significant difference among the three treatment groups with regard to overall survival. The rate of grade 3, 4, or 5 hematologic adverse events was higher with bendamustine plus rituximab (61%) than with ibrutinib or ibrutinib plus rituximab (41% and 39%, respectively), whereas the rate of grade 3, 4, or 5 nonhematologic adverse events was lower with bendamustine plus rituximab (63%) than with the ibrutinib-containing regimens (74% with each regimen).


Among older patients with untreated CLL, treatment with ibrutinib was superior to treatment with bendamustine plus rituximab with regard to progression-free survival. There was no significant difference between ibrutinib and ibrutinib plus rituximab with regard to progression-free survival. (Funded by the National Cancer Institute and Pharmacyclics; number, NCT01886872 .).

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