Tait D Shanafelt1, Xin V Wang1, Neil E Kay1, Curtis A Hanson1, Susan O'Brien1, Jacqueline Barrientos1, Diane F Jelinek1, Esteban Braggio1, Jose F Leis1, Cong C Zhang1, Steven E Coutre1, Paul M Barr1, Amanda F Cashen1, Anthony R Mato1, Avina K Singh1, Michael P Mullane1, Richard F Little1, Harry Erba1, Richard M Stone1, Mark Litzow1, Martin Tallman1. 1. From Stanford University, Stanford (T.D.S., S.E.C.), the University of California, Irvine, Medical Center, Orange (S.O.), and Kaiser Permanente National Cancer Institute Community Oncology Research Program (NCORP)-Permanente Medical Group, Oakland (C.C.Z.) - all in California; Dana-Farber Cancer Institute, Boston (X.V.W., R.M.S.); Mayo Clinic, Rochester (N.E.K., C.A.H., J.F.L., M.L.), and Minnesota Oncology, Burnsville (A.K.S.) - both in Minnesota; Northwell Health Cancer Institute, Donald and Barbara Zucker School of Medicine at Hofstra-Northwell, Lake Success (J.B.), and University of Rochester, Rochester (P.M.B.) - both in New York; Mayo Clinic, Phoenix, AZ (D.F.J., E.B.); Washington University School of Medicine, St. Louis (A.F.C.); Memorial Sloan Kettering Cancer Center, New York (A.R.M., M.T.); Aurora Cancer Care, West Allis, WI (M.P.M.); National Cancer Institute, Bethesda, MD (R.F.L.); and the University of Alabama, Tuscaloosa (H.E.).
Abstract
BACKGROUND: Data regarding the efficacy of treatment with ibrutinib-rituximab, as compared with standard chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab, in patients with previously untreated chronic lymphocytic leukemia (CLL) have been limited. METHODS: In a phase 3 trial, we randomly assigned (in a 2:1 ratio) patients 70 years of age or younger with previously untreated CLL to receive eitheribrutinib and rituximab for six cycles (after a single cycle of ibrutinib alone), followed by ibrutinib until disease progression, or six cycles of chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. The primary end point was progression-free survival, and overall survival was a secondary end point. We report the results of a planned interim analysis. RESULTS: A total of 529 patients underwent randomization (354 patients to the ibrutinib-rituximab group, and 175 to the chemoimmunotherapy group). At a median follow-up of 33.6 months, the results of the analysis of progression-free survival favored ibrutinib-rituximab over chemoimmunotherapy (89.4% vs. 72.9% at 3 years; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.22 to 0.56; P<0.001), and the results met the protocol-defined efficacy threshold for the interim analysis. The results of the analysis of overall survival also favored ibrutinib-rituximab over chemoimmunotherapy (98.8% vs. 91.5% at 3 years; hazard ratio for death, 0.17; 95% CI, 0.05 to 0.54; P<0.001). In a subgroup analysis involving patients without immunoglobulin heavy-chain variable region (IGHV) mutation, ibrutinib-rituximab resulted in better progression-free survival than chemoimmunotherapy (90.7% vs. 62.5% at 3 years; hazard ratio for progression or death, 0.26; 95% CI, 0.14 to 0.50). The 3-year progression-free survival among patients with IGHV mutation was 87.7% in the ibrutinib-rituximab group and 88.0% in the chemoimmunotherapy group (hazard ratio for progression or death, 0.44; 95% CI, 0.14 to 1.36). The incidence of adverse events of grade 3 or higher (regardless of attribution) was similar in the two groups (in 282 of 352 patients [80.1%] who received ibrutinib-rituximab and in 126 of 158 [79.7%] who received chemoimmunotherapy), whereas infectious complications of grade 3 or higher were less common with ibrutinib-rituximab than with chemoimmunotherapy (in 37 patients [10.5%] vs. 32 [20.3%], P<0.001). CONCLUSIONS: The ibrutinib-rituximab regimen resulted in progression-free survival and overall survival that were superior to those with a standard chemoimmunotherapy regimen among patients 70 years of age or younger with previously untreated CLL. (Funded by the National Cancer Institute and Pharmacyclics; E1912 ClinicalTrials.gov number, NCT02048813.).
RCT Entities:
BACKGROUND: Data regarding the efficacy of treatment with ibrutinib-rituximab, as compared with standard chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab, in patients with previously untreated chronic lymphocytic leukemia (CLL) have been limited. METHODS: In a phase 3 trial, we randomly assigned (in a 2:1 ratio) patients 70 years of age or younger with previously untreated CLL to receive either ibrutinib and rituximab for six cycles (after a single cycle of ibrutinib alone), followed by ibrutinib until disease progression, or six cycles of chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. The primary end point was progression-free survival, and overall survival was a secondary end point. We report the results of a planned interim analysis. RESULTS: A total of 529 patients underwent randomization (354 patients to the ibrutinib-rituximab group, and 175 to the chemoimmunotherapy group). At a median follow-up of 33.6 months, the results of the analysis of progression-free survival favored ibrutinib-rituximab over chemoimmunotherapy (89.4% vs. 72.9% at 3 years; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.22 to 0.56; P<0.001), and the results met the protocol-defined efficacy threshold for the interim analysis. The results of the analysis of overall survival also favored ibrutinib-rituximab over chemoimmunotherapy (98.8% vs. 91.5% at 3 years; hazard ratio for death, 0.17; 95% CI, 0.05 to 0.54; P<0.001). In a subgroup analysis involving patients without immunoglobulin heavy-chain variable region (IGHV) mutation, ibrutinib-rituximab resulted in better progression-free survival than chemoimmunotherapy (90.7% vs. 62.5% at 3 years; hazard ratio for progression or death, 0.26; 95% CI, 0.14 to 0.50). The 3-year progression-free survival among patients with IGHV mutation was 87.7% in the ibrutinib-rituximab group and 88.0% in the chemoimmunotherapy group (hazard ratio for progression or death, 0.44; 95% CI, 0.14 to 1.36). The incidence of adverse events of grade 3 or higher (regardless of attribution) was similar in the two groups (in 282 of 352 patients [80.1%] who received ibrutinib-rituximab and in 126 of 158 [79.7%] who received chemoimmunotherapy), whereas infectious complications of grade 3 or higher were less common with ibrutinib-rituximab than with chemoimmunotherapy (in 37 patients [10.5%] vs. 32 [20.3%], P<0.001). CONCLUSIONS: The ibrutinib-rituximab regimen resulted in progression-free survival and overall survival that were superior to those with a standard chemoimmunotherapy regimen among patients 70 years of age or younger with previously untreated CLL. (Funded by the National Cancer Institute and Pharmacyclics; E1912 ClinicalTrials.gov number, NCT02048813.).
Authors: M Hallek; K Fischer; G Fingerle-Rowson; A M Fink; R Busch; J Mayer; M Hensel; G Hopfinger; G Hess; U von Grünhagen; M Bergmann; J Catalano; P L Zinzani; F Caligaris-Cappio; J F Seymour; A Berrebi; U Jäger; B Cazin; M Trneny; A Westermann; C M Wendtner; B F Eichhorst; P Staib; A Bühler; D Winkler; T Zenz; S Böttcher; M Ritgen; M Mendila; M Kneba; H Döhner; S Stilgenbauer Journal: Lancet Date: 2010-10-02 Impact factor: 79.321
Authors: Kirsten Fischer; Jasmin Bahlo; Anna Maria Fink; Valentin Goede; Carmen Diana Herling; Paula Cramer; Petra Langerbeins; Julia von Tresckow; Anja Engelke; Christian Maurer; Gabor Kovacs; Marco Herling; Eugen Tausch; Karl-Anton Kreuzer; Barbara Eichhorst; Sebastian Böttcher; John F Seymour; Paolo Ghia; Paula Marlton; Michael Kneba; Clemens-Martin Wendtner; Hartmut Döhner; Stephan Stilgenbauer; Michael Hallek Journal: Blood Date: 2015-10-20 Impact factor: 22.113
Authors: Jennifer A Woyach; Amy S Ruppert; Nyla A Heerema; Weiqiang Zhao; Allison M Booth; Wei Ding; Nancy L Bartlett; Danielle M Brander; Paul M Barr; Kerry A Rogers; Sameer A Parikh; Steven Coutre; Arti Hurria; Jennifer R Brown; Gerard Lozanski; James S Blachly; Hatice G Ozer; Brittny Major-Elechi; Briant Fruth; Sreenivasa Nattam; Richard A Larson; Harry Erba; Mark Litzow; Carolyn Owen; Charles Kuzma; Jeremy S Abramson; Richard F Little; Scott E Smith; Richard M Stone; Sumithra J Mandrekar; John C Byrd Journal: N Engl J Med Date: 2018-12-01 Impact factor: 91.245
Authors: Stephan Stilgenbauer; Andrea Schnaiter; Peter Paschka; Thorsten Zenz; Marianna Rossi; Konstanze Döhner; Andreas Bühler; Sebastian Böttcher; Matthias Ritgen; Michael Kneba; Dirk Winkler; Eugen Tausch; Patrick Hoth; Jennifer Edelmann; Daniel Mertens; Lars Bullinger; Manuela Bergmann; Sabrina Kless; Silja Mack; Ulrich Jäger; Nancy Patten; Lin Wu; Michael K Wenger; Günter Fingerle-Rowson; Peter Lichter; Mario Cazzola; Clemens M Wendtner; Anna M Fink; Kirsten Fischer; Raymonde Busch; Michael Hallek; Hartmut Döhner Journal: Blood Date: 2014-03-20 Impact factor: 22.113
Authors: Jan A Burger; Mariela Sivina; Nitin Jain; Ekaterina Kim; Tapan Kadia; Zeev Estrov; Graciela M Nogueras-Gonzalez; Xuelin Huang; Jeffrey Jorgensen; Jianling Li; Mei Cheng; Fong Clow; Maro Ohanian; Michael Andreeff; Thomas Mathew; Philip Thompson; Hagop Kantarjian; Susan O'Brien; William G Wierda; Alessandra Ferrajoli; Michael J Keating Journal: Blood Date: 2018-12-07 Impact factor: 22.113
Authors: Michael Hallek; Bruce D Cheson; Daniel Catovsky; Federico Caligaris-Cappio; Guillermo Dighiero; Hartmut Döhner; Peter Hillmen; Michael Keating; Emili Montserrat; Nicholas Chiorazzi; Stephan Stilgenbauer; Kanti R Rai; John C Byrd; Barbara Eichhorst; Susan O'Brien; Tadeusz Robak; John F Seymour; Thomas J Kipps Journal: Blood Date: 2018-03-14 Impact factor: 22.113
Authors: Philip A Thompson; Constantine S Tam; Susan M O'Brien; William G Wierda; Francesco Stingo; William Plunkett; Susan C Smith; Hagop M Kantarjian; Emil J Freireich; Michael J Keating Journal: Blood Date: 2015-10-22 Impact factor: 22.113
Authors: Jan A Burger; Alessandra Tedeschi; Paul M Barr; Tadeusz Robak; Carolyn Owen; Paolo Ghia; Osnat Bairey; Peter Hillmen; Nancy L Bartlett; Jianyong Li; David Simpson; Sebastian Grosicki; Stephen Devereux; Helen McCarthy; Steven Coutre; Hang Quach; Gianluca Gaidano; Zvenyslava Maslyak; Don A Stevens; Ann Janssens; Fritz Offner; Jiří Mayer; Michael O'Dwyer; Andrzej Hellmann; Anna Schuh; Tanya Siddiqi; Aaron Polliack; Constantine S Tam; Deepali Suri; Mei Cheng; Fong Clow; Lori Styles; Danelle F James; Thomas J Kipps Journal: N Engl J Med Date: 2015-12-06 Impact factor: 91.245
Authors: Dan A Landau; Clare Sun; Daniel Rosebrock; Sarah E M Herman; Joshua Fein; Mariela Sivina; Chingiz Underbayev; Delong Liu; Julia Hoellenriegel; Sarangan Ravichandran; Mohammed Z H Farooqui; Wandi Zhang; Carrie Cibulskis; Asaf Zviran; Donna S Neuberg; Dimitri Livitz; Ivana Bozic; Ignaty Leshchiner; Gad Getz; Jan A Burger; Adrian Wiestner; Catherine J Wu Journal: Nat Commun Date: 2017-12-19 Impact factor: 14.919
Authors: Neda Alrawashdh; Joann Sweasy; Brian Erstad; Ali McBride; Daniel O Persky; Ivo Abraham Journal: Ann Hematol Date: 2021-07-19 Impact factor: 3.673
Authors: Paul J Hampel; Timothy G Call; Kari G Rabe; Wei Ding; Eli Muchtar; Saad S Kenderian; Yucai Wang; Jose F Leis; Thomas E Witzig; Amber B Koehler; Amie L Fonder; Susan M Schwager; Daniel L Van Dyke; Esteban Braggio; Susan L Slager; Neil E Kay; Sameer A Parikh Journal: Oncologist Date: 2020-09-20
Authors: Anthony Mato; Chadi Nabhan; Nicole Lamanna; Neil E Kay; David L Grinblatt; Christopher R Flowers; Charles M Farber; Matthew S Davids; Arlene S Swern; Kristen Sullivan; E Dawn Flick; Sarah M Gressett Ussery; Mecide Gharibo; Pavel Kiselev; Jeff P Sharman Journal: Blood Adv Date: 2020-04-14