Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia
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, RESONATE-2 Investigators, 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, Michael Keating, Thomas J Kipps, Jie Jen, Pavel Jindra, Martin Simkovič, Andrei Braester, Rosa Ruchlemer, Roberto Foà, Gianpietro Semenzato, Timothy Hawkins, Carolina Moreno Atanasio, Fatih Demirkan, Leylagul Kaynar, Halyna Pylypenko, Christopher Fox, Michael Thirman, Philip Campbell, Paul Coughlin, Rosemary Harrup, Bryone Kuss, Paul Turner, Ka Lung Wu, Loree Larratt, Riva Fineman, Roberto Marasca, Pier Luigi Zinzani, Gillian Corbett, Pau Abrisqueta, Julio Delgado, Eva González-Barca, Jaime Pérez de Oteyza, Onder Arsland, Polina Kaplan, Hanna Oliynyk, Michael Hamblin, James Atkins, Jaqueline Barrientos, Slavisa Gasic, Jing-Zhou Hou, Edwin Kingsley, Mazyar Shadman, Xavier Badoux, Devinder Gill, Stephen Opat, Dominique Bron, Eric Van Den Neste, Hongmei Jing, Jun Zhu, Elisabeth Vandenberghe, Tamar Tadmor, Agostino Cortelezzi, Peter Ganly, Robert Weinkove, Andrzej Pluta, Alexander Pristupa, José Antonio García Marco, Filiz Vural, Műnci Yağci, Muzhdaba Kasych, Andrew Duncombe, Christopher Fegan, Robert Quackenbush, Nagendra Tirumali, 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, RESONATE-2 Investigators, 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, Michael Keating, Thomas J Kipps, Jie Jen, Pavel Jindra, Martin Simkovič, Andrei Braester, Rosa Ruchlemer, Roberto Foà, Gianpietro Semenzato, Timothy Hawkins, Carolina Moreno Atanasio, Fatih Demirkan, Leylagul Kaynar, Halyna Pylypenko, Christopher Fox, Michael Thirman, Philip Campbell, Paul Coughlin, Rosemary Harrup, Bryone Kuss, Paul Turner, Ka Lung Wu, Loree Larratt, Riva Fineman, Roberto Marasca, Pier Luigi Zinzani, Gillian Corbett, Pau Abrisqueta, Julio Delgado, Eva González-Barca, Jaime Pérez de Oteyza, Onder Arsland, Polina Kaplan, Hanna Oliynyk, Michael Hamblin, James Atkins, Jaqueline Barrientos, Slavisa Gasic, Jing-Zhou Hou, Edwin Kingsley, Mazyar Shadman, Xavier Badoux, Devinder Gill, Stephen Opat, Dominique Bron, Eric Van Den Neste, Hongmei Jing, Jun Zhu, Elisabeth Vandenberghe, Tamar Tadmor, Agostino Cortelezzi, Peter Ganly, Robert Weinkove, Andrzej Pluta, Alexander Pristupa, José Antonio García Marco, Filiz Vural, Műnci Yağci, Muzhdaba Kasych, Andrew Duncombe, Christopher Fegan, Robert Quackenbush, Nagendra Tirumali
Abstract
Background: Chronic lymphocytic leukemia (CLL) primarily affects older persons who often have coexisting conditions in addition to disease-related immunosuppression and myelosuppression. We conducted an international, open-label, randomized phase 3 trial to compare two oral agents, ibrutinib and chlorambucil, in previously untreated older patients with CLL or small lymphocytic lymphoma.
Methods: We randomly assigned 269 previously untreated patients who were 65 years of age or older and had CLL or small lymphocytic lymphoma to receive ibrutinib or chlorambucil. The primary end point was progression-free survival as assessed by an independent review committee.
Results: The median age of the patients was 73 years. During a median follow-up period of 18.4 months, ibrutinib resulted in significantly longer progression-free survival than did chlorambucil (median, not reached vs. 18.9 months), with a risk of progression or death that was 84% lower with ibrutinib than that with chlorambucil (hazard ratio, 0.16; P<0.001). Ibrutinib significantly prolonged overall survival; the estimated survival rate at 24 months was 98% with ibrutinib versus 85% with chlorambucil, with a relative risk of death that was 84% lower in the ibrutinib group than in the chlorambucil group (hazard ratio, 0.16; P=0.001). The overall response rate was higher with ibrutinib than with chlorambucil (86% vs. 35%, P<0.001). The rates of sustained increases from baseline values in the hemoglobin and platelet levels were higher with ibrutinib. Adverse events of any grade that occurred in at least 20% of the patients receiving ibrutinib included diarrhea, fatigue, cough, and nausea; adverse events occurring in at least 20% of those receiving chlorambucil included nausea, fatigue, neutropenia, anemia, and vomiting. In the ibrutinib group, four patients had a grade 3 hemorrhage and one had a grade 4 hemorrhage. A total of 87% of the patients in the ibrutinib group are continuing to take ibrutinib.
Conclusions: Ibrutinib was superior to chlorambucil in previously untreated patients with CLL or small lymphocytic lymphoma, as assessed by progression-free survival, overall survival, response rate, and improvement in hematologic variables. (Funded by Pharmacyclics and others; RESONATE-2 ClinicalTrials.gov number, NCT01722487.).
Figures
Source: PubMed