Page 109 - Haematologica Vol. 107 - September 2022

ARTICLE - Chronic Lymphocytic Leukemia
First-line treatment of chronic lymphocytic leukemia with ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab: final analysis of the randomized, phase III iLLUMINATE trial
Carol Moreno,1,2 Richard Greil,3 Fatih Demirkan,4 Alessandra Tedeschi,5 Bertrand Anz,6 Loree Larratt,7 Martin Simkovic,8 Jan Novak,9 Vladimir Strugov,10 Devinder Gill,11 John G. Gribben,12 Kevin Kwei,13 Sandra Dai,13 Emily Hsu,13 James P. Dean13 and Ian W. Flinn14
1Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain; 2Josep Carreras Leukemia Research Institute, Barcelona, Spain; 33rd Medical Department, Paracelsus Medical University, Salzburg Cancer Research Institute-CCCIT, Salzburg, Austria; 4Dokuz Eylul University, Division of Hematology, Izmir, Turkey; 5Niguarda Ca Granda Hospital, Milan, Italy; 6Tennessee Oncology, Chattanooga, TN, USA; 7University of Alberta Hospital, Edmonton, Alberta, Canada; 8Department of Internal Medicine, Haematology, University Hospital and Medical School Hradec, Králové, Czech Republic; 9University Hospital Kralovske Vinohrady and Third Faculty of Medicine, Charles University, Prague, Czech Republic; 10Almazov National Medical Research Centre, St. Petersburg, Russia; 11Princess Alexandra Hospital, Brisbane, Queensland, Australia; 12Barts Cancer Institute, London, UK; 13Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA, USA and 14Sarah Cannon Research Institute, Nashville, TN, USA
Abstract
iLLUMINATE is a randomized, open-label phase III study of ibrutinib plus obinutuzumab (n=113) versus chlorambucil plus obinutuzumab (n=116) as first-line therapy for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma. Eligible patients were aged ≥65 years, or <65 years with coexisting conditions. Patients received oral ibrutinib 420 mg once daily until disease progression or unacceptable toxicity or six cycles of oral chlorambucil, each in combination with six cycles of intravenous obinutuzumab. After a median follow-up of 45 months (range, 0.2-52), median progression-free survival continued to be significantly longer in the ibrutinib plus obinutuzumab arm than in the chlorambucil plus obinu- tuzumab arm (median not reached versus 22 months; hazard ratio=0.25; 95% confidence interval: 0.16-0.39; P<0.0001). The best overall rate of undetectable minimal residual disease (<0.01% by flow cytometry) remained higher with ibrutinib plus obinutuzumab (38%) than with chlorambucil plus obinutuzumab (25%). With a median treatment duration of 42 months, 13 months longer than the primary analysis, no new safety signals were identified for ibrutinib. As is typical for ibrutinib-based regimens, common grade ≥3 adverse events were most prevalent in the first 6 months of ibrutinib plus obinutuzumab treatment and generally decreased over time, except for hypertension. In this final analysis with up to 52 months of follow-up (median 45 months), ibrutinib plus obinutuzumab showed sustained clinical benefit, in terms of pro- gression-free survival, in first-line treatment of chronic lymphocytic leukemia, including in patients with high-risk features. ClinicalTrials.gov identifier: NCT02264574.
Introduction
Over the past decade, the introduction of novel therapies targeting B-cell receptor signaling has shifted the treat- ment landscape for patients with chronic lymphocytic leukemia (CLL), including for patients with high-risk ge- nomic features who previously had limited treatment op- tions.1 Ibrutinib is an oral, once-daily inhibitor of Bruton tyrosine kinase (BTK) approved for the treatment of pa-
tients with CLL, including in combination with the anti- CD20 monoclonal antibody obinutuzumab based on the primary results of the iLLUMINATE study.2,3 In two first- line studies ibrutinib or ibrutinib-based combination ther- apy was associated with superior progression-free survival (PFS) and overall survival (OS) compared with chlorambu- cil4 or fludarabine, cyclophosphamide, and rituximab (FCR)5 regimens in patients with CLL/small lymphocytic lymphoma (SLL). Ibrutinib (with or without rituximab) was also associated with superior PFS compared to benda-
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Correspondence: C. Moreno cmorenoa@santpau.cat
Received: Accepted: Prepublished:
May 5, 2021. November 4, 2021. January 13, 2022.
https://doi.org/10.3324/haematol.2021.279012
©2022 Ferrata Storti Foundation Published under a CC BY-NC license