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Blood. 2019 May 9;133(19):2031-2042. doi: 10.1182/blood-2018-08-870238. Epub 2019 Mar 6.

Long-term follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab.

Author information

1
The Ohio State University Comprehensive Cancer Center, Columbus, OH.
2
The Leeds Teaching Hospitals, St. James Institute of Oncology, Leeds, United Kingdom.
3
UC Irvine, Chao Family Comprehensive Cancer Center, Irvine, CA.
4
Zucker School of Medicine at Hofstra/Northwell, Lake Success, NY.
5
Vanderbilt-Ingram Cancer Center, Nashville, TN.
6
Stanford University School of Medicine, Stanford, CA.
7
Department of Haematology, Peter MacCallum Cancer Centre and St. Vincent's Hospital, Melbourne, VIC, Australia.
8
Royal North Shore Hospital, Sydney, NSW, Australia.
9
Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.
10
University of Rochester Medical Center, Rochester, NY.
11
Weill Cornell Medical College/New York Presbyterian Hospital, New York, NY.
12
UCSD Moores Cancer Center, San Diego, CA.
13
Beaumont Hospital, Dublin, Ireland.
14
Hospital de la Santa Creu Sant Pau, Barcelona, Spain.
15
Niguarda Ca' Granda Hospital, Milan, Italy.
16
Swedish Cancer Institute Hematologic Malignancies Program, Seattle, WA.
17
University of Texas MD Anderson Cancer Center, Houston, TX.
18
Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA; and.
19
CLL Center, Dana-Farber Cancer Institute, Boston, MA.

Abstract

Ibrutinib, a once-daily oral inhibitor of Bruton tyrosine kinase, has greatly improved outcomes for patients with chronic lymphocytic leukemia (CLL). The phase 3 RESONATE trial, which compared single-agent ibrutinib to ofatumumab in high-risk, relapsed patients with CLL, provided support for approval of ibrutinib in the United States and Europe. We describe long-term follow-up of patients treated in RESONATE, where continued superiority of progression-free survival (PFS) (hazard ratio [HR], 0.133; 95% confidence interval [CI], 0.099-0.178) was observed. Overall survival benefit continues (HR, 0.591; 95% CI, 0.378-0.926), although with decreased magnitude relative to that seen before crossover to ibrutinib was implemented for patients on ofatumumab (HR, 0.426; 95% CI, 0.220-0.823). Notably, overall response to ibrutinib increased over time, with 91% of patients attaining a response. The PFS benefit with ibrutinib was independent of baseline risk factors, although patients with ≥2 prior therapies had shorter PFS than those with <2 prior therapies, and the presence of TP53 or SF3B1 mutations showed a trend toward shorter PFS vs without these factors. Median duration of ibrutinib was 41 months, with 46% remaining on treatment at a median follow-up of 44 months. Grade ≥3 adverse events generally decreased over time, causing only a small proportion of patients to cease therapy. Ibrutinib was discontinued due to progressive disease in 27% of patients. This long-term study provides support for sustained efficacy and safety of ibrutinib in relapsed/refractory CLL and consideration of study provisions that allow crossover to investigational therapy when benefit has been clearly demonstrated. This trial was registered at www.clinicaltrials.gov as #NCT01578707.

PMID:
30842083
PMCID:
PMC6509542
[Available on 2020-05-09]
DOI:
10.1182/blood-2018-08-870238

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