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CLL-137 SEQUOIA: Results of a Phase 3 Randomized Study of Zanubrutinib Versus Bendamustine + Rituximab (BR) in Patients With Treatment-Naïve (TN) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/ SLL)
BS. Kahl, K. Giannopoulos, W. Jurczak, M. Šimkovič, M. Shadman, A. Österborg, L. Laurenti, P. Walker, S. Opat, H. Chan, H. Ciepluch, R. Greil, M. Tani, M. Trnéný, DM. Brander, IW. Flinn, S. Grosicki, E. Verner, JR. Brown, P. Ghia, J. Li, T. Tian,...
Language English Country United States
Document type Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial
- MeSH
- Lymphoma, B-Cell * drug therapy MeSH
- Bendamustine Hydrochloride therapeutic use MeSH
- Leukemia, Lymphocytic, Chronic, B-Cell * drug therapy pathology MeSH
- Cyclophosphamide therapeutic use MeSH
- Protein Kinase Inhibitors * adverse effects MeSH
- Humans MeSH
- Piperidines adverse effects MeSH
- Agammaglobulinaemia Tyrosine Kinase MeSH
- Antineoplastic Combined Chemotherapy Protocols * adverse effects MeSH
- Pyrazoles adverse effects MeSH
- Pyrimidines adverse effects MeSH
- Rituximab therapeutic use MeSH
- Aged MeSH
- Check Tag
- Humans MeSH
- Aged MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase III MeSH
- Randomized Controlled Trial MeSH
CONTEXT: The Bruton tyrosine kinase (BTK) inhibitor, zanubrutinib, was designed for high BTK specificity and minimal toxicity. SEQUOIA (NCT03336333) is a global, open-label, randomized phase 3 study in treatment-naïve patients with CLL/SLL without del(17p) who were unsuitable for fludarabine/cyclophosphamide/rituximab. DESIGN: Patients were randomized to receive zanubrutinib (160 mg twice daily) or bendamustine (day 1-2: 90 mg/m2) and rituximab (cycle 1: 375 mg/m2; cycles 2-6: 500 mg/m2); stratification factors were age (<65 years vs ≥65 years), Binet Stage, IGHV mutation, and geographic region. MAIN OUTCOME MEASURES: Primary endpoint was an independent review committee (IRC)-assessed progression-free survival (PFS). Secondary endpoints included investigator-assessed (INV) PFS, overall response rate (ORR), overall survival (OS), and safety. RESULTS: From October 31, 2017, to July 22, 2019, 479 patients were enrolled (zanubrutinib=241; BR=238). Baseline characteristics (zanubrutinib vs BR): median age, 70.0 years versus 70.0 years; unmutated IGHV, 53.4% versus 52.4%; del(11q), 17.8% versus 19.3%. With median follow-up of 26.2 months, PFS was significantly prolonged with zanubrutinib by IRC (HR 0.42; 2-sided P<.0001) and INV (HR 0.42; 2-sided P=.0001). Zanubrutinib treatment benefit occurred across age, Binet stage, bulky disease, del(11q) status, and unmutated IGHV (HR 0.24; 2-sided P<.0001), but not mutated IGHV (HR 0.67; 2-sided P=.1858). For zanubrutinib versus BR, 24-month PFS-IRC=85.5% versus 69.5%; ORR-IRC=94.6% versus 85.3%; complete response rate=6.6% versus 15.1%; ORR-INV=97.5% versus 88.7%; and 24-month OS=94.3% versus 94.6%. Select adverse event (AE) rates (zanubrutinib vs BR): atrial fibrillation (3.3% vs 2.6%), bleeding (45.0% vs 11.0%), hypertension (14.2% vs 10.6%), infection (62.1% vs 55.9%), and neutropenia (15.8% vs 56.8%). Treatment discontinuation due to AEs (zanubrutinib vs BR)=20 patients (8.3%) versus 31 patients (13.7%); AEs leading to death=11 patients (4.6%) versus 11 patients (4.8%). No sudden deaths occurred. CONCLUSIONS: In summary, zanubrutinib significantly improved PFS-IRC versus BR and was well tolerated, supporting the potential utility of frontline zanubrutinib in treatment-naïve CLL/SLL.
4th Department of Internal Medicine Haematology University Hospital Hradec Kralove Czech Republic
Cancer Cluster Salzburg Salzburg Austria
Concord Repatriation General Hospital Concord Australia
Copernicus Regional Oncology Center Gdansk Poland
Dana Farber Cancer Institute Boston USA
Department of Hematology Karolinska University Hospital Stockholm Sweden
Department of Medicine University of Washington Seattle USA
Department of Oncology Pathology Karolinska Institutet Stockholm Sweden
Experimental Hematooncology Department Medical University of Lublin Lublin Poland
Faculty of Medicine Charles University Prague Czech Republic
Fondazione Policlinico Universitario A Gemelli UCSC Rome Italy
Fred Hutchinson Cancer Research Center Seattle USA
Hematologic Malignancies and Cellular Therapy Duke University School of Medicine Durham USA
Hematology Department St John's Cancer Centre Lublin Poland
Hematology Unit Santa Maria delle Croci Hospital Ravenna Italy
Maria Sklodowska Curie National Research Institute of Oncology Krakow Poland
Medical University of Lodz Lodz Poland
Monash Health Clayton Australia
Monash University Clayton Australia
North Shore Hospital Auckland New Zealand
Peninsula Private Hospital Frankston Australia
Peter MacCallum Cancer Centre Melbourne Australia
Royal Melbourne Hospital Parkville Australia
Salzburg Cancer Research Institute Salzburg Austria
Sarah Cannon Research Institute Tennessee Oncology Nashville USA
St James's University Hospital Leeds United Kingdom
St Vincent's Hospital Melbourne Fitzroy Australia
Università Vita Salute San Raffaele and IRCCS Ospedale San Raffaele Milano Italy
University of Melbourne Parkville Australia
References provided by Crossref.org
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