Kirsten Fischer1, Othman Al-Sawaf1, Jasmin Bahlo1, Anna-Maria Fink1, Maneesh Tandon1, Mark Dixon1, Sandra Robrecht1, Simon Warburton1, Kathryn Humphrey1, Olga Samoylova1, Anna M Liberati1, Javier Pinilla-Ibarz1, Stephen Opat1, Liliya Sivcheva1, Katell Le Dû1, Laura M Fogliatto1, Carsten U Niemann1, Robert Weinkove1, Sue Robinson1, Thomas J Kipps1, Sebastian Boettcher1, Eugen Tausch1, Rod Humerickhouse1, Barbara Eichhorst1, Clemens-Martin Wendtner1, Anton W Langerak1, Karl-Anton Kreuzer1, Matthias Ritgen1, Valentin Goede1, Stephan Stilgenbauer1, Mehrdad Mobasher1, Michael Hallek1. 1. From Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf, University Hospital Cologne and University of Cologne (K.F., O.A.-S., J.B., A.-M.F., S. Robrecht, B.E., K.-A.K., M.H.), the Oncogeriatric Unit, Department of Geriatric Medicine, St. Marien Hospital (V.G.), CECAD (Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases) (M.H.), Center for Molecular Medicine Cologne (M.H.), Cologne, Department III of Internal Medicine, University Hospital Rostock, Rostock (S.B.), Department III of Internal Medicine, Ulm University, Ulm (E.T., S.S.), the Departments of Hematology, Oncology, Immunology, Palliative Care, Infectious Diseases, and Tropical Medicine, Klinikum Schwabing, Munich (C.-M.W.), Department II of Internal Medicine, Campus Kiel, University of Schleswig-Holstein, Kiel (M.R.), and the Department of Hematology, Oncology, and Rheumatology, Saarland University Medical School, Homburg (S.S.) - all in Germany; Roche Products, Welwyn Garden City, United Kingdom (M.T., M.D., S.W., K.H.); Regional Clinical Hospital N.A. Semashko, Nizhny Novgorod, Russia (O.S.); the Division of Onco-Hematology, Santa Maria Terni Hospital, University of Perugia, Perugia, Italy (A.M.L.); the Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL (J.P.-I.); the Haematology Department, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia (S.O.); First Internal Department, Multiprofile Hospital for Active Treatment Hristo Botev, Vratsa, Bulgaria (L.S.); the Hematology Department, Clinique Victor Hugo, Le Mans, France (K.L.D.); Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil (L.M.F.); the Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen (C.U.N.); Wellington Blood and Cancer Centre, Capital and Coast District Health Board, and Malaghan Institute of Medical Research, Wellington, New Zealand (R.W.); Queen Elizabeth II Health Sciences Centre, Halifax, NS, Canada (S. Robinson); Moores Cancer Center, University of California San Diego, San Diego (T.J.K.), and Genentech, South San Francisco (M.M.) - both in California; AbbVie, North Chicago, IL (R.H.); and the Department of Immunology, Laboratory Medical Immunology, Erasmus MC, Rotterdam, the Netherlands (A.W.L.).
Abstract
BACKGROUND: The BCL2 inhibitor venetoclax has shown activity in patients with chronic lymphocytic leukemia (CLL), but its efficacy in combination with other agents in patients with CLL and coexisting conditions is not known. METHODS: In this open-label, phase 3 trial, we investigated fixed-duration treatment with venetoclax and obinutuzumab in patients with previously untreated CLL and coexisting conditions. Patients with a score of greater than 6 on theCumulative Illness Rating Scale (scores range from 0 to 56, with higher scores indicating more impaired function of organ systems) or a calculated creatinine clearance of less than 70 ml per minute were randomly assigned to receive venetoclax-obinutuzumab or chlorambucil-obinutuzumab. The primary end point was investigator-assessed progression-free survival. The safety of each regimen was also evaluated. RESULTS: In total, 432 patients (median age, 72 years; median Cumulative Illness Rating Scale score, 8; median creatinine clearance, 66.4 ml per minute) underwent randomization, with 216 assigned to each group. After a median follow-up of 28.1 months, 30 primary end-point events (disease progression or death) had occurred in the venetoclax-obinutuzumab group and 77 had occurred in the chlorambucil-obinutuzumab group (hazard ratio, 0.35; 95% confidence interval [CI], 0.23 to 0.53; P<0.001). The Kaplan-Meier estimate of the percentage of patients with progression-free survival at 24 months was significantly higher in the venetoclax-obinutuzumab group than in the chlorambucil-obinutuzumab group: 88.2% (95% CI, 83.7 to 92.6) as compared with 64.1% (95% CI, 57.4 to 70.8). This benefit was also observed in patients with TP53 deletion, mutation, or both and in patients with unmutated immunoglobulin heavy-chain genes. Grade 3 or 4 neutropenia occurred in 52.8% of patients in the venetoclax-obinutuzumab group and in 48.1% of patients in the chlorambucil-obinutuzumab group, and grade 3 or 4 infections occurred in 17.5% and 15.0%, respectively. All-cause mortality was 9.3% in the venetoclax-obinutuzumab group and 7.9% in the chlorambucil-obinutuzumab group. These differences were not significant. CONCLUSIONS: Among patients with untreated CLL and coexisting conditions, venetoclax-obinutuzumab was associated with longer progression-free survival than chlorambucil-obinutuzumab. (Funded by F. Hoffmann-La Roche and AbbVie; ClinicalTrials.gov number, NCT02242942.).
RCT Entities:
BACKGROUND: The BCL2 inhibitor venetoclax has shown activity in patients with chronic lymphocytic leukemia (CLL), but its efficacy in combination with other agents in patients with CLL and coexisting conditions is not known. METHODS: In this open-label, phase 3 trial, we investigated fixed-duration treatment with venetoclax and obinutuzumab in patients with previously untreated CLL and coexisting conditions. Patients with a score of greater than 6 on the Cumulative Illness Rating Scale (scores range from 0 to 56, with higher scores indicating more impaired function of organ systems) or a calculated creatinine clearance of less than 70 ml per minute were randomly assigned to receive venetoclax-obinutuzumab or chlorambucil-obinutuzumab. The primary end point was investigator-assessed progression-free survival. The safety of each regimen was also evaluated. RESULTS: In total, 432 patients (median age, 72 years; median Cumulative Illness Rating Scale score, 8; median creatinine clearance, 66.4 ml per minute) underwent randomization, with 216 assigned to each group. After a median follow-up of 28.1 months, 30 primary end-point events (disease progression or death) had occurred in the venetoclax-obinutuzumab group and 77 had occurred in the chlorambucil-obinutuzumab group (hazard ratio, 0.35; 95% confidence interval [CI], 0.23 to 0.53; P<0.001). The Kaplan-Meier estimate of the percentage of patients with progression-free survival at 24 months was significantly higher in the venetoclax-obinutuzumab group than in the chlorambucil-obinutuzumab group: 88.2% (95% CI, 83.7 to 92.6) as compared with 64.1% (95% CI, 57.4 to 70.8). This benefit was also observed in patients with TP53 deletion, mutation, or both and in patients with unmutated immunoglobulin heavy-chain genes. Grade 3 or 4 neutropenia occurred in 52.8% of patients in the venetoclax-obinutuzumab group and in 48.1% of patients in the chlorambucil-obinutuzumab group, and grade 3 or 4 infections occurred in 17.5% and 15.0%, respectively. All-cause mortality was 9.3% in the venetoclax-obinutuzumab group and 7.9% in the chlorambucil-obinutuzumab group. These differences were not significant. CONCLUSIONS: Among patients with untreated CLL and coexisting conditions, venetoclax-obinutuzumab was associated with longer progression-free survival than chlorambucil-obinutuzumab. (Funded by F. Hoffmann-La Roche and AbbVie; ClinicalTrials.gov number, NCT02242942.).