Andrew W Roberts1, Matthew S Davids, John M Pagel, Brad S Kahl, Soham D Puvvada, John F Gerecitano, Thomas J Kipps, Mary Ann Anderson, Jennifer R Brown, Lori Gressick, Shekman Wong, Martin Dunbar, Ming Zhu, Monali B Desai, Elisa Cerri, Sari Heitner Enschede, Rod A Humerickhouse, William G Wierda, John F Seymour. 1. From the Department of Clinical Haematology and the Bone Marrow Transplantation Unit, Royal Melbourne Hospital (A.W.R., M.A.A.), the Division of Cancer and Haematology, Walter and Eliza Hall Institute of Medical Research (A.W.R., M.A.A.), and the Victorian Comprehensive Cancer Centre (A.W.R., J.F.S.), Parkville, VIC, and the University of Melbourne (A.W.R., J.F.S.) and Peter MacCallum Cancer Centre (J.F.S.), Melbourne, VIC - all in Australia; Dana-Farber Cancer Institute, Boston (M.S.D., J.R.B.); the Swedish Medical Center, Seattle (J.M.P.); Washington University, St. Louis (B.S.K.); University of Arizona, Tucson (S.D.P.); Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York (J.F.G.); University of California, San Diego, San Diego (T.J.K.); AbbVie, North Chicago, IL (L.G., S.W., M.D., M.Z., M.B.D., E.C., S.H.E., R.A.H.); and University of Texas M.D. Anderson Cancer Center, Houston (W.G.W.).
Abstract
BACKGROUND: New treatments have improved outcomes for patients with relapsed chronic lymphocytic leukemia (CLL), but complete remissions remain uncommon. Venetoclax has a distinct mechanism of action; it targets BCL2, a protein central to the survival of CLL cells. METHODS: We conducted a phase 1 dose-escalation study of daily oral venetoclax in patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL) to assess safety, pharmacokinetic profile, and efficacy. In the dose-escalation phase, 56 patients received active treatment in one of eight dose groups that ranged from 150 to 1200 mg per day. In an expansion cohort, 60 additional patients were treated with a weekly stepwise ramp-up in doses as high as 400 mg per day. RESULTS: The majority of the study patients had received multiple previous treatments, and 89% had poor prognostic clinical or genetic features. Venetoclax was active at all dose levels. Clinical tumor lysis syndrome occurred in 3 of 56 patients in the dose-escalation cohort, with one death. After adjustments to the dose-escalation schedule, clinical tumor lysis syndrome did not occur in any of the 60 patients in the expansion cohort. Other toxic effects included mild diarrhea (in 52% of the patients), upper respiratory tract infection (in 48%), nausea (in 47%), and grade 3 or 4 neutropenia (in 41%). A maximum tolerated dose was not identified. Among the 116 patients who received venetoclax, 92 (79%) had a response. Response rates ranged from 71 to 79% among patients in subgroups with an adverse prognosis, including those with resistance to fludarabine, those with chromosome 17p deletions (deletion 17p CLL), and those with unmutated IGHV. Complete remissions occurred in 20% of the patients, including 5% who had no minimal residual disease on flow cytometry. The 15-month progression-free survival estimate for the 400-mg dose groups was 69%. CONCLUSIONS: Selective targeting of BCL2 with venetoclax had a manageable safety profile and induced substantial responses in patients with relapsed CLL or SLL, including those with poor prognostic features. (Funded by AbbVie and Genentech; ClinicalTrials.gov number, NCT01328626.).
BACKGROUND: New treatments have improved outcomes for patients with relapsed chronic lymphocytic leukemia (CLL), but complete remissions remain uncommon. Venetoclax has a distinct mechanism of action; it targets BCL2, a protein central to the survival of CLL cells. METHODS: We conducted a phase 1 dose-escalation study of daily oral venetoclax in patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL) to assess safety, pharmacokinetic profile, and efficacy. In the dose-escalation phase, 56 patients received active treatment in one of eight dose groups that ranged from 150 to 1200 mg per day. In an expansion cohort, 60 additional patients were treated with a weekly stepwise ramp-up in doses as high as 400 mg per day. RESULTS: The majority of the study patients had received multiple previous treatments, and 89% had poor prognostic clinical or genetic features. Venetoclax was active at all dose levels. Clinical tumor lysis syndrome occurred in 3 of 56 patients in the dose-escalation cohort, with one death. After adjustments to the dose-escalation schedule, clinical tumor lysis syndrome did not occur in any of the 60 patients in the expansion cohort. Other toxic effects included mild diarrhea (in 52% of the patients), upper respiratory tract infection (in 48%), nausea (in 47%), and grade 3 or 4 neutropenia (in 41%). A maximum tolerated dose was not identified. Among the 116 patients who received venetoclax, 92 (79%) had a response. Response rates ranged from 71 to 79% among patients in subgroups with an adverse prognosis, including those with resistance to fludarabine, those with chromosome 17p deletions (deletion 17p CLL), and those with unmutated IGHV. Complete remissions occurred in 20% of the patients, including 5% who had no minimal residual disease on flow cytometry. The 15-month progression-free survival estimate for the 400-mg dose groups was 69%. CONCLUSIONS: Selective targeting of BCL2 with venetoclax had a manageable safety profile and induced substantial responses in patients with relapsed CLL or SLL, including those with poor prognostic features. (Funded by AbbVie and Genentech; ClinicalTrials.gov number, NCT01328626.).
Authors: B D Cheson; S J Horning; B Coiffier; M A Shipp; R I Fisher; J M Connors; T A Lister; J Vose; A Grillo-López; A Hagenbeek; F Cabanillas; D Klippensten; W Hiddemann; R Castellino; N L Harris; J O Armitage; W Carter; R Hoppe; G P Canellos Journal: J Clin Oncol Date: 1999-04 Impact factor: 44.544
Authors: Thorsten Zenz; John G Gribben; Michael Hallek; Hartmut Döhner; Michael J Keating; Stephan Stilgenbauer Journal: Blood Date: 2012-03-06 Impact factor: 22.113
Authors: John C Byrd; John G Gribben; Bercedis L Peterson; Michael R Grever; Gerard Lozanski; David M Lucas; Ben Lampson; Richard A Larson; Michael A Caligiuri; Nyla A Heerema Journal: J Clin Oncol Date: 2005-12-12 Impact factor: 44.544
Authors: A C Rawstron; S Böttcher; R Letestu; N Villamor; C Fazi; H Kartsios; R M de Tute; J Shingles; M Ritgen; C Moreno; K Lin; A R Pettitt; M Kneba; E Montserrat; F Cymbalista; M Hallek; P Hillmen; P Ghia Journal: Leukemia Date: 2012-07-31 Impact factor: 11.528
Authors: Amelia Cimmino; George Adrian Calin; Muller Fabbri; Marilena V Iorio; Manuela Ferracin; Masayoshi Shimizu; Sylwia E Wojcik; Rami I Aqeilan; Simona Zupo; Mariella Dono; Laura Rassenti; Hansjuerg Alder; Stefano Volinia; Chang-Gong Liu; Thomas J Kipps; Massimo Negrini; Carlo M Croce Journal: Proc Natl Acad Sci U S A Date: 2005-09-15 Impact factor: 11.205
Authors: Kirsten Fischer; Paula Cramer; Raymonde Busch; Stephan Stilgenbauer; Jasmin Bahlo; Carmen D Schweighofer; Sebastian Böttcher; Peter Staib; Michael Kiehl; Michael J Eckart; Gabriele Kranz; Valentin Goede; Thomas Elter; Andreas Bühler; Dirk Winkler; Michael Kneba; Hartmut Döhner; Barbara F Eichhorst; Michael Hallek; Clemens-Martin Wendtner Journal: J Clin Oncol Date: 2011-08-15 Impact factor: 44.544
Authors: Ranjana H Advani; Joseph J Buggy; Jeff P Sharman; Sonali M Smith; Thomas E Boyd; Barbara Grant; Kathryn S Kolibaba; Richard R Furman; Sara Rodriguez; Betty Y Chang; Juthamas Sukbuntherng; Raquel Izumi; Ahmed Hamdy; Eric Hedrick; Nathan H Fowler Journal: J Clin Oncol Date: 2012-10-08 Impact factor: 44.544
Authors: Panagiotis Baliakas; Sabine Jeromin; Michalis Iskas; Anna Puiggros; Karla Plevova; Florence Nguyen-Khac; Zadie Davis; Gian Matteo Rigolin; Andrea Visentin; Aliki Xochelli; Julio Delgado; Fanny Baran-Marszak; Evangelia Stalika; Pau Abrisqueta; Kristina Durechova; George Papaioannou; Virginie Eclache; Maria Dimou; Theodoros Iliakis; Rosa Collado; Michael Doubek; M Jose Calasanz; Neus Ruiz-Xiville; Carolina Moreno; Marie Jarosova; Alexander C Leeksma; Panayiotis Panayiotidis; Helena Podgornik; Florence Cymbalista; Achilles Anagnostopoulos; Livio Trentin; Niki Stavroyianni; Fred Davi; Paolo Ghia; Arnon P Kater; Antonio Cuneo; Sarka Pospisilova; Blanca Espinet; Anastasia Athanasiadou; David Oscier; Claudia Haferlach; Kostas Stamatopoulos Journal: Blood Date: 2019-01-02 Impact factor: 22.113
Authors: Shyril O'Steen; Damian J Green; Ajay K Gopal; Johnnie J Orozco; Aimee L Kenoyer; Yukang Lin; D Scott Wilbur; Donald K Hamlin; Darrell R Fisher; Mark D Hylarides; Theodore A Gooley; Amelia Waltman; Brian G Till; Oliver W Press Journal: Cancer Res Date: 2017-05-31 Impact factor: 12.701
Authors: Matthew D Blunt; Stefan Koehrer; Rachel C Dobson; Marta Larrayoz; Sarah Wilmore; Alice Hayman; Jack Parnell; Lindsay D Smith; Andrew Davies; Peter W M Johnson; Pamela B Conley; Anjali Pandey; Jonathan C Strefford; Freda K Stevenson; Graham Packham; Francesco Forconi; Greg P Coffey; Jan A Burger; Andrew J Steele Journal: Clin Cancer Res Date: 2016-10-03 Impact factor: 12.531
Authors: Marina Konopleva; Daniel A Pollyea; Jalaja Potluri; Brenda Chyla; Leah Hogdal; Todd Busman; Evelyn McKeegan; Ahmed Hamed Salem; Ming Zhu; Justin L Ricker; William Blum; Courtney D DiNardo; Tapan Kadia; Martin Dunbar; Rachel Kirby; Nancy Falotico; Joel Leverson; Rod Humerickhouse; Mack Mabry; Richard Stone; Hagop Kantarjian; Anthony Letai Journal: Cancer Discov Date: 2016-08-12 Impact factor: 39.397