title: Extended Treatment with Single-Agent Ibrutinib at the 420 mg Dose Leads to Durable Responses in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma.
abstract: Purpose:Ibrutinib, a first-in-class, once-daily, oral inhibitor of Bruton tyrosine kinase, promotes apoptosis, and inhibits B-cell proliferation, adhesion, and migration. Ibrutinib has demonstrated single-agent efficacy and acceptable tolerability at doses of 420 and 840 mg in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who were treatment-naïve (TN) or had relapsed/refractory (R/R) CLL after ≥1 prior therapy in a phase Ib/II study (PCYC-1102). Subsequently, the ibrutinib 420 mg dose was approved in CLL.Experimental Design:We report data with 44 months of follow-up on 94 patients with TN and R/R CLL/SLL receiving ibrutinib 420 mg once-daily in PCYC-1102 and the long-term extension study PCYC-1103.Results:Ninety-four CLL/SLL patients (27 TN, 67 R/R) were treated with ibrutinib (420 mg/day). Patients with R/R disease had received a median of four prior therapies (range, 1-12). Responses were rapid and durable and median duration of response was not reached. Best overall response was 91% [85% TN (complete response, CR 26%) and 94% R/R (9% CR)]. Median progression-free survival (PFS) was not reached in either group. The 30-month PFS rate was 96% and 76% for TN and R/R patients, respectively. Ibrutinib was well tolerated with extended follow-up; rates of grade ≥3 cytopenias and fatigue, as well as discontinuations due to toxicities decreased over time.Conclusions:Single-agent ibrutinib at 420 mg once-daily resulted in durable responses and was well tolerated with up to 44 months follow-up in patients with TN and R/R CLL/SLL. Currently, 66% of patients continue on ibrutinib.Clin Cancer Res; 23(5); 1149-55. ©2017 AACR.
authors.affiliation: Stanford Cancer Center, Stanford University School of Medicine, Stanford, California. coutre@stanford.edu.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Coutré
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Furman
authors.affiliation: Sarah Cannon Research Institute, Nashville, Tennessee.
authors.forename: Ian W
authors.initials: IW
authors.lastname: Flinn
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Burger
authors.affiliation: The Ohio State University, Columbus, Ohio.
authors.forename: Kristie
authors.initials: K
authors.lastname: Blum
authors.affiliation: Willamette Valley Cancer Institute and Research Center/US Oncology Research, Springfield, Oregon.
authors.forename: Jeff
authors.initials: J
authors.lastname: Sharman
authors.affiliation: The Ohio State University, Columbus, Ohio.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Jones
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: William
authors.initials: W
authors.lastname: Wierda
authors.affiliation: The Ohio State University, Columbus, Ohio.
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Zhao
authors.affiliation: The Ohio State University, Columbus, Ohio.
authors.forename: Nyla A
authors.initials: NA
authors.lastname: Heerema
authors.affiliation: The Ohio State University, Columbus, Ohio.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Johnson
authors.affiliation: Pharmacyclics LLC, an AbbVie Company, Sunnyvale, California.
authors.forename: Anh
authors.initials: A
authors.lastname: Tran
authors.affiliation: Pharmacyclics LLC, an AbbVie Company, Sunnyvale, California.
authors.forename: Cathy
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Pharmacyclics LLC, an AbbVie Company, Sunnyvale, California.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Bilotti
authors.affiliation: Pharmacyclics LLC, an AbbVie Company, Sunnyvale, California.
authors.forename: Danelle F
authors.initials: DF
authors.lastname: James
authors.affiliation: The Ohio State University, Columbus, Ohio.
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000368:Aged; D000369:Aged, 80 and over; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions / Q000145:classification / Q000473:pathology*; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D008297:Male; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects; D012074:Remission Induction
chemical_list: D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D000225:Adenine