title: Impact of ibrutinib dose adherence on therapeutic efficacy in patients with previously treated CLL/SLL.
abstract: Ibrutinib, an oral inhibitor of Bruton's tyrosine kinase (BTK), at a once-daily dose of 420 mg achieved BTK active-site occupancy in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) that was maintained at 24 hours. It is unknown if intermittent interruption of ibrutinib therapy contributes to altered clinical outcomes. We therefore evaluated the effect of ibrutinib dose adherence on patient outcomes in the phase 3 RESONATE trial. The overall mean dose intensity (DI) was 95% with median treatment duration of ∼9 months. Pharmacokinetic assessment of ibrutinib exposure at 420-mg dose suggested similar exposure regardless of patient weight or age. As assessed by independent review committee, patients with higher DI experienced longer median progression-free survival (PFS) compared with those with lower DI regardless of del17p and/orTP53status. Of 79 patients requiring a drug hold, treatment was restarted at the original dose in 73 (92%) patients. Mean duration of a missed-dose event was 18.7 days (range, 8-56). Patients missing ≥8 consecutive days of ibrutinib had a shorter median PFS vs those missing <8 days (10.9 months vs not reached). These results support sustained adherence to once-daily ibrutinib dosing at 420 mg as clinically feasible to achieve optimal outcomes in patients with previously treated CLL. The trial was registered at www.clinicaltrials.gov as #NCT01578707.
authors.affiliation: Wilmot Cancer Institute, University of Rochester, Rochester, NY.
authors.forename: Paul M
authors.identifier: 0000-0002-9733-401X
authors.initials: PM
authors.lastname: Barr
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Brown
authors.affiliation: The Leeds Teaching Hospitals, St. James Institute of Oncology, Leeds, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Hillmen
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
authors.affiliation: Hofstra Northwell School of Medicine, Hempstead, NY.
authors.forename: Jacqueline C
authors.initials: JC
authors.lastname: Barrientos
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, TN.
authors.forename: Nishitha M
authors.initials: NM
authors.lastname: Reddy
authors.affiliation: Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA.
authors.forename: Steven
authors.initials: S
authors.lastname: Coutre
authors.affiliation: Royal North Shore Hospital, Sydney, NSW, Australia.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Mulligan
authors.affiliation: Division of Hematology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Jaeger
authors.affiliation: Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Furman
authors.affiliation: Hôpital Avicenne, Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Cymbalista
authors.affiliation: Niguarda Ca' Granda Hospital, Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Montillo
authors.affiliation: Royal Marsden Hospital, London, United Kingdom.
authors.forename: Claire
authors.initials: C
authors.lastname: Dearden
authors.affiliation: Department of Hematology, Medical University of Lodz, Lodz, Poland.
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Robak
authors.affiliation: Hospital de la Santa Creu Sant Pau, Barcelona, Spain.
authors.forename: Carol
authors.initials: C
authors.lastname: Moreno
authors.affiliation: Swedish Cancer Institute, Seattle, WA.
authors.forename: John M
authors.initials: JM
authors.lastname: Pagel
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Burger
authors.affiliation: Pharmacyclics LLC, AbbVie, Sunnyvale, CA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Pharmacyclics LLC, AbbVie, Sunnyvale, CA.
authors.forename: Juthamas
authors.initials: J
authors.lastname: Sukbuntherng
authors.affiliation: Pharmacyclics LLC, AbbVie, Sunnyvale, CA.
authors.forename: George
authors.initials: G
authors.lastname: Cole
authors.affiliation: Pharmacyclics LLC, AbbVie, Sunnyvale, CA.
authors.forename: Danelle F
authors.initials: DF
authors.lastname: James
authors.affiliation: The Ohio State University Medical Center, The Ohio State University, Columbus, OH.
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D009154:Mutation; D010349:Patient Compliance; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D016159:Tumor Suppressor Protein p53; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D000225:Adenine