title: The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia.
abstract: The safety and efficacy of ibrutinib, an oral inhibitor of Bruton tyrosine kinase, were evaluated with chemoimmunotherapy (CIT) in a multicenter phase 1b study. Patients with relapsed/refractory chronic lymphocytic leukemia received bendamustine and rituximab (BR) or fludarabine, cyclophosphamide, and rituximab (FCR) for up to 6 cycles with daily ibrutinib (420 mg) until progressive disease or unacceptable toxicity. Enrollment to FCR-ibrutinib closed early due to a lack of fludarabine-naïve previously treated patients. No patients treated with BR-ibrutinib (n = 30) or FCR-ibrutinib (n = 3) experienced prolonged hematologic toxicity in cycle 1 (primary end point). Tolerability was as expected with either CIT or single-agent ibrutinib. The overall response rate (ORR) with BR-ibrutinib was 93.3%, including 16.7% complete responses (CRs) initially, which increased to 40% with the extension period. Including 1 patient with partial response with lymphocytosis, the best ORR was 96.7%. Sixteen of 21 patients with baseline cytopenias had sustained hematologic improvement. At 12 and 36 months, 86.3% and 70.3% remained progression-free, respectively. All 3 patients treated with ibrutinib-FCR achieved CR. Ibrutinib may enhance CIT efficacy without additive toxicities, providing the rationale for studying this combination in an ongoing phase 3 trial. The study is registered to www.clinicaltrials.gov as #NCT01292135.
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Brown
authors.affiliation: Hofstra North Shore-Long Island Jewish Medical Center School of Medicine at Hofstra University, Hempstead, NY;
authors.forename: Jacqueline C
authors.initials: JC
authors.lastname: Barrientos
authors.affiliation: Hematology/Oncology Division, James P. Wilmot Cancer Center, University of Rochester, Rochester, NY;
authors.forename: Paul M
authors.initials: PM
authors.lastname: Barr
authors.affiliation: Sarah Cannon Research Institute, Tennessee Oncology, Nashville, TN;
authors.forename: Ian W
authors.initials: IW
authors.lastname: Flinn
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, TX; and.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Burger
authors.affiliation: Pharmacyclics, Sunnyvale, CA.
authors.forename: Anh
authors.initials: A
authors.lastname: Tran
authors.affiliation: Pharmacyclics, Sunnyvale, CA.
authors.forename: Fong
authors.initials: F
authors.lastname: Clow
authors.affiliation: Pharmacyclics, Sunnyvale, CA.
authors.forename: Danelle F
authors.initials: DF
authors.lastname: James
authors.affiliation: Pharmacyclics, Sunnyvale, CA.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Graef
authors.affiliation: Hematology/Oncology Division, James P. Wilmot Cancer Center, University of Rochester, Rochester, NY;
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Friedberg
authors.affiliation: Hofstra North Shore-Long Island Jewish Medical Center School of Medicine at Hofstra University, Hempstead, NY;
authors.forename: Kanti
authors.initials: K
authors.lastname: Rai
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, TX; and.
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000328:Adult; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010880:Piperidines; D011379:Prognosis; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D015996:Survival Rate
chemical_list: D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000225:Adenine