title: Leukemia cell proliferation and death in chronic lymphocytic leukemia patients on therapy with the BTK inhibitor ibrutinib.
abstract: BACKGROUND.Ibrutinib is an effective targeted therapy for patients with chronic lymphocytic leukemia (CLL) that inhibits Bruton's tyrosine kinase (BTK), a kinase involved in B cell receptor signaling.METHODS.We used stable isotopic labeling with deuterated water (2H2O) to measure directly the effects of ibrutinib on leukemia cell proliferation and death in 30 patients with CLL.RESULTS.The measured average CLL cell proliferation ("birth") rate before ibrutinib therapy was 0.39% of the clone per day (range 0.17%-1.04%); this decreased to 0.05% per day (range 0%-0.36%) with treatment. Death rates of blood CLL cells increased from 0.18% per day (average, range 0%-0.7%) prior to treatment to 1.5% per day (range 0%-3.0%) during ibrutinib therapy, and they were even higher in tissue compartments.CONCLUSIONS.This study provides the first direct in vivo measurements to our knowledge of ibrutinib's antileukemia actions, demonstrating profound and immediate inhibition of CLL cell proliferation and promotion of high rates of CLL cell death.TRIAL REGISTRATION.This trial was registered at clinicaltrials.gov (NCT01752426).FUNDING.This study was supported by a Cancer Center Support Grant (National Cancer Institute grant P30 CA016672), an NIH grant (CA081554) from the National Cancer Institute, MD Anderson's Moon Shots Program in CLL, and Pharmacyclics, an AbbVie company.
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Burger
authors.affiliation: KineMed Inc., Emeryville, California, USA.
authors.forename: Kelvin W
authors.initials: KW
authors.lastname: Li
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Keating
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Mariela
authors.initials: M
authors.lastname: Sivina
authors.affiliation: Department of Diagnostic Radiology and.
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Amer
authors.affiliation: Department of Diagnostic Radiology and.
authors.forename: Naveen
authors.initials: N
authors.lastname: Garg
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ferrajoli
authors.affiliation: Department of Biostatistics, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Xuelin
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: William G
authors.initials: WG
authors.lastname: Wierda
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
authors.affiliation: Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, California, USA.
authors.forename: Marc K
authors.initials: MK
authors.lastname: Hellerstein
authors.affiliation: KineMed Inc., Emeryville, California, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Turner
authors.affiliation: KineMed Inc., Emeryville, California, USA.
authors.forename: Claire L
authors.initials: CL
authors.lastname: Emson
authors.affiliation: Karches Center for Chronic Lymphocytic Leukemia Research, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York, USA.
authors.forename: Shih-Shih
authors.initials: SS
authors.lastname: Chen
authors.affiliation: Karches Center for Chronic Lymphocytic Leukemia Research, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York, USA.
authors.forename: Xiao-Jie
authors.initials: XJ
authors.lastname: Yan
authors.affiliation: Department of Mathematics and Department of Ecology and Evolutionary Biology, University of California, Irvine, Irvine, California, USA.
authors.forename: Dominik
authors.initials: D
authors.lastname: Wodarz
authors.affiliation: Karches Center for Chronic Lymphocytic Leukemia Research, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Chiorazzi
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase / Q000037:antagonists & inhibitors; D000368:Aged; D016923:Cell Death; D049109:Cell Proliferation; D017666:Deuterium Oxide; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011720:Pyrazoles / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*
chemical_list: D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D000077329:Agammaglobulinaemia Tyrosine Kinase; D017666:Deuterium Oxide; D000225:Adenine