title: Clonal evolution leading to ibrutinib resistance in chronic lymphocytic leukemia.
abstract: Disease progression in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib has been attributed to histologic transformation or acquired mutations inBTKandPLCG2.The rate of resistance and clonal composition of PD are incompletely characterized. We report on CLL patients treated with single-agent ibrutinib on an investigator-initiated phase 2 trial. With median follow-up of 34 months, 15 of 84 evaluable patients (17.9%) progressed. Relapsed/refractory disease at study entry,TP53aberration, advanced Rai stage, and high β-2 microglobulin were independently associated with inferior progression-free survival (P< .05 for all tests). Histologic transformation occurred in 5 patients (6.0%) and was limited to the first 15 months on ibrutinib. In contrast, progression due to CLL in 10 patients (11.9%) occurred later, diagnosed at a median 38 months on study. At progression, mutations inBTK(Cys481) and/orPLCG2(within the autoinhibitory domain) were found in 9 patients (10.7%), in 8 of 10 patients with progressive CLL, and in 1 patient with prolymphocytic transformation. Applying high-sensitivity testing (detection limit ∼1 in 1000 cells) to stored samples, we detected mutations up to 15 months before manifestation of clinical progression (range, 2.9-15.4 months). In 5 patients (6.0%), multiple subclones carrying different mutations arose independently, leading to subclonal heterogeneity of resistant disease. For a seamless transition to alternative targeted agents, patients progressing with CLL were continued on ibrutinib for up to 3 months, with 19.8 months median survival from the time of progression. This trial was registered at www.clinicaltrials.gov as #NCT01500733.
authors.affiliation: Medical Oncology Service, National Cancer Institute, and.
authors.forename: Inhye E
authors.initials: IE
authors.lastname: Ahn
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Chingiz
authors.initials: C
authors.lastname: Underbayev
authors.affiliation: NeoGenomics Laboratories, Irvine, CA; and.
authors.forename: Adam
authors.initials: A
authors.lastname: Albitar
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Sarah E M
authors.initials: SE
authors.lastname: Herman
authors.affiliation: Office of Biostatistics Research, National Heart, Lung, and Blood Institute.
authors.forename: Xin
authors.initials: X
authors.lastname: Tian
authors.affiliation: Department of Laboratory Medicine, Clinical Center, and.
authors.forename: Irina
authors.initials: I
authors.lastname: Maric
authors.affiliation: Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Diane C
authors.initials: DC
authors.lastname: Arthur
authors.affiliation: Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Laura
authors.initials: L
authors.lastname: Wake
authors.affiliation: Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Stefania
authors.initials: S
authors.lastname: Pittaluga
authors.affiliation: Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Constance M
authors.initials: CM
authors.lastname: Yuan
authors.affiliation: Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Maryalice
authors.initials: M
authors.lastname: Stetler-Stevenson
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Susan
authors.initials: S
authors.lastname: Soto
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Janet
authors.initials: J
authors.lastname: Valdez
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Pia
authors.initials: P
authors.lastname: Nierman
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lotter
authors.affiliation: Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Liqiang
authors.initials: L
authors.lastname: Xi
authors.affiliation: Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Mark
authors.initials: M
authors.lastname: Raffeld
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Farooqui
authors.affiliation: NeoGenomics Laboratories, Irvine, CA; and.
authors.forename: Maher
authors.initials: M
authors.lastname: Albitar
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Adrian
authors.initials: A
authors.lastname: Wiestner
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000368:Aged; D002471:Cell Transformation, Neoplastic; D060965:Clonal Evolution; D018450:Disease Progression; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005500:Follow-Up Studies; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000401:mortality / Q000473:pathology* / Q000503:physiopathology; D051966:Phospholipase C gamma / Q000235:genetics; D010880:Piperidines; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011720:Pyrazoles / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*
chemical_list: D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D051966:Phospholipase C gamma; D000225:Adenine