title: Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial.
abstract: BACKGROUND
  Patients with chronic lymphocytic leukaemia (CLL) with TP53 aberrations respond poorly to first-line chemoimmunotherapy, resulting in early relapse and short survival. We investigated the safety and activity of ibrutinib in previously untreated and relapsed or refractory CLL with TP53 aberrations.
  
  
  METHODS
  In this investigator-initiated, single-arm phase 2 study, we enrolled eligible adult patients with active CLL with TP53 aberrations at the National Institutes of Health Clinical Center (Bethesda, MD, USA). Patients received 28-day cycles of ibrutinib 420 mg orally once daily until disease progression or the occurrence of limiting toxicities. The primary endpoint was overall response to treatment at 24 weeks in all evaluable patients. This study is registered with ClinicalTrials.gov, number NCT01500733, and is fully enrolled.
  
  
  RESULTS
  Between Dec 22, 2011, and Jan 2, 2014, we enrolled 51 patients; 47 had CLL with deletion 17p13.1 and four carried a TP53 mutation in the absence of deletion 17p13.1. All patients had active disease requiring therapy. 35 enrolled patients had previously untreated CLL and 16 had relapsed or refractory disease. Median follow-up was 24 months (IQR 12.9-27.0). 33 previously untreated patients and 15 patients with relapsed or refractory CLL were evaluable for response at 24 weeks. 32 (97%; 95% CI 86-100) of 33 previously untreated patients achieved an objective response, including partial response in 18 patients (55%) and partial response with lymphocytosis in 14 (42%). One patient had progressive disease at 0.4 months. 12 (80%; 95% CI 52-96) of the 15 patients with relapsed or refractory CLL had an objective response: six (40%) achieved a partial response and six (40%) a partial response with lymphocytosis; the remaining three (20%) patients had stable disease. Grade 3 or worse treatment-related adverse events were neutropenia in 12 (24%) patients (grade 4 in one [2%] patient), anaemia in seven (14%) patients, and thrombocytopenia in five (10%) patients (grade 4 in one [2%] patient). Grade 3 pneumonia occurred in three (6%) patients, and grade 3 rash in one (2%) patient.
  
  
  CONCLUSIONS
  The activity and safety profile of single-agent ibrutinib in CLL with TP53 aberrations is encouraging and supports its consideration as a novel treatment option for patients with this high-risk disease in both first-line and second-line settings.
  
  
  BACKGROUND
  Intramural Research Program of the National Heart, Lung, and Blood Institute and the National Cancer Institute, Danish Cancer Society, Novo Nordisk Foundation, National Institutes of Health Medical Research Scholars Program, and Pharmacyclics Inc.
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Mohammed Z H
authors.initials: MZ
authors.lastname: Farooqui
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
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, USA.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Martyr
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Georg
authors.initials: G
authors.lastname: Aue
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Nakhle
authors.initials: N
authors.lastname: Saba
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Carsten U
authors.initials: CU
authors.lastname: Niemann
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Sarah E M
authors.initials: SE
authors.lastname: Herman
authors.affiliation: Office of Biostatistics Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Tian
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Gerald
authors.initials: G
authors.lastname: Marti
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Soto
authors.affiliation: Clinical Center Pharmacy Department, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Hughes
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA; Medical Scholars Research Program, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Jade
authors.initials: J
authors.lastname: Jones
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Lipsky
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Stefania
authors.initials: S
authors.lastname: Pittaluga
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Maryalice
authors.initials: M
authors.lastname: Stetler-Stevenson
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Constance
authors.initials: C
authors.lastname: Yuan
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Yuh Shan
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Lone B
authors.initials: LB
authors.lastname: Pedersen
authors.affiliation: Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Christian H
authors.initials: CH
authors.lastname: Geisler
authors.affiliation: Department of Laboratory Medicine, Clinical Research Center, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Calvo
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Diane C
authors.initials: DC
authors.lastname: Arthur
authors.affiliation: Department of Laboratory Medicine, Clinical Research Center, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Maric
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Childs
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Neal S
authors.initials: NS
authors.lastname: Young
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: wiestnera@mail.nih.gov.
authors.forename: Adrian
authors.initials: A
authors.lastname: Wiestner
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D010880:Piperidines; D011379:Prognosis; D011720:Pyrazoles / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D016037:Single-Blind Method; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C551803:ibrutinib; D000225:Adenine