title: Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial.
abstract: BACKGROUND
  Chemoimmunotherapy has led to improved numbers of patients achieving disease response, and longer overall survival in young patients with chronic lymphocytic leukaemia; however, its application in elderly patients has been restricted by substantial myelosuppression and infection. We aimed to assess safety and activity of ibrutinib, an orally administered covalent inhibitor of Bruton tyrosine kinase (BTK), in treatment-naive patients aged 65 years and older with chronic lymphocytic leukaemia.
  
  
  METHODS
  In our open-label phase 1b/2 trial, we enrolled previously untreated patients at clinical sites in the USA. Eligible patients were aged at least 65 years, and had symptomatic chronic lymphocytic leukaemia or small lymphocytic lymphoma requiring therapy. Patients received 28 day cycles of once-daily ibrutinib 420 mg or ibrutinib 840 mg. The 840 mg dose was discontinued after enrolment had begun because comparable activity of the doses has been shown. The primary endpoint was the safety of the dose-fixed regimen in terms of frequency and severity of adverse events for all patients who received treatment. This study is registered with ClinicalTrials.gov, number NCT01105247.
  
  
  RESULTS
  Between May 20, 2010, and Dec 18, 2012, we enrolled 29 patients with chronic lymphocytic leukaemia and two patients with small lymphocytic lymphoma. Median age was 71 years (range 65-84), and 23 (74%) patients were at least 70 years old. Toxicity was mainly of mild-to-moderate severity (grade 1-2). 21 (68%) patients had diarrhoea (grade 1 in 14 [45%] patients, grade 2 in three [10%] patients, and grade 3 in four [13%] patients). 15 (48%) patients developed nausea (grade 1 in 12 [39%] patients and grade 2 in three [10%] patients). Ten (32%) patients developed fatigue (grade 1 in five [16%] patients, grade 2 in four [13%] patients, and grade 3 in one [3%] patient). Three (10%) patients developed grade 3 infections, although no grade 4 or 5 infections occurred. One patient developed grade 3 neutropenia, and one developed grade 4 thrombocytopenia. After a median follow-up of 22.1 months (IQR 18.4-23.2), 22 (71%) of 31 patients achieved an objective response (95% CI 52.0-85.8); four patients (13%) had a complete response, one patient (3%) had a nodular partial response, and 17 (55%) patients had a partial response.
  
  
  CONCLUSIONS
  The safety and activity of ibrutinib in elderly, previously untreated patients with symptomatic chronic lymphocytic leukaemia, or small lymphocytic lymphoma is encouraging, and merits further investigation in phase 3 trials.
  
  
  BACKGROUND
  Pharmacyclics, Leukemia and Lymphoma Society, D Warren Brown Foundation, Mr and Mrs Michael Thomas, Harry Mangurian Foundation, P50 CA140158 to Prof J C Byrd MD.
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: sobrien@mdanderson.org.
authors: Susan
authors: S
authors: O'Brien
authors: Department of Medicine, Division of Hematology-Oncology, Weill Cornell Medical College, New York, NY, USA.
authors: Richard R
authors: RR
authors: Furman
authors: Division of Hematology and Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA, USA.
authors: Steven E
authors: SE
authors: Coutre
authors: Willamette Valley Cancer Institute and Research Center/US Oncology Research, Springfield, OR, USA.
authors: Jeff P
authors: JP
authors: Sharman
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Jan A
authors: JA
authors: Burger
authors: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
authors: Kristie A
authors: KA
authors: Blum
authors: Vermont Cancer Center, University of Vermont, VT, USA.
authors: Barbara
authors: B
authors: Grant
authors: Texas Oncology, US Oncology Research, Tyler, TX, USA.
authors: Donald A
authors: DA
authors: Richards
authors: Department of Medicine, Division of Hematology-Oncology, Weill Cornell Medical College, New York, NY, USA.
authors: Morton
authors: M
authors: Coleman
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: William G
authors: WG
authors: Wierda
authors: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
authors: Jeffrey A
authors: JA
authors: Jones
authors: Department of Pathology, The Ohio State University, Columbus, OH, USA.
authors: Weiqiang
authors: W
authors: Zhao
authors: Department of Pathology, The Ohio State University, Columbus, OH, USA.
authors: Nyla A
authors: NA
authors: Heerema
authors: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
authors: Amy J
authors: AJ
authors: Johnson
authors: Pharmacyclics, Sunnyvale, CA, USA.
authors: Raquel
authors: R
authors: Izumi
authors: Pharmacyclics, Sunnyvale, CA, USA.
authors: Ahmed
authors: A
authors: Hamdy
authors: Pharmacyclics, Sunnyvale, CA, USA.
authors: Betty Y
authors: BY
authors: Chang
authors: Pharmacyclics, Sunnyvale, CA, USA.
authors: Thorsten
authors: T
authors: Graef
authors: Pharmacyclics, Sunnyvale, CA, USA.
authors: Fong
authors: F
authors: Clow
authors: Pharmacyclics, Sunnyvale, CA, USA.
authors: Joseph J
authors: JJ
authors: Buggy
authors: Pharmacyclics, Sunnyvale, CA, USA.
authors: Danelle F
authors: DF
authors: James
authors: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
authors: John C
authors: JC
authors: Byrd
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000009:adverse effects / Q000627:therapeutic use*; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D000225:Adenine