***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 aim ed 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 Clinical Trials.gov , number NCT01105247 . FINDINGS 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 . INTERPRETATION 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 . FUNDING 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 BACKGROUND Ibrutinib is approved in the EU , USA , and other countries for patients with mantle cell lymphoma who received one previous therapy . In a previous phase 2 study with single-agent ibrutinib , the proportion of patients who achieved an objective response was 68 % ; 38 ( 34 % ) of 111 patients had transient lymphocytosis . We hypothesised that adding rituximab could target mantle cell lymphoma cells associated with redistribution lymphocytosis , leading to more potent antitumour activity . METHODS Patients with a confirmed mantle cell lymphoma diagnosis ( based on CD20-positive and cyclin D1-positive cells in tissue biopsy specimens ) , no upper limit on the number of previous treatments received , and an Eastern Cooperative Oncology Group performance status score of 2 or less were enrolled in this single-centre , open-label , phase 2 study . Patients received continuous oral ibrutinib ( 560 mg ) daily until progressive disease or unacceptable toxic effects . Rituximab 375 mg/m(2 ) was given intravenously once per week for 4 weeks during cycle 1 , then on day 1 of cycles 3 - 8 , and thereafter once every other cycle up to 2 years . The primary endpoint was the proportion of patients who achieved an objective response in the intention-to-treat population and safety assessed in the as-treated population . The study is registered with Clinical Trials.gov , number NCT01880567 , and is still ongoing , but no longer accruing patients . FINDINGS Between July 15 , 2013 , and June 30 , 2014 , 50 patients were enrolled . Median age was 67 years ( range 45 - 86 ) , and the median number of previous regimens was three ( range 1 - 9 ) . At a median follow-up of 16·5 months ( IQR 12·09 - 19·28 ) , 44 ( 88 % , 95 % CI 75·7 - 95·5 ) patients achieved an objective response , with 22 ( 44 % , 30·0 - 58·7 ) patients achieving a complete response , and 22 ( 44 % , 30·0 - 58·7 ) a partial response . The only grade 3 adverse event in > = 10 % of patients was atrial fibrillation , which was noted in six ( 12 % ) patients . Grade 4 diarrhoea and neutropenia occurred in one patient each . Adverse events led to discontinuation of therapy in five ( 10 % ) patients ( atrial fibrillation in three [ 6 % ] patients , liver infection in one [ 2 % ] , and bleeding in one [ 2 % ] ) . Two patients died while on- study from cardiac arrest and septic shock ; the latter was deemed possibly related to treatment . INTERPRETATION Ibrutinib combined with rituximab is active and well tolerated  in patients with relapsed or refractory mantle cell lymphoma . Our results provide preliminary evidence for the activity of this combination in clinical practice . A phase 3 trial is warranted for more definitive data . FUNDING Pharmacyclics LLC , an AbbVie Company LBA7005 Background : The phase III HELIOS study evaluated the first-in-class , oral covalent BTK inhibitor ibrutinib in combination with BR ( BR+ibr ) vs BR plus placebo ( BR+plb ) in patients ( pts ) with previously treated CLL/SLL . The preplanned interim analysis reported here showed that the primary end point was met , upon which the IDMC recommended unblinding the study . METHODS Pts received BR ( ≤ 6 cycles ) and were r and omized 1:1 to ibr ( 420 mg daily ) or plb . Purine analog refractoriness was a stratification factor . Pts with del17p ( > 20 % of cells ) were excluded . Primary end point was independent review committee (IRC)-assessed progression-free survival ( PFS ) . Secondary end points included overall survival ( OS ) and overall response rate ( ORR ) per IRC . RESULTS 578 pts were r and omized ( 289 per arm ) ; median age 64 yrs ; 38 % Rai Stage III/IV ; median 2 prior therapies . 6 cycles of BR were completed in 83 % and 78 % of pts in the ibr and plb arms , respectively . At a median follow-up of 17.2 months , IRC-assessed PFS was significantly longer with BR+ibr vs BR+plb ( median not reached vs 13.3 months ; HR : 0.203 , 95 % CI : 0.150 - 0.276 , P < 0.0001 ) ; PFS results were consistent across high-risk subgroups . ORR and CR/CRi rates were 82.7 % vs 67.8 % ( P < 0.0001 ) and 10.4 % vs 2.8 % . Median OS was not reached . 90 pts ( 31 % ) in the BR+plb arm with confirmed PD crossed over to receive ibr , as permitted per the protocol . Incidence of most AEs was similar between arms . The most common all- grade AEs with BR+ibr and BR+plb were neutropenia ( 58.2 % vs 54.7 % ) and nausea ( 36.9 % vs 35.2 % ) ; most common grade 3/4 AEs were neutropenia ( 53.7 % vs 50.5 % ) and thrombocytopenia ( 15.0 % each arm ) . Rates of grade 3/4 atrial fibrillation were 2.8 % and 0.7 % , and major hemorrhage were 2.1 % and 1.7 % . Fatigue ( FACIT-Fatigue ) was improved with BR+ibr vs BR+plb . CONCLUSIONS The addition of ibr to BR reduced the risk of progression or death by 80 % compared with BR+plb . ORR was also significantly improved . Safety of BR+ibr was consistent with the known profiles for BR and ibr . The data further support ibr as an important treatment option for pts with previously treated CLL/SLL . CLINICAL TRIAL INFORMATION EudraCT No. 2012 - 000600 - 15 ; UTN No. U1111 - 1135 - 3745 Background and Purpose — Stroke risk increases with age in patients who have nonvalvular atrial fibrillation . It is uncertain whether the efficacy of stroke prevention therapies in atrial fibrillation changes as patients age . The objective of this study was to determine the effect of age on the relative efficacy of oral anticoagulants ( OAC ) and antiplatelet ( AP ) therapy ( including acetylsalicylic acid and triflusal ) on ischemic stroke , serious bleeding , and vascular events in patients with atrial fibrillation . Methods — This is an analysis of the Atrial Fibrillation Investigators data base , which contains patient level- data from r and omized trials of stroke prevention in atrial fibrillation . We used Cox regression models with age as a continuous variable that controlled for sex , year of r and omization , and history of cerebrovascular disease , diabetes , hypertension , and congestive heart failure . Outcomes included ischemic stroke , serious bleeding ( intracranial hemorrhage or systemic bleeding requiring hospitalization , transfusion , or surgery ) , and cardiovascular events ( ischemic stroke , myocardial infa rct ion , systemic embolism , or vascular death ) . Results — The analysis included 8932 patients and 17 685 years of observation from 12 trials . Patient age increased risk of ischemic stroke ( adjusted hazard ratio per decade increase 1.45 ; 95 % CI , 1.26 to 1.66 ) , serious bleeding ( 1.61 ; 1.47 to 1.77 ) , and cardiovascular events ( 1.43 ; 1.33 to 1.53 ) . Compared with placebo , OAC and AP significantly reduced the risk of ischemic stroke ( OAC , 0.36 ; 0.29 to 0.45 ; AP , 0.81 ; 0.72 to 0.90 ) and cardiovascular outcomes ( OAC , 0.59 ; 0.52 to 0.66 ; AP , 0.81 ; 0.75 to 0.88 ) , whereas OAC increased risk of serious bleeding ( 1.56 ; 1.03 to 2.37 ) . The relative benefit of OAC versus placebo or AP did not vary by patient age for any outcome . Compared with placebo , the relative benefit of AP  for preventing ischemic stroke decreased significantly as patients aged ( P=0.01 ) . Conclusions — As patients with atrial fibrillation age , the relative efficacy of AP to prevent ischemic stroke appears to decrease , whereas it does not change for OAC . Because stroke risk increases with age , the absolute benefit of OAC increases as patients get older Ibrutinib represents a therapeutic advance in chronic lymphocytic leukemia ( CLL ) but as monotherapy produces few complete remissions in previously treated patients . Anti-CD20 antibodies have improved response and progression-free survival ( PFS ) when combined with chemotherapy . We evaluated the safety and activity of adding ofatumumab to ibrutinib in 3 different administration sequences . Patients with CLL/small lymphocytic lymphoma ( SLL ) , prolymphocytic leukemia , or Richter 's transformation who failed ≥2 prior therapies were enrolled . Patients received ibrutinib 420 mg daily and 12 doses of ofatumumab 300/2000 mg in 3 schedules : ibrutinib lead-in ( group 1 ; n = 27 ) , concurrent start ( group 2 ; n = 20 ) , or ofatumumab lead-in ( group 3 ; n = 24 ) . Seventy-one patients were treated ; most had high-risk disease including del(17)(p13.1 ) ( 44 % 
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The risk of these adverse events was not different between subgroups on the basis of pathology , treatment setting , dose , and duration of ibrutinib exposure .
Conclusion : The risks of Afib/Aflutter and all‐ grade bleeding were significantly higher in the ibrutinib group .