***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 Most patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma relapse after initial therapy . Bendamustine plus rituximab is often used in the relapsed or refractory setting . We assessed the efficacy and safety of adding ibrutinib , an oral covalent inhibitor of Bruton 's tyrosine kinase ( BTK ) , to bendamustine plus rituximab in patients with previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma . METHODS The HELIOS trial was an international , double-blind , placebo-controlled , phase 3 study in adult patients ( ≥18 years of age ) who had active chronic lymphocytic leukaemia or small lymphocytic lymphoma with measurable lymph node disease ( > 1·5 cm ) by CT scan , and had relapsed or refractory disease following one or more previous lines of systemic therapy consisting of at least two cycles of a chemotherapy-containing regimen , an Eastern Cooperative Oncology Group ( ECOG ) performance status of 0 - 1 , and adequate bone marrow , liver , and kidney function . Patients with del(17p ) were excluded because of known poor response to bendamustine plus rituximab . Patients who had received previous treatment with ibrutinib or other BTK inhibitors , refractory disease or relapse within 24 months with a previous bendamustine-containing regimen , or haemopoietic stem-cell transplant were also excluded . Patients were r and omly assigned ( 1:1 ) by a web-based system to receive bendamustine plus rituximab given in cycles of 4 weeks ' duration ( bendamustine : 70 mg/m(2 ) intravenously on days 2 - 3 in cycle 1 , and days 1 - 2 in cycles 2 - 6 ; rituximab : 375 mg/m(2 ) on day 1 of cycle 1 , and 500 mg/m(2 ) on day 1 of cycles 2 - 6 for a maximum of six cycles ) with either ibrutinib ( 420 mg daily orally ) or placebo until disease progression or unacceptable toxicity . Patients were stratified according to whether they were refractory to purine analogues and by number of previous lines of therapy . The primary endpoint was independent review committee (IRC)-assessed progression-free survival . Crossover to ibrutinib was permitted for patients in the placebo group with IRC-confirmed disease progression . Analysis was by intention-to-treat and is continuing for further long-term follow-up . The trial is registered with Clinical Trials.gov , number NCT01611090 . FINDINGS Between Sept 19 , 2012 , and Jan 21 , 2014 , 578 eligible patients were r and omly assigned to  ibrutinib or placebo in combination with bendamustine plus rituximab ( 289 in each group ) . The primary endpoint was met at the preplanned interim analysis ( March 10 , 2015 ) . At a median follow-up of 17 months ( IQR 13·7 - 20·7 ) , progression-free survival was significantly improved in the ibrutinib group compared with the placebo group ( not reached in the ibrutinib group ( 95 % CI not evaluable ) vs 13·3 months ( 11·3 - 13·9 ) in the placebo group ( hazard ratio [ HR ] 0·203 , 95 % CI 0·150 - 0·276 ; p<0·0001 ) . IRC-assessed progression-free survival at 18 months was 79 % ( 95 % CI 73 - 83 ) in the ibrutinib group and 24 % ( 18 - 31 ) in the placebo group ( HR 0·203 , 95 % CI 0·150 - 0·276 ; p<0·0001 ) . The most frequent all- grade adverse events were neutropenia and nausea . 222 ( 77 % ) of 287 patients in the ibrutinib group and 212 ( 74 % ) of 287 patients in the placebo group reported grade 3 - 4 events ; the most common grade 3 - 4 adverse events in both groups were neutropenia ( 154 [ 54 % ] in the ibrutinib group vs 145 [ 51 % ] in the placebo group ) and thrombocytopenia ( 43 [ 15 % ] in each group ) . A safety profile similar to that previously reported with ibrutinib and bendamustine plus rituximab individually was noted . INTERPRETATION In patients eligible for bendamustine plus rituximab , the addition of ibrutinib to this regimen results in significant improvements in outcome with no new safety signals identified from the combination and a manageable safety profile . FUNDING Janssen Research & Development BACKGROUND The TP53 gene , encoding tumour suppressor protein p53 , is located on the short arm of chromosome 17 ( 17p ) . Patients with 17p deletion ( del17p ) chronic lymphocytic leukaemia have poor responses and survival after chemoimmunotherapy . We assessed the activity and safety of ibrutinib , an oral covalent inhibitor of Bruton 's tyrosine kinase , in relapsed or refractory patients with del17p chronic lymphocytic leukaemia or small lymphocytic lymphoma . METHODS We did a multicentre , international , open-label , single-arm study at 40 sites in the USA , Canada , Europe , Australia , and New Zeal and . Patients ( age ≥18 years ) with previously treated del17p chronic lymphocytic leukaemia or small lymphocytic lymphoma received oral ibrutinib 420 mg once daily until progressive disease or unacceptable toxicity . The primary endpoint was overall response in the all-treated population per International Workshop on Chronic Lymphocytic Leukaemia 2008 response criteria modified for treatment-related lymphocytosis . Preplanned exploratory analyses were progression-free survival , overall survival , sustained haematological improvement , and immunological improvement . Patient enrolment is complete , but follow-up is ongoing . Treatment discontinuation owing to adverse events , unacceptable toxicity , or death were collected as a single combined category . This study is registered with Clinical Trials.gov , number NCT01744691 . FINDINGS Between Jan 29 , 2013 , and June 19 , 2013 , 145 patients were enrolled . The all-treated population consisted of 144 patients with del17p chronic lymphocytic leukaemia or small lymphocytic lymphoma who received at least one dose of study drug , with a median age of 64 years ( IQR 57 - 72 ) and a median of two previous treatments ( IQR 1 - 3 ) . At the prespecified primary analysis after a median follow-up of 11·5 months ( IQR 11·1 - 13·8 ) , 92 ( 64 % , 95 % CI 56 - 71 ) of 144 patients had an overall response according to independent review committee assessment ; 119 patients ( 83 % , 95 % CI 76 - 88 ) had an overall response according to investigator assessment . In an extended analysis with median follow-up of 27·6 months ( IQR 14·6 - 27·7 ) , the investigator-assessed overall response was reported in 120 patients ( 83 % , 95 % CI 76 - 89 ) . 24-month progression-free survival was 63 % ( 95 % CI 54 - 70 ) and 24-month overall survival was 75 % ( 67 - 81 ) . Sustained haematological improvement was noted in 72 ( 79 % ) of 91 patients with any baseline cytopenia . No clinical ly relevant changes were noted from baseline to 6 months or 24 months in IgA ( median 0·4 g/L at baseline , 0·6 g/L at 6 months , and 0·7 g/L at 24 months ) , IgG ( 5·0 g/L , 5·3 g/L , and 4·9 g/L ) , or IgM ( 0·3 g/L at each timepoint ) concentrations . Common reasons for treatment discontinuation were progressive disease in 34 ( 24 % ) patients and adverse events , unacceptable toxicity , or death in 24 ( 17 % ) patients . Major bleeding occurred in 13 ( 9 % ) patients ( 11 [ 8 % ] grade 3 - 4 ) . Grade 3 or worse infections occurred in 43 ( 30 % ) patients , including pneumonia in 19 ( 13 % ) patients . In the extended analysis , 38 patients died , 18 as a result of adverse events ( four pneumonia , three chronic lymphocytic leukaemia , two Richter 's syndrome , two sepsis , and one each of acute myocardial infa rct ion , septic shock , encephalopathy , general deterioration in physical health , abnormal hepatic function , myocardial infa rct ion , and renal infa rct ion ) . INTERPRETATION A high proportion of patients had an overall response to ibrutinib and the risk : benefit profile was favourable , providing further evidence for use of ibrutinib in the most difficult subset of patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma . Ibrutinib represents a clinical advance in the treatment of patients with del17p chronic lymphocytic leukaemia and has been incorporated into treatment algorithms as a primary treatment for these patients . FUNDING Pharmacyclics LLC , an AbbVie Company In a phase 1 trial , idelalisib ( GS-1101 , CAL-101 ) , a selective inhibitor of the lipid kinase PI3Kδ , was evaluated in 54 patients with relapsed/refractory chronic lymphocytic leukemia ( CLL ) with adverse characteristics including bulky lymphadenopathy ( 80 % ) , extensive prior therapy ( median 5 [ range 2 - 14 ] prior regimens ) , treatment-refractory disease ( 70 % ) , unmutated IGHV ( 91 % ) , and del17p and /or TP53 mutations ( 24 % ) . Patients were treated at 6 dose levels of oral idelalisib ( range 50 - 350 mg once or twice daily ) and remained on continuous therapy while deriving clinical benefit . Idelalisib-mediated inhibition of PI3Kδ led to abrogation of Akt phosphorylation in patient CLL cells and significantly reduced serum levels of CLL-related chemokines . The most commonly observed grade ≥3 adverse events were pneumonia ( 20 % ) , neutropenic fever ( 11 % ) , and diarrhea ( 6 % ) . Idelalisib treatment result ed in nodal responses in 81 % of patients . The overall response rate was 72 % , with 39 % of patients meeting the criteria for partial response per IWCLL 2008 and 33 % meeting the recently up date d criteria of PR with treatment-induced lymphocytosis.(1,2 ) The median progression-free survival for all patients was 15.8 months . This study demonstrates the clinical utility of inhibiting the PI3Kδ pathway with idelalisib . Our findings support the further development of idelalisib in patients with CLL . These trials were registered at clinical trials.gov as # NCT00710528 and # NCT01090414 Despite promising results with targeted drugs , chemoimmunotherapy with fludarabine , cyclophosphamide ( FC ) , and rituximab ( R ) remains the st and ard therapy for fit patients with untreated chronic lymphocytic leukemia ( CLL ) . Herein , we present the long-term follow-up of the r and omized CLL8 trial reporting safety and efficacy of FC and FCR treatment of 817 treatment-naïve patients with CLL . The primary end point was progression-free survival ( PFS ) . With a median follow-up of 5.9 years , median PFS were 56.8 and 32.9 months for the FCR and FC group ( hazard ratio [ HR ] , 0.59 ; 95 % confidence interval [ CI ] , 0.50 - 0.69 , P < .001 ) . Median overall survival ( OS ) was not reached for the FCR group and was 86.0 months for the FC group ( HR , 0.68 ; 95 % CI , 0.54 - 0.89 , P = .001 ) . In patients with mutated IGHV ( IGHV MUT ) , FCR  improved PFS and OS compared with FC ( PFS : HR , 0.47 ; 95 % CI , 0.33 - 0.68 , P < .001 ; OS : HR , 0.62 ; 95 % CI , 0.34 - 1.11 , P = .1 ) . This improvement remained applicable for all cytogenetic subgroups other than del(17p ) . Long-term safety analyses showed that FCR had a higher rate of prolonged neut 
    Output:
    
No statistically significant difference in any aspect of meta- analysis was noted between ibrutinib and idelalisib