***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 with fludarabine , cyclophosphamide , and rituximab is the st and ard therapy for physically fit patients with advanced chronic lymphocytic leukaemia . This international phase 3 study compared the efficacy and tolerance of the st and ard therapy with a potentially less toxic combination consisting of bendamustine and rituximab . METHODS Treatment-naive fit patients with chronic lymphocytic leukaemia ( aged 33 - 81 years ) without del(17p ) were enrolled after undergoing a central screening process . Patients were r and omly assigned ( 1:1 ) with a computer-generated r and omisation list using r and omly permuted blocks with a block size of eight and were stratified according to participating country and Binet stage . Patients were allocated to receive six cycles of intravenous fludarabine ( 25 mg/m(2 ) per day ) and cyclophosphamide ( 250 mg/m(2 ) per day ) for the first 3 days or to intravenous bendamustine ( 90 mg/m(2 ) per day ) for the first 2 days of each cycle . Rituximab 375 mg/m(2 ) was given intravenously in both groups on day 0 of cycle 1 and subsequently was given at 500 mg/m(2 ) during the next five cycles on day 1 . The primary endpoint was progression-free survival with the objective to assess non-inferiority of bendamustine and rituximab to the st and ard therapy . We aim ed to show that the 2-year progression-free survival  with bendamustine and rituximab was not 67·5 % or less with a corresponding non-inferiority margin of 1·388 for the hazard ratio ( HR ) based on the 90·4 % CI . The final analysis was done by intention to treat . The study is registered with Clinical Trials.gov , number NCT%2000769522 . FINDINGS 688 patients were recruited between Oct 2 , 2008 , and July 11 , 2011 , of which 564 patients who met inclusion criteria were r and omly assigned . 561 patients were included in the intention-to-treat population : 282 patients in the fludarabine , cyclophosphamide , and rituximab group and 279 in the bendamustine and rituximab group . After a median observation time of 37·1 months ( IQR 31·0 - 45·5 ) median progression-free survival was 41·7 months ( 95 % CI 34·9 - 45·3 ) with bendamustine and rituximab and 55·2 months ( 95 % CI not evaluable ) with fludarabine , cyclophosphamide , and rituximab ( HR 1·643 , 90·4 % CI 1·308 - 2·064 ) . As the upper limit of the 90·4 % CI was greater than 1·388 the null hypothesis for the corresponding non-inferiority hypothesis was not rejected . Severe neutropenia and infections were more frequently observed with fludarabine , cyclophosphamide , and rituximab ( 235 [ 84 % ] of 279 vs 164 [ 59 % ] of 278 , and 109 [ 39 % ] vs 69 [ 25 % ] , respectively ) during the study . The increased frequency of infectious complications  with fludarabine , cyclophosphamide , and rituximab was more pronounced in patients older than 65 years . INTERPRETATION The combination of fludarabine , cyclophosphamide , and rituximab remains the st and ard front-line therapy in fit patients with chronic lymphocytic leukaemia , but bendamustine and rituximab is associated with less toxic effects . FUNDING Roche Pharma AG , Mundipharma , German Federal Ministry of Education and Research Summary Background Uncontrolled studies comparing pentostatin ( P ) , cyclophosphamide ( C ) , and rituximab ( R ) ( PCR ) to fludarabine plus C+R ( FCR ) suggest similar efficacy with fewer infectious complications with PCR . We compared FCR and PCR in previously-untreated or minimally-treated B-cell chronic lymphocytic leukemia ( CLL ) . Treatment FCR ( F 20 mg/m2 Days 1–5 , C 600 mg/m2 Day 1 , R 375 mg/m2 Day 1 ) ( 28-day cycles ) or PCR ( P 4 mg/m2 Day 1 , C 600 mg/m2 Day 1 , R 375 mg/m2 Day 1 ) ( 21-day cycles ) . Dose 1 of R : 100 mg/m2 was given on Day 8 Cycle 1 and the remainder on Day 9 ; in subsequent cycles the entire dose was given on Day 1 . Results Ninety-two patients were r and omly assigned to each group ( N = 184 ) . Groups were balanced ; ~20 % had received prior chemotherapy . The infection rate ( FCR/PCR ) was 31%/36 % , the infective event rate was 38%/45 % ; 30 (35%)/37 ( 44 % ) patients were hospitalized ; total hospitalization days was 271/404 . 12 (14%)/6 ( 7 % ) patients achieved complete remissions ( CR ) ; the overall response rate ( ORR ) including CR+nodular PR (nPR)+PR was 59%/49 % . Grade 3–4 treatment related AEs : neutropenia ( 69%/57 % ) , leukopenia ( 34%/17 % ) , thrombocytopenia ( 13%/6 % ) . Grade 3–4 infections : febrile neutropenia ( 8%/6 % ) , fever ( 2%/6 % ) , infection ( 1%/3 % ) , urinary tract infection ( 1%/0 % ) , pneumonia ( 3%/1 % ) , and sepsis ( 1%/2 % ) ; 5 deaths ( 1 FCR/4 PCR ) were treatment-related . Conclusions PCR and FCR have significant activity in CLL and can be given safely in the community setting despite significant toxicity . ORRs were lower than expected ; the CR rate was higher ( NS ) with FCR . This trial did not demonstrate a lower infection rate with PCR The high complete remission rate with first-line combined fludarabine , cyclophosphamide , and rituximab ( FCR ) begs the question of the value of minimal residual disease (MRD)-negative status as a treatment end point . We report on 237 patients with chronic lymphocytic leukemia who received first-line FCR .  MRD was prospect ively assessed by 4-color flow cytometry in bone marrow after course 3 and at final response assessment . After course 3 and at final response assessment , 17 % and 43 % of patients were MRD negative in bone marrow , respectively . A mutated immunoglobulin heavy chain variable gene and trisomy 12 were independently associated with MRD-negative status both after 3 courses of FCR and at final response assessment in multivariable analyses ( MVAs ) . MRD-negative status was independently associated with significantly longer progression-free survival ( PFS ) and overall survival ( OS ) in MVA ( P = .03 and .02 , respectively ) . This association was confirmed also on l and mark MVA at the time of MRD assessment ( P = .04 and .05 , respectively ) . MRD-negative patients had comparable PFS and OS , independent of the number of courses received or interim staging . Early MRD eradication may be a desirable goal , prompting consideration of early discontinuation of treatment . This trial was registered at www . clinical trials.gov as # NCT00759798 BACKGROUND Chronic lymphocytic leukemia ( CLL ) primarily affects older persons who often have coexisting conditions in addition to disease-related immunosuppression and myelosuppression . We conducted an international , open-label , r and omized phase 3 trial to compare two oral agents , ibrutinib and chlorambucil , in previously untreated older patients with CLL or small lymphocytic lymphoma . METHODS We r and omly assigned 269 previously untreated patients who were 65 years of age or older and had CLL or small lymphocytic lymphoma to receive ibrutinib or chlorambucil . The primary end point was progression-free survival as assessed by an independent review committee . RESULTS The median age of the patients was 73 years . During a median follow-up period of 18.4 months , ibrutinib result ed in significantly longer progression-free survival than did chlorambucil ( median , not reached vs. 18.9 months ) , with a risk of progression or death that was 84 % lower with ibrutinib than that with chlorambucil ( hazard ratio , 0.16 ; P<0.001 ) . Ibrutinib significantly prolonged overall survival ; the estimated survival rate at 24 months was 98 % with ibrutinib versus 85 % with chlorambucil , with a relative risk of death that was 84 % lower in the ibrutinib group than in the chlorambucil group ( hazard ratio , 0.16 ; P=0.001 ) . The overall response rate was higher with ibrutinib than with chlorambucil ( 86 % vs. 35 % , P<0.001 ) . The rates of sustained increases from baseline values in the hemoglobin and platelet levels were higher with ibrutinib . Adverse events of any grade that occurred in at least 20 % of the patients receiving ibrutinib included diarrhea , fatigue , cough , and nausea ; adverse events occurring in at least 20 % of those receiving chlorambucil included nausea , fatigue , neutropenia , anemia , and vomiting . In the ibrutinib group , four patients had a grade 3 hemorrhage and one had a grade 4 hemorrhage . A total of 87 % of the patients in the ibrutinib group are continuing to take ibrutinib . CONCLUSIONS Ibrutinib was superior to chlorambucil in previously untreated patients with CLL or small lymphocytic lymphoma , as assessed by progression-free survival , overall survival , response rate , and improvement in hematologic variables . ( Funded by Pharmacyclics and others ; RESONATE-2 Clinical Trials.gov number , NCT01722487 . ) 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 neutropenia during the first year after treatment ( 16.6 % vs 8.8 % ; P = .007 ) . Secondary malignancies including Richter 's transformation occurred in 13.1 % in the FCR group and in 17.4 % in the FC group ( P = .1 ) . First-line chemoimmunotherapy with FCR induces long-term remissions and highly relevant improvement in OS in specific genetic subgroups of fit patients with CLL , in particular those with IGHV MUT . This trial was registered at www . clinical trials.gov as # NCT00281918 Background The results of R and omized Controlled Trials ( RCTs ) on time-to-event outcomes that are usually reported are median time to events and Cox Hazard Ratio . These do not constitute the sufficient statistics required for meta- analysis or cost-effectiveness analysis , and their use in secondary analyses requires strong assumptions that may not have been adequately tested . In order to enhance the quality of secondary data analyses , we propose a method which derives from the published Kaplan Meier survival curves a close approximation to the original individual patient time-to-event data from which they were generated . Methods We develop an algorithm that maps from digitised curves back to KM data by finding numerical solutions to the inverted KM equations , using where available information on number of 
    Output:
    
FCR improved complete remission , PFS and overall survival vs the comparator ; median PFS was not reached in the subgroup of CLL patients with mutated IGHV