***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: Long-term responses have been reported after autologous stem cell transplantation ( ASCT ) for chronic lymphocytic leukemia ( CLL ) . We conducted a prospect i ve , r and omized trial of ASCT in previously untreated CLL patients . We enrolled 241 patients < 66 years of age with Binet stage B or C CLL . They received 3 courses of mini-CHOP ( cyclophosphamide , hydroxydaunorubicin , oncovin , and prednisone/prednisolone ) and then 3 courses of fludarabine . Patients in complete response ( CR ) were then r and omized to ASCT or observation , whereas the other patients were r and omized to dexamethasone , high-dose aracytin , cisplatin ( DHAP ) salvage followed by either ASCT or 3 courses of fludarabine plus cyclophosphamide ( FC ) . The primary end point was event-free survival ( EFS ) . After up-front treatment , 105 patients entered CR and were r and omized between ASCT ( n = 52 ) and observation ( n = 53 ) ; their respective 3-year EFS rates were 79.8 % and 35.5 % ; the adjusted hazard ratio was 0.3 ( 95 % CI : 0.1 - 0.7 ; P = .003 ) . Ninety-four patients who did not enter CR were r and omized between ASCT ( n = 46 ) and FC ( n = 48 ) ; their respective 3-year EFS rates were 48.9 % and 44.4 % , respectively ; the adjusted hazard ratio was 1.7 ( 95 % CI : 0.9 - 3.2 ; P = .13 ) . No difference in overall survival was found between the 2 response subgroups . In young CLL patients in CR , ASCT consolidation markedly delayed disease progression . No difference was observed between ASCT and FC in patients requiring DHAP salvage The relevance of high-dose chemotherapy followed by auto-SCT in CLL remains to be defined . The aim of the prospect i ve , r and omized , GOELAMS LLC 98 trial was to compare two strategies in previously untreated CLL patients aged < 60 years .  Conventional chemotherapy ( Arm A ) consisted of six monthly courses of CHOP followed by six CHOP courses in every 3 months in those achieving a complete or PR . Arm A was compared with high-dose therapy with auto-SCT ( Arm B ) , used as consolidation after three CHOP courses in case of CR or very good PR . A total of 86 patients were enrolled , of which 39 and 43 patients were evaluable in arm A and arm B , respectively . The primary endpoint was PFS . On an intent-to-treat basis and with a median follow-up time of 77.1 ( range 1–135.5 ) months , the median PFS was 22 months in Arm A and 53 months in Arm B ( P<0.0001 ) . Median survival time was 104.7 months in arm A and 107.4 months in arm B. This trial demonstrates that frontline high-dose therapy with auto-SCT prolongs PFS but does not translate into a survival advantage in advanced CLL patients in the pre-rituximab era PURPOSE This study was undertaken to evaluate the feasibility and therapeutic effect of high-dose chemoradiotherapy with autologous or allogeneic bone marrow transplantation ( BMT ) in patients with advanced chronic lymphocytic leukemia ( CLL ) who relapse after fludarabine treatment . PATIENTS AND METHODS Twenty-two patients with advanced CLL received high-dose cyclophosphamide , total-body irradiation , and BMT .  Eleven patients with relapsed CLL received autologous BMT with marrow collected during a prior fludarabine-induced remission ; leukemia cells were depleted from the autologous marrow in seven patients using an anti-CD19 monoclonal antibody and immunomagnetic separation . Eleven patients received allogeneic or syngeneic BMT , seven of whom had refractory Rai stage III or IV disease . RESULTS Six autologous transplant recipients achieved a complete remission ( CR ) , four a nodular CR ( nCR ) , and one a partial remission ( PR ) . Two recurred with CLL , and three developed Richter 's transformation . Two patients had recurrence of immune cytopenias while in morphologic remission ; one of these patients died of cytomegalovirus pneumonia . Six of 11 patients survive in remission 2 to 29 months following BMT . Of the 11 patients who received allogeneic or syngeneic BMT , seven achieved a CR , two a nCR , and one a PR ; 10 survive 2 to 36 months following BMT . CONCLUSION These data indicate that high-dose chemotherapy with allogeneic BMT is effective at producing CRs in patients with CLL . Autologous transplantation in CLL is feasible and is capable of producing remissions in patients with advanced CLL . Further studies are warranted to assess the role of BMT in the treatment of CLL The importance of early therapy intensification in B-cell CLL ( B-CLL ) patients remains to be defined . Even though several studies have been published , no r and omized trials comparing directly autologous stem cell transplant ( ASCT ) and the accepted conventional therapy ( that is , rituximab , fludarabine and CY ; R-FC ) have been reported so far . To assess the benefit of a first-line aggressive therapy , we design ed a multicenter , r and omized , phase 3 trial comparing R-FC and high-dose chemotherapy supported by ASCT in patients under 65 years of age , with stage B(II ) or C B-CLL . Primary end point was CR :  96 patients were enrolled ( 48 in each arm ) . On an intent-to-treat basis , the CR rates in the ASCT and R-FC arms were 62.5 % and 58 % , respectively . After 5 years of follow-up , PFS was 60.4 % in the ASCT arm and 65.1 % in the R-FC arm , time to progression 65.8 and 70.5 % , and overall survival 88 % vs 88.1 % , respectively . Our trial demonstrates , for the first time in a r and omized manner , that frontline ASCT does not translate into a survival advantage when compared with benchmark chemoimmunotherapy in B-CLL patients ; the possibility of its clinical benefit in certain subgroups remains uncertain BACKGROUND On the basis of promising results that were reported in several phase 2 trials , we investigated whether the addition of the monoclonal antibody rituximab to first-line chemotherapy with fludarabine and cyclophosphamide would improve the outcome of patients with chronic lymphocytic leukaemia . METHODS Treatment-naive , physically fit patients ( aged 30 - 81 years ) with CD20-positive chronic lymphocytic leukaemia were r and omly assigned in a one-to-one ratio to receive six courses of intravenous fludarabine ( 25 mg/m(2 ) per day ) and cyclophosphamide ( 250 mg/m(2 ) per day ) for the first 3 days of each 28-day treatment course with or without rituximab ( 375 mg/m(2 ) on day 0 of first course , and 500 mg/m(2 ) on day 1 of second to sixth courses ) in 190 centres in 11 countries . Investigators and patients were not masked to the computer-generated treatment assignment . The primary endpoint was progression-free survival ( PFS ) . Analysis was by intention to treat . This study is registered with Clinical Trials.gov , number NCT00281918 . FINDINGS 408 patients were assigned to fludarabine , cyclophosphamide , and rituximab ( chemoimmunotherapy group ) and 409 to fludarabine and cyclophosphamide  ( chemotherapy group ) ; all patients were analysed . At 3 years after r and omisation , 65 % of patients in the chemoimmunotherapy group were free of progression compared with 45 % in the chemotherapy group ( hazard ratio 0·56 [ 95 % CI 0·46 - 0·69 ] , p<0·0001 ) ; 87 % were alive versus 83 % , respectively ( 0·67 [ 0·48 - 0·92 ] ; p=0·01 ) . Chemoimmunotherapy was more frequently associated with grade 3 and 4 neutropenia ( 136 [ 34 % ] of 404 vs 83 [ 21 % ] of 396 ; p<0·0001 ) and leucocytopenia ( 97 [ 24 % ] vs 48 [ 12 % ] ; p<0·0001 ) . Other side-effects , including severe infections , were not increased . There were eight ( 2 % ) treatment-related deaths in the chemoimmunotherapy group compared with ten ( 3 % ) in the chemotherapy group . INTERPRETATION Chemoimmunotherapy with fludarabine , cyclophosphamide , and rituximab improves progression-free survival and overall survival in patients with chronic lymphocytic leukaemia . Moreover , the results suggest that the choice of a specific first-line treatment changes the natural course of chronic lymphocytic leukaemia . FUNDING F Hoffmann-La Roche Mutations in TP53 , NOTCH1 , and SF3B1 were analyzed in the CLL8 study evaluating first-line therapy with fludarabine and cyclophosphamide ( FC ) or FC with rituximab ( FCR ) among patients with untreated chronic lymphocytic leukemia ( CLL ) . TP53 , NOTCH1 , and SF3B1 were mutated in 11.5 % , 10.0 % , and 18.4 % of patients , respectively . NOTCH1(mut ) and SF3B1(mut ) virtually showed mutual exclusivity ( 0.6 % concurrence ) , but TP53(mut ) was frequently found in NOTCH1(mut ) ( 16.1 % ) and in SF3B1(mut ) ( 14.0 % ) patients . There were few significant associations with clinical and laboratory characteristics , but genetic markers had a strong influence on response and survival . In multivariable analyses , an independent prognostic impact was found for FCR , thymidine kinase ( TK ) ≥10 U/L , unmutated IGHV , 11q deletion , 17p deletion , TP53(mut ) , and SF3B1(mut ) on progression-free survival ; and for FCR , age ≥65 years , Eastern Cooperative Oncology Group performance status ≥1 , β2-microglobulin ≥3.5 mg/L , TK ≥10 U/L , unmutated IGHV , 17p deletion , and TP53(mut ) on overall survival . Notably , predictive marker analysis identified an interaction of NOTCH1 mutational status and treatment in that rituximab failed to improve response and survival in patients with NOTCH1(mut ) . In conclusion , TP53 and SF3B1 mutations appear among the strongest prognostic markers in CLL patients receiving current-st and ard first-line therapy .  NOTCH1(mut ) was identified as a predictive marker for decreased benefit from the addition of rituximab to FC . This study is registered at www . clinical trials.gov as # NCT00281918 BACKGROUND The treatment of relapsed chronic lymphocytic leukemia ( CLL ) has result ed in few durable remissions . Bruton 's tyrosine kinase ( BTK ) , an essential component of B-cell-receptor signaling , mediates interactions with the tumor microenvironment and promotes the survival and proliferation of CLL cells . METHODS We conducted a phase 1b-2 multicenter study to assess the safety , efficacy , pharmacokinetics , and pharmacodynamics of ibrutinib ( PCI-32765 ) , a first-in-class , oral covalent inhibitor of BTK design ed for treatment of B-cell cancers , in patients with relapsed or refractory CLL or small lymphocytic lymphoma . A total of 85 patients , the majority of whom were considered to have high-risk disease , received ibrutinib orally once daily ; 51 received 420 mg , and 34 received 840 mg . RESULTS Toxic effects were predominantly grade 1 or 2 and included transient diarrhea , fatigue , and upper respiratory tract infection ; thus , patients could receive extended treatment with minimal hematologic toxic effects . The overall response rate was the same in the group that received 420 mg and the group that received 840 mg ( 71 % ) , and an additional 20 % and 15 % of patients in the respective groups had a partial response with lymphocytosis . The response was independent of clinical and genomic risk factors present before treatment , including advanced-stage disease , the number of previous therapies , and the 17p13.1 deletion . At 26 months , the estimated progression-free survival rate was 75 % and the rate of overall survival was 83 % . CONCLUSIONS Ibrutinib was associated with a high frequency of durable remissions in patients with relapsed or refractory CLL and small lymphocytic lymphoma , including patients with high-risk genetic lesions . ( Funded by Pharmacyclics and others ; Clinical Trials.gov number , NCT01105247 . ) BACKGROUND Patients with relapsed chronic lymphocyt 
    Output:
    
Offering HDT/auto-HCT as front-line consolidation in patients with CLL does not improve OS .