***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: Optimal management of patients with relapsed/refractory chronic lymphocytic leukemia ( CLL ) is dictated by patient characteristics , prior therapy , and response to prior therapy . We report the final analysis of combined fludarabine , cyclophosphamide , and rituximab ( FCR ) for previously treated patients with CLL and identify patients who benefit most from this therapy . We explore efficacy of FCR in patients beyond first relapse , patients with prior exposure to fludarabine and alkylating agent combinations , and patients with prior exposure to rituximab .  The FCR regimen was administered to 284 previously treated patients with CLL . Patients were assessed for response and progression by 1996 National Cancer Institute-Working Group ( NCI-WG ) criteria for CLL and followed for survival . The overall response rate was 74 % , with 30 % complete remission . The estimated median overall survival was 47 months and median progression-free survival for all patients was 21 months . Subgroup analyses indicated that the following patients were most suitable for FCR treatment : patients with up to 3 prior treatments , fludarabine-sensitive patients irrespective of prior rituximab exposure , and patients without chromosome 17 abnormalities . FCR is an active and well-tolerated therapy for patients with relapsed CLL . The addition of rituximab to FC improved quality and durability of response in this patient population Background The efficacy and safety of adding rituximab to fludarabine and cyclophosphamide ( R-FC ) for the treatment of chronic lymphocytic leukaemia ( CLL ) has been demonstrated in two r and omised trials : CLL-8 was conducted in previously untreated patients , and REACH was conducted in previously treated patients . In both trials , progression-free survival was increased in the R-FC treatment groups compared with the FC treatment groups . In CLL-8 , overall survival was also significantly increased . Objective To develop an economic model to assess the cost effectiveness , from the Australian healthcare perspective , of rituximab when used as a treatment for both previously untreated and relapsed/refractory CLL . Methods A Markov model with three health states ( unprogressed , progressed and death ) was developed to extrapolate the trial results over a 15-year time horizon . A treatment algorithm was developed with Australian haematologists to inform the treatments to be modelled . The base-case compares up to three courses of six cycles of R-FC ( ‘ first-line ’ treatment ) followed by three courses of post-progression salvage ( ‘ Salvage ’ ) treatment ( including rituximab ) with three courses of FC followed by three courses of Salvage treatment ( excluding rituximab ) . Subsequent treatments are incorporated into the model by repeating the unprogressed and progressed health states for each treatment . Time-dependent transition probabilities for the model were estimated from an analysis of individual patient data from CLL-8 and REACH . Comparisons of the hazard rates for the CLL-8 and REACH trials enabled an assessment of the impact on the transitions of receiving the same regimen as the first or second treatment , and hence inform assumptions regarding transitions for third and subsequent treatments . Costs applied in the model were based on published Australian prices in 2009 . Results The model predicts patients receive an average of approximately two courses of treatment , and the addition of rituximab results in an incremental gain of 0.94 quality -adjusted life-years ( QALYs ) . The incremental cost associated with the addition of rituximab is A$ 40,268 , and hence the cost per QALY gained ( QALYG ) is A$ 42,906 . Conclusion Rituximab , in combination with chemotherapy , when used multiple times throughout the treatment algorithm , appears to be cost effective for CLL from the Australian healthcare perspective , with a cost/QALYG within the range generally accepted as providing value BACKGROUND The monoclonal anti-CD20 antibody rituximab , combined with chemotherapeutic agents , has been shown to prolong overall survival in physically fit patients with previously untreated chronic lymphocytic leukemia ( CLL ) but not in those with coexisting conditions . We investigated the benefit of the type 2 , glycoengineered antibody obinutuzumab ( also known as GA101 ) as compared with that of rituximab , each combined with chlorambucil , in patients with previously untreated CLL and coexisting conditions . METHODS We r and omly assigned 781 patients with previously untreated CLL and a score higher than 6 on the Cumulative Illness Rating Scale ( CIRS ) ( range , 0 to 56 , with higher scores indicating worse health status ) or an estimated creatinine clearance of 30 to 69 ml per minute to receive chlorambucil , obinutuzumab plus chlorambucil , or rituximab plus chlorambucil . The primary end point was investigator-assessed progression-free survival . RESULTS The patients had a median age of 73 years , creatinine clearance of 62 ml per minute , and CIRS score of 8 at baseline . Treatment with obinutuzumab-chlorambucil or rituximab-chlorambucil , as compared with chlorambucil monotherapy , increased response rates and prolonged progression-free survival ( median progression-free survival , 26.7 months with obinutuzumab-chlorambucil vs. 11.1 months with chlorambucil alone ; hazard ratio for progression or death , 0.18 ; 95 % confidence interval [ CI ] , 0.13 to 0.24 ; P<0.001 ; and 16.3 months with rituximab-chlorambucil vs. 11.1 months with chlorambucil alone ; hazard ratio , 0.44 ; 95 % CI , 0.34 to 0.57 ; P<0.001 ) . Treatment with obinutuzumab-chlorambucil , as compared with chlorambucil alone , prolonged overall survival ( hazard ratio for death , 0.41 ; 95 % CI , 0.23 to 0.74 ; P=0.002 ) . Treatment with obinutuzumab-chlorambucil , as compared with rituximab-chlorambucil , result ed in prolongation of progression-free survival ( hazard ratio , 0.39 ; 95 % CI , 0.31 to 0.49 ; P<0.001 ) and higher rates of complete response ( 20.7 % vs. 7.0 % ) and molecular response . Infusion-related reactions and neutropenia were more common with obinutuzumab-chlorambucil than with rituximab-chlorambucil , but the risk of infection was not increased . CONCLUSIONS Combining an anti-CD20 antibody with chemotherapy improved outcomes in patients with CLL and coexisting conditions . In this patient population , obinutuzumab was superior to rituximab when each was combined with chlorambucil . ( Funded by F. Hoffmann-La Roche ; Clinical Trials.gov number , NCT01010061 . ) Chronic lymphocytic leukemia ( CLL ) has an extremely heterogeneous prognosis . Nowadays , the median survival of patients with this form of leukemia is 8–10 years , compared with 5–6 years in series reported in the 1970s . This is largely due to the higher number of patients who are now being diagnosed in early phase ( up to 80 % ) and , hence , with better prognosis [ 1 , 2 ] . Individual survival , however , is highly variable . Classically , clinical stages have been used to predict the behavior of the disease [ 3 , 4 ] . Although easy to apply and reproducible ( a necessary condition for any prognostic factor to be accepted as such ) , staging systems have some weaknesses . For example , the mechanisms accounting for cytopenias ( i.e. bone marrow infiltration , hypersplenism , autoimmune basis ) are not taken into consideration . As a result , patients are classified as being in advanced stage independently of the origin of the anemia or thrombocytopenia . Yet there is some indication that the mechanism of the cytopenia is also a factor in prognosis [ 5 ] . Even more important is the prognostic heterogeneity within each of the clinical stages . Thus , staging systems do not allow identification of individuals in early stage who are likely to progress and those in whom the disease will have an indolent course . This is important , since patients in early stage who are likely to progress might benefit from being treated immediately after diagnosis , before progression occurs , and also because of the uncertainty of the prognosis in individuals otherwise in good clinical condition in whom the diagnosis has been made on a routine medical examination . Conversely , some patients presenting in advanced stage run an indolent course and for long periods of time may not require therapy ; the staging systems do not identify these patients either . All this is essentially due to the fact that clinical stages are a mere reflection of the biological diversity of the disease [ 6 , 7 ] . Such heterogeneity , fortunately , is rapidly unfolding . For example , cytogenetic abnormalities , as studied by fluorescence in situ hybridization , can be detected in up to 90 % of the patients . Although they are not specific , there are interesting correlates between some cytogenetic aberrations and clinical features . Thus , patients with del(13q ) as sole abnormality have good prognosis ; in contrast , those with del(11q ) or del(17p ) tend to have a rapidly evolving disease and do not respond to treatment . Furthermore , trisomy 12 is associated with atypical morphology and immunophenotype , and del(6q ) may be observed more frequently in cases with plasmacytoid features [ 8–11 ] . On the other h and , CLL has long been considered a homogeneous disease of naı̈ve CD5 + B cells , pre-germinal cells not exposed to antigenic stimulation . In 1999 , two different groups made an important breakthrough in the underst and ing of CLL by showing that , whereas in some cases IgVH genes are unmutated , in others they are [ 12 , 13 ] . Since somatic mutation takes place in the germinal center of lymphoid follicles , CLL can be a tumor of either preor post-germinalcenter B cells . These two forms , however , share the same genetic signature as determined by microarrays and , because of this , CLL is considered to be a single disease with two variants ( i.e. mutated and unmutated ) [ 14 ] . The mutational status of IgVH genes separates CLL into two forms with distinct presenting features and outcome . Compared with those with IgVH mutations , patients with unmutated IgVH genes have a more malignant disease , including advanced stage , atypical cell morphology , adverse cytogenetic features and resistance to therapy [ 12 , 13 ] . Unfortunately , study ing IgVH mutations on a routine basis is not yet easy . CD38 expression correlates , although not absolutely , with IgVH mutations ; in addition , CD38 expression may vary over time [ 15 ] . Recently , it has been demonstrated that ZAP-70 expression , as evaluated by cytofluorometry or PCR , correlates strongly with IgVH mutations and has important prognostic significance by itself [ 16–19 ] . Of great importance , these new biological prognostic parameters have independent prognostic value and discriminate , among patients in early clinical stage , those who are likely to progress and those who will remain stable . As the mysteries of the biology of CLL are revealed , important biological prognostic parameters are cl aim ing a place in the prognostic assessment of the disease . The staging systems developed in the early 1970s have been crucial in the progress of our underst and ing on CLL . Because of their simplicity and reproducibility they have been widely employed . They have also been critical in conducting r and omized treatment studies in comparable series of patients , and in attracting the interest of a new generation of younger physicians and investigators to an old disease . To ab and on the clinical staging systems would be not only precipitous , but unwise . Rather than replace clinical stages and other simple prognostic parameters ( e.g. degree of bone marrow infiltration , white blood cell count , doubling time ) , these new factors should currently be employed to refine the prognostic power of classical prognostic factors . Finally , clinical staging systems and other prognostic factors were developed in an era in which no effective therapy existed for CLL . Since prognostic indicators may change as more effective therapies become available , prognosis should be assessed prospect ively in patients treated with the newer and more effective therapies . Only in that manner will the most relevant prognostic factors for CLL eventually be identified , a quarter of a century after the introduction of clinical stages . Annals of Oncology 15 : 1450–1451 , 2004 Early results of the fludarabine , cyclophosphamide , and rituximab ( FCR ) regimen in 224 patients showed that it was highly active as initial therapy of chronic lymphocytic leukemia . In this report , we present the final results of all 300 study patients at a median follow up of 6 years . The overall response rate was 95 % , with complete remission in 72 % , nodular partial remission in 10 % , partial remission due to cytopenia in 7 % , and partial remission due to residual disease in 6 % . Two patients ( < 1 % ) died within 3 months of starting therapy . Six-year overall and failure-free survival were 77 % and 51 % , respectively . Median time to progression was 80 months . Pretreatment characteristics independently associated with inferior response were age 70 years or older , beta2-microglobulin twice the upper limit of normal ( 2N ) or more , white cell count 150 x 10(9)/L or more , abnormal chromosome 17 , 
    Output:
    
While the cohort Markov approach has been acceptable to the National Institute for Health and Care Excellence , the review identifies a number of key uncertainties with these models , including the extrapolation of survival outcomes beyond the period observed by the trial , the effectiveness of second-line therapies , and estimates of health state utility .