***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: 6510 Background : In the r and omized phase III DASISION trial of dasatinib v IM in newly diagnosed CML-CP , dasatinib showed higher and faster rates of complete cytogenetic response ( CCyR ) and major molecular response ( MMR ) ( Shah Blood 2010 116 abs 206 ) . METHODS Pts received dasatinib 100 mg once daily ( QD ) ( n=259 ) or IM 400 mg QD ( n=260 ) . Primary endpoint was confirmed CCyR ( cCCyR ; CCyR on 2 consecutive tests ) by 12 mos . RESULTS After 19.7 mos ' median follow-up ( range 0.1 - 31.4 ) , 81 % and 80 % remained on dasatinib and IM . 18-mo response rates for dasatinib v IM were : cCCyR 78 % v 70 % , P=0.0366 ; CCyR 84 % v 78 % , P=0.0932 ; and MMR 56 % v 37 % , P<0.0001 . MMR occurred more often with dasatinib in all Hasford groups . For dasatinib v IM , 13 % v 7 % had a BCR-ABL level ≤0.0032 % . In time to response analyses , dasatinib pts were 1.8-/1.5-fold more likely to have MMR/CCyR ( both P<0.0001 ) . For dasatinib v IM , 6 ( 2.3 % ) v 9 ( 3.5 % ) pts transformed to accelerated/blast phase ( AP/BP ) on study ; 1 other pt transformed 183 days after discontinuing dasatinib . For dasatinib v IM , 18-mo rates ( follow-up ongoing ) were overall survival : 96 % v 98 % ; progression-free survival ( no AP/BP or loss of response ) : 95 % v 94 % ; failure-free survival ( ELN 2006 criteria ): 93 % v 90 % ; and maximum clinical benefit ( no progression , failure or intolerance ) : 87 % v 86 % . Drug-related adverse events ( AEs ) are shown ( Table ) . Grade 3/4 nonhematologic AE rates were ≤1 % . Pleural effusions seen only with dasatinib ( 2 % gr 1 , 9 % gr 2 , < 1 % gr 3 ) did not seem to impact efficacy . Most cytopenias ( 75 % ) arose within 4 mos . Gr 3/4 lab abnormality rates were ≤3 % except hypophosphatemia ( dasatinib 5 % , IM 24 % ) . For dasatinib v IM , 56 % v 39 % had dose interruption , 25 % v 14 % had dose reduction and 6 % v 4 % discontinued due to drug-related AEs . Minimum 24-mo follow-up will be presented . CONCLUSIONS At 18 mos , dasatinib continues to show superior efficacy over IM and acceptable tolerability , supporting first-line dasatinib use in newly diagnosed CML-CP . [ Table : see text ] BACKGROUND Chronic myelogenous leukemia ( CML ) is caused by the BCR-ABL tyrosine kinase , the product of the Philadelphia chromosome . Imatinib mesylate , formerly STI571 , is a selective inhibitor of this kinase . METHODS A total of 532 patients with late -- chronic-phase CML in whom previous therapy with interferon alfa had failed were treated with 400 mg of oral imatinib daily . Patients were evaluated for cytogenetic and hematologic responses . Time to progression , survival , and toxic effects were also evaluated . RESULTS Imatinib induced major cytogenetic responses in 60 percent of the 454 patients with confirmed chronic-phase CML and complete hematologic responses in 95 percent . After a median follow-up of 18 months , CML had not progressed to the accelerated or blast phases in an estimated 89 percent of patients , and 95 percent of the patients were alive . Grade 3 or 4 nonhematologic toxic effects were infrequent , and hematologic toxic effects were manageable . Only 2 percent of patients discontinued treatment because of drug-related adverse events , and no treatment-related deaths occurred . CONCLUSIONS Imatinib induced high rates of cytogenetic and hematologic responses in patients with chronic-phase CML in whom previous interferon therapy had failed Nilotinib , an orally bioavailable , selective Bcr-Abl tyrosine kinase inhibitor , is 30-fold more potent than imatinib in pre- clinical models , and overcomes most imatinib resistant BCR-ABL mutations . In this phase 2 open-label study , 400 mg nilotinib was administered orally twice daily to 280 patients with Philadelphia chromosome-positive ( Ph(+ ) ) chronic myeloid leukemia in chronic phase ( CML-CP ) after imatinib failure or intolerance . Patients had at least 6 months of follow-up and were evaluated for hematologic and cytogenetic responses , as well as for safety and overall survival . At 6 months , the rate of major cytogenetic response ( Ph < or = 35 % ) was 48 % : complete ( Ph = 0 % ) in 31 % , and partial ( Ph = 1%-35 % ) in 16 % . The estimated survival at 12 months was 95 % . Nilotinib was effective in patients harboring BCR-ABL mutations associated with imatinib resistance ( except T315I ) , and also in patients with a resistance mechanism independent of BCR-ABL mutations . Adverse events were mostly mild to moderate , and there was minimal cross-intolerance with imatinib . Grade s 3 to 4 neutropenia and thrombocytopenia were observed in 29 % of patients ; pleural or pericardial effusions were observed in 1 % ( none were severe ) . In summary , nilotinib is highly active and safe in patients with CML-CP after imatinib failure or intolerance . This clinical trial is registered at http:// clinical trials.gov as ID no. NCT00109707 Each year , approximately 4300 people in the United States receive a diagnosis of chronic myelogenous leukemia ( CML ) at a median age of 50 years [ 1 ] . Median survival is 3 to 6 years , and death usually results from progression to acute leukemia [ 2 ] . Although several studies [ 3 - 6 ] have shown improved survival with the use of certain chemotherapeutic agents , bone marrow transplantation is the only proven curative therapy . For patients younger than 50 years of age who have an HLA-identical related donor , transplantation within the first year after diagnosis is recommended [ 7 - 11 ] . The use of HLA-compatible unrelated donor transplantation has been advocated for patients without a related donor , but this recommendation is controversial because unrelated donor transplantation is associated with high morbidity and mortality rates [ 12 , 13 ] . In contrast to patients with many other diseases for which transplantation is considered , patients with chronic-phase CML generally feel well , continue to work , and require few medications or medical interventions . Treatment is necessary only to control symptoms and blood counts .  Hydroxyurea is an inexpensive , relatively nontoxic , effective oral medication . Interferon- is more expensive , is toxic , and must be administered by subcutaneous injection , but it is also effective and may prolong survival . Patients may be stratified into broad prognostic groups on the basis of their clinical characteristics at the time of diagnosis [ 2 , 14 - 19 ] . However , no clinical features accurately predict an individual patient 's progression to acute leukemia [ 20 ] . Once progression occurs , both st and ard chemotherapy and transplantation have minimal success in prolonging survival [ 7 , 21 - 24 ] . The process of deciding whether and when to undergo unrelated donor transplantation is complicated by the extreme unpredictability of outcomes . The risk for unsalvageable progression of CML must be weighed against the substantial risk for illness and death that may result from the acute and chronic side effects of transplantation [ 25 ] . Some physicians advise waiting until disease progression is evident or interferon- therapy has failed before proceeding to transplantation , accepting the risks of the delay in exchange for the possibility of postponing or avoiding transplantation . Others advise performing a transplantation as soon as possible to afford the best chance of a successful transplantation outcome and long-term survival . We used decision analytic techniques to combine historical data on risk for CML progression with data from the International Bone Marrow Transplant Registry ( IBMTR ) and the National Marrow Donor Program ( NMDP ) on transplantation outcomes . A Markov model [ 26 ] was constructed to allow comparison of the treatment options available to a patient with a new diagnosis of chronic-phase CML . This approach allows the simultaneous and quantitative consideration of patient age , quality of life , risk aversion , risk for CML progression , and likelihood of transplantation success to help guide decision making . Methods Markov Model A Markov model is an analytic structure that tracks the clinical events occurring in a hypothetical cohort of patients in various scenarios . We constructed a model to analyze the decision faced by a patient with a new diagnosis of chronic-phase CML who is considering having unrelated donor bone marrow transplantation .  Five strategies were compared : no transplantation ; transplantation within the first year ; transplantation 1 to 2 years after diagnosis ; transplantation delayed until 2 to 3 years after diagnosis ; and transplantation delayed until more than 3 years after diagnosis . At any time point , the model considered a patient to be in one of the following clinical states : alive with chronic-phase CML ; alive without chronic graft-versus-host disease after transplantation ; alive with chronic graft-versus-host disease after transplantation ; or dead from progressive CML , complications of transplantation , or other causes ( Figure 1 ) . Time spent in each state was adjusted for the quality of life experienced while in that state , and a discount factor was applied . Using the model , we calculated discounted , quality -adjusted life expectancy for each strategy , considering competing risks for illness and death from CML and transplantation . A cycle length of 6 months was chosen to match the available clinical data . All analyses were done with DATA ( TreeAge Software , Inc. , Williamstown , Massachusetts ) , a decision analysis program . Figure 1 . Structure of the Markov model . Data Sources Data from the medical literature , transplant registries , and physician assessment s were used in the model . Prognosis of Patients with Chronic Myelogenous Leukemia Who Do Not Receive Transplants The life expectancy of patients with CML who do not undergo transplantation was calculated by using the survival curves from six published studies , including interferon trials and prognostic staging studies [ 4 - 615 , 19 , 26 , 27 ] . After published information ended , the survival curves were extrapolated by using a function fitted to the clinical data until the entire cohort had died . Life expectancy estimates for 35-year-old patients with CML who do not undergo transplantation are shown in Table 1 . Similar analyses were performed for 25- and 45-year-old patients ( data not shown ) . For the 15 survival curves analyzed , the mean undiscounted expected survival was 5.15 years ( range , 3.66 to 7.58 years ) . A survival curve derived from patients with intermediate-prognosis CML ( Table 1 , rank 6 ) who had an expected survival of 5.31 years was chosen as the baseline curve [ 15 ] . Sensitivity analysis was performed by using data from the best ( Table 1 , rank 1 ) [ 15 ] and worst ( Table 1 , rank 15 ) [ 19 ] survival curves to illustrate results for patients with the best and worst prognoses . The life expectancy of the Sokal low-risk group ( Table 1 , rank 1 ) is superior to that in the groups r and omly assigned to receive interferon in the major studies [ 4 - 6 , 27 ] and thus was chosen to represent the patients with the best prognosis . Table 1 . Life Expectancy of a 35-Year-Old Patient with Chronic Myelogenous Leukemia Who Does Not Have Bone Marrow Transplantation , Based on Published Studies Outcomes of Unrelated Donor Bone Marrow Transplantation Data from 778 unrelated donor transplantations performed between 1987 and 1994 for chronic-phase CML were provided by the IBMTR and the NMDP . To eliminate overlap from patients reported to both registries , we combined patients reported to the NMDP ( transplantations done in the United States ; n = 465 ) with those reported to the IBMTR ( transplantations done outside of the United States ; n = 313 ) . The final population included both 5/6 and 6/6 serologic matches . Each Kaplan-Meier curve is based on data from time of transplantation to death , and a separate Kaplan-Meier curve was calculated for each stratum . Kaplan-Meier survival curves through 5 years after transplantation were stratified by patient age ( 15 to 29 years of age , 30 to 39 years of age , 40 years of age ) and time from diagnosis to transplantation ( < 1 year , 1 to 2 years , 2 to 3 years , > 3 years ) to generate 12 strata containing 40 to 125 patients each . Finer stratification was not possible because of the size of the entire population . Fifty-eight percent of patients were male , median age at the time of transplantation was 36 years , and median time from diagnosis to transplantation was 
    Output:
    
From the two trials available , dasatinib and nilotinib have a statistically significant advantage compared with imatinib as measured by MMR or CCyR. Taking into account the treatment pathways for patients with CML , i.e. assuming the use of second-line nilotinib , first-line nilotinib appears to be more cost-effective than first-line imatinib .