***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: Imatinib at 400 mg daily is st and ard treatment for chronic myeloid leukemia in chronic phase . We here describe the correlation of  imatinib  trough plasma concentrations ( C(mins ) ) with clinical responses , event-free survival ( EFS ) , and adverse events ( AEs ) . Trough level plasma sample s were obtained on day 29 ( steady state , n = 351 ) . Plasma concentrations of  imatinib  and its metabolite CGP74588 were determined by liquid chromatography/mass spectrometry . The overall mean ( + /- SD , CV% ) steady-state C(min ) for imatinib and CGP74588 were 979 ng/mL ( + /- 530 ng/mL , 54.1 % ) and 242 ng/mL ( + /- 106 ng/mL , 43.6 % ) , respectively . Cumulative estimated complete cytogenetic response ( CCyR ) and major molecular response ( MMR ) rates differed among the quartiles of imatinib trough levels ( P = .01 for CCyR , P = .02 for MMR ) . C(min ) of imatinib  was significantly higher in patients who achieved CCyR ( 1009 + /- 544 ng/mL vs 812 + /- 409 ng/mL , P = .01 ) . Patients with high  imatinib exposure  had better rates of CCyR and MMR and EFS . An exploratory analysis demonstrated that  imatinib trough levels were predictive of higher CCyR independently of Sokal risk group . AE rates were similar among the imatinib quartile categories except fluid retention , rash , myalgia , and anemia , which were more common at higher imatinib concentrations . These results suggest that an adequate plasma concentration of imatinib is important for a good clinical response . This study is registered at http:// clinical trials.gov as NCT00333840 We conducted a trial in 103 patients with newly diagnosed chronic phase chronic myeloid leukemia ( CP-CML ) using imatinib 600 mg/day , with dose escalation to 800 mg/day for suboptimal response . The estimated cumulative incidences of complete cytogenetic response ( CCR ) by 12 and 24 months were 88 % and 90 % , and major molecular responses ( MMRs ) were 47 % and 73 % . In patients who maintained a daily average of 600 mg of imatinib for the first 6 months ( n = 60 ) , MMR rates by 12 and 24 months were 55 % and 77 % compared with 32 % and 53 % in patients averaging less than 600 mg ( P = .037 and .016 , respectively ) . Dose escalation was indicated for 17 patients before 12 months for failure to achieve , or maintain , major cytogenetic response at 6 months or CCR at 9 months but was only possible in 8 patients ( 47 % ) . Dose escalation was indicated for 73 patients after 12 months because their BCR-ABL level remained more than 0.01 % ( international scale ) and was possible in 45 of 73 ( 62 % ) . Superior responses achieved in patients able to tolerate imatinib at 600 mg suggests that early dose intensity may be critical to optimize response in CP-CML . The trial was registered at www.ANZCTR.org.au as # ACTRN12607000614493 Imatinib mesylate has become the treatment of choice for chronic myeloid leukemia ( CML ) : the st and ard dose for chronic- phase ( CP ) CML is 400 mg daily . Response rates are different according to Sokal score , being significantly lower in intermediate and high Sokal risk patients . Phase 1 and 2 trials have shown a dose-response effect and high-dose imatinib trials in early CP CML showed better results compared with st and ard dose . Our study is the first prospect i ve trial planned to evaluate the efficacy and tolerability of high-dose imatinib in previously untreated intermediate Sokal risk CML patients . Seventy-eight patients were treated with 400 mg  imatinib  twice daily : complete cytogenetic response ( CCgR ) rates at 12 and 24 months were 88 % and 91 % ; moreover , at 12 and 24 months 56 % and 73 % of CCgR patients achieved a major molecular response . The incidence of adverse events was slightly higher than reported by the most important st and ard-dose trials . With a median follow-up of 24 months , 3 patients progressed to advanced phase . In intermediate Sokal risk newly diagnosed CML patients , high-dose imatinib induced rapid and high response rates , apparently faster than those documented in the International R and omized Study of IFN and Imatinib for the same risk category . These clinical trials are registered at www . clinical trials.gov as no. NCT00510926 Blast crisis is the most advanced stage of chronic myelogenous leukemia ( CML ) and is highly refractory to therapy . CML is caused by expression of the chimeric BCR-ABL tyrosine kinase oncogene , the product of the t(9;22 ) Philadelphia translocation . Imatinib ( Glivec , formerly STI571 ) is a rationally developed , orally administered inhibitor of the Bcr-Abl tyrosine kinase . A total of 260 patients with CML were enrolled in a phase II trial , of whom 229 had a confirmed diagnosis of CML in blast crisis . Patients were treated with imatinib in daily oral doses of 400 mg or 600 mg . Imatinib induced hematologic responses in 52 % of patients and sustained hematologic responses lasting at least 4 weeks in 31 % of patients , including complete hematologic responses in 8 % . For patients with a sustained response , the estimated median response duration was 10 months . Imatinib induced major cytogenetic responses in 16 % of patients , with 7 % of the responses being complete . Median survival time was 6.9 months . Nonhematologic adverse reactions were frequent but generally mild or moderate . Episodes of severe cytopenia were also frequent and were attributable to the underlying condition and treatment with imatinib . Drug-related adverse events led to discontinuation of therapy in 5 % of patients , most often because of cytopenia , skin disorders , or gastrointestinal reactions . These results demonstrate that imatinib has substantial activity and a favorable safety profile when used as a single agent in patients with CML in blast crisis . Additional clinical studies are warranted to explore the efficacy and feasibility of imatinib used in combination with other antileukemic drugs We investigated whether increasing the dose of imatinib mesylate might overcome drug resistance in patients with Philadelphia chromosome-positive ( Ph(+ ) ) chronic myelogenous leukemia ( CML ) whose disease manifests relapse or refractoriness to therapy . Fifty-four patients with Ph(+ ) CML in chronic phase and with hematologic or cytogenetic resistance or relapse on imatinib mesylate therapy at 400 mg orally daily were treated with a higher dose of 400 mg orally twice daily ( 800 mg daily , 47 patients ; or 600 mg daily increased from 300 mg daily , 7 patients ) . Among 20 patients treated for hematologic resistance or relapse , 13 ( 65 % ) achieved a complete ( n = 9 ) or partial ( n = 4 ) hematologic response , but only 1 had a cytogenetic partial response ( Ph reduction from 100 % to 10 % ) and 1 had a minor response ( Ph reduction from 100 % to 50 % ) . Among 34 patients treated for cytogenetic resistance or relapse , 19 ( 56 % ) achieved a complete ( n = 6 ) or partial ( n = 7 ) cytogenetic response . We conclude that higher doses of imatinib mesylate may overcome disease-poor response to conventional doses and that this approach deserves further evaluation as frontline therapy for newly diagnosed CML BACKGROUND BCR-ABL is a constitutively activated tyrosine kinase that causes chronic myeloid leukemia ( CML ) . Since tyrosine kinase activity is essential to the transforming function of BCR-ABL , an inhibitor of the kinase could be an effective treatment for CML . METHODS We conducted a phase 1 , dose-escalating trial of STI571 ( formerly known as CGP 57148B ) , a specific inhibitor of the BCR-ABL tyrosine kinase . STI571 was administered orally to 83 patients with CML in the chronic phase in whom treatment with interferon alfa had failed . Patients were successively assigned to 1 of 14 doses ranging from 25 to 1000 mg per day . RESULTS Adverse effects of STI571 were minimal ; the most common were nausea , myalgias , edema , and diarrhea . A maximal tolerated dose was not identified . Complete hematologic responses were observed in 53 of 54 patients treated with daily doses of 300 mg or more and typically occurred in the first four weeks of therapy . Of the 54 patients treated with doses of 300 mg or more , cytogenetic responses occurred in 29 , including 17 ( 31 percent of the 54 patients who received this dose ) with major responses ( 0 to 35 percent of cells in metaphase positive for the Philadelphia chromosome ) ; 7 of these patients had complete cytogenetic remissions . CONCLUSIONS STI571 is well tolerated and has significant antileukemic activity in patients with CML in whom treatment with interferon alfa had failed . Our results provide evidence of the essential role of BCR-ABL tyrosine kinase activity in CML and demonstrate the potential for the development of anticancer drugs based on the specific molecular abnormality present in a human cancer PURPOSE Treatment of chronic-phase ( CP ) chronic myeloid leukemia ( CML ) with imatinib 400 mg/d can be unsatisfactory . Optimization of treatment is warranted . PATIENTS AND METHODS In all , 1,014 newly diagnosed CP-CML patients were r and omly assigned to imatinib 800 mg/d ( n = 338 ) , imatinib 400 mg/d ( n = 325 ) , or imatinib 400 mg/d plus interferon alfa ( IFN-α ; n = 351 ) . Dose adaptation to avoid higher- grade toxicity was recommended . First primary end point was major molecular remission ( MMR ) at 12 months . RESULTS A higher rate of MMR at 12 months occurred with tolerability-adapted imatinib 800 mg/d than with imatinib 400 mg/d ( 59 % [ 95 % CI , 53 % to 65 % ] v 44 % [ 95 % CI , 37 % to 50 % ] ; P < .001 ) or imatinib 400 mg/d plus IFN-α ( 59 % v 46 % [ 95 % CI , 40 % to 52 % ] ; P = .002 ) . Median dose in the 800-mg/d arm was 628 mg/d with a maximum dose of 737 mg/d during months 4 to 6 and a maintenance dose of 600 mg/d . All three treatment approaches were well tolerated with similar grade 3 and 4 adverse events . Independent of treatment approach , MMR at 12 months showed better progression-free survival ( 99 % v 94 % ; P = .0023 ) and overall survival ( 99 % v 93 % ; P = .0011 ) at 3 years when compared with > 1 % on the international scale or no MMR but showed no difference in 0.1 % to < 1 % on the international scale , which closely correlates with complete cytogenetic remission . CONCLUSION Treatment of early-phase CML  with imatinib can be optimized . Early high-dose therapy followed by rapid adaptation to good tolerability increases the rate of MMR at 12 months . Achievement of MMR by month 12 is directly associated with improved survival Imatinib mesylate ( IM ) , 400 mg daily , is the st and ard treatment of Philadelphia-positive ( Ph(+ ) ) chronic myeloid leukemia ( CML ) . Pre clinical data and results of single-arm studies raised the suggestion that better results could be achieved with a higher dose . To investigate whether the systematic use of a higher dose of IM could lead to better results , 216 patients with Ph(+ ) CML at high risk ( HR ) according to the Sokal index were r and omly assigned to receive IM 800 mg or 400 mg daily , as front-line therapy , for at least 1 year . The CCgR rate at 1 year was 64 % and 58 % for the high-dose arm and for the st and ard-dose arm , respectively ( P = .435 ) . No differences were detectable in the CgR at 3 and 6 months , in the molecular response rate at any time , as well as in the rate of other events . Twenty-four ( 94 % ) of 25 patients who could tolerate the full 800-mg dose achieved a CCgR , and only 4 ( 23 % ) of 17 patients who could tolerate less than 350 mg achieved a CCgR. This study does not support the extensive use of high-dose IM ( 800 mg daily ) front-line in all CML HR 
    Output:
    
There is currently insufficient evidence to support the routine use of higher doses of imatinib as frontline treatment for CP-CML .