***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: 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 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 Nilotinib has a higher binding affinity and selectivity for BCR-ABL with respect to imatinib and is an effective treatment of chronic myeloid leukemia ( CML ) after imatinib failure . In a phase 2 study , 73 early chronic-phase , untreated , Ph(+ ) CML patients , received nilotinib at a dose of 400 mg twice daily . The primary endpoint was the complete cytogenetic response ( CCgR ) rate at 1 year . With a median follow-up of 15 months , the CCgR rate at 1 year was 96 % , and the major molecular response rate 85 % . Responses were rapid , with 78 % CCgR and 52 % major molecular response at 3 months . During the first year , the treatment was interrupted at least once in 38 patients ( 52 % ) . The mean daily dose ranged between 600 and 800 mg in 74 % of patients , 400 and 599 mg in 18 % of patients , and was less than 400 mg in 8 % of patients . Dose interruptions were mainly due to nonhematologic and biochemical side effects . Myelosuppression was irrelevant . One patient progressed to blastic crisis after 6 months ; one went off-treatment for lipase increase grade 4 ( no pancreatitis ) . Nilotinib is safe and very active in early chronic-phase CML . These data support a role for nilotinib for the frontline treatment of CML . This study was registered at Clinical Trials.gov as NCT00481052 BACKGROUND Imatinib , a selective inhibitor of the BCR-ABL tyrosine kinase , produces high response rates in patients with chronic-phase chronic myeloid leukemia ( CML ) who have had no response to interferon alfa . We compared the efficacy of imatinib with that of interferon alfa combined with low-dose cytarabine in newly diagnosed chronic-phase CML . METHODS We r and omly assigned 1106 patients to receive imatinib ( 553 patients ) or interferon alfa plus low-dose cytarabine ( 553 patients ) . Crossover to the alternative group was allowed if stringent criteria defining treatment failure or intolerance were met . Patients were evaluated for hematologic and cytogenetic responses , toxic effects , and rates of progression . RESULTS After a median follow-up of 19 months , the estimated rate of a major cytogenetic response ( 0 to 35 percent of cells in metaphase positive for the Philadelphia chromosome ) at 18 months was 87.1 percent ( 95 percent confidence interval , 84.1 to 90.0 ) in the imatinib group and 34.7 percent ( 95 percent confidence interval , 29.3 to 40.0 ) in the group given interferon alfa plus cytarabine ( P<0.001 ) . The estimated rates of complete cytogenetic response were 76.2 percent ( 95 percent confidence interval , 72.5 to 79.9 ) and 14.5 percent ( 95 percent confidence interval , 10.5 to 18.5 ) , respectively ( P<0.001 ) . At 18 months , the estimated rate of freedom from progression to accelerated-phase or blast-crisis CML was 96.7 percent in the imatinib group and 91.5 percent in the combination-therapy group ( P<0.001 ) . Imatinib was better tolerated than combination therapy . CONCLUSIONS In terms of hematologic and cytogenetic responses , tolerability , and the likelihood of progression to accelerated-phase or blast-crisis CML , imatinib was superior to interferon alfa plus low-dose cytarabine as first-line therapy in newly diagnosed chronic-phase CML BACKGROUND In a r and omized trial , 1106 patients with chronic myeloid leukemia ( CML ) in chronic phase were assigned to imatinib or interferon alfa plus cytarabine as initial therapy . We measured levels of BCR-ABL transcripts in the blood of all patients in this trial who had a complete cytogenetic remission . METHODS Levels of BCR-ABL transcripts were measured by a quantitative real-time polymerase-chain-reaction assay . Results were expressed relative to the median level of BCR-ABL transcripts in the blood of 30 patients with untreated CML in chronic phase . RESULTS In patients who had a complete cytogenetic remission , levels of BCR-ABL transcripts after 12 months of treatment had fallen by at least 3 log in 57 percent of those in the imatinib group and 24 percent of those in the group given interferon plus cytarabine ( P=0.003 ) . On the basis of the rates of complete cytogenetic remission of 68 percent in the imatinib group and 7 percent in the group given interferon plus cytarabine at 12 months , an estimated 39 percent of all patients treated with imatinib but only 2 percent of all those given interferon plus cytarabine had a reduction in BCR-ABL transcript levels of at least 3 log ( P<0.001 ) . For patients who had a complete cytogenetic remission and a reduction in transcript levels of at least 3 log at 12 months , the probability of remaining progression-free was 100 percent at 24 months , as compared with 95 percent for such patients with a reduction of less than 3 log and 85 percent for patients who were not in complete cytogenetic remission at 12 months ( P<0.001 ) . CONCLUSIONS The proportion of patients with CML who had a reduction in BCR-ABL transcript levels of at least 3 log by 12 months of therapy was far greater with imatinib treatment than with treatment with interferon plus cytarabine . Patients in the imatinib group with this degree of molecular response had a negligible risk of disease progression during the subsequent 12 months BACKGROUND The cause of chronic myeloid leukemia ( CML ) is a constitutively active BCR-ABL tyrosine kinase . Imatinib inhibits this kinase , and in a short-term study was superior to interferon alfa plus cytarabine for newly diagnosed CML in the chronic phase . For 5 years , we followed patients with CML who received imatinib as initial therapy . METHODS We r and omly assigned 553 patients to receive imatinib and 553 to receive interferon alfa plus cytarabine  and then evaluated them for overall and event-free survival ; progression to accelerated-phase CML or blast crisis ; hematologic , cytogenetic , and molecular responses ; and adverse events . RESULTS The median follow-up was 60 months . Kaplan-Meier estimates of cumulative best rates of complete cytogenetic response among patients receiving imatinib were 69 % by 12 months and 87 % by 60 months . An estimated 7 % of patients progressed to accelerated-phase CML or blast crisis , and the estimated overall survival of patients who received imatinib as initial therapy was 89 % at 60 months . Patients who had a complete cytogenetic response or in whom levels of BCR-ABL transcripts had fallen by at least 3 log had a significantly lower risk of disease progression than did patients without a complete cytogenetic response ( P<0.001 ) . Grade 3 or 4 adverse events diminished over time , and there was no clinical ly significant change in the profile of adverse events . CONCLUSIONS After 5 years of follow-up , continuous treatment of chronic-phase CML with imatinib as initial therapy was found to induce durable responses in a high proportion of patients . ( Clinical Trials.gov number , NCT00006343 [ Clinical Trials.gov ] . Biologic and clinical observations suggest that combining imatinib with IFN-α may improve treatment outcome in chronic myeloid leukemia ( CML ) . We r and omized newly diagnosed chronic-phase CML patients with a low or intermediate Sokal risk score and in imatinib-induced complete hematologic remission either to receive a combination of pegylated IFN-α2b ( Peg-IFN-α2b ) 50 μg weekly and imatinib 400 mg daily ( n = 56 ) or to receive imatinib 400 mg daily monotherapy ( n = 56 ) . The primary endpoint was the major molecular response ( MMR ) rate at 12 months after r and omization . In both arms , 4 patients ( 7 % ) discontinued imatinib treatment ( 1 because of blastic transformation in imatinib arm ) . In addition , in the combination arm , 34 patients ( 61 % ) discontinued Peg-IFN-α2b , most because of toxicity . The MMR rate at 12 months was significantly higher in the imatinib plus Peg-IFN-α2b arm ( 82 % ) compared with the imatinib monotherapy arm ( 54 % ; intention-to-treat , P = .002 ) . The MMR rate increased with the duration of Peg-IFN-α2b treatment ( < 12-week MMR rate 67 % , > 12-week MMR rate 91 % ) . Thus , the addition of even relatively short periods of Peg-IFN-α2b to imatinib markedly increased the MMR rate at 12 months of therapy . Lower doses of Peg-IFN-α2b may enhance tolerability while retaining efficacy and could be considered in future protocol s with curative intent This study examines the prognostic significance of early molecular response using an exp and ed data set in chronic myeloid leukemia patients enrolled in the International R and omized Study of Interferon and STI571 ( IRIS ) . Serial molecular studies demonstrate decreases in BCR-ABL transcripts over time . 
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Importantly , rate of progression to accelerated phase/blastic crisis was significantly lower with the newer tyrosine kinase inhibitors throughout all time points .
We conclude that 2(nd ) generation tyrosine kinase inhibitors can be added safely to the first-line treatment armamentarium of chronic phase chronic myelogenous leukemia patients .
Although an advantage is suggested by surrogate parameters , longer follow up is necessary to see if this translates into superior overall survival