the discovery of imatinib mesylate ( i m ) , a bcr abl tyrosine kinase inhibitor ( tki ) has dramatically altered the natural history of chronic myeloid leukemia ( cml ) . when the eln and nccn guidelines to monitor disease are applied , a third of all chronic phase cml ( cp cml ) patients are likely to be categorized as resistant to i m 400 mg . resistance can result from bcr abl dependent mechanisms through mutations in the abl kinase domain ( kd ) or those independent of the bcr abl domain . for patients with resistance , i m dose escalation , 2nd generation tkis ( dasatinib and nilotinib ) , allo geneic stem cell transplantation sct are options . there is conflicting data on the efficacy of dose escalation in patients resistant to i m 400 mg . due to financial reasons i m dose escalation remains the only option for most patients in our country . this analysis aimed at analyzing kd mutations and response to dose escalation for patients in cp - cml at resistance to standard dose i m . all the patients who had loss of response or no response to imatinib were included in the study . all these patients underwent imatinib resistant mutation analysis ( irma ) and dose escalation of imatinib from 400 mg to 800 mg once a day . there were 90 patients with a median age of 36 years ( range , 18 - 65 ) . base line characteristics ( n = 90 ) twenty - nine ( 32.2% ) patients had detectable kd mutations . thirteen ( 12.2% ) of all patients ( 38% of all mutations ) had a p loop mutation . n374y is a novel mutation has not been reported before . no clinical or laboratory factors predicted for detection of kd mutation . mutations detected , n = 29 ( 32.2% ) all patients with resistance were escalated from 400 mg to 800 mg . 90 patients were followed - up for response , event free survival ( efs ) , transformation - free survival ( tfs ) and overall survival ( os ) . the median time to cytogenetic response was 11 months ( range , 6 - 18 ) . predictors for achieving a major cytogenetic response ( mcr ) have been shown in table 3 . response to dose escalation predictors of major cytogenetic response at a median follow - up of 18 months ( range , 3 - 40 ) , 35 patients ( 39% ) were event free and 84 patients ( 93% ) are alive . the following are the events in 55 patients ( 61% ) : failure to achieve complete haematological response : 37 ( 67.2% ) , loss of hematologic response : 2 ( 3.6% ) , failure to achieve cytogenetic response : 7 ( 12.7% ) , progression to accelerated phase / blast crises : 3 ( 5.4% ) and deaths : 6 ( 11% ) . for those with cytogenetic failure , the 2-year efs and tfs were 73 and 95% respectively . the median efs for those who achieved mcr to dose escalation have not been reached and the projected 2 year efs is 67% . patients with cytogenetic failure who achieved a mcr had more sustained responses compared to those with hematologic failures with mcr , median efs not reached versus 31 months ( 2 year efs 90 vs.51% , p = 0.0006 ) . dose decreases were necessary in 16 ( 18% ) and dose interruptions in 31 ( 34% ) . 60 patients ( 76% ) were able to continue i m at a dose more than 600 mg . 90 patients were followed - up for response , event free survival ( efs ) , transformation - free survival ( tfs ) and overall survival ( os ) . the median time to cytogenetic response was 11 months ( range , 6 - 18 ) . predictors for achieving a major cytogenetic response ( mcr ) have been shown in table 3 . at a median follow - up of 18 months ( range , 3 - 40 ) , 35 patients ( 39% ) were event free and 84 patients ( 93% ) are alive . the following are the events in 55 patients ( 61% ) : failure to achieve complete haematological response : 37 ( 67.2% ) , loss of hematologic response : 2 ( 3.6% ) , failure to achieve cytogenetic response : 7 ( 12.7% ) , progression to accelerated phase / blast crises : 3 ( 5.4% ) and deaths : 6 ( 11% ) . for those with cytogenetic failure , the 2-year efs and tfs were 73 and 95% respectively . the median efs for those who achieved mcr to dose escalation have not been reached and the projected 2 year efs is 67% . patients with cytogenetic failure who achieved a mcr had more sustained responses compared to those with hematologic failures with mcr , median efs not reached versus 31 months ( 2 year efs 90 vs.51% , p = 0.0006 ) . dose decreases were necessary in 16 ( 18% ) and dose interruptions in 31 ( 34% ) . 60 patients ( 76% ) were able to continue i m at a dose more than 600 mg . in this analysis 32.2% of patients in cp at diagnosis of resistance to i m had a kd mutation with p loop mutations being more common . unlike in previous studies t315i was much higher ( 31% of all mutations and 10% of all patients)than previously reported . our results with dose escalation are more encouraging than previously reported . however , for those resistant to standard dose i m , dasatinib is superior to i m dose escalation in terms of cytogenetic responses and disease free survival . the responses and efs to i m dose escalation in our study were inferior to that reported previously . we attribute the lower mcr rate in our study to the higher percentage of patients being in hematologic failure at the time of dose escalation . in previously reported studies , patients with hematologic failures at dose escalation had poorer responses and time to treatment failure compared to those with cytogenetic failures . i m dose escalation is likely to be effective only in those harboring no or relatively sensitive kd mutations . the type of failure at dose escalation and achievement of mcr to dose escalation predicted for improved efs . our results suggest that i m dose escalation is a useful strategy for those with cytogenetic failures these results emphasize the importance of proper monitoring to detect failures early leading to timely intervention and improved outcomes .
imatinib has shown unprecendeted success in the treatment of chronic myeloid leukemia ( cml ) . however , over few years there have been reports regarding the primary and secondary resistance to imatinib dampening the overall outcome in cml patients . in this study 
 we have tried to assess the effect of dose escalation in patients resistant to standard dose of imatinib and correlate it with presence of abl kinase domain ( kd ) mutations . there were 90 patients resistant to imatinib , out which 29 patients were identified with kd mutations . 
 the most common mutation was t315i , 9 out of 29 patients had it . 
 35 ( 38% ) responded to dose escalation and had 67% event free survival ( efs ) at estimated 2 years . 
 our results showed that dose escalation can over come resistance in some patients especially those in cytogenetic failure .