***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    Input: Most patients with chronic myeloid leukemia ( CML ) treated with imatinib  will relapse if treatment is withdrawn . We conducted a prospect i ve clinical trial of imatinib withdrawal in 40 chronic-phase CML patients who had sustained undetectable minimal residual disease ( UMRD ) by conventional quantitative polymerase chain reaction ( PCR ) on imatinib for at least 2 years . Patients stopped imatinib and were monitored frequently for molecular relapse . At 24 months , the actuarial estimate of stable treatment-free remission was 47.1 % . Most relapses occurred within 4 months of stopping imatinib , and no relapses beyond 27 months were seen . In the 21 patients treated with  interferon  before imatinib , a shorter duration of interferon treatment before imatinib was significantly associated with relapse risk , as was slower achievement of UMRD after switching to imatinib . Highly sensitive patient-specific BCR-ABL DNA PCR showed persistence of the original CML clone in all patients with stable UMRD , even several years after imatinib withdrawal . No patients with molecular relapse after discontinuation have progressed or developed BCR-ABL mutations ( median follow-up , 42 months ) . All patients who relapsed remained sensitive to imatinib re-treatment . These results confirm the safety and efficacy of a trial of imatinib withdrawal in stable UMRD with frequent , sensitive molecular monitoring and early rescue of molecular relapse Recent studies suggest that a proportion of chronic myeloid leukemia ( CML ) patients in deep molecular remission can discontinue the tyrosine kinase inhibitor ( TKI ) treatment without disease relapse . In this multi-center , prospect i ve clinical trial ( EURO-SKI , NCT01596114 ) we analyzed the function and phenotype of T and NK cells and their relation to successful TKI cessation . Lymphocyte subclasses were measured from 100 imatinib-treated patients at baseline and 1 month after the discontinuation , and functional characterization of NK and T cells was done from 45 patients . The proportion of NK cells was associated with the molecular relapse-free survival as patients with higher than median NK-cell percentage at the time of drug discontinuation had better probability to stay in remission . Similar association was not found with T or B cells or their subsets . In non-relapsing patients the NK-cell phenotype was mature , whereas patients with more naïve CD56bright NK cells had decreased relapse-free survival . In addition , the TNF-α/IFN-γ cytokine secretion by NK cells correlated with the successful drug discontinuation . Our results highlight the role of NK cells in sustaining remission and strengthen the status of CML as an immunogenic tumor warranting novel clinical trials with immunomodulating agents Purpose ENESTfreedom is evaluating treatment-free remission ( TFR ) following frontline nilotinib in patients with chronic myeloid leukemia ( CML ) in chronic phase . Following our primary analysis at 48 weeks , we here provide an up date d 96-week analysis . Methods Attempting TFR required ≥ 3 years of nilotinib , a molecular response of MR4.5 [ BCR-ABL1 ≤ 0.0032 % on the International Scale ( BCR-ABL1IS ) ] , and sustained deep molecular response ( DMR ) during a 1-year consolidation phase . Patients restarted nilotinib following loss of major molecular response ( MMR ; BCR-ABL1IS ≤ 0.1 % ) . Results Ninety-six weeks after stopping treatment ( 3.6-year median prior nilotinib duration ) , 93 of 190 patients ( 48.9 % ) remained in TFR . Of 88 patients who restarted nilotinib following loss of MMR , 87 regained MMR and 81 regained MR4.5 by the data cut-off . Ninety-six-week TFR rates were 61.3 , 50.0 , and 28.6 % in patients with low , intermediate , and high Sokal risk scores at diagnosis , respectively . Patients consistently in MR4.5 during consolidation had higher TFR rates ( 50.6 % ) than patients with ≥ 1 assessment without MR4.5 during consolidation ( 35.0 % ) . In a l and mark analysis , 96-week TFR rates for patients with MR4.5 , MR4 ( BCR-ABL1IS ≤ 0.01 % ) but not MR4.5 , and MMR but not MR4 at TFR week 12 were 82.6 , 23.1 , and 0 % , respectively . There were no reports of disease progression or death due to CML ; overall adverse event frequency decreased following TFR . Within the follow-up period , TFR did not adversely affect disease outcomes . Conclusions These results demonstrate the feasibility and durability of TFR following frontline nilotinib and emphasize the importance of sustained DMR for TFR Chronic myeloid leukemia ( CML ) results from DNA damage leading to a chromosomal translocation that produces the Philadelphia chromosome and result ing chimeric tyrosine kinase , BCR-ABL1 ( 14 ) . The BCR-ABL1 tyrosine kinase inhibitors ( TKIs ) have dramatically improved outcomes for patients with CML ( 5 ) . This type of leukemia progresses through 3 phases : chronic phase , accelerated phase , and blast crisis . However , with BCR-ABL1 TKI therapy , patients may remain in the chronic phase for more than a decade , with a life expectancy similar to that of the general population ( 57 ) . Imatinib , nilotinib , dasatinib , and bosutinib are TKIs approved for use as frontline therapies ; additional TKIs are available for later-line setting s ( 8) . During TKI treatment , patients ' molecular responses ( that is , BCR-ABL1 transcript levels ) are monitored with real-time quantitative polymerase chain reaction ( RQ-PCR ) assays ( 8) . Molecular response levels are reported relative to a st and ard reference representing an untreated BCR-ABL1 level ( the International Scale [ IS ] ) . Established response benchmarks include major molecular response ( MMR ) ( BCR-ABL1 IS 0.1 % ) , MR4 ( BCR-ABL1 IS 0.01 % ) , and MR4.5 ( BCR-ABL1 IS 0.0032 % ) ( 8) . Treatment-free remission ( TFR ) after achievement of sustained deep molecular response ( DMR ) ( for example , MR4 or MR4.5 ) ( 9 , 10 ) represents an emerging treatment goal for patients with CML in chronic phase . Potential motivators and benefits of achieving TFR may include relief of treatment side effects , reduced risk for long-term TKI toxicity , and the ability to plan a family ( 1113 ) . In the STIM1 ( Stop Imatinib 1 ) trial , 38 % of patients with sustained DMR while receiving long-term imatinib treatment had molecular recurrencefree survival at 5 years ( median follow-up , 77 months ) ( 14 , 15 ) . These results , along with findings from other TFR trials ( mostly after frontline imatinib treatment ) ( 12 , 1622 ) , confirm the feasibility of TFR after sustained DMR in patients receiving TKIs . When TFR is a treatment goal , achievement of DMR is a key prerequisite . For patients receiving frontline imatinib therapy who did not reach DMR , the ENESTcmr ( Evaluating Nilotinib Efficacy and Safety in Clinical TrialsComplete Molecular Response ) study demonstrated that switching to nilotinib may provide a path to achieving DMR . Among the ENESTcmr participants who did not have MR4.5 at baseline , by 2 years after enrollment , the MR4.5 rate was 43 % for those r and omly assigned to a nilotinib switch ( n= 98 ) versus 21 % for those assigned to continued imatinib therapy ( n= 96 ) ( 23 ) . Thus , switching to nilotinib may allow more of these patients to reach a molecular response level at which treatment discontinuation may be considered . Although studies have evaluated TFR after cessation of dasatinib or nilotinib therapy ( 1922 ) , TFR in patients who achieved sustained DMR after switching from imatinib to nilotinib has not been investigated in a dedicated study . We present findings from the single-group , phase 2 ENESTop ( Treatment-Free Remission After Achieving Sustained MR4.5 on Nilotinib ) trial ( Clinical Trials.gov : NCT01698905 ) . To our knowledge , ENESTop is the first large prospect i ve study to evaluate TFR specifically in patients who achieved sustained DMR only after switching from imatinib to nilotinib . The primary objective of ENESTop was to determine the TFR rate at 48 weeks after treatment discontinuation in this patient population . Methods Patients and Study Design Eligible patients were aged 18 years or older , had Philadelphia chromosomepositive CML in chronic phase , and had an Eastern Cooperative Oncology Group performance grade of 0 to 2 . Patients must have received previous TKI therapy for at least 3 years ( > 4 weeks with imatinib , then 2 years with nilotinib ) and achieved MR4.5 while receiving nilotinib after switching from imatinib therapy . The study design is shown in Figure 1 . Figure 1 . ENESTop study design . Patients entered a 1-year consolidation phase and received nilotinib at the same dosage as before enrollment ( 300 or 400 mg twice daily or other dosage ) . Patients who maintained MR4.5 during the consolidation phase ( that is , had no confirmed loss of MR4.5 in consecutive assessment s within 4 wk ) were eligible to enter the TFR phase and stop nilotinib treatment . Patients with loss of MMR or confirmed loss of MR4 ( in 2 consecutive assessment s within 4 wk ) during the TFR phase restarted nilotinib therapy at 300 or 400 mg twice daily in the treatment reinitiation phase . BCR-ABL1 IS= BCR-ABL1 st and ardized to the International Scale ; CML= chronic myeloid leukemia ; ENESTop= Treatment-Free Remission After Achieving Sustained MR4.5 on Nilotinib ; MMR= major molecular response ( BCR-ABL1 IS 0.1 % ) ; MR4= BCR-ABL1 IS 0.01 % ; MR4.5= BCR-ABL1 IS 0.0032 % ; RQ-PCR= real-time quantitative polymerase chain reaction ( st and ardized to the International Scale ) ; TFR= treatment-free remission ; TKI= tyrosine kinase inhibitor . * Confirmed loss of MR4.5 was defined as BCR-ABL1 IS > 0.0032 % , confirmed in a second assessment within 4 wk . Confirmed loss of MR4 was defined as BCR-ABL1 IS > 0.01 % in 2 consecutive assessment s. Patients with confirmed loss of MR4.5 during the continuation phase continued nilotinib treatment in the prolonged continuation phase until 264 wk after the last patient entered the TFR phase or until discontinuation due to unacceptable toxicity , disease progression , investigator discretion , or withdrawal of consent . End Points and Assessment s The primary efficacy end point was the proportion of patients without loss of MMR , confirmed loss of MR4 , or treatment reinitiation within the first 48 weeks of the TFR phase . Mutational analyses ( Sanger sequencing ) were performed in patients with MMR loss or confirmed MR4 loss who had sufficient BCR-ABL1 copies . Adverse events ( AEs ) were assessed according to the Common Terminology Criteria for Adverse Events , version 4.03 ( 24 ) . Safety was evaluated throughout the study and up to 30 days after the last dose of study drug or the last day in TFR phase . Statistical Analysis Sample -size calculation was based on the number of patients required to provide 90 % power to test the null hypothesis ( TFR rate 10 % at 48 weeks ) , as detailed in the Supplement . Because of rapid recruitment , actual enrollment was higher than planned . Efficacy and safety data were reported for all patients who entered the TFR phase ( TFR population ) on the basis of a cutoff date of 26 November 2015 , when all patients who entered the TFR phase had remained in TFR for 48 weeks or more , reinitiated treatment , or dropped out of the study ; additional , longer-term analyses were based on a cutoff date of 7 November 2016 . The primary end point ( TFR rate at 48 weeks ) was presented as a percentage with an exact 95 % ClopperPearson CI . If the lower limit of the 95 % CI exceeded 10 % , the null hypothesis would be rejected . For the primary analysis , patients who left the study before week 48 of the TFR phase were considered nonresponders and included in the TFR population . Patients who lost MR4 for the first time ( that is , not confirmed ) at week 48 of the TFR phase but did not lose MMR were considered responders for the primary analysis . Supplement . Methods Treatment-free survival was defined as the time from the TFR start date to the date of the earliest occurrence of MMR loss , confirmed MR4 loss , nilotinib reinitiation , progression to accelerated phase or blast crisis , or death from any cause . Progression-free survival was defined as the time from the TFR start date to the date of the earliest occurrence of progression to accelerated phase or blast crisis or death from any cause . Overall survival was defined as the time from the TFR start date to the date of death from any cause . Treatment-free , progression-free , and overall survival were analyzed by using the KaplanMeier method . For patients who reinitiated treatment , time to recovery of a molecular response was assessed by plotting the cumulative rates of MR4 
    Output:
    
Conclusions : TFR as an extension of an approach to optimize management of CML is clinical ly feasible in approximately 59 % of patients with sufficient TKI response .
In the remaining 41 % of patients with molecular relapse , discontinuing TKIs had no negative impact on clinical outcomes .