***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: BACKGROUND The level of minimal residual disease during remission induction is the most important prognostic indicator in patients with acute lymphoblastic leukaemia ( ALL ) . We aim ed to establish the clinical significance of minimal residual disease in a prospect i ve trial that used sequential minimal residual disease measurements to guide treatment decisions . METHODS Between June 7 , 2000 , and Oct 24 , 2007 , 498 assessable patients with newly diagnosed ALL were enrolled in a clinical trial at St Jude Children 's Research Hospital . We provisionally classified the risk of relapse as low , st and ard , or high according to patients ' baseline clinical and laboratory features . Final risk assignment to establish treatment intensity was based mainly on minimal residual disease levels measured on days 19 and 46 of remission induction , and on week 7 of maintenance treatment . Additional measurements of minimal residual disease were made on weeks 17 , 48 , and 120 ( end of treatment ) . The primary aim was to establish the association between event-free survival and patients ' minimal residual disease levels during remission induction and sequentially post-remission . This trial was registered at Clinical Trials.gov , number NCT00137111 . FINDINGS Irrespective of the provisional risk classification , 10-year event-free survival was significantly worse for patients with 1 % or greater minimal residual disease levels on day 19 compared with patients with lower minimal residual disease levels ( 69·2 % , 95 % CI 49·6 - 82·4 , n=36 vs 95·5 % , 91·7 - 97·5 , n=244 ; p<0·001 for the provisional low-risk group and 65·1 % , 50·7 - 76·2 , n=56 vs 82·9 % , 75·6 - 88·2 , n=142 ; p=0·01 for the provisional st and ard-risk group ) . 12 patients with provisional low-risk ALL and 1 % or higher minimal residual disease levels on day 19 but negative minimal residual disease ( < 0·01 % ) on day 46 were treated for st and ard-risk ALL and had a 10-year event-free survival of 88·9 % ( 43·3 - 98·4 ) . For the 280 provisional low-risk patients , a minimal residual disease level of less than 1 % on day 19 predicted a better outcome , irrespective of the minimal residual disease level on day 46 . Of provisional st and ard-risk patients with minimal residual disease of less than 1 % on day 19 , the 15 with persistent minimal residual disease on day 46 seemed to have an inferior 10-year event-free survival compared with the 126 with negative minimal residual disease ( 72·7 % , 42·5 - 88·8 vs 84·0 % , 76·3 - 89·4 ; p=0·06 ) after receiving the same post-remission treatment for st and ard-risk ALL . Of patients attaining negative minimal residual disease status after remission induction , minimal residual disease re-emerged in four of 382 studied on week 7 , one of 448 at week 17 , and one of 437 at week 48 ; all but one of these six patients died despite additional treatment . By contrast , relapse occurred in only two of the 11 patients who had decreasing minimal residual disease levels between the end of induction and week 7 of maintenance therapy and were treated with chemotherapy alone . INTERPRETATION Minimal residual disease levels during remission induction treatment have important prognostic and therapeutic implication s even in the context of minimal residual disease-guided treatment . Sequential minimal residual disease monitoring after remission induction is warranted for patients with detectable minimal residual disease . FUNDING National Institutes of Health and American Lebanese Syrian Associated Charities The efficacy of allografting in acute lymphoblastic leukemia ( ALL ) is heavily influenced by remission status at the time of transplant . Using polymerase chain reaction (PCR)-based minimal residual disease ( MRD ) analysis , we have investigated retrospectively the impact of su bmi croscopic leukemia on outcome in 64 patients receiving allogeneic bone marrow transplantation ( BMT ) for childhood ALL . Remission BM specimens were taken 6 to 81 days ( median , 23 ) before transplant . All patients received similar conditioning therapy ; 50 received grafts from unrelated donors and 14 from related donors .  Nineteen patients were transplanted in first complete remission ( CR1 ) and 45 in second or subsequent CR . MRD was analyzed by PCR of Ig or T-cell receptor delta or gamma rearrangements , electrophoresis , and allele-specific oligoprobing . Sample s were rated high-level positive ( clonal b and evident after electrophoresis ; sensitivity 10(-2 ) to 10(-3 ) ) , low-level positive ( MRD detected only after oligoprobing ; sensitivity 10(-3 ) to 10(-5 ) ) , or negative . Excluding 8 patients transplanted in CR2 for isolated extramedullary relapse ( all MRD- ) , MRD was detected at high level in 12 patients , low level in 11 , and was undetectable in 33 . Two-year event-free survival for these groups was 0 % , 36 % , and 73 % , respectively ( P < .001 ) . Follow-up in patients remaining in continuing remission is 20 to 96 months ( median , 35 ) . These results suggest that MRD analysis could be used routinely in this setting . This would allow identification of patients with resistant leukemia ( who may benefit from innovative BMT protocol s ) and of those with more responsive disease ( who may be c and i date s for r and omized trials of BMT versus modern intensive relapse chemotherapy ) Minimal residual disease ( MRD ) is a major predictive factor of the cure rate of acute lymphoblastic leukaemia ( ALL ) .  Haematopoietic cell transplantation is a treatment option for patients at high risk of relapse . Between 2005 and 2008 , we conducted a prospect i ve study evaluating the feasibility and efficacy of the reduction of immunosuppressive medication shortly after a non‐ex vivo T depleted myeloablative transplantation . Immunoglobulin (Ig)H/T‐cell receptor MRD 30 d before transplant could be obtained in 122 of the 133 cases of high‐risk paediatric ALL enrolled . There were no significant demographic differences except remission status ( first or second complete remission ) between the 95 children with MRD < 10−3 and the 27 with MRD ≥10−3 . Multivariate analysis identified sex match and MRD as being significantly associated with 5‐year survival . MRD ≥10−3 compromised the 5‐year cumulative incidence of relapse ( 43·6 vs. 16·7 % ) . Complete remission status and stem cell source did not modify the relationship between MRD and prognosis . Thus , pre‐transplant MRD is still a major predictor of outcome for ALL . The MRD‐guided strategy result ed in survival for 72·3 % of patients with MRD<10−3 and 40·4 % of those with MRD ≥10−3 Relapse of pediatric acute lymphoblastic leukemia ( ALL ) remains the main cause of treatment failure after allogeneic stem cell transplantation ( alloSCT ) . A high level of minimal residual disease ( MRD ) before alloSCT has been shown to predict these relapses . Patients at risk might benefit from a preemptive alloimmune intervention . In this first prospect i ve , MRD-guided intervention study , 48 patients were stratified according to pre-SCT MRD level . Eighteen children with MRD level ⩾1 × 10−4 were eligible for intervention , consisting of early cyclosporine A tapering followed by consecutive , incremental donor lymphocyte infusions ( n=1–4 ) . The intervention was associated with graft versus host disease ⩾ grade II in only 23 % of patients . Event-free survival in the intervention group was 19 % . However , in contrast with the usual early recurrence of leukemia , relapses were delayed up to 3 years after SCT . In addition , several relapses presented at unusual extramedullary sites suggesting that the immune intervention may have altered the pattern of leukemia recurrence . In 8 out of 11 evaluable patients  , relapse was preceded by MRD recurrence ( median 9 weeks , range 0–30 ) . We conclude that in children with high-risk ALL , immunotherapy-based regimens after SCT are feasible and may need to be further intensified to achieve total eradication of residual leukemic cells PURPOSE Minimal residual disease ( MRD ) before allogeneic stem-cell transplantation was shown to predict outcome in children with relapsed acute lymphoblastic leukemia ( ALL ) in retrospective analysis . To verify this , the Acute Lymphoblastic Leukemia Relapse Berlin-Frankfurt-Münster ( ALL-REZ BFM ) Study Group conducted a prospect i ve trial . PATIENTS AND METHODS Between March 1999 and July 2005 , 91 children with relapsed ALL treated according to the ALL-REZ BFM 96 or 2002 protocol s and receiving stem-cell transplantation in > or= second remission were enrolled . MRD quantification  was performed by real-time polymerase chain reaction using T-cell receptor and immunoglobulin gene rearrangements . RESULTS Probability of event-free survival ( pEFS ) and cumulative incidence of relapse ( CIR ) in 45 patients with MRD > or= 10(-4 ) leukemic cells was 0.27 and 0.57 compared with 0.60 and 0.13 in 46 patients with MRD less than 10(-4 ) leukemic cells ( EFS , P = .004 ; CIR , P < .001 ) . Intermediate-risk patients ( strategic group S1 ) with MRD > or= 10(-4 ) leukemic cells ( n = 14 ) had a pEFS of 0.20 and CIR of 0.73 , whereas patients with MRD less than 10(-4 ) leukemic cells ( n = 21 ) had a pEFS of 0.68 and CIR of 0.09 ( EFS , P = .020 ; CIR , P < .001 ) . High-risk patients ( S3/4 , third complete remission ) who received transplantation with an MRD load of less than 10(-4 ) leukemic cells ( n = 25 ) showed a pEFS and CRI of 0.53 and 0.18 , respectively . In contrast , pEFS and CRI were 0.30 and 0.50 in patients who received transplantation with an MRD load of > or= 10(-4 ) leukemic cells . Multivariate Cox regression analysis revealed MRD as the only independent parameter predictive for EFS ( P = .006 ) . CONCLUSION MRD is an important predictor for post-transplantation outcome . As a result , new strategies with modified stem-cell transplantation procedures will be evaluated in ALL-BFM trials Relapse is the main reason for treatment failure in childhood acute lymphoblastic leukemia . Despite improvements in the up-front therapy , survival after relapse is still relatively poor , especially for high-risk relapses . The aims of this study were to assess outcomes following  acute lymphoblastic leukemia relapse after common initial Nordic Society of Paediatric Haematology and Oncology protocol treatment ; to vali date currently used risk stratifications , and identify additional prognostic factors for overall survival . Altogether , 516 of 2735 patients ( 18.9 % ) relapsed between 1992 and 2011 and were included in the study . There were no statistically significant differences in outcome between the up-front protocol s or between the relapse protocol s used , but an improvement over time was observed . The 5-year overall survival for patients relapsing in the period 2002–2011 was 57.5±3.4 % , but 44.7±3.2 % ( P<0.001 ) if relapse occurred in the period 1992–2001 . Factors independently predicting mortality after relapse included short duration of first remission , bone marrow involvement , age ten years or over , unfavorable cytogenetics , and Down syndrome . T-cell immunophenotype was not an independent prognostic factor unless in combination with hyperleukocytosis at diagnosis . The outcome for early combined pre-B relapses was unexpectedly poor ( 5-year overall survival 38.0±10.6 % ) , which supports the notion that these patients need further risk adjustment . Although survival outcomes have improved over time , the development of novel approaches is urgently needed to increase survival in relapsed childhood acute lymphoblastic leukemia BACKGROUND We sought to improve outcome in patients with childhood acute myeloid leukaemia ( AML ) by applying risk-directed therapy that was based on genetic abnormalities of the leukaemic cells and measurements of minimal residual disease ( MRD ) done by flow cytometry during treatment . METHODS From Oct 13 , 2002 , to June 19 , 2008 , 232 patients with de-novo AML ( n=206 ) , therapy-related or myelodysplasia-related AML ( n=12 ) , or mixed-lineage leukaemia ( n=14 ) were enrolled at eight centres . 230 patients were assigned by block , 
    Output:
    
However , positive MRD prior to transplantation was not associated with a higher rate of nonrelapse mortality .