Need For Treatment Escalation Research Articles

P322 Impact of the presence of Epstein–Barr virus in intestinal mucosa of inflammatory bowel disease patients

Abstract Background To evaluate the importance of positive Epstein–Barr virus (EBV) status in intestinal biopsy in patients with inflammatory bowel disease (IBD), its association with active disease and immunosuppressive (IM) therapy and its influence on the clinical evolution of IBD. Methods We retrospectively analysed patients with IBD who were tested for EBV in intestinal mucosa between November 2009 and June 2017. Pathologists decided EBV testing based on the presence of severe histologic activity with/without prominent lymphoplasmacytic infiltrate or refractory disease to various treatments. We analysed phenotypic characteristics, previous treatments, active therapies at the time of EBV testing, EBV status by immunohistochemistry, presence of lymphoma, treatment decision making after EBV testing and subsequent clinical evolution based on hospital admissions and treatment escalation requirement. Results We included 56 patients, 28 with Crohn’s disease (CD) and 28 with ulcerative colitis (UC). The predominant phenotype of patients with CD was A2L3C1. Regarding patients with UC, 14 patient had left-sided and 14 extensive colitis. EBV was positive (EBV+) in 26 cases (46%), one of them associated with a lymphoproliferative disorder. EBV+ status was associated with clinically active disease (53.3% vs. 25%, p = 0.08); severe endoscopic (54.5% vs. 37.5%, p = 0.02) and severe histological activity (72.2% vs. 33.3%, p = 0.007) and the presence of a prominent lymphoplasmacytic infiltrate (68.8% vs. 16.7%, p < 0.0005). In addition, active steroid treatment, but not IM and/or biological therapy, at the time of EBV testing was associated with EBV+ status (61.5% vs. 33.3%, p = 0.03). Only the presence of a prominent lymphoplasmacytic infiltrate showed significant association with EBV+ in the multivariate analysis (p = 0001). IM therapy was de-escalated in 6/26 EBV-positive patients. In EBV- patients, IM treatment was escalated in 10/30. After a mean follow-up of 53.3 months, 17 patients required hospital admission and 26 escalation of therapy. Both risk of admissions and escalation of treatment during follow-up were higher in EBV+ patients (38.5% vs. 23.3%, p = 0.2; and 65.4% vs. 30%, p = 0.008, respectively). Only female sex was associated with a greater possibility of hospital admission and EBV+ with the need for treatment escalation (p = 0.03) in the multivariate analysis. None of the patients developed lymphoma during follow-up. Conclusion EBV+ status in intestinal mucosa is associated with histological activity. Prominent lymphoplasmacytic infiltrate is the only factor associated with EBV+ status independently of immunosuppression status. EBV+ is associated with subsequent poor clinical evolution and a greater need for escalation of IM therapy.

P317 Key features of bowel ultrasonography in managing inflammatory bowel disease patients

Abstract Background Bowel ultrasonography (BUS) is an accurate imaging method for detecting and monitoring inflammatory bowel disease (IBD) patients. This technique is recommended by current guidelines besides gold standard endoscopic assessment in managing IBD patients. Several BUS characteristics strongly correlate with biological markers of inflammation suggesting that these tests could be used in monitoring IBD patients but is yet unknown how these features predict the patient’s evolution. Methods Our study included 95 consecutive IBD patients (24 diagnosed with ulcerative colitis, 71 with Crohn’s disease) with both active and inactive disease at presentation. IBD diagnosis was established endoscopically and histologically. Patients with superimposed infection (viral or bacterial) and patients that had solely rectal involvement of the disease were excluded. BUS was conducted at baseline by one skilled examiner blinded to biological data. Biological markers were evaluated at baseline and all cases were prospectively followed-up for the need of therapy escalation during the next 6 months. The following BUS characteristics were registered in every patient: bowel wall thickness, alteration of wall structure, thickened mucosa or submucosa, presence of hyperechoic spots in the mucosal wall, irregularity of the external wall, Doppler signal, presence of mesenteric hypertrophy, presence of lymph nodes, and an overall assessment of the examination. No special preparation was needed before BUS. Results Of all the monitored sonographic features, the following characteristics correlated with the need of increasing treatment in the following 6 months: bowel wall thickness, altered structure of the wall, hypertrophic mucosa, Doppler signal, and the overall assessment of the examination (p < 0.001). The presence of the lymph nodes, hyperechoic spots in the mucosa, thickened submucosa and the irregularity of the external wall were not statistically significant correlated with the need for treatment escalation. The strongest correlation with the need for increasing treatment was documented for a mean bowel wall thickness > 5 mm and for Doppler signal presence in the bowel wall (p < 0.00001). In the multivariate analysis, Doppler signal presence was the only independent predictor for the need treatment escalation during a 6-month follow-up. Conclusion The most important sonographic features with an impact on therapeutic decision making in IBD patients are: bowel wall thickness, Doppler signal, altered stratification of the wall and mesenteric hypertrophy. In our analysis, the Doppler signal was the only independent predictor for the need for step-up therapy.

A blood-based prognostic biomarker in IBD

ObjectiveWe have previously described a prognostic transcriptional signature in CD8 T cells that separates patients with IBD into two phenotypically distinct subgroups, termed IBD1 and IBD2. Here we sought to...

Combination of colonoscopy and magnetic resonance enterography is more useful for clinical decision making than colonoscopy alone in patients with complicated Crohn's disease

Background/aimsThe small bowel is affected in more than half of patients with Crohn’s disease (CD) at the time of diagnosis, and small bowel involvement has a negative impact on the long-term outcome. Many patients reportedly have active lesions in the small intestine even in patients in clinical remission. This study was performed to compare findings of magnetic resonance enterography (MRE) and ileocolonoscopy.MethodsA single-center retrospective study was conducted in 50 patients (60 imaging series) with CD, for whom MRE was additionally performed during the bowel preparation for subsequent ileocolonoscopy. Endoscopic remission was defined as a Simple Endoscopic Score for CD (SES-CD) of <5. MRE remission was defined as a Magnetic Resonance Index of Activity (MaRIA) score of <50. The time to treatment escalation was assessed by the log-rank test.ResultsImportantly, 7 of 29 patients (24.1%) with endoscopic remission had a MaRIA score of ≥50. Both SES-CD and MaRIA correlated with the need for treatment escalation (P = 0.025, P = 0.009, respectively). MRE predicted the need for treatment escalation even in patients with endoscopic remission. Although no correlation was present between SES-CD and MaRIA score in patients with structuring/penetrating disease, or insufficient ileal insertion (<10cm), a high MaRIA score still correlated with the need for treatment escalation in stricturing or penetrating disease (P = 0.0306).ConclusionsThe MaRIA score predicts the need for treatment escalation even in patients with endoscopic remission, indicating that addition of MRE to conventional ileocolonoscopy alone can be a useful, noninvasive tool for monitoring CD especially in stricturing or penetrating disease.

Presence of pseudopolyps in ulcerative colitis is associated with a higher risk for treatment escalation.

BackgroundPseudopolyps in ulcerative colitis (UC) are considered as indicators of previous episodes of severe inflammation and ulceration of the mucosa. The aim of the study was to investigate the long-term outcomes of patients treated for UC, with or without pseudopolyps.MethodsThis was a retrospective single-center study. Consecutive patients with UC and available endoscopic data from 2000 until 2016 were eligible for the study and were followed until June 2017. Patients with incomplete medical/endoscopic charts or interrupted follow up were excluded from the study. Primary outcomes included time to treatment escalation, treatment escalation to biological agents or surgery, and UC-related hospitalization.ResultsEighty-three UC patients were included in the study, of whom 25 (30%) had pseudopolyps. The median duration of follow up was 2.8 years (interquartile range: 1.1-4.9). Multiple Cox regression analysis identified the presence of pseudopolyps as the only variable independently associated with treatment escalation (hazard ratio [HR] 2.3, 95% confidence interval [CI] 1.2-4.3; P=0.014) and escalation to biological agents or surgery (HR 6.3, 95%CI 1.9-20.7; P=0.002).ConclusionThis retrospective single-center study provides the first preliminary evidence that patients with UC and pseudopolyps may represent a subpopulation with a higher inflammatory burden and a greater need for treatment escalation, including to biological agents or surgery. Large, prospective multicenter studies are certainly warranted to confirm these findings.

Validation and Investigation of the Operating Characteristics of the Ulcerative Colitis Endoscopic Index of Severity

The Ulcerative Colitis Endoscopic Index of Severity (UCEIS) is a novel instrument to evaluate endoscopic disease activity. It has been demonstrated to outperform the more widely used Mayo endoscopic score (MES) in predicting long-term prognosis, including the need for colectomy. Despite its potential benefits, many clinicians still prefer to use MES because its operating characteristics are better defined and its grades are more readily applicable to clinical decision-making. The aims of our study were to quantify the UCEIS cutoff most closely associated with the need for treatment escalation and to perform a validation exercise using MES and clinical, biochemical, and histological measures of disease activity. Endoscopies performed in UC patients between November 2016 and January 2018 were retrospectively reviewed. Agreement between the UCEIS and MES was quantified using Kappa (κ) statistics. A UCEIS cutoff for treatment escalation was calculated using chi-square, receiver operating characteristic curve, and area under the curve (AUC) analyses. The Pearson correlation coefficient was used to compare linear relationships between UCEIS and clinical (Simple Clinical Colitis Activity Index [SCCAI]), biochemical (C-reactive protein [CRP]), and histological (Nancy Histological Index [NHI]) activity. Two hundred one (56%) procedures documented both UCEIS and MES, demonstrating substantial agreement (κ = 0.713; P < 0.001). Treatment was escalated after 199 (56%) procedures. Receiver operating characteristic curve analysis of need for treatment escalation showed the highest sensitivity and specificity for UCEIS ≥4 (0.80 and 0.93, respectively; AUC, 0.93). Of 170 patients with a UCEIS ≥4, treatment was escalated in 159 (94%), but not for 11 (6%). Of 185 patients with a UCEIS ≤3, 40 (22%) were escalated, whereas 145 (78%) were not (P < 0.001). UCEIS correlated strongly with NHI (0.723; P < 0.001), moderately with SCCAI (0.671; P < 0.001), and weakly with CRP (0.279; P < 0.001). A UCEIS ≥4 was significantly associated with treatment escalation. This cutoff could therefore be used to support clinical decision-making based on endoscopic findings. Strong and moderate correlations were found between UCEIS and histological and clinical disease activity, respectively, whereas a weak correlation was found with CRP.

Physician and advanced nurse practitioner decision-making in the management of multiple sclerosis

The aim of this service evaluation study was to establish the extent of concordance in decision-making between the senior attending neurologist and the advanced nurse practitioner (ANP) in neurology, regarding identification and management of 15 participants with multiple sclerosis and reporting potential new/escalating neurological symptoms via the ANP telephone support service. Results showed 100% agreement between neurologist and ANP regarding whether to manage patient concerns via telephone or in the outpatient clinic. In the patients seen in clinic, no inconsistencies were noted in neurological findings recorded by both clinicians. Diagnostic concordance was 93.4%, with 80% management concordance between the ANP and neurologist. There was 100% agreement between the ANP and neurologist regarding the need for treatment escalation. The analysis of this study suggests that diagnostic and management decision-making provided by the ANP for patients with potential relapses and/or treatment escalation is on a par with that of the neurologist, which is the traditional model of care. Our findings support the increasing role of the ANP in the active and independent care of patients with MS.

Red Blood Cell Distribution Width and Itʼs Association With Inflammatory Bowel Disease Management

BACKGROUND: Inflammatory Bowel Diseases (IBD) require close monitoring over a person's lifetime to prevent long term negative sequelae and promote better outcomes. At present, the gold standard monitoring tool is endoscopic evaluation. Several non-invasive alternatives have been evaluated, however their benefit is unclear. The data we present evaluates red blood cell distribution width (RDW) as a predictive measure of active disease prior to endoscopy and if it is a useful prognostic tool. To date, the literature has noted a relationship between a high RDW and level of activity in many chronic inflammatory diseases, including IBD. This has been attributed to both the inflammatory nature of these diseases along with the associated anemia. Lastly, the benefits of RDW lie in its non-invasive nature and that it comes readily available in a commonly ordered lab test, a complete blood count (CBC), at no additional cost. METHODS: Data on patients with IBD who had an RDW within one month prior to colonoscopy from January 1, 2015 to December 31, 2015 was pulled in a retrospective chart review. Both clinical and descriptive data were obtained for the study as well as patients' Harvey Bradshaw Indices and Mayo Scores. Endoscopic data including the Mayo Endoscopic Score, Simplified Endoscopic Scoring System, and histologic data were also noted. Each endoscopy report was reviewed by two separate Gastroenterologists. Data exclusion criteria were: patients with hemoglobinopathies, organ transplant, hemoglobin less than 7, and for patients under the age of 18. The Mann-Whitney U Test was used to compare the difference among RDW values. Correlation between continuous variables was assessed using the Spearman Correlation Test. Statistical significance for all comparisons was set at 5%. RESULTS: Sixty patients met inclusion criteria. Median age for the cohort was 35 years (SD=17.1). Evaluating other patient demographics, 46.9% of participants were males and most were Caucasian (68%). There was a relationship between RDW and need for medication escalation after endoscopy. Medication increase post-colonoscopy was more frequently noted in patients with RDWs above the normal value. There was a significant difference in RDW between patients with Ulcerative Colitis who had a change in management compared with those who did not require a change in treatment (U=18, P=0.027). Similarly, there was a significant difference in RDW value for patients with Crohn's Disease who underwent change in treatment compared with patients who did not (U=101, P=0.043). CONCLUSION(S): Based on the findings from our retrospective data collection, elevated RDW was associated with the need for escalation of treatment in patients with IBD. This relationship was present on subgroup analysis for patients with Ulcerative Colitis and with Crohn's Disease.

Effect of Early Versus Late Azathioprine Therapy in Pediatric Ulcerative Colitis.

We aimed at describing the efficacy of azathioprine (AZA) in pediatric ulcerative colitis, comparing the outcomes of early (0-6 months) versus late (6-24 months) initiation of therapy. Children with ulcerative colitis treated with AZA within 24 months of diagnosis were included. Corticosteroid (CS)-free remission and mucosal healing (MH), assessed by endoscopy or fecal calprotectin, at 12 months were the primary outcomes. Patients were also compared for CS-free remission and MH, need for treatment escalation or surgery, number of hospitalizations, and adverse events during a 24-month follow-up. A total of 121 children entered the study (median age 10.5 ± 4.0 years, 59% girls). Seventy-six (63%) started AZA between 0 and 6 months (early group) and 45 (37%) started between 6 and 24 months (late group). Seventy-five percent and 53% of patients in the early and late group, respectively, received CS at the diagnosis (P = 0.01). CS-free remission at 1 year was achieved by 30 (50%) of the early and 23 (57%) of the late patients (P = 0.54). MH occurred in 37 (37%) patients at 1 year, with no difference between the 2 groups (33% early, 42% late; P = 0.56). No difference was found for the other outcomes. Introduction of AZA within 6 months of diagnosis seems not more effective than later treatment to achieve CS-free remission in pediatric ulcerative colitis. MH does not depend on the timing of AZA initiation; however, because of the incomplete comparability of the 2 groups at the diagnosis and the use of fecal calprotectin as a surrogate marker of MH, our results should be further confirmed by prospective studies.

Confocal laser endomicroscopy: a novel method for prediction of relapse in Crohn’s disease

Confocal laser endomicroscopy (CLE) has been shown to predict relapse in ulcerative colitis in remission, but little is currently known about its role in Crohn's disease. The aim of this study was to identify reproducible CLE features in patients with Crohn's disease and to examine whether these are risk factors for relapse. This was a single-center prospective feasibility study of CLE imaging in patients with Crohn's disease. CLE imaging was performed in the terminal ileum and four colorectal sites, and was correlated with histopathology and macroscopic appearance. Clinical relapse, defined as the need for treatment escalation or surgical intervention, was recorded during follow-up. The study included 50 patients: 39 with Crohn's disease (20 in remission), and 11 controls. Ileal fluorescein leakage and microerosions were significantly more frequent in patients with endoscopically active Crohn's disease compared with patients with inactive Crohn's disease and controls (P = 0.005 and (P = 0.006, respectively). The same applied to colorectal fluorescein leakage and vascular alterations ((P = 0.043 and (P = 0.034, respectively). During a 12-month follow-up period, ileal fluorescein leakage and microerosions were significant risk factors for relapse in the subgroup of patients in remission (log rank (P = 0.009 and (P = 0.007, respectively) as well as in the entire group of patients with Crohn's disease (log rank (P = 0.006 and (P = 0.01, respectively). Inter- and intraobserver reproducibility was almost perfect (κ > 0.80) or substantial (κ > 0.60) for the majority of CLE parameters. CLE can identify reproducible microscopic changes in the terminal ileum that are risk factors for relapse in patients with otherwise inactive Crohn's disease. ClinicalTrials.gov (NCT01738529).

Efficacy of oral methotrexate in paediatric Crohn’s disease: a multicentre propensity score study

BackgroundOral methotrexate (MTX) administration avoids weekly injections, reduces costs and may improve quality of life of patients with Crohn’s disease (CD), especially children. Routes of administration have never been systematically...

Diagnosis and treatment of multiple sclerosis: MENACTRIMS consensus guidelines

With evolving diagnostic criteria and the advent of new oral and parenteral therapies for MS, most current diagnostic and treatment algorithms need re-evaluation and updating. The purpose of the revised MENACTRIMS guidelines is to provide actual recommendations and algorithms on diagnosis and treatment of MS based on scientific evidence and clinical experience. The diagnosis of MS relies on incorporating clinical and paraclinical findings to prove dissemination in space and in time, and exclude alternative diseases that can explain the findings at hand. The 2010 Mc Donald criteria are the cornerstone for diagnosis of all forms of MS. The differential diagnostic workup should be guided by clinical and laboratory red flags to avoid unnecessary tests. The guidelines include a detailed list of red flags, differential diagnoses based on presenting clinical syndromes, and appropriate laboratory tests. Appropriate multiple sclerosis (MS) therapy selection is critical to maximize patient benefit. The current guidelines review the scientific evidence supporting current therapies and provide recommendations for treatment of acute relapses, clinically isolated syndrome, relapsing remitting MS, secondary progressive MS, and primary progressive MS. Recommendations on defining suboptimal response and therefore the need for treatment escalation are provided based on current scientific evidence. A significant number of patients will fulfill criteria for suboptimal response while on treatment with first line drugs. There is currently no class I evidence supporting the choice of a second line therapy. Recommendations for escalation therapy are made based on available scientific data and personal experience. Algorithms for treatment of clinically isolated syndrome and relapsing remitting MS will be presented. With evolving diagnostic criteria and the advent of new oral and parenteral therapies for MS, most current diagnostic and treatment algorithms need re-evaluation and updating. The purpose of the revised MENACTRIMS guidelines is to provide actual recommendations and algorithms on diagnosis and treatment of MS based on scientific evidence and clinical experience. The diagnosis of MS relies on incorporating clinical and paraclinical findings to prove dissemination in space and in time, and exclude alternative diseases that can explain the findings at hand. The 2010 Mc Donald criteria are the cornerstone for diagnosis of all forms of MS. The differential diagnostic workup should be guided by clinical and laboratory red flags to avoid unnecessary tests. The guidelines include a detailed list of red flags, differential diagnoses based on presenting clinical syndromes, and appropriate laboratory tests. Appropriate multiple sclerosis (MS) therapy selection is critical to maximize patient benefit. The current guidelines review the scientific evidence supporting current therapies and provide recommendations for treatment of acute relapses, clinically isolated syndrome, relapsing remitting MS, secondary progressive MS, and primary progressive MS. Recommendations on defining suboptimal response and therefore the need for treatment escalation are provided based on current scientific evidence. A significant number of patients will fulfill criteria for suboptimal response while on treatment with first line drugs. There is currently no class I evidence supporting the choice of a second line therapy. Recommendations for escalation therapy are made based on available scientific data and personal experience. Algorithms for treatment of clinically isolated syndrome and relapsing remitting MS will be presented.

FRI0361 The use of leflunomide in a paediatric rheumatology clinic

BackgroundMethotrexate (MTX) is the anchor drug used in the treatment of juvenile idiopathic arthritis (JIA). Leflunomide (LFD) has comparable efficacy to MTX in adults with rheumatoid arthritis, and there is...

Treating rheumatoid arthritis to target: Evidence-based recommendations for enhanced disease management

The approach to managing rheumatoid arthritis (RA) is still variable. Questions or issues that frequently arise relating to the application of types and sequences of therapeutic agents as well as to the extent and frequencies of follow up examinations, types of assessments and needs for therapeutic adaptations. In light of these occasional ambiguities, recommendations for the management of rheumatoid arthritis have been recently published.1 In addition, an international expert committee elaborated a guideline document adopting a “treat to target” (T2T) approach for RA; in line with the presentation of the T2T strategy, detailed standard procedures were provided to enable its implementation into daily clinical practice by the rheumatology community.2 While the definition of quantifiable treatment targets is new to RA management, stringent therapeutic aims have already been implemented in a number of other chronic diseases: in diabetes care, aiming for an HbA1c below 7.0% is widely recognized to be the task in every counseling visit, since the achievement of this threshold is understood to drive long-term disease outcomes. Similar procedures are used in treating hypertension, hyperlipidemia, and other conditions, as opposed to the avoidance of adverse outcomes in the distant future; an absolute number that displays a level of good disease control, or, if unmet, the need for treatment escalation is well perceived by doctors and patients alike. Presumably, this facilitates shared treatment decision-making, and also encourages patients to be adherent and responsive during their chronic condition.

Treating rheumatoid arthritis to target: Evidence-based recommendations for enhanced disease management

The approach to managing rheumatoid arthritis (RA) is still ariable. Questions or issues that frequently arise relate to the pplication of types and sequences of therapeutic agents as well s to the extent and frequencies of control examinations, types of ssessments and needs for therapeutic adaptations. In light of these ccasional ambiguities, recommendations for the management of heumatoid arthritis have been recently published.1 In addition, an nternational expert committee elaborated a guidance document dopting a “treat to target” (T2T) approach for RA; in line with a espective presentation of the T2T strategy, detailed standard proedures were provided to enable the implementation into daily linical practice by the rheumatology community.2 While the definition of quantifiable treatment targets at center tage is new to RA management, stringent therapeutic aims have lready been implemented in a number of other chronic diseases: in iabetes care, aiming for an HbA1c below 7.0% is widely recognized o be the task in every counseling visit, since the achievement of this hreshold is understood to drive long-term disease outcomes. Simlar proceedings are used in treating hypertension, hyperlipidemia, nd other conditions, as opposed to the formulation of adverse utcomes to avoid in the distant future, an absolute number that isplays the level of good disease control, or, if not met indicates he need for treatment escalation, is well perceivable for doctors nd patients alike. Presumably, this facilitates shared treatment ecision-making, and also encourages patients to be adherent and esponsive during their chronic condition. The adoption of T2T for RA has been initiated by an international ask force of 20 experts in rheumatology and a patient with RA, who rst convened in 2008. As an initial step, the group assigned a sysematic literature review (SLR) to compile all published evidence n targeted treatment in RA, when compared to standard care.3 In the process of the systematic literature search, the screenng of 5881 titles and abstracts identified in electronic databases

Evaluating the Role of a Triage Electrocardiogram Protocol at an Urban Emergency Department

ObjectiveOur emergency department (ED) performs triage ECG for a variety of complaints to identify patients in need of treatment escalation. The aim of this study was to evaluate the existing triage ECG protocol as a means of treatment decision making.MethodsThis prospective observational study was conducted in an urban ED over one week. We recruited all patients aged 18 years and above with an undiagnosed complaint requiring a triage ECG based on the existing departmental protocol. As part of the protocol, an experienced emergency doctor then reviewed the ECG to determine the need for treatment escalation. Explicit data collection was performed using our electronic database. The outcome measures were proportions of triage treatment escalations, reasons for escalation and disposition status. Analysis was by descriptive statistics.Results739 patients were recruited from a total attendance of 3228. The rate of triage ECG was 23%. There were 22 (3%) triage escalations. Usually each escalation resulted from a combination of reasons. These included important ECG changes (77%), abnormal vital signs (5%) and ongoing symptoms (95%).ConclusionsThe triage ECG protocol resulted in important escalations in a small proportion of presentations. Future research is needed to refine guidelines on the use of triage ECG for different ED complaints.

Measurement of Minimal Residual Disease (MRD) after Consolidation Therapy as a Means of Early Detection of Relapse in Adult Acute Lymphoblastic Leukemia (ALL).

Outcome for patients with adult ALL after relapse is poor, even if a second remission is achieved by salvage therapy and is consolidated by an allogeneic stem cell transplantation. There is considerable evidence from studies in childhood ALL and other hematologic malignancies that administration of salvage therapy in early molecular relapse may improve prognosis. We therefore investigated the value of continuous MRD-monitoring in prospectively monitored standard risk patients of the German Multicenter ALL-studies 06/99 and 07/03 during and after maintenance treatment beyond the first year of therapy. MRD was assessed by quantitative realtime PCR using clone-specific primers for the leukemia-specific Ig/TCR gene rearrangements. MRD high risk-patients (those with MRD > 10−4 at two successive time points after induction during the first year of therapy) are candidates for early therapy escalation according to the study protocol and were thus excluded from this analysis. Of the 108 remaining patients (77 male, 31 female), 30 (28%) became MRD-positive again after a median follow-up of 18 months after the end of consolidation treatment. Of these, 17 (57%) already relapsed. When only considering patients with MRD measurable within the quantitative range of the PCR 16/19 (84%) already relapsed. Of the MRD-negative patients only 5 of 78 (6%) have relapsed after a median follow up of 23 month after end of initial therapy. After conversion to MRD positivity, the median time to relapse was 9.5 months, with a median time to relapse of only 2.5 months once the patients' MRD was within the quantitative range of the PCR assay. Taken together, these data indicate that, if done at regular intervals, MRD-monitoring allows for accurate and timely identification of patients in need for treatment escalation in the vast majority of cases and may help to avoid overtreatment for those patients who are cured by conventional chemotherapy alone.