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1.  Systematic Review and Meta-analysis of Randomized Trials of Central Nervous System Directed Therapy for Childhood Acute Lymphoblastic Leukaemia 
Pediatric blood & cancer  2012;60(2):185-195.
Treatment of the central nervous system (CNS) is an essential therapy component for childhood acute lymphoblastic leukaemia (ALL). Individual patient data from 47 trials addressing 16 CNS treatment comparisons were analyzed. Event-free survival (EFS) was similar for radiotherapy versus IT, and radiotherapy plus IT versus IVMTX plus IT. Triple intrathecal therapy (TIT) gave similar EFS but poorer survival than ITMTX, but additional IVMTX improved both outcomes. One trial resulted in similar EFS and survival with IVMTX plus ITMTX versus TIT alone. Radiotherapy can generally be replaced by IT therapy. TIT should be used with effective systemic therapy such as IVMTX.
PMCID: PMC3461084  PMID: 22693038
Leukaemia; Meta-analysis; childhood leukaemia; CNS; triple intrathecal therapy
2.  A proposal for reducing the effect of one of many causes of publication bias 
Trials  2013;14:41.
In order to avoid publication bias, all trials should be registered at initiation and their results made easily accessible. However, some trial results are more difficult to publish than others. This report describes one such trial and highlights the need for a way of making results of trials widely available even if not presented in the traditional format. Until such time as it is required by law both to register all trials and enter their final results into the database, a lack of resources will mean that some trial results are never published. The scale of the problem of non-publication is unknown and for valid trial results any form of publication is better than none. Therefore it is essential that a quick and easy way is available to act as a safety net to catch trial results that would otherwise be lost.
PMCID: PMC3598957  PMID: 23402474
Publication bias; Randomized trial; Polycythaemia; Busulphan; Radioactive phosphorous; Venesection
3.  Outcomes after Induction Failure in Childhood Acute Lymphoblastic Leukemia 
The New England Journal of Medicine  2012;366(15):1371-1381.
Failure of remission-induction therapy is a rare but highly adverse event in children and adolescents with acute lymphoblastic leukemia (ALL).
We identified induction failure, defined by the persistence of leukemic blasts in blood, bone marrow, or any extramedullary site after 4 to 6 weeks of remission-induction therapy, in 1041 of 44,017 patients (2.4%) 0 to 18 years of age with newly diagnosed ALL who were treated by a total of 14 cooperative study groups between 1985 and 2000. We analyzed the relationships among disease characteristics, treatments administered, and outcomes in these patients.
Patients with induction failure frequently presented with high-risk features, including older age, high leukocyte count, leukemia with a T-cell phenotype, the Philadelphia chromosome, and 11q23 rearrangement. With a median follow-up period of 8.3 years (range, 1.5 to 22.1), the 10-year survival rate (±SE) was estimated at only 32±1%. An age of 10 years or older, T-cell leukemia, the presence of an 11q23 rearrangement, and 25% or more blasts in the bone marrow at the end of induction therapy were associated with a particularly poor outcome. High hyperdiploidy (a modal chromosome number >50) and an age of 1 to 5 years were associated with a favorable outcome in patients with precursor B-cell leukemia. Allogeneic stem-cell transplantation from matched, related donors was associated with improved outcomes in T-cell leukemia. Children younger than 6 years of age with precursor B-cell leukemia and no adverse genetic features had a 10-year survival rate of 72±5% when treated with chemotherapy only.
Pediatric ALL with induction failure is highly heterogeneous. Patients who have T-cell leukemia appear to have a better outcome with allogeneic stem-cell transplantation than with chemotherapy, whereas patients who have precursor B-cell leukemia without other adverse features appear to have a better outcome with chemotherapy. (Funded by Deutsche Krebshilfe and others.)
PMCID: PMC3374496  PMID: 22494120
4.  Variation in CDKN2A at 9p21.3 influences childhood acute lymphoblastic leukemia risk 
Nature genetics  2010;42(6):492-494.
Using data from a genome-wide association study of 907 individuals with childhood acute lymphoblastic leukemia (cases) and 2,398 controls and with validation in samples totaling 2,386 cases and 2,419 controls, we have shown that common variation at 9p21.3 (rs3731217, intron 1 of CDKN2A) influences acute lymphoblastic leukemia risk (odds ratio = 0.71, P = 3.01 × 10−11), irrespective of cell lineage.
PMCID: PMC3434228  PMID: 20453839
5.  How to Catch All Those Mutations—The Report of the Third Human Variome Project Meeting, UNESCO Paris, May 2010 
Human mutation  2010;31(12):1374-1381.
The third Human Variome Project (HVP) Meeting “Integration and Implementation” was held under UNESCO Patronage in Paris, France, at the UNESCO Headquarters May 10–14, 2010. The major aims of the HVP are the collection, curation, and distribution of all human genetic variation affecting health. The HVP has drawn together disparate groups, by country, gene of interest, and expertise, who are working for the common good with the shared goal of pushing the boundaries of the human variome and collaborating to avoid unnecessary duplication. The meeting addressed the 12 key areas that form the current framework of HVP activities: Ethics; Nomenclature and Standards; Publication, Credit and Incentives; Data Collection from Clinics; Overall Data Integration and Access—Peripheral Systems/Software; Data Collection from Laboratories; Assessment of Pathogenicity; Country Specific Collection; Translation to Healthcare and Personalized Medicine; Data Transfer, Databasing, and Curation; Overall Data Integration and Access—Central Systems; and Funding Mechanisms and Sustainability. In addition, three societies that support the goals and the mission of HVP also held their own Workshops with the view to advance disease-specific variation data collection and utilization: the International Society for Gastrointestinal Hereditary Tumours, the Micronutrient Genomics Project, and the Neurogenetics Consortium.
PMCID: PMC3119486  PMID: 20960468
mutation; variation; genomics; genetic disease
6.  Meta-analysis of randomized trials comparing thiopurines in childhood acute lymphoblastic leukaemia 
Leukemia  2011;25(6):953-959.
Mercaptopurine has been used in continuing treatment for childhood acute lymphoblastic leukaemia since the mid 1950s. Recent advances in the understanding of thiopurine pharmacology indicated thioguanine might be more effective than mercaptopurine. The US and UK cooperative groups began randomized thiopurine trials and agreed prospectively to a meta-analysis. All randomized trials of thioguanine versus mercaptopurine were sought and data on individual patients were analysed by standard methods. Combining three trials (from US, UK and Germany), the overall event free survival (EFS) was not significantly improved with thioguanine (Odds ratio (OR) = 0.89; 95% confidence interval 0·78–1·03). Apparent differences in results between trials may be partly explained by the different types of patients studied. The larger treatment effect reported in males in the US trial was confirmed in the other trials. There was heterogeneity between sex/age subgroups (p=0·001), with significant EFS benefit of thioguanine only seen for males aged under 10 years old (OR=0·70; 0·58–0·84), although this did not result in a significant difference in overall survival (OR=0·83; 0·62–1·10). Additional toxicity occurs with thioguanine. Mercaptopurine remains the standard thiopurine of choice, but further study of thioguanine may be warranted to determine whether it may benefit particular subgroups.
PMCID: PMC3112460  PMID: 21372841
Thiopurine; mercaptopurine; thioguanine; leukaemia; childhood; systematic review
7.  The impact of therapy for childhood acute lymphoblastic leukaemia on intelligence quotients; results of the risk-stratified randomized central nervous system treatment trial MRC UKALL XI 
The MRC UKALLXI trial tested the efficacy of different central nervous system (CNS) directed therapies in childhood acute lymphoblastic leukaemia (ALL). To evaluate morbidity 555/1826 randomised children underwent prospective psychological evaluations. Full Scale, verbal and performance IQs were measured at 5 months, 3 years and 5 years. Scores were compared in; (1) all patients (n = 555) versus related controls (n = 311), (2) low-risk children (presenting white cell count (WCC) < 50 × 109/l) randomised to intrathecal methotrexate (n = 197) versus intrathecal and high-dose intravenous methotrexate (HDM) (n = 202), and (3) high-risk children (WCC ≥ 50 × 109/l, age ≥ 2 years) randomised to HDM (n = 79) versus cranial irradiation (n = 77).
There were no significant differences in IQ scores between the treatment arms in either low- or high-risk groups. Despite similar scores at baseline, results at 3 and 5 years showed a significant reduction of between 3.6 and 7.3 points in all three IQ scores in all patient groups compared to controls (P < 0.002) with a higher proportion of children with IQs < 80 in the patient groups (13% vs. 5% at 3 years p = 0.003).
Children with ALL are at risk of CNS morbidity, regardless of the mode of CNS-directed therapy. Further work needs to identify individuals at high-risk of adverse CNS outcomes.
Trial registration
PMCID: PMC3219592  PMID: 21996369
acute lymphoblastic leukaemia; IQ; central nervous system; morbidity; cranial radiotherapy; methotrexate; neuropsychometric; paediatric
8.  Prognostic Implications of NOTCH1 and FBXW7 Mutations in Adults With T-Cell Acute Lymphoblastic Leukemia Treated on the MRC UKALLXII/ECOG E2993 Protocol 
Journal of Clinical Oncology  2009;27(26):4352-4356.
Notch pathway activation by mutations in either NOTCH1 and/or FBXW7 is one of the most common molecular events in T-cell acute lymphoblastic leukemia (T-ALL) and, in pediatric disease, predicts for favorable outcome. Their prognostic significance in adult T-ALL is unclear. We sought to evaluate the outcome according to mutation status of patients with adult T-ALL treated on the United Kingdom Acute Lymphoblastic Leukaemia XII (UKALLXII)/Eastern Cooperative Oncology Group (ECOG) E2993 protocol.
NOTCH1 and FBXW7 were screened by a combination of denaturing high-performance liquid chromatography and sequencing in 88 adult patients with T-ALL treated on the UKALLXII/ECOG E2993 protocol and compared with clinical characteristics and outcome.
NOTCH1 and FBXW7 mutations were common (60% and 18%, respectively) and were not associated with age or WBC count. NOTCH1 heterodimerization domain mutations were associated with FBXW7 mutations (P = .02), and NOTCH1 proline, glutamic acid, serine, threonine (PEST) rich domain and FBXW7 mutations were mutually exclusive. There were an equal number of high- and standard-risk patients in the NOTCH1 and FBXW7 mutated (MUT) groups. Patients wild type (WT) for both markers trended toward poorer event-free survival (EFS; MUT v WT, 51% v 27%, P = .10; hazard ratio, 0.6). Analysis by each marker individually was not significantly predictive of outcome (NOTCH1 MUT v WT, EFS 49% v 34%, P = .20; FBXW7 MUT v WT, EFS 53% v 41%, P.72).
NOTCH1 and FBXW7 mutant-positive patients do not fare sufficiently well to warrant an individualized treatment approach in future studies.
PMCID: PMC2744275  PMID: 19635999
9.  Temporal changes in incidence and pattern of central nervous system relapses in children with acute lymphoblastic leukaemia treated on four consecutive Medical Research Council Trials, 1985–2001 
Leukemia  2009;24(2):450-459.
Despite the success of contemporary treatment protocols in childhood acute lymphoblastic leukaemia (ALL), relapse within the central nervous system (CNS) remains a challenge. To better understand this phenomenon, we have analysed the changes in incidence and pattern of CNS relapses in 5564 children enrolled on four successive MRC-ALL trials between 1985 and 2001. Changes in the incidence and pattern of CNS relapses were examined and the relationship with patient characteristics assessed. Factors affecting post-relapse outcome were determined. Overall, relapses declined by 49%. Decreases occurred primarily in non-CNS and combined relapses with a progressive shift towards later (≥30 months from diagnosis) relapses (p<0·0001). Although isolated CNS relapses declined, the proportional incidence and timing of relapse remained unchanged. Age and presenting white cell count were risk factors for CNS relapse. On multivariate analysis, the time to relapse and the trial period influenced post-relapse outcomes. Relapse trends differed within biological subtypes. In ETV6-RUNX1 ALL, relapse patterns mirrored overall trends while in High Hyperdiploidy ALL, these appear to have plateaued over the latter two trial periods. Intensive systemic and intrathecal chemotherapy have decreased the overall CNS relapse rates and changed the patterns of recurrence. The heterogeneity of therapeutic response in the biological subtypes suggests room for further optimisation using currently available chemotherapy.
PMCID: PMC2820451  PMID: 20016529
childhood acute lymphoblastic leukemia; relapse; CNS; UK
10.  Long-term follow-up of the United Kingdom Medical Research Council protocols for childhood acute Lymphoblastic leukaemia, 1980–2001 
Leukemia  2009;24(2):406-418.
Between 1980 and 2001, the United Kingdom Medical Research Council Childhood Leukemia Working Party has conducted 4 clinical trial in acute lymphoblastic leukemia, which have recruited a total of 6516 patients. UKALL VIII examined the role of daunorubicin in induction chemotherapy, and UKALL X examined the role of post-induction intensification. Both resulted in major improvement in the outcomes. UKALL XI examined the efficacy of different methods of CNS-directed therapy and the effects of an additional intensification. ALL97, which was initially based on the UKALL X D template (two intensification phases), examined the role of different steroids in induction and different thiopurines through continuing chemotherapy. A reappraisal of results from UKALL XI compared to other cooperative group results led to a redesign in 1999, which subsequently resulted in a major improvement in outcomes. Additionally, ALL97 and 97/99 demonstrated a significant advantage for the use of dexamethasone rather than prednisolone; although the use of 6-thioguanine resulted in fewer relapses, this advantage was offset by an increased incidence of deaths in remission. Over the era encompassed by these four trials there has been a major improvement in both event-free and overall survival for children in the UK with ALL.
PMCID: PMC2820452  PMID: 20010621
acute leukemia; therapy; clinical trial

Results 1-10 (10)