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PURPOSE A dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine and prednisone plus rituximab (DA-EPOCH-R) regimen has been shown to deliver excellent survival for adults with primary mediastinal large B-cell lymphoma (PMLBL) without the use of radiotherapy. No international prospective evaluation of this regimen has previously been reported in children and adolescents. PATIENTS AND METHODS We conducted an international single-arm phase II trial involving patients younger than age 18 years with PMLBL who were to receive six courses of DA-EPOCH-R. The primary end point was event-free survival (EFS). Overall survival and toxicity were also assessed. This trial was registered (ClinicalTrials.gov identifier: NCT01516567 ). RESULTS Analyses were based on 46 patients. The median age was 15.4 years (interquartile range: 14-16 years). The median follow-up was 59.0 months (interquartile range: 52.6-69.2 months). Fourteen events were observed (eight relapses or progressions (including three parenchymal CNS relapses), four residual lymphoma, and two second malignancies). The 4-year EFS was 69.6% (95% CI, 55.2 to 80.9), which did not differ from the rate observed historically ( P = .59). Seven deaths occurred (six disease-related and one second malignancy). The overall survival was 84.8% (95% CI, 71.8 to 92.4). Twenty-two patients (48%) reached dose levels ≥ 4. Nonhematologic adverse events grade ≥ 3 or cardiac adverse events grade ≥ 2 occurred in 47 of 276 (17%) courses and 30 of 46 patients (65%). CONCLUSION DA-EPOCH-R did not improve the EFS compared with a historical control in this first prospective multisite international study of children and adolescents with PMLBL. Further studies are required to determine the optimum therapy for children and adolescents with this lymphoma.

PURPOSE Reduced-intensity conditioning (RIC) regimens have extended the curative potential of allogeneic stem-cell transplantation to older adults with high-risk acute myeloid leukemia (AML) and myelodysplasia (MDS) but are associated with a high risk of disease relapse. Strategies to reduce recurrence are urgently required. Registry data have demonstrated improved outcomes using a sequential transplant regimen, fludarabine/amsacrine/cytarabine-busulphan (FLAMSA-Bu), but the impact of this intensified conditioning regimen has not been studied in randomized trials. PATIENTS AND METHODS Two hundred forty-four patients (median age, 59 years) with high-risk AML (n = 164) or MDS (n = 80) were randomly assigned 1:1 to a fludarabine-based RIC regimen or FLAMSA-Bu. Pretransplant measurable residual disease (MRD) was monitored by flow cytometry (MFC-MRD) and correlated with outcome. RESULTS There was no difference in 2-year overall survival (hazard ratio 1.05 [85% CI, 0.80 to 1.38] P = .81) or cumulative incidence of relapse (CIR) (hazard ratio 0.94 [95%CI, 0.60 to 1.46] P = .81) between the control and FLAMSA-Bu arms. Detectable pretransplant MFC-MRD was associated with an increased CIR (2-year CIR 41.0% v 20.0%, P = .01) in the overall trial cohort with a comparable prognostic impact when measured by an unsupervised analysis approach. There was no evidence of interaction between MRD status and conditioning regimen intensity for relapse or survival. Acquisition of full donor T-cell chimerism at 3 months abrogated the adverse impact of pretransplant MRD on CIR and overall survival. CONCLUSION The intensified RIC conditioning regimen, FLAMSA-Bu, did not improve outcomes in adults transplanted for high-risk AML or MDS regardless of pretransplant MRD status. Our data instead support the exploration of interventions with the ability to accelerate acquisition of full donor T-cell chimerism as a tractable strategy to improve outcomes in patients allografted for AML.

The objective of this phase IIa, open-label, single-centre, single-arm, two-stage clinical trial was to evaluate the safety and activity of 177-lutetium DOTATATE (LuDO) molecular radiotherapy in neuroblastoma. Children with relapsed or refractory metastatic high-risk neuroblastoma were treated with up to four courses of LuDO. The administered activity was 75 to 100 MBq kg−1 per course, spaced at 8- to 12-week intervals. Outcomes were assessed by the International Neuroblastoma Response Criteria (primary outcome), progression-free survival (PFS), and overall survival (OS). The trial recruited 21 patients; eight received the planned four courses. There was dose-limiting haematologic toxicity in one case, but no other significant haematologic or renal toxicities. None of 14 evaluable patients had an objective response at 1 month after completion of treatment (Wilson 90% CI 0.0, 0.16; and 95% CI is 0.0, 0.22). The trial did not therefore proceed to the second stage. The median PFS was 2.96 months (95% CI 1.71, 7.66), and the median OS was 13.0 months (95% CI 2.99, 21.52). In the absence of any objective responses, the use of LuDO as a single agent at the dose schedule used in this study is not recommended for the treatment of neuroblastoma. There are several reasons why this treatment schedule may not have resulted in objective responses, and as other studies do show benefit, the treatment should not be regarded as being of no value. Further trials designed to overcome this schedule’s limitations are required. ISRCTN98918118; URL: https://www.isrctn.com/search?q=98918118

PURPOSE The VIT-0910 trial was conducted to evaluate efficacy and safety of the vincristine-irinotecan combination with and without temozolomide (VIT and VI, respectively) in relapsed or refractory rhabdomyosarcoma (RMS). METHODS In this randomized European phase II trial, patients age 0.5-50 years received 21-day cycles combining vincristine (1.5 mg/m2 once a day on day 1 and day 8) and irinotecan (50 mg/m2 once a day from day 1 to day 5) with and without temozolomide (125 mg/m2 once a day from day 1 to day 5 and 150 mg/m2 once a day from cycle 2), until progression or unacceptable toxicity. The primary end point was objective response rate after two cycles. Secondary end points included best response, progression-free survival, overall survival, and adverse events. A Simon 2-stage design was initially planned to separately analyze 40 patients/arm. After amendment, the trial sample size was increased to 120 and a comparison between arms, adjusted for confounding factors, was added to the statistical plan (ClinicalTrials.gov, NCT01355445 ). RESULTS Overall, 120 patients (60 per arm) were recruited in 37 European centers. The median age was 11 years (range, 0.75-45); 89% of patients had a relapsed RMS. The objective response rate was 44% (24 of 55 evaluable patients) for VIT versus 31% (18 of 58) for VI (adjusted odds ratio, 0.50; 95% CI, 0.22 to 1.12; P = .09). The VIT arm achieved significantly better overall survival (adjusted hazard ratio, 0.55; 95% CI, 0.35 to 0.84; P = .006) compared with VI, with consistent progression-free survival results (adj-hazard ratio, 0.68; 95% CI, 0.46 to 1.01; P = .059). Overall, patients experienced adverse events ≥ grade 3 more frequently with VIT than VI (98% v 78%, respectively; P = .009), including a significant excess of hematologic toxicity (81% v 61%; P = .025). CONCLUSION The addition of temozolomide to VI improved chemotherapy efficacy for patients with relapsed RMS, with manageable increase in toxicity. VIT is considered the new standard treatment in these patients in the European paediatric Soft Tissue Sarcoma Group and will be the control arm in the next randomized trial.

Intelligibility of speech is a key outcome in speech and language therapy (SLT) and research. SLT students frequently participate as raters of intelligibility but we lack information about whether they rate intelligibility in the same way as the general public. This paper aims to determine if there is a difference in the intelligibility ratings made by SLT students (trained in speech related topics) compared to individuals from the general public (untrained). The SLT students were in year 2 of a BSc programme or the first 6 months of a MSc programme. We recorded 10 speakers with Parkinson’s disease (PD) related speech reading aloud the words and sentences from the Assessment of Intelligibility of Dysarthric Speech. These speech recordings were rated for intelligibility by ‘trained’ raters and ‘untrained’ raters. The effort required to understand the speech was also reported. There were no significant differences in the measures of intelligibility from the trained and untrained raters for words or sentences after adjusting for speaker by including them as a covariate in the model. There was a slight increase in effort reported by the untrained raters for the sentences. This difference in reported effort was not evident with the words. SLT students can be recruited alongside individuals from the general public as naïve raters for evaluating intelligibility in people with speech disorders.

Background FMS-like tyrosine kinase 3 (FLT3) is the most frequent mutation in AML. With two FLT3 inhibitors recently approved by the FDA (midostaurin and gilteritinib), there is a need to evaluate these targeted agents. Purpose To assess the clinical effectiveness of FLT3 inhibitors in AML patients. Methods Standard systematic review methods were utilised. Searches were conducted to July 2020 for completed and in-progress randomised controlled trials of FLT3 inhibitors in AML. A fixed-effect meta-analysis was undertaken. Results Eight completed trials involving 2656 patients and assessing five different FLT3 inhibitors (sorafenib, lestaurtinib, midostaurin, gilteritinib and quizartinib) were included. The pooled results were as follows (FLT3 inhibitor/control): overall survival hazard ratio (HR) = 0.83 (95% confidence interval [CI] 0.75 to 0.92, p = 0.0005), event-free survival HR = 0.85 (95% CI 0.77 to 0.94, p = 0.002), relapse-free survival HR = 0.76 (95% CI 0.64 to 0.90, p = 0.001), complete remission relative risk (RR) = 1.11 (95% CI 1.00 to 1.22. p = 0.05) and 60-day mortality RR = 1.04 (95% CI 0.77 to 1.40, p = 0.79). Relative risk of grade 3 and above vascular, dermatological, respiratory and hepatobiliary adverse events were found to be statistically significantly higher in the FLT3 inhibitor group compared to control, but the actual numbers of events were relatively small. Nineteen ongoing trials are still in progress, only one of which specifically targets older patients with AML. Conclusions There is evidence to support the use of FLT3 inhibitors in patients with AML, but more data is needed to verify the optimum use of the drugs regarding type of inhibitor, disease stage and patient characteristics, not only in relation to disease control, but adverse events and quality of life. There are a large number of ongoing trials; therefore, the results of this review are not a fait accompli; thus, is it recommended that the review be updated in a couple of years’ time. Given the challenges in extracting the complete data set required to assess clinical effectiveness, it is highly recommended that ongoing and future trials improve transparency and consistency of reporting of all trial outcomes, particularly disease control and adverse events, to enable a global clinical effectiveness assessment. Systematic review registration PROSPERO CRD42017055581

[Background] Although there have been multiple randomised trials in newly diagnosed Ewing sarcoma family of tumours (ESFT) and these have been conducted over many years and involved many international cooperative groups, the outcomes for all stages of disease have plateaued. Internationally, the standard treatment of ESFT is not defined, and there is a need to add new agents other than conventional chemotherapy to improve outcomes. This trial will compare two different induction/consolidation chemotherapy regimens: (1) vincristine, ifosfamide, doxorubicin and etoposide (VIDE) induction and vincristine, actinomycin D, ifosfamide or cyclophosphamide, or busulfan and mephalan (VAI/VAC/BuMel) consolidation and (2) vincristine, doxorubicin, cyclophosphamide, ifosfamide and etoposide (VDC/IE) induction and ifosfamide and etoposide, vincristine and cyclophosphamide, vincristine, actinomycin D and ifosfamide, or busulfan and mephalan (IE/VC/VAI/BuMel) consolidation (randomisation 1, or R1). A second randomisation (R2) will determine whether the addition of zoledronic acid to consolidation chemotherapy, as assigned at R1, is associated with improved clinical outcome., [Methods] EURO EWING 2012 is an international, multicentre, phase III, open-label randomised controlled trial. There are two randomisations: R1 and R2. Patients are randomly assigned at two different time points: at entry to the trial (R1) and following local control therapy (R2). The primary outcome measure is event-free survival. The secondary outcome measures include overall survival, adverse events and toxicity, histological response of the primary tumour, response of the primary tumour, regional lymph nodes or metastases (or both), and achievement of local control at the end of treatment., [Discussion] This study will establish which is the “standard regimen” of chemotherapy, taking into account both clinical outcomes and toxicity. This will form the chemotherapy backbone for future interventional studies where we may want to add new targeted agents. It will also determine the role of zoledronic acid in conjunction with the separate EE2008 trial. Any trial in ESFT needs to take into account the rarity of the tumour and consider that international cooperation is needed to provide answers in a timely manner., [Trial registration] Registered with EudraCT number 2012-002107-17 on 26 February 2012. Registered with ISRCTN number 92192408 on 4 November 2013., This project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement n°602856. The NCC in France, CLB, receives additional funding from SFCE and Ligue contre le cancer. The coordinating sponsor (the University of Birmingham, Birmingham, UK) is funded by Cancer Research UK (grant award reference C5952/A14745).

Purpose: Azacitidine (AZA) is a novel therapeutic option in older patients with acute myeloid leukemia (AML), but its rational utilization is compromised by the fact that neither the determinants of clinical response nor its mechanism of action are defined. Co-administration of histone deacetylase inhibitors, such as vorinostat (VOR), is reported to improve the clinical activity of AZA, but this has not been prospectively studied in patients with AML. Experimental Design: We compared outcomes in 259 adults with AML (n = 217) and MDS (n = 42) randomized to receive either AZA monotherapy (75 mg/m2 × 7 days every 28 days) or AZA combined with VOR 300 mg twice a day on days 3 to 9 orally. Next-generation sequencing was performed in 250 patients on 41 genes commonly mutated in AML. Serial immunophenotyping of progenitor cells was performed in 47 patients. Results: Co-administration of VOR did not increase the overall response rate (P = 0.84) or overall survival (OS; P = 0.32). Specifically, no benefit was identified in either de novo or relapsed AML. Mutations in the genes CDKN2A (P = 0.0001), IDH1 (P = 0.004), and TP53 (P = 0.003) were associated with reduced OS. Lymphoid multipotential progenitor populations were greatly expanded at diagnosis and although reduced in size in responding patients remained detectable throughout treatment. Conclusions: This study demonstrates no benefit of concurrent administration of VOR with AZA but identifies a mutational signature predictive of outcome after AZA-based therapy. The correlation between heterozygous loss of function CDKN2A mutations and decreased OS implicates induction of cell-cycle arrest as a mechanism by which AZA exerts its clinical activity. Clin Cancer Res; 23(21); 6430–40. ©2017 AACR.

Neuroblastoma may be treated with molecular radiotherapy, 131I meta-Iodobenzylguanidine and 177Lu Lutetium DOTATATE, directed at distinct molecular targets: Noradrenaline Transporter Molecule (NAT) and Somatostatin Receptor (SSTR2), respectively. This study used immunohistochemistry to evaluate target expression in archival neuroblastoma tissue, to determine whether it might facilitate clinical use of molecular radiotherapy. Tissue bank samples of formalin fixed paraffin embedded neuroblastoma tissue from patients for whom clinical outcome data were available were sectioned and stained with haematoxylin and eosin, and monoclonal antibodies directed against NAT and SSTR2. Sections were examined blinded to clinical information and scored for the percentage and intensity of tumour cells stained. These data were analysed in conjunction with clinical data. Tissue from 75 patients was examined. Target expression scores varied widely between patients: NAT median 45%, inter-quartile range 25% - 65%; and SSTR2 median 55%, interquartile range 30% – 80%; and in some cases heterogeneity of expression between different parts of a tumour was observed. A weak positive correlation was observed between the expression scores of the different targets: correlation coefficient = 0.23, p = 0.05. MYCN amplified tumours had lower SSTR2 scores: mean difference 23% confidence interval 8% - 39%, p

Disease relapse is the major cause of treatment failure after allogeneic stem cell transplantation (allo-SCT) in acute myeloid leukemia (AML). To identify AML-associated genes prognostic of AML relapse post–allo-SCT, we resequenced 35 genes in 113 adults at diagnosis, 49 of whom relapsed. Two hundred sixty-two mutations were detected in 102/113 (90%) patients. An increased risk of relapse was observed in patients with mutations in WT1 (P = .018), DNMT3A (P = .045), FLT3 ITD (P = .071), and TP53 (P = .06), whereas mutations in IDH1 were associated with a reduced risk of disease relapse (P = .018). In 29 patients, we additionally compared mutational profiles in bone marrow at diagnosis and relapse to study changes in clonal structure at relapse. In 13/29 patients, mutational profiles altered at relapse. In 9 patients, mutations present at relapse were not detected at diagnosis. In 15 patients, additional available pre–allo-SCT samples demonstrated that mutations identified posttransplant but not at diagnosis were detectable immediately prior to transplant in 2 of 15 patients. Taken together, these observations, if confirmed in larger studies, have the potential to inform the design of novel strategies to reduce posttransplant relapse highlighting the potential importance of post–allo-SCT interventions with a broad antitumor specificity in contrast to targeted therapies based on mutational profile at diagnosis.

Summary Background The INTERVAL trial showed that, over a 2-year period, inter-donation intervals for whole blood donation can be safely reduced to meet blood shortages. We extended the INTERVAL trial for a further 2 years to evaluate the longer-term risks and benefits of varying inter-donation intervals, and to compare routine versus more intensive reminders to help donors keep appointments. Methods The INTERVAL trial was a parallel group, pragmatic, randomised trial that recruited blood donors aged 18 years or older from 25 static donor centres of NHS Blood and Transplant across England, UK. Here we report on the prespecified analyses after 4 years of follow-up. Participants were whole blood donors who agreed to continue trial participation on their originally allocated inter-donation intervals (men: 12, 10, and 8 weeks; women: 16, 14, and 12 weeks). They were further block-randomised (1:1) to routine versus more intensive reminders using computer-generated random sequences. The prespecified primary outcome was units of blood collected per year analysed in the intention-to-treat population. Secondary outcomes related to safety were quality of life, self-reported symptoms potentially related to donation, haemoglobin and ferritin concentrations, and deferrals because of low haemoglobin and other factors. This trial is registered with ISRCTN, number ISRCTN24760606, and has completed. Findings Between Oct 19, 2014, and May 3, 2016, 20 757 of the 38 035 invited blood donors (10 843 [58%] men, 9914 [51%] women) participated in the extension study. 10 378 (50%) were randomly assigned to routine reminders and 10 379 (50%) were randomly assigned to more intensive reminders. Median follow-up was 1·1 years (IQR 0·7–1·3). Compared with routine reminders, more intensive reminders increased blood collection by a mean of 0·11 units per year (95% CI 0·04–0·17; p=0·0003) in men and 0·06 units per year (0·01–0·11; p=0·0094) in women. During the extension study, each week shorter inter-donation interval increased blood collection by a mean of 0·23 units per year (0·21–0·25) in men and 0·14 units per year (0·12–0·15) in women (both p0.0001 for tests of linear trend by inter-donation intervals) other than a higher reported frequency of doctor-diagnosed low iron concentrations and prescription of iron supplements in men (p

Background:\ud The ASTRAL trial showed no difference in clinical outcomes between medical therapy and revascularization for atherosclerotic renal vascular disease (ARVD). Here we report a sub-study using echocardiography to assess differences in cardiac structure and function at 12 months.\ud \ud Methods:\ud ASTRAL patients from 7 participating centres underwent echocardiography at baseline and 12 months after randomisation. Changes in left ventricular ejection fraction (LVEF), left ventricular mass (LVM), left atrial diameter (LAD), aortic root diameter (AoRD), E:A, and E deceleration time (EDT) were compared between study arms. Analyses were performed using t-tests and multivariate linear regression.\ud \ud Results:\ud Ninety two patients were included (50 medical versus 42 revascularization). There was no difference between arms in any baseline echocardiographic parameter. Comparisons of longitudinal changes in echocardiographic measurements were: δLVEF medical 0.8 ± 8.7% versus revascularization − 2.8 ± 6.8% (p = 0.05), δLVM − 2.9 ± 33 versus − 1.7 ± 39 g (p = 0.9), δLAD 0.1 ± 0.4 versus 0.01 ± 0.5 cm (p = 0.3), δAoRD 0.002 ± 0.3 versus 0.06 ± 0.3 cm (p = 0.4), δE:A − 0.0005 ± 0.6 versus 0.03 ± 0.7 (p = 0.8), δEDT − 1.1 ± 55.5 versus − 9.0 ± 70.2 ms (p = 0.6). In multivariate models, there were no differences between treatment groups for any parameter at 12 months. Likewise, change in blood pressure did not differ between arms (mean δsystolic blood pressure medical 0 mmHg [range − 56 to + 54], revascularization − 3 mmHg [− 61 to + 59], p = 0.60).\ud \ud Conclusions:\ud This sub-study did not show any significant differences in cardiac structure and function accompanying renal revascularization in ASTRAL. Limitations include the small sample size, the relative insensitivity of echocardiography, and the fact that a large proportion of ASTRAL patient population had only modest renal artery stenosis as described in the main study.

Objective To determine whether extending initial prednisolone treatment from eight to 16 weeks in children with idiopathic steroid sensitive nephrotic syndrome improves the pattern of disease relapse. Design Double blind, parallel group, phase III randomised placebo controlled trial, including a cost effectiveness analysis. Setting 125 UK National Health Service district general hospitals and tertiary paediatric nephrology centres. Participants 237 children aged 1-14 years with a first episode of steroid sensitive nephrotic syndrome. Interventions Children were randomised to receive an extended 16 week course of prednisolone (total dose 3150 mg/m 2 ) or a standard eight week course of prednisolone (total dose 2240 mg/m 2 ). The drug was supplied as 5 mg tablets alongside matching placebo so that participants in both groups received the same number of tablets at any time point in the study. A minimisation algorithm ensured balanced treatment allocation by ethnicity (South Asian, white, or other) and age (5 years or less, 6 years or more). Main outcome measures The primary outcome measure was time to first relapse over a minimum follow-up of 24 months. Secondary outcome measures were relapse rate, incidence of frequently relapsing nephrotic syndrome and steroid dependent nephrotic syndrome, use of alternative immunosuppressive treatment, rates of adverse events, behavioural change using the Achenbach child behaviour checklist, quality adjusted life years, and cost effectiveness from a healthcare perspective. Analysis was by intention to treat. Results No significant difference was found in time to first relapse (hazard ratio 0.87, 95% confidence interval 0.65 to 1.17, log rank P=0.28) or in the incidence of frequently relapsing nephrotic syndrome (extended course 60/114 (53%) v standard course 55/109 (50%), P=0.75), steroid dependent nephrotic syndrome (48/114 (42%) v 48/109 (44%), P=0.77), or requirement for alternative immunosuppressive treatment (62/114 (54%) v 61/109 (56%), P=0.81). Total prednisolone dose after completion of the trial drug was 6674 mg for the extended course versus 5475 mg for the standard course (P=0.07). There were no statistically significant differences in serious adverse event rates (extended course 19/114 (17%) v standard course 27/109 (25%), P=0.13) or adverse event rates, with the exception of behaviour, which was poorer in the standard course group. Scores on the Achenbach child behaviour checklist did not, however, differ. Extended course treatment was associated with a mean increase in generic quality of life (0.0162 additional quality adjusted life years, 95% confidence interval −0.005 to 0.037) and cost savings (difference −£1673 ($2160; €1930), 95% confidence interval −£3455 to £109). Conclusions Clinical outcomes did not improve when the initial course of prednisolone treatment was extended from eight to 16 weeks in UK children with steroid sensitive nephrotic syndrome. However, evidence was found of a short term health economic benefit through reduced resource use and increased quality of life. Trial registration ISRCTN16645249; EudraCT 2010-022489-29.

BackgroundThe optimal corticosteroid regimen for treating the presenting episode of steroid-sensitive nephrotic syndrome (SSNS) remains uncertain. Most UK centres use an 8-week regimen, despite previous systematic reviews indicating that longer regimens reduce the risk of relapse and frequently relapsing nephrotic syndrome (FRNS).ObjectivesThe primary objective was to determine whether or not an extended 16-week course of prednisolone increases the time to first relapse. The secondary objectives were to compare the relapse rate, FRNS and steroid-dependent nephrotic syndrome (SDNS) rates, requirement for alternative immunosuppressive agents and corticosteroid-related adverse events (AEs), including adverse behaviour and costs.DesignRandomised double-blind parallel-group placebo-controlled trial, including a cost-effectiveness analysis.SettingOne hundred and twenty-five UK paediatric departments.ParticipantsTwo hundred and thirty-seven children presenting with a first episode of SSNS. Participants aged between 1 and 15 years were randomised (1 : 1) according to a minimisation algorithm to ensure balance of ethnicity (South Asian, white or other) and age (≤ 5 or ≥ 6 years).InterventionsThe control group (n = 118) received standard course (SC) prednisolone therapy: 60 mg/m2/day of prednisolone in weeks 1–4, 40 mg/m2of prednisolone on alternate days in weeks 5–8 and matching placebo on alternate days in weeks 9–18 (total 2240 mg/m2). The intervention group (n = 119) received extended course (EC) prednisolone therapy: 60 mg/m2/day of prednisolone in weeks 1–4; started at 60 mg/m2of prednisolone on alternate days in weeks 5–16, tapering by 10 mg/m2every 2 weeks (total 3150 mg/m2).Main outcome measuresThe primary outcome measure was time to first relapse [Albustix®(Siemens Healthcare Limited, Frimley, UK)-positive proteinuria +++ or greater for 3 consecutive days or the presence of generalised oedema plus +++ proteinuria]. The secondary outcome measures were relapse rate, incidence of FRNS and SDNS, other immunosuppressive therapy use, rates of serious adverse events (SAEs) and AEs and the incidence of behavioural change [using Achenbach Child Behaviour Checklist (ACBC)]. A comprehensive cost-effectiveness analysis was performed. The analysis was by intention to treat. Participants were followed for a minimum of 24 months.ResultsThere was no significant difference in time to first relapse between the SC and EC groups (hazard ratio 0.87, 95% confidence interval 0.65 to 1.17; log-rankp = 0.3). There were also no differences in the incidence of FRNS (SC 50% vs. EC 53%;p = 0.7), SDNS (44% vs. 42%;p = 0.8) or requirement for other immunosuppressive therapy (56% vs. 54%;p = 0.8). The total prednisolone dose received following completion of study medication was 5475 mg vs. 6674 mg (p = 0.07). SAE rates were not significantly different (25% vs. 17%;p = 0.1) and neither were AEs, except poor behaviour (yes/no), which was less frequent with EC treatment. There were no differences in ACBC scores. EC therapy was associated with a mean increase in generic health benefit [0.0162 additional quality-adjusted life-years (QALYs)] and cost savings (£4369 vs. £2696).LimitationsStudy drug formulation may have prevented some younger children who were unable to swallow whole or crushed tablets from participating.ConclusionsThis trial has not shown any clinical benefit for EC prednisolone therapy in UK children. The cost-effectiveness analysis suggested that EC therapy may be cheaper, with the possibility of a small QALY benefit.Future workStudies investigating EC versus SC therapy in younger children and further cost-effectiveness analyses are warranted.Trial registrationCurrent Controlled Trials ISRCTN16645249 and EudraCT 2010-022489-29.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 23, No. 26. See the NIHR Journals Library website for further project information.

We previously reported the safety and efficacy of low dose BaP [Bezafibrate (Bez) and Medroxyprogesterone acetate (MPA)] in 20 acute myeloid leukaemia (AML) patients for whom chemotherapy was not an option. This study provided evidence that BaP had anti-AML activity and improved haemopoiesis; absence of haematological toxicity allowed continuous daily administration. Similarly a previous trial in endemic Burkitt lymphoma demonstrated anti-B cell lymphoma activity of low and high dose BaP again in the absence of toxicity.We conducted a study to further evaluate the safety and activity of high dose BaP therapy in adults with AML (and high risk Myelodysplastic Syndromes (MDS)), chronic lymphocytic leukaemia (CLL) or B-cell Non-Hodgkin Lymphoma (BHNL). Eighteen patients were recruited to the study over 20 months, 16 AML/MDS, 1 CLL, and 1 BNHL. Although MPA was well tolerated throughout the study, only 2 patients were able to tolerate Bez treatment for their whole trial duration, indicating that Bez escalation is not feasible in the setting of adult AML/MDS. Thus there has been no obvious benefit in improved haemopoiesis or overt anti-leukaemia activity from the attempts to escalate BaP dose over previous published studies. Since current therapeutic options in MDS are restricted it may be now of value to continue to evaluate low dose BaP based approaches in low risk MDS rather than AML/high risk MDS. Furthermore, screening of low dose BaP against libraries of other already available dugs may identify an addition to BaP that augments the anti-neoplastic efficacy without significant toxicity. Keywords: Clinical trials, Myeloid leukaemia, Lymphoid malignancies, Therapy, Bezafibrate, Progesterone

PURPOSE The R2Pulm trial was conducted to evaluate the effect of busulfan-melphalan high-dose chemotherapy with autologous stem-cell rescue (BuMel) without whole-lung irradiation (WLI) on event-free survival (main end point) and overall survival, compared with standard chemotherapy with WLI in Ewing sarcoma (ES) presenting with pulmonary and/or pleural metastases. METHODS From 2000 to 2015, we enrolled patients younger than 50 years of age with newly diagnosed ES and with only pulmonary or pleural metastases. Patients received chemotherapy with six courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) and one course of vincristine, dactinomycin, and ifosfamide (VAI) before either BuMel or seven courses of VAI and WLI (VAI plus WLI) by randomized assignment. The analysis was conducted as intention to treat. The estimates of the hazard ratio (HR), 95% CI, and P value were corrected for the three previous interim analyses by the inverse normal method. RESULTS Of 543 potentially eligible patients, 287 were randomly assigned to VAI plus WLI (n = 143) or BuMel (n = 144). Selected patients requiring radiotherapy to an axial primary site were excluded from randomization to avoid excess organ toxicity from interaction between radiotherapy and busulfan. Median follow-up was 8.1 years. We did not observe any significant difference in survival outcomes between treatment groups. Event-free survival was 50.6% versus 56.6% at 3 years and 43.1% versus 52.9% at 8 years, for VAI plus WLI and BuMel patients, respectively, resulting in an HR of 0.79 (95% CI, 0.56 to 1.10; P = .16). For overall survival, the HR was 1.00 (95% CI, 0.70 to 1.44; P = .99). Four patients died as a result of BuMel-related toxicity, and none died after VAI plus WLI. Significantly more patients in the BuMel arm experienced severe acute toxicities than in the VAI plus WLI arm. CONCLUSION In ES with pulmonary or pleural metastases, there is no clear benefit from BuMel compared with conventional VAI plus WLI.

BackgroundCochrane reviews of physiotherapy (PT) and occupational therapy (OT) for Parkinson’s disease found insufficient evidence of effectiveness, but previous trials were methodologically flawed with small sample size and short-term follow-up.ObjectivesTo evaluate the clinical effectiveness and cost-effectiveness of individualised PT and OT in Parkinson’s disease.DesignLarge pragmatic randomised controlled trial.SettingThirty-eight neurology and geriatric medicine outpatient clinics in the UK.ParticipantsSeven hundred and sixty-two patients with mild to moderate Parkinson’s disease reporting limitations in activities of daily living (ADL).InterventionPatients were randomised online to either both PT and OT NHS services (n = 381) or no therapy (n = 381). Therapy incorporated a patient-centred approach with individual assessment and goal setting.Main outcome measuresThe primary outcome was instrumental ADL measured by the patient-completed Nottingham Extended Activities of Daily Living (NEADL) scale at 3 months after randomisation. Secondary outcomes were health-related quality of life [Parkinson’s Disease Questionnaire-39 (PDQ-39); European Quality of Life-5 Dimensions (EQ-5D)], adverse events, resource use and carer quality of life (Short Form questionnaire-12 items). Outcomes were assessed before randomisation and at 3, 9 and 15 months after randomisation.ResultsData from 92% of the participants in each group were available at the primary time point of 3 months, but there was no difference in NEADL total score [difference 0.5 points, 95% confidence interval (CI) –0.7 to 1.7;p = 0.4] or PDQ-39 summary index (0.007 points, 95% CI –1.5 to 1.5;p = 1.0) between groups. The EQ-5D quotient was of borderline significance in favour of therapy (–0.03, 95% CI –0.07 to –0.002;p = 0.04). Contact time with therapists was for a median of four visits of 58 minutes each over 8 weeks (mean dose 232 minutes). Repeated measures analysis including all time points showed no difference in NEADL total score, but PDQ-39 summary index (curves diverging at 1.6 points per annum, 95% CI 0.47 to 2.62;p = 0.005) and EQ-5D quotient (0.02, 95% CI 0.00007 to 0.03;p = 0.04) showed significant but small differences in favour of the therapy arm. Cost-effective analysis showed that therapy was associated with a slight but not significant gain in quality-adjusted life-years (0.027, 95% CI –0.010 to 0.065) at a small incremental cost (£164, 95% CI –£141 to £468), resulting in an incremental cost-effectiveness ratio of under £4000 (£3493, 95% –£169,371 to £176,358). There was no difference in adverse events or serious adverse events.ConclusionsNHS PT and OT did not produce immediate or long-term clinically meaningful improvements in ADL or quality of life in patients with mild to moderate Parkinson’s disease. This evidence does not support the use of low-dose, patient-centred, goal-directed PT and OT in patients in the early stages of Parkinson’s disease. Future research should include the development and testing of more structured and intensive PT and OT programmes in patients with all stages of Parkinson’s disease.Trial registrationCurrent Controlled Trials ISRCTN17452402.FundingThis project was funded by the NIHR Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 20, No. 63. See the NIHR Journals Library website for further project information. The Birmingham Clinical Trials Unit, University of Birmingham, received support from the UK Department of Health up to March 2012. Catherine Sackley was supported by a NIHR senior investigator award, Collaboration for Leadership in Applied Health Research and Care East of England and West Midlands Strategic Health Authority Clinical Academic Training award.

Background Surgery is the only curative treatment for primary cutaneous melanoma, therefore it is important to determine excision margins that minimise risk of local recurrence, distant recurrence and death. Methods MEDLINE, EMBASE and Cochrane CENTRAL were searched from 2009 to 2015. Inclusion criteria were: population/setting – patients with primary melanoma; comparison – narrow versus wide margins; outcomes – overall survival, melanoma-specific survival, recurrence-free survival, and loco-regional recurrence; design – randomized controlled trials (RCTs). Results were pooled using meta-analysis and data explored using likelihood Bayesian probability plots. Results Six RCTs with 4233 patients were included. Narrow margins were defined as 1 or 2cm of clinically normal skin around the melanoma; wide margins as 3, 4 or 5cm. Hazard ratios (HR) were as follows (HR>1 indicates wide margin better): overall survival 1.09 (95% CI 0.98–1.22; p =0.1); melanoma-specific survival 1.17 (CI 1.03–1.34; p =0.02); recurrence-free survival 1.08 (CI 0.97–1.20; p =0.2); loco-regional recurrence 1.10 (CI 0.96–1.26; p =0.2), with no evidence of heterogeneity between trials for any end point or within subgroup analyses. There was an 94% probability that overall survival was worse with a narrow margin and a 43% probability that it was more than 10% worse in proportional terms (i.e. HR>1.1). Probabilities that narrow margins were worse were 99%, 92% and 92% for melanoma-specific survival, recurrence-free survival and loco-regional recurrence respectively. Conclusions Contrary to recommendations in several national guidelines that narrow margins are safe, this systematic review and meta-analysis provides evidence that a narrow margin may lead to a worse outcome than a wide margin.

11500 Background: In 2010, different chemotherapy regimens were standard in Europe and the USA for newly diagnosed ES. In the absence of novel agents to investigate, comparison of these two strategies was considered worthwhile. Methods: Newly diagnosed localised or metastatic ES patients aged 5-50 were eligible. Patients were randomized to receive either the European regimen (Arm A) of VIDE (vincristine [V], ifosfamide [I], doxorubicin [D] and etoposide [E]) induction and VAI or VAC (V, actinomycin D and I or cyclophosphamide [C]) consolidation or the USA regimen (Arm B) of compressed VDC/IE induction and IE/VC consolidation. The primary outcome measure was event-free survival (EFS); secondary outcomes included overall survival (OS) and toxicity. The design was Bayesian with interpretation based on posterior probabilities (with non-informative priors) – i.e. probability that true hazard ratio (HR) < 1.0 given the data [Pr(HR200 ml); country (37% UK, 31% France, 32% other). Median follow-up was 1.7 years. The HRs (95% CrI) were 0.70 (0.51, 0.95) for EFS and 0.64 (0.42, 0.96) for OS in favour of Arm B, with posterior probabilities of 98% for both that Arm B was better. Subgroup analyses showed no evidence that this benefit differed depending the baseline features, with no HT being close to significance (table). There were no major differences in acute toxicity: 68% of patients in Arm A experienced serious adverse events and 67% in Arm B. Conclusions: VDC/IE chemotherapy is superior to VIDE for both EFS and OS, with no excess toxicity. This benefit is consistent across all baseline stratification parameters. Clinical trial information: ISRCTN92192408 . [Table: see text]

11524 Background: Survival for RR-ES at 5 years remains < 15%, so novel treatments are needed. Almost all Phase II trials for RR-ES use response as the primary outcome measure. It is unclear whether response is a valid surrogate for survival outcomes. Methods: Patients (pts) were eligible if they had RR-ES and were evaluable for imaging response (primary outcome) if they had measurable disease by RECIST 1.1. The randomization was initially between four chemotherapy regimens: topotecan-cyclophosphamide, irinotecan-temozolomide, gemcitabine-docetaxel (GD), high-dose ifosfamide. Response was assessed after 2, 4 (primary) and 6 cycles of therapy and was classified as complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD). PFS and OS were secondary outcomes. Survival from each assessment point by response status was analyzed, by Cox models, with hazard ratios (HR) given for PR v. SD and CR+PR v. SD. Results: From 2015-19, 241 pts with response data were entered. The relationship between response status and PFS and OS is shown in the table (HR < 1.0 indicates better outcome for PR or CR+PR than SD). Both PFS and OS were similar for pts with PR or CR+PR compared to those with SD. OS was inferior for patients with PD (all p < 0.01) (PFS is by definition zero for patients with PD at that timepoint). Small numbers mean CR results are not reliable. Results were consistent across all treatments and between refractory and relapsed disease. At the first interim assessment the GD arm was dropped, with risk ratios for response compared to the other three arms (blinded as still open) of 0.3, 0.5 and 0.5. If a new outcome – disease control (CR+PR+SD) – is defined, the risk ratios are 0.7, 0.8 and 0.7; i.e. still inferior for GD, but less so. Conclusions: Response does not correlate with survival outcomes in RR-ES, so considering PR, or even CR, a success and SD a failure when evaluating treatments may be misleading. We propose PFS as a better primary outcome for future trials and it will be introduced as such in the rEECur trial. Clinical trial information: ISRCTN36453794 . [Table: see text]

BACKGROUND: Surveillance magnetic resonance imaging (MRI) is routinely used to detect recurrence in children with high-grade central nervous system (CNS) tumors, although no consensus has been reached regarding its effectiveness and whether earlier detection is associated with improved patient outcomes. This review aimed to evaluate this practice and any associated benefits and harms. METHODS: Systematic searches for relevant studies were undertaken in a number of databases, including MEDLINE and EMBASE, from 1985 to August 2018. Study selection and data extraction was undertaken independently by two reviewers. Due to heterogeneity between studies, no pooling of data was undertaken. Reporting followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: No comparative studies were identified. Three retrospective observational studies involving 306 patients were reviewed. All had high risk of bias by virtue of study design. Two studies reported outcomes by symptomatic status-both recurrence rates and overall survival for asymptomatic patients were comparable with those for clinically symptomatic patients. No quality-of-life outcomes were reported. CONCLUSION: There is a paucity of evidence to guide clinical practice as to the effectiveness of MRI surveillance in pediatric patients with high-grade CNS tumors. These studies do not clearly demonstrate benefit or harm for the practice. With more research needed, there is a role for researchers to build into future trials data collection on surveillance imaging to give more information for the assessment of imaging frequency and duration in asymptomatic patients. This is an important question not only to clinicians and patients and their families but also from a health service resource perspective.

Magnetic resonance imaging (MRI) is routinely used as a surveillance tool to detect early asymptomatic tumour recurrence with a view to improving patient outcomes. This systematic review aimed to assess its utility in children with low-grade CNS tumours. Using standard systematic review methods, twelve databases were searched up to January 2017. Seven retrospective case series studies (n = 370 patients) were included, with average follow-up ranging from 5.6 to 7 years. No randomised controlled trials (RCTs) were identified. Due to study heterogeneity only a descriptive synthesis could be undertaken. Imaging was most frequent in the first year post-surgery (with 2–4 scans) reducing to around half this frequency in year two and annually thereafter for the duration of follow-up. Diagnostic yield ranged from 0.25 to 2%. Recurrence rates ranged from 5 to 41%, with most recurrences asymptomatic (range 65–100%). Collectively, 56% of recurrences had occurred within the first year post-treatment (46% in the first 6-months), 68% by year two and 90% by year five. Following recurrence, 90% of patients underwent treatment changes, mainly repeat surgery (72%). Five-year OS ranged from 96 to 100%, while five-year recurrence-free survival ranged from 67 to 100%. None of the studies reported quality of life measures. This systematic review highlights the paucity of evidence currently available to assess the utility of MRI surveillance despite it being routine clinical practice and costly to patients, their families and healthcare systems. This needs to be evaluated within the context of an RCT.

Background We assessed whether relapse-free survival (RFS; time until recurrence/death) is a valid surrogate for overall survival (OS) among resected stage II-III melanoma patients through a meta-analysis of randomized controlled trials. Methods Individual patient data (IPD) on RFS and OS were collected from 5826 patients enrolled in 11 randomized adjuvant trials comparing interferon (IFN) to observation. In addition, IPD from two studies comparing IFN and vaccination in 989 patients were included. A two-level modeling approach was used for assessing Spearman's patient-level correlation (rho) of RFS and OS and the trial-level coefficient of determination (R²) of the treatment effects on RFS and on OS. The results were validated externally in 13 adjuvant studies without available IPD. We then tested the results on the European Organisation for Research and Treatment of Cancer (EORTC) 18071 double-blind trial comparing ipilimumab 10 mg/kg with placebo, which showed a statistically significant impact of the checkpoint inhibitor on RFS and OS. All statistical tests were two-sided. Results With a median follow-up of seven years, 12 of 13 trials showed a consistency between the IFN vs No IFN differences regarding RFS (hazard ratio [HR]RFS = 0.88) and OS (HROS = 0.91), but the small trial, Eastern Cooperative Oncology Group 2696, was an outlier (HRRFS = 0.72 vs HROS = 1.11). Therefore, even if rho was high, R² was low and could not reliably be estimated. Based on the 12 trials, rho remained high (0.89), and the hazard ratios for RFS and OS were strongly correlated (R² = 0.91). The surrogate threshold effect for RFS was estimated to be 0.77. For the EORTC 18071 trial, the hazard ratio for RFS was 0.75, predicting an effect of ipilimumab on OS. This was subsequently confirmed (HROS = 0.72, 95.1% confidence interval = 0.58 to 0.88, P = .001). Conclusions In high-risk stage II-III melanoma, RFS appeared to be a valid surrogate end point for OS for adjuvant randomized studies assessing interferon or a checkpoint inhibitor. In future similar adjuvant studies, a hazard ratio for RFS of 0.77 or less would predict a treatment impact on OS.

Background The purpose of this study was to determine the extent to which summary index scores from the short form Parkinson's Disease Questionnaire (PDQ-8) replicate those from the parent form (PDQ-39) in a longitudinal study. Methods Longitudinal data gained from the PD-MED trial were examined (n = 1867), to determine the extent the PDQ-8 replicates results from the PDQ-39 at baseline and follow up. The sensitivity to change of the PDQ-8 was also compared with that of the PDQ-39. Finally, results on the two measures were compared with those from the Hoehn and Yahr (HY) clinical staging scale. Results Results of the Single Index summary score gained from the PDQ-8 were found to closely replicate those gained from the PDQ-39 at each of the three time points. Furthermore at each time point the intraclass correlation coefficient between the two measures was very high (ICC range 0.93–0.96). Similarly, the two measures gave very similar accounts of change (e.g. from baseline to follow up at one year effect sizes were 0.18 for the single index calculated using the PDQ-39, and 0.09 when calculated using the PDQ-8). Similar levels of correlation were found between the two indices when correlated with the HY scale. Conclusions The PDQ-8 closely replicates results gained from the PDQ-39 when calculating single indices. In instances where a single summary score of the impact of PD on self-reported quality of life is needed, it is likely the PDQ-8 will provide reliable and accurate information.

Background There is no consensus on the association between exposure to hydrocarbons and the risk of Parkinson's disease (PD). We conducted a systematic review and meta-analysis to summarise the epidemiological evidence and included a new large case-control study. Methods Data were extracted following a predefined protocol. Risk estimates regarding the association between hydrocarbon exposure and PD were consolidated to produce a summary odds ratio (OR), 95% confidence intervals (CI), and p-value. In our case-control study, 1463 PD patients and 685 controls were recruited from clinical trials and completed a structured questionnaire describing their previous working exposure to hydrocarbons and other demographic measures. The association between exposure to hydrocarbons and risk of PD was evaluated using logistic regression. Results The systematic search identified 13 case-control studies matching the inclusion criteria. The meta-analysis included 3020 PD cases and 6494 controls. The summary OR was 1.32 (95% CI 1.08–1.62, p = 0.006) for hydrocarbon exposure (ever versus never). In the PD GEN study, occupational exposure to hydrocarbons significantly increased the risk of PD (OR = 1.61; 95% CI 1.10–2.36, p = 0.014), and risk dose-dependently increased for subjects exposed greater than 10 years compared to subjects never exposed (OR = 2.19; 95% CI 1.13–4.26, p = 0.021). The addition of PD GEN data increased the total numbers to 4483 PD cases and 7179 controls and strengthened the significant association (summary OR = 1.36; 95% CI 1.13–1.63, p = 0.001). Conclusions This systematic review supports a positive association between hydrocarbon exposure and PD. Data from prospective studies are required to reinforce the relationship between hydrocarbon exposure and PD.

Summary Background Limits on the frequency of whole blood donation exist primarily to safeguard donor health. However, there is substantial variation across blood services in the maximum frequency of donations allowed. We compared standard practice in the UK with shorter inter-donation intervals used in other countries. Methods In this parallel group, pragmatic, randomised trial, we recruited whole blood donors aged 18 years or older from 25 centres across England, UK. By use of a computer-based algorithm, men were randomly assigned (1:1:1) to 12-week (standard) versus 10-week versus 8-week inter-donation intervals, and women were randomly assigned (1:1:1) to 16-week (standard) versus 14-week versus 12-week intervals. Participants were not masked to their allocated intervention group. The primary outcome was the number of donations over 2 years. Secondary outcomes related to safety were quality of life, symptoms potentially related to donation, physical activity, cognitive function, haemoglobin and ferritin concentrations, and deferrals because of low haemoglobin. This trial is registered with ISRCTN, number ISRCTN24760606, and is ongoing but no longer recruiting participants. Findings 45 263 whole blood donors (22 466 men, 22 797 women) were recruited between June 11, 2012, and June 15, 2014. Data were analysed for 45 042 (99·5%) participants. Men were randomly assigned to the 12-week (n=7452) versus 10-week (n=7449) versus 8-week (n=7456) groups; and women to the 16-week (n=7550) versus 14-week (n=7567) versus 12-week (n=7568) groups. In men, compared with the 12-week group, the mean amount of blood collected per donor over 2 years increased by 1·69 units (95% CI 1·59–1·80; approximately 795 mL) in the 8-week group and by 0·79 units (0·69–0·88; approximately 370 mL) in the 10-week group (p

Background: A marginal interaction between sex and the type of alkylating agent was observed for event‐free survival in the Euro‐EWING99‐R1 randomized controlled trial (RCT) comparing cyclophosphamide and ifosfamide in Ewing sarcoma. To further evaluate this interaction, we performed an individual patient data meta‐analysis of RCTs assessing cyclophosphamide versus ifosfamide in any type of cancer. Methods: A literature search produced two more eligible RCTs (EICESS92 and IRS‐IV). The endpoints were progression‐free survival (PFS, main endpoint) and overall survival (OS). The hazard ratios (HRs) of the treatment‐by‐sex interaction and their 95% confidence interval (95% CI) were assessed using stratified multivariable Cox models. Heterogeneity of the interaction across age categories and trials was explored. We also assessed this interaction for severe acute toxicity using logistic models. Results: The meta‐analysis comprised 1,528 pediatric and young adult sarcoma patients from three RCTs: Euro‐EWING99‐R1 (n = 856), EICESS92 (n = 155), and IRS‐IV (n = 517). There were 224 PFS events in Euro‐EWING99‐R1 and 200 in the validation set (EICESS92 + IRS‐IV), and 171 and 154 deaths in each dataset, respectively. The estimated treatment‐by‐sex interaction for PFS in Euro‐EWING99‐R1 (HR = 1.73, 95% CI = 1.00–3.00) was not replicated in the validation set (HR = 0.97, 95% CI = 0.55–1.72), without heterogeneity across trials (P = 0.62). In the pooled analysis, the treatment‐by‐sex interaction was not significant (HR = 1.31, 95% CI = 0.89–1.95, P = 0.17), without heterogeneity across age categories (P = 0.88) and trials (P = 0.36). Similar results were observed for OS. No significant treatment‐by‐sex interaction was observed for leucopenia/neutropenia (P = 0.45), infection (P = 0.64), or renal toxicity (P = 0.20). Conclusion: Our meta‐analysis did not confirm the hypothesis of a treatment‐by‐sex interaction on efficacy or toxicity outcomes. Refereed/Peer-reviewed

Many randomised trials assessing interferon-α (IFN-α) as adjuvant therapy for high-risk malignant melanoma have been undertaken. To better assess the role of IFN-α, an individual patient data (IPD) meta-analysis of these trials was undertaken.IPD was sought from all randomised trials of adjuvant IFN-α versus no IFN-α for high-risk melanoma. Primary outcomes were event-free survival (EFS) and overall survival (OS). Standard methods for quantitative IPD meta-analysis were used. Subgroup analyses by dose, duration of treatment and various patient and disease-specific parameters were performed.Fifteen trials were included in the analysis (eleven with IPD). EFS was significantly improved with IFN-α (hazard ratio [HR] = 0.86, CI 0.81-0.91; P 0.00001), as was OS (HR = 0.90, CI 0.85-0.97; P = 0.003). The absolute differences in EFS at 5 and 10 years were 3.5% and 2.7%, and for OS were 3.0% and 2.8% respectively in favour of IFN-α. There was no evidence that the benefit of IFN-α differed depending on dose or duration of treatment, or by age, gender, site of primary tumour, disease stage, Breslow thickness, or presence of clinical nodes. Only for ulceration was there evidence of an interaction (test for heterogeneity: P = 0.04 for EFS; P = 0.002 for OS); only patients with ulcerated tumours appeared to obtain benefit from IFN-α.This meta-analysis provides clear evidence that adjuvant IFN-α significantly reduces the risk of relapse and improves survival and shows no benefit for higher doses compared to lower doses. The increased benefit in patients with ulcerated tumours, and lack of benefit in patients without ulceration, needs further investigation.

INTRODUCTION: Allogeneic stem cell transplantation (allo-SCT) is an important curative strategy in adults with high risk acute myeloid leukemia (AML) and myelodysplasia (MDS). Disease relapse represents the major cause of treatment failure and whilst retrospective analyses have identified that pre-transplant measurable residual disease (MRD) is an important predictor of transplant outcome this has never been examined prospectively. The advent of reduced intensity conditioning (RIC) regimens has substantially increased the number of older adults eligible for allo-SCT but the optimal RIC regimen in high risk AML remains unknown. Registry data have demonstrated improved outcomes using a sequential transplant regimen utilizing cytosine arabinoside (araC)/amsacrine (AMSA) cytoreduction followed by a fludarabine (Flu)/busulfan (Bu) based RIC regimen (FLAMSA-Bu). However, although the FLAMSA-Bu regimen is now widely used in adults with high risk AML and MDS its benefit has not been evaluated in a randomized trial. We report the results of a randomized trial evaluating the FLAMSA-Bu regimen compared with standard RIC regimens which also represents the first prospective evaluation of the impact of pre-transplant MRD levels on transplant outcome. PATIENTS AND METHODS: 244 patients (median age 59 yrs) with high risk AML (n=164) or high risk myelodysplasia (n=80) were randomized 1:1 to a control arm determined by investigator's choice of either Flu/B2/ATG (Flu, Bu 3.2 mg/kg x 2 days, ATG 2.5 mg/kg x 2 days); Flu/Mel/Alemtuzumab (A) (Flu, Mel 140 mg/m2, A 50 mg) or Flu/Bu2/A (Flu, Bu 3.2 mg/kg x 2 days, A 50 mg) versus an experimental arm of FLAMSA-Bu (Flu, araC 2g/m2 x 4 days, AMSA 100mg/m2 x 4 days, Bu -total dose 11.2 mg/kg). Patients over the age of 60 received an adjusted FLAMSA-Bu regimen utilising a reduced dose of araC (1mg/m2 x 4 days) and a total Bu dose of 6.4 mg/kg. Patients were transplanted using either an HLA identical sibling (n=49) or matched (10/10 or 9/10) unrelated donor (n=195). All patients received cyclosporine GVHD prophylaxis. 155 patients with AML were in CR1 or CR2 at the time of transplant and 9 had primary refractory disease. MRD was monitored by flow cytometry (applying different-from-normal analysis when no diagnostic/relapse leukemic aberrant immunophenotype was available). Pre-transplant MRD levels were measured up to four weeks prior to transplantation in 201 patients (MRD positive = 80 (40%), MRD negative = 94 (47%), inadequate sample = 27 (13%)). MRD results were not reported to clinicians. The primary outcome was overall survival. RESULTS: Baseline characteristics including CR1/CR2 status, adverse cytogenetics and MRD levels were similar between regimens. Median follow up was 35 months. Transplant outcomes were comparable between patients allografted in the control and FLAMSA-Bu arms. 2 yr overall survival (OS) and cumulative incidence of relapse (CIR) were 61% and 30% respectively in the control arm vs 62% and 26% for the FLAMSA-Bu arm. Transplant related mortality at 100 days was 3.0% in patients allografted using the control regimen vs 14% in patients allografted using the FLAMSA-Bu regimen and 17% vs 21% at 1 year. In the study cohort pre-transplant MRD positivity was associated with both an increased CIR compared to patients testing MRD negative (2 yr CIR 42% vs 19%, p=0.009) and decreased OS (2 yr OS 52% vs 71%, p=0.048). The FLAMSA-Bu regimen failed to improve OS or reduce CIR in either MRD positive or MRD negative patients. CONCLUSIONS: This trial, the largest randomized trial of RIC regimens in AML to date, did not detect any benefit of intensification of the conditioning regimen in adults with high risk AML or MDS. Specifically, the FLAMSA-Bu regimen was not associated with improved transplant outcome in patients who were MRD positive pre-transplant. These data include the first demonstration in a prospective analysis that the presence of pre-transplant MRD measured in real time is associated with reduced OS consequent upon an increased risk of disease relapse. Further randomized studies of novel conditioning regimens in adult AML, crucially with integrated MRD studies, are now required but these results support exploration of alternative strategies, such as pre or post-transplant pharmacological intervention, as the most promising strategy to reduce the risk of disease relapse post allograft. Disclosures Russell: Jazz: Consultancy, Honoraria, Speakers Bureau; DSI: Consultancy, Honoraria, Speakers Bureau; Pfizer Inc: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy, Honoraria, Speakers Bureau. Freeman:Jazz Pharmaceuticals: Speakers Bureau. OffLabel Disclosure: We report data using the combination of fludarabine, busulphan, amsacrine and cytosine arabinsoide as a conditioning regimen in patients allografted for high risk acute myeloid leukemia

Introduction Most children with acute myeloid leukaemia (AML) harbour fusion genes which are ideal targets for molecular minimal residual disease (MRD) monitoring. However, evidence of prognostic significance is currently lacking and consequently most current paediatric AML treatment protocols rely on flow cytometric (FCM) evaluation to allocate treatment. Molecular MRD techniques provide significantly greater sensitivity and specificity and could allow more accurate outcome prediction, and consequently more personalised therapy, which is highly relevant in a disease where treatment related mortality, morbidity and relapse remain significant. Methods Between June 2016 and February 2019, MyeChild01 enrolled 170 children aged 0-18y with newly diagnosed AML who were randomly assigned to induction therapy with liposomal daunorubicin or mitoxantrone with cytarabine with or without gemtuzumab ozogamicin. Consolidation treatment was determined by karyotype, mutational profile and MRD status. Comprehensive centralised diagnostic assessment consisted of: Karyotype and fluorescence in-situ hybridisation (FISH) using a custom panel of probes to detect paediatric AML-associated gene fusions.PCR based screening for mutations in FLT3, NPM1 and CEPBA.Targeted capture of known fusion loci and paired end sequencing.RNA-seq using the Illumina TruSight fusion panel. Where a fusion gene was identified, RT-qPCR assays were designed and optimised for each patient. NPM1 mutation was also used as an MRD target if present. Paired PB and BM samples were requested after each cycle of treatment. Patients could have sequential monitoring after completion of therapy although this was not mandated. For this analysis, patients with core-binding factor (CBF) leukaemias i.e. inv(16)(p13q22) or t(8;21)(q22q22) with transcript levels above previously defined thresholds (Yin et al, 2012) were considered MRD positive. For all other targets, amplification in at least 2/3 replicates at For patients with CBF or NPM1 mutation, both molecular and FCM MRD status contributed to treatment allocation. Otherwise, FCM MRD was used unless there was no FCM target. Allogeneic stem cell transplantation (HSCT) was recommended for all patients with poor risk cytogenetics, those with intermediate risk cytogenetics who were MRD positive after cycle 2, and those with favourable risk cytogenetics who were MRD positive at the end of cycle 3. After completion of treatment, no specific advice was given regarding management of positive MRD results. Results We identified fusion genes in 126/170 patients (74%). We designed 55 unique RT-qPCR assays to specifically amplify 27 fusions with calculated sensitivity between 1:104 and 1:106. 62/126 children provided a complete set of samples: 31 (60%) with favourable, 18 (29%) with intermediate and 13 (21%) with high risk cytogenetic / molecular profiles. We analysed the effect of molecular MRD status at the end of protocol specified treatment, which included SCT in 17/62 (27%). One year event-free survival from diagnosis was 70% (95% confidence interval 52-82%) in patients who tested MRD negative compared to 11% (1-39%) in patients who tested MRD positive at the end of treatment (p Four patients received non-protocol specified SCT due to physician / family preference based on persistently positive or serially rising transcript levels after completion of treatment. At last follow up 4/4 were alive in complete remission. Rising transcript levels were observed in a further 8 patients to whom no pre-emptive treatment was given due to individual preference or lack of appropriate therapy. Haematological relapse subsequently occurred in 8/8. Conclusion Molecular MRD monitoring is feasible in the majority of children with AML, permitting refinement of response-adapted therapy. Molecular MRD status at the end of treatment is highly predictive of outcome, identifying molecular complete remission as a treatment goal for these children. Serially rising MRD levels reliably predict relapse in the absence of therapeutic intervention. Disclosures Dillon: Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; TEVA: Consultancy, Honoraria. Vyas:Astellas: Speakers Bureau; Abbvie: Speakers Bureau; Forty Seven, Inc.: Research Funding; Celgene: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Pfizer: Speakers Bureau; Daiichi Sankyo: Speakers Bureau. Amrolia:UCLB: Patents & Royalties. Baruchel:Bellicum: Consultancy; Servier: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.

Background BEACON-Neuroblastoma is a randomized phase II trial to assess the activity of backbone chemotherapy regimens for children with RR-HRNB and to determine if inhibiting angiogenesis with bevacizumab adds to the activity of this chemotherapy. Methods Patients aged 1-21 years with RR-HRNB with adequate organ function and performance status were randomized in a factorial design to: temozolomide (T) versus irinotecan-temozolomide (IT) or topotecan-temozolomide (TTo), with or without bevacizumab (Bev). The Bev randomization (Bev versus no-Bev) had two parts: Part 1 had a 2-stage Minimax Jung design with overall response (OR) as primary endpoint. Part 1 success criterion was ≥4 more responses in Bev arm compared to no-Bev. Protocol was amended to incorporate Part 2 (40 additional patients), including progression-free survival (PFS) as co-primary endpoint. OR was defined as complete or partial response (CR, PR) by RECIST (INRC for patients without measurable disease). OR and toxicity data for the Bev randomization is reported. Results For Part 1 (n=106), 17 of 52 pts on Bev had responses [33%] and 8 of 54 pts on no-Bev had responses [15%]. The trial success criterion for the primary endpoint of ORR was met. Including Part 2 (total n=154), 21 of 77 patients on Bev (7CR, 14PR) and 13 of 77 patients on no-Bev (1CR, 12PR) had responses. Response data was not available for 6 patients; 13 patients not assessable for response (discontinued before first assessment) were considered to be non-responders. OR rate [with 90% CI] was 27% [18-35%] for patients on Bev and 17% [10-24%] for patients on no-Bev. In subgroup analysis, there was no interaction between T, IT and TTo and treatment with/without Bev (heterogeneity test, p=0.8). 86% Bev and 58% no-Bev patients had grade ≥3 toxicities as per CTCAE v4.0; the most common grade ≥3 toxicities associated with Bev were platelet count decrease and anemia. Conclusions Bev reached the Phase II success criterion for OR within Part 1 of the trial when added to temozolomide-based chemotherapy in RR-HRNB. The toxicity profile for Bev is acceptable. Longer follow-up is needed before assessing whether it impacts PFS or overall survival. Clinical trial identification NCT02308527; EudraCT: 2012-000072-42. Legal entity responsible for the study University of Birmingham. Funding Roche. Disclosure L. Moreno: Honoraria (self), Travel / Accommodation / Expenses: Celgene; Honoraria (self), Advisory / Consultancy: Novartis; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche; Advisory / Consultancy: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy, Travel / Accommodation / Expenses: Mundipharma; Licensing / Royalties, I am member of Siopen Executive Committee, Siopen receives royalties for the sales of dinutuximab beta: Eusa Pharma. D. Valteau-Couanet: Advisory / Consultancy, Travel / Accommodation / Expenses, Licensing / Royalties, Member of Siopen Executive Committee, SIOPEN receives royalties for the sales of dinutuximab beta: Eusa Pharma; Research grant / Funding (institution): Ophelia; Travel / Accommodation / Expenses: Jazz Pharma. K. Nysom: Advisory / Consultancy: Bayer. N. Gerber: Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Loxo; Research grant / Funding (institution): Novartis. R. Ladenstein: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses, Licensing / Royalties, Royalties to the institution for dinutuximab beta: Apeiron; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses, Licensing / Royalties, Royalties to the institution for dinutuximab beta: Eusa Pharma; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim. A.D. Pearson: Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Genentech. All other authors have declared no conflicts of interest.

10000 Background: Vincristine with Irinotecan (VI) is effective in patients with relapsed RMS but outcomes remain poor. The addition of temozolomide to VI (VIT) is attractive owing to different resistance mechanisms and distinct toxicity profiles. Methods: The VIT-0910 trial, an EpSSG-ITCC randomized phase 2 trial, evaluated efficacy and safety of VI and VIT in patients (pts) aged 0.5-50 years with relapsed/refractory RMS. Pts received Vincristine 1.5 mg/m2 d1, d8, Irinotecan 50mg/m2 d1-d5 +/- Temozolomide 125 mg/m² d1-d5 (150 mg/m² from cycle 2 if no toxicity > grade 2); 21-day cycles were given until progression/unacceptable toxicity. The primary endpoint was centrally reviewed objective response rate (ORR) after 2 cycles (primary lesion, WHO response criteria: metastatic sites, RECIST 1.1 ). Secondary endpoints included progression-free survival (PFS), overall survival (OS) and adverse events (NCI-CTCAE v4). Initially a Simon 2-stage design was used to analyse separately 40 pts/arm. After amendment, the trial sample size was increased to 120, and a comparison between arms, adjusted for confounding factors, was added to the statistical plan. Results: 120 pts (60 VIT, 60 VI) were recruited in 37 European centers from 03/2012-04/2018. Median age was 11 years (0.75-46), 89% pts relapsed RMS. ORR was 24/55 (44%) for VIT vs 18/58 (31%) for VI; adjusted odds ratio =0.50, 95%CI, 0.22-1.12, p=0.09. The VIT arm achieved significantly better PFS (adjusted Hazard Ratio (HR)=0.65, 95%Cl, 0.43-0.97, p=0.036) and OS (HR=0.53, 95%CI, 0.33-0.83, p=0.005) compared to VI. PFS and OS results were similar when only relapsed patients were included. Adverse events ≥ grade 3 were more frequent in VIT compared to VI, but only hematological toxicity was significantly increased (81% for VIT, 59% for VI, odds ratio=1.36, 95%CI, 1.06-1.76, P=0.02). Conclusions: The addition of temozolomide to VI improves PFS and OS of pts with relapsed/refractory RMS. VIT is now standard treatment for relapsed RMS in Europe. Clinical trial information: NCT01355445.

10001 Background: BEACON-Neuroblastoma is a randomized Phase II trial to assess the activity of backbone chemotherapy regimens for children with RR-HRNB and to determine if inhibiting angiogenesis with bevacizumab adds to the activity of this chemotherapy. Methods: Patients aged 1-21 years with RR-HRNB with adequate organ function and performance status were randomized in a 2x2 factorial design to: temozolomide (T) versus irinotecan-temozolomide (IT), with or without bevacizumab. Here we report the results of the irinotecan randomization (T vs. IT), which had a probability-based Bayesian design. Primary endpoint was best overall response (complete or partial) during the first 6 courses, by RECIST for measurable disease patients and International Neuroblastoma Response Criteria for evaluable disease patients for which overall response rate (ORR) was calculated. Results: From 2013 to 2018, 61 patients were randomized to treatment with T and 60 to IT. Median age was 5.8 years. 85 and 36 had measurable and evaluable disease respectively; 55 and 66 had refractory and relapsed disease; 22 had MYCN amplification. Baseline characteristics were balanced between the arms. Response data was not yet available for 2 patients on T. Response was not assessable for 17 patients (did not have treatment or stopped early) who were considered non-responders. The ORR was 24% for T and 17% for IT (risk ratio (RR) = 0.70, 95% credible interval 0.32 to 1.44). The probability that the RR for ORR was >1.0 was 17%, meaning that IT did not show greater activity than T. There was no interaction between treatment with/without bevacizumab (heterogeneity test, p=0.7). 27 (44%) T and 35 (58%) IT patients had grade ≥3 toxicities as per CTCAE v4.0. Diarrhea occurred in no patients on T and 7 (12%) on IT; hematological toxicities included anemia (6 T, 4 IT), neutropenia (14 T, 22 IT) and thrombocytopenia (14 T, 11 IT). Conclusions: Irinotecan does not improve the response rate when added to temozolomide in RR-HRNB, but does increase diarrhea. Longer follow-up is needed before assessing whether it impacts progression-free or overall survival. Number of responses by treatment arm. Clinical trial information: NCT02308527. [Table: see text]

11007 Background: 5-year survival of RR-ES is about 15%. Several chemotherapy regimens are used, but without robust evidence. rEECur, the first randomised controlled trial in this setting, is defining a standard of care, balancing efficacy and toxicity. Methods: Patients aged 4 to 50 with RR-ES and fit to receive chemotherapy were randomised 2, 3 or 4 ways between topotecan & cyclophosphamide (TC), irinotecan & temolozomide (IT), gemcitabine & docetaxel (GD) or high-dose ifosfamide (IFOS). Primary outcome measure was objective response (OR) after 4 cycles by RECIST 1.1. Secondary outcomes included PFS, OS and toxicity. A probability-based Bayesian approach was used. The first interim assessment to determine which arm should be closed occurred when 50 evaluable patients had been recruited to 3 arms and evaluated for the primary outcome measure. Results: 242 patients (89% RECIST-evaluable) recruited between 18/12/14 and 21/06/18 were randomised to TC (n=75), IT (71), GD (66) and IFOS (30). Median age was 21 years (range 4 to 49). Patients had: refractory ES (20%), 1st recurrence (63%), >1st recurrence (17%); initial primary disease arose in bone in 60%; disease progression sites were primary site (17%), pleuropulmonary (29%) or other metastatic (54%). Median follow up was 11.3 months. Outcomes in the GD arm were: response rate 11.5% (95% CI: 4.4 to 23%), median PFS 3.0 months (95% CI: 1.6 to 8.0), median OS 13.7 months (95% CI: 10.1 to 23.9). The table shows, for each pairwise comparison of GD with the other arms (randomly labelled A, B, C to maintain blinding of open arms), the probabilities given the observed data that OR, PFS and OS were better for GD than for each other arm (RR: relative risk, HR: hazard ratio). For OR and PFS, all comparisons favoured the other arms. There were fewer grade 3/4 adverse events with GD than with the other arms pooled (58% v. 74%). Conclusions: rEECur has shown that GD is a less effective treatment than TC, IT or IFOS in reducing tumour burden or prolonging PFS in RR-ES. Recruitment continues to the remaining arms. Clinical trial information: ISRCTN36453794. [Table: see text]

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: Our overall objectives are to perform a systematic review of maintenance therapies in patients with MM to assess benefits (OS, PFS, response, and quality of life) and harms (adverse events and treatment‐related mortality) among patients with MM. Furthermore, if maintenance therapy is beneficial, which regimen is the most optimal.

BACKGROUND:\ud Patients with chronic kidney disease (CKD) are at risk of progression to end-stage renal disease and cardiovascular disease. Data from other populations and animal experiments suggest that neprilysin inhibition (which augments the natriuretic peptide system) may reduce these risks, but clinical trials among patients with CKD are required to test this hypothesis.\ud METHODS:\ud UK Heart and Renal Protection III (HARP-III) is a multicentre, double-blind, randomized controlled trial comparing sacubitril/valsartan 97/103 mg two times daily (an angiotensin receptor-neprilysin inhibitor) with irbesartan 300 mg one time daily among 414 patients with CKD. Patients ≥18 years of age with an estimated glomerular filtration rate (eGFR) of ≥45 but 20 mg/mmol or eGFR ≥20 but

Summary Background Surgical intervention for advanced Parkinson's disease is an option if medical therapy fails to control symptoms adequately. We aimed to assess whether surgery and best medical therapy improved self-reported quality of life more than best medical therapy alone in patients with advanced Parkinson's disease. Methods The PD SURG trial is an ongoing randomised, open-label trial. At 13 neurosurgical centres in the UK, between November, 2000, and December, 2006, patients with Parkinson's disease that was not adequately controlled by medical therapy were randomly assigned by use of a computerised minimisation procedure to immediate surgery (lesioning or deep brain stimulation at the discretion of the local clinician) and best medical therapy or to best medical therapy alone. Patients were analysed in the treatment group to which they were randomised, irrespective of whether they received their allocated treatment. The primary endpoint was patient self-reported quality of life on the 39-item Parkinson's disease questionnaire (PDQ-39). Changes between baseline and 1 year were compared by use of t tests. This trial is registered with Current Controlled Trials, number ISRCTN34111222. Findings 366 patients were randomly assigned to receive immediate surgery and best medical therapy (183) or best medical therapy alone (183). All patients who had surgery had deep brain stimulation. At 1 year, the mean improvement in PDQ-39 summary index score compared with baseline was 5·0 points in the surgery group and 0·3 points in the medical therapy group (difference −4·7, 95% CI −7·6 to −1·8; p=0·001); the difference in mean change in PDQ-39 score in the mobility domain between the surgery group and the best medical therapy group was −8·9 (95% CI −13·8 to −4·0; p=0·0004), in the activities of daily living domain was −12·4 (−17·3 to −7·5; p

Acute myeloid leukemia (AML) in older adults carries a poor prognosis, and the optimum treatment remains to be determined. In younger patients, treatment stratification is frequently based upon diagnostic karyotype, which was the most important prognostic factor in the UK Medical Research Council (MRC) AML10 trial. Considered here is whether karyotype is also predictive in older adults; this is done by studying 1065 cases from MRC AML11 (median age, 66 years). Three prognostic groups were distinguished on the basis of response to induction therapy and overall survival (OS). Those with t(15;17), t(8;21), or inv(16) composed the favorable risk group. Overall, these abnormalities predicted a superior complete remission (CR) rate (72%), reflecting relatively low levels of resistant disease (RD) (8%), and lower relapse risk (RR) (56%) associated with superior OS (34% at 5 years). Normal karyotype (CR, 63%; RD, 17%; RR, 78%; OS, 15%) and other noncomplex abnormalities (CR, 53%; RD, 32%; RR, 85%; OS, 10%) composed the intermediate group; while complex karyotype predicted an extremely poor prognosis (CR, 26%; RD, 56%; RR, 91%; OS, 2%). Combining MRC AML10 and AML11 (n = 2677) revealed that the most favorable changes were rarer in older patients (younger than 55 years, 24%; 55 years or older, 7%), while complex abnormalities were more common (6% vs 13%). This study suggests that hierarchical cytogenetic classification identifies biologically distinct subsets of AML that are represented in all age groups. Furthermore, it highlights the importance of karyotype as a critical independent determinant of outcome in older patients with AML, providing a potential framework for stratified treatment approaches.

Multiple factors are likely to contribute to the pathogenesis of thrombosis in Essential thrombocythaemia (ET) including platelet number, activation of platelets and leukocytes; the formation of platelet leucocyte aggregates, and circulating prothrombotic and endothelial factors. The normal functional activity of platelets depends on the presence of platelet glycoprotein complexes, which play an important role in platelet adhesion and aggregation. A number of polymorphisms in platelet glycoproteins have been correlated with thrombotic events in hematologically normal patients. Particular polymorphisms of interest include three within the glycoprotein Ibα gene: −5T/C (affecting a Kozak sequence), 1018C/T (T145M, encoding Human Platelet Antigen − 2), a variable number of tandem repeats (VNTR) in a region encoding the macroglycopeptide and one polymorphism C807T, within the glycoprotein Ia gene. To date whether there is a relationship between these platelet glycoprotein polymorphisms and the clinical features of ET has not been determined. In this study samples obtained from 797 ET patients recruited to the 3 large prospective PT–1 trials were genotyped for the polymorphisms of interest and the results were correlated with clinical events including haemorrhagic and arterial or venous thrombotic events in the year prior to diagnosis and following trial entry (median 30 months). The VNTR data were analysed using the sum of the number of repeats of both alleles and treated as a continuous variable using logistic regression for retrospective and a Cox survival model for prospective analyses; other polymorphisms were analysed using the Chi-squared test for the retrospective clinical events, and log-rank survival analysis for the prospective clinical events. Neither the C807T, −5T/C Kozak nor the T145M polymorphism was associated with clinical events in the ET patient cohort. Interestingly the number of VNTR repeats was inversely associated with (p=0.02) rate of arterial events after trial entry in this patient cohort, but not for events in the year prior to diagnosis or post trial entry venous thrombotic or haemorrhagic events. This analysis suggested that a decreasing sum of VNTR were associated with an increased risk of arterial thrombosis, the degree of increase in risk was 75% per repeat (95% confidence interval 1.0–2.9). After multivariate analysis of this data with correction for age, sex, JAK2V617F and MPLW515L/K status the effect of the number of VNTR repeats remained significant (p=0.048). These results suggest that the C807T, T145M and −5T/C Kozak polymorphisms do not correlate with clinical events in ET. However a reduction in the number of VNTR within the glycoprotein Ibα gene was progressively associated with arterial events post trial entry (p=0.024) and remained significant on multivariate analysis (p=0.048).

OBJECTIVE: To review the clinical features, treatment, and outcome of children in the UK with Down's syndrome and acute myeloid leukaemia (AML). DESIGN: A retrospective study of 59 children with Down's syndrome and AML presenting between 1987 and 1995. Data were obtained from hospital case notes, trial records, and by questionnaire. RESULTS: The patients were unusually young (median age, 23 months) with a predominance of megakaryoblastic AML. Two of the seven infants who presented with abnormal myelopoesis aged 2 months or younger achieved complete spontaneous remission. Most of the older children with AML (32 of 52) were treated on recognised intensive protocols but 13 received individualised treatment and seven symptomatic treatment alone. Only four received a bone marrow transplant (BMT) in first remission. For the 45 older children who received chemotherapy the overall survival was 55% (median follow up 4.5 years). Patients on individualised protocols had a similar overall survival and toxic death rate but marginally higher relapse rate than those on standard (intensive) protocols. Children with Down's syndrome treated on the national AML 10 trial had a similar overall survival (70% v 59%) at five years to children of comparable age without Down's syndrome: their improved relapse risk (12% v 38%) offset the slight increase in deaths as a result of treatment toxicity (19% v 11%). CONCLUSION: Neonates with Down's syndrome and abnormal myelopoesis may achieve spontaneous remission, and older children with Down's syndrome and AML can be treated successfully with intensive chemotherapy, without BMT.

HG-54. THE ROLE OF HIGH-DOSE MYELOABLATIVE CHEMOTHERAPY (HDCT) WITH HAEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT) IN CHILDREN WITH HIGH GRADE GLIOMAS (HGG) OR DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG): RESULTS OF A SYSTEMATIC REVIEW Caroline Main1, Madeline Adams2, Katherine Cooper3, Sophie Wilne4, Bob Phillips5, Martin English6, Pamela R. Kearns1,6, Barry Pizer3, Simon P. Stevens1, Keith Wheatley1, and Jayne S. Wilson1; Cancer Research UK Clinical Trials Unit; University of Birmingham, Birmingham, UK; Bristol Children’s Hospital, Bristol, UK; Alder Hey Children’s NHS Foundation Trust, Liverpool, UK; Nottingham University Hospitals’ NHS Trust, Nottingham, UK; UK Centre for Reviews and Dissemination, University of York, UK; Birmingham Children’s Hospital NHS Foundation Trust, Birmingham, UK OBJECTIVES: To assess the impact of HDCT/HSCT in children with HGG or DIPG. METHODS: Ten electronic databases were searched from 1985 to Oct 2015 for studies assessing HDCT/HSCT in HGG and DIPG. Outcomes included overall survival (OS), response rates (RR), adverse events and treatment related mortality (TRM). Standard systematic review methods were used to minimise bias. RESULTS: For HGG, 167 patients were included, 56% newly diagnosed and 44% relapsed. Mean age was 8.7 years. Mean follow-up was 2.8-years (range: 0.2-5.4). HDCT mainly consisted of one cycle, with preor post radiotherapy (RT) used in 59% of patients. Median OS for newly diagnosed HGG was between 9-14 months (range: 1-65) (n 1⁄4 27), with one and four year OS 73%+13% (n 1⁄4 11) and 43% (n 1⁄4 21) respectively. Overall RR was 30% (n 1⁄4 26). For relapsed HGG median OS was 12.7months (n 1⁄4 18). Across the studies nine TRM occurred. Sixty-two patients with DIPG were included, 68% newly diagnosed and 32% relapsed. Mean age was 6.8-years. Median follow-up was 1.5 years (range: 0.1-7). HDCT consisted of one cycle, with 77% patients receiving prior RT. For newly diagnosed patients with DIPG, median OS was 10-11.4 months (range: 6.4-17.1) (n 1⁄4 42), and for relapsed patients 4.8 months (0.1-18.7) (n 1⁄4 16). Across the studies five toxicity related deaths occurred (8%). CONCLUSIONS: The limited evidence on HDCT/HSCT in children with HGG or DIPG does not allow reliable conclusions to be drawn. However, use of HDCT/HSCT in these patient groups is associated with a significant toxicity profile and TRM. Neuro-Oncology 18:iii48–iii77, 2016. doi:10.1093/neuonc/now073.50 #The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

BackgroundCare home residents with stroke-related disabilities have significant activity limitations. Phase II trial results suggested a potential benefit of occupational therapy (OT) in maintaining residents’ capacity to engage in functional activity.ObjectiveTo evaluate the clinical effectiveness and cost-effectiveness of a targeted course of OT in maintaining functional activity and reducing further health risks from inactivity for UK care home residents living with stroke-related disabilities.DesignPragmatic, parallel-group, cluster randomised controlled trial with economic evaluation. Cluster randomisation occurred at the care-home level. Homes were stratified according to trial administrative centre and type of care provided (nursing or residential), and they were randomised 1 : 1 to either the intervention or the control arm.SettingThe setting was 228 care homes which were local to 11 trial administrative centres across England and Wales.ParticipantsCare home residents with a history of stroke or transient ischaemic attack, including residents with communication and cognitive impairments, not receiving end-of-life care.InterventionPersonalised 3-month course of OT delivered by qualified therapists. Care workers participated in training workshops to support personal activities of daily living. The control condition consisted of usual care for residents.Main outcome measuresOutcome data were collected by a blinded assessor. The primary outcome at the participant level was the Barthel Index of Activities of Daily Living (BI) score at 3 months. The secondary outcomes included BI scores at 6 and 12 months post randomisation, and the Rivermead Mobility Index, Geriatric Depression Scale-15 and European Quality of Life-5 Dimensions, three levels, questionnaire scores at all time points. Economic evaluation examined the incremental cost per quality-adjusted life-year (QALY) gain. Costs were estimated from the perspective of the NHS and Personal Social Services.ResultsOverall, 568 residents from 114 care homes were allocated to the intervention arm and 474 residents from another 114 care homes were allocated to the control arm, giving a total of 1042 participants. Randomisation occurred between May 2010 and March 2012. The mean age of participants was 82.9 years, and 665 (64%) were female. No adverse events attributable to the intervention were recorded. Of the 1042 participants, 870 (83%) were included in the analysis of the primary outcome (intervention,n = 479; control,n = 391). The primary outcome showed no significant differences between groups. The adjusted mean difference in the BI score between groups was 0.19 points higher in the intervention arm [95% confidence interval (CI) –0.33 to 0.70,p = 0.48; adjusted intracluster correlation coefficient 0.09]. Secondary outcome measures showed no significant differences at all time points. Mean incremental cost of the Occupational Therapy intervention for residents with stroke living in UK Care Homes intervention was £438.78 (95% CI –£3360.89 to £1238.46) and the incremental QALY gain was 0.009 (95% CI –0.030 to 0.048).LimitationsA large proportion of participants with very severe activity-based limitations and cognitive impairment may have limited capacity to engage in therapy.ConclusionA 3-month individualised course of OT showed no benefit in maintaining functional activity in an older care home population with stroke-related disabilities.Future workThere is an urgent need to reduce health-related complications caused by inactivity and to provide an enabling built environment within care homes.Trial registrationCurrent Controlled Trials ISRCTN00757750.FundingThis project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 20, No. 15. See the Health Technology Assessment programme website for further project information.

The AML16 trial evaluated the combination of the farnesyltransferase inhibitor, tipifarnib, and low dose cytarabine (LDAC) in older acute myeloid leukaemia (AML) patients in a 'Pick a Winner' design. The aim was to double remission rates compared to LDAC, with initial evaluation after 100 patients. Failure to improve remission would result in discontinuation. A total of 65 patients, median age 74 years (range 62-86), were randomized. After reviewing the first 45 patients, the Data Monitoring Committee concluded that the overall aspirations would not be met and recommended closure. The addition of tipifarnib had no effect on response, toxicity or survival.

Introduction: Standard treatment for Hodgkin lymphoma (HL) is poorly tolerated in older patients and results are disappointing. Brentuximab vedotin (BV) is a CD30 targeted antibody‐drug conjugate licenced for the treatment of relapsed or refractory HL on the basis of excellent safety and efficacy demonstrated in the pivotal phase 2 clinical trial. BREVITY trial was designed to evaluate the efficacy and tolerability of BV monotherapy in previously untreated patients (pts) with HL unfit for standard treatment due to age, frailty or co‐morbidity. Methods: This response adaptive phase II, Simon 2‐stage, single arm study required 30 evaluable pts. Primary outcome was complete metabolic response (CMR, Deauville Score 1‐3) by centrally reviewed PET‐CT after 4 cycles of BV. Secondary outcomes included PFS, OS, toxicity and comorbidity assessment (CIRS‐G). Inclusion criteria were previously untreated HL stage 2 (with B symptoms and/or mediastinal bulk) to stage 4 with cardio‐respiratory compromise (at any age), or ECOG PS ≤3 and considered unfit for standard chemotherapy (in pts ≥60 yrs). BV dose was 1.8 mg/kg every 3 weeks, reduced to 1.2 mg/kg for toxicity. Pts responding after 4 doses of BV continued to a maximum of 16 cycles if CT/PET‐CT every 4 cycles confirmed ongoing response. Pts also underwent exploratory blinded PET‐CT after cycle 2. Results: 38 pts were recruited from Feb 2014‐Oct 2015 at 12 UK centres; demographics are shown in Table 1. 35 treated pts were evaluable for toxicity, 31 were evaluable for response. A median of 4 cycles was given (range 1‐16). Dose was reduced in 28 cycles across 14 pts due to toxicity and 11 pts stopped treatment due to adverse events (AEs). 716 AEs were reported, 626 (88%) were grade 1/2. 27 (77%) pts had at least one AE ≥ grade 3, most commonly infection, myelosuppression or neuropathy. CMR at PET4 was 26% (95% CI 14, 43) and overall objective response was 84% (95%CI: 67, 93). There was a significant correlation of interim PET2 with PET4 (Rho = 0.67, p < 0.001) with a CMR rate at PET 2 of 32% (95% CI 17, 52). To date 28 of 31 evaluable pts have progressed and median PFS is 7.4 months (95% CI 5.3, 10.2). Conclusions: In this study BV monotherapy produced a high overall response rate although the CMR rate after 4 cycles did not meet the pre‐specified 40% level, and PFS was short. Toxicity was greater than in the pivotal study in a younger/fitter population and led to treatment termination in some pts. A follow‐on study aims to improve CMR and PFS by using a lower dose of BV in combination with other agents. Table 1Patient Characteristicn=38 Median (Range)Age 76 (59, 90) CIRS‐G ScoreNo. categories endorsed Severity Total score 3 (0, 7) 1.5 (0, 3) 6 (0, 11) n (%) GenderMale Female 22 (57.9) 16 (42.1) StageStage 2 Stage 3 Stage 4 7 (18.4) 13 (34.2) 18 (47.4) B symptoms 27 (71.1) Bulky Disease 5 (13.2) Extranodal disease 22 (57.9) ECOG Performance Status0 1 2 3 4 3 (7.9) 16 (42.1) 11 (28.9) 7 (18.4) 1 (2.6)

Background: Evidence from clinical trials with monoamine oxidase type B inhibitors (TEMPO, ADAGIO and DATATOP) and levodopa (ELLDOPA) suggests that Parkinson's disease patients may benefit from treatment being commenced immediately on diagnosis rather than waiting for functional disability to develop, as is traditional clinical practice. Methods: We performed a narrative literature review and meta‐analysis of delayed‐start design trials in Parkinson's disease. Results: There was inconsistency in the results of the two rasagiline delayed‐start design trials, with early treatment with a 2 mg dose significantly superior in the TEMPO trial, but the 1 mg dose significantly better in the ADAGIO trial, making interpretation difficult. Further, the benefits of immediate treatment were small in terms of total unified Parkinson's disease rating scale scores, with a mean difference of 0.91 units (95% confidence interval 0.01, 1.80; P=0.05) in a meta‐analysis of the TEMPO and ADAGIO delayed‐start design trials. Such small differences are unlikely to be of clinical relevance. There is also little information on whether immediate treatment has a beneficial effect on patient quality of life with an acceptable adverse reaction profile, and we have no data on whether imediate treatment is cost‐effective. Discussion: Based on the evidence available, changing clinical practice to immediate therapy on diagnosis is not warranted and further trials are needed. © 2011 Movement Disorder Society

Background: Levodopa initially provides good symptomatic control of the symptoms of Parkinson's disease, but motor complications often develop after long-term use. Other classes of antiparkinsonian drugs including dopamine agonists, catechol-O-methyl transferase inhibitors, or monoamine oxidase type B inhibitors are then added as adjuvant therapy. It is unclear whether one class of drug is more effective than another. This meta-analysis evaluates the comparative benefits and risks of these agents as adjuvant treatment in Parkinson's disease patients with motor complications. Methods: A systematic review of the literature from 1966 to the end of June 2010 was conducted to identify randomized trials involving a dopamine agonist, catechol-O-methyl transferase inhibitor, or monoamine oxidase type B inhibitor versus placebo, as adjuvant to levodopa therapy. Results: Forty-five trials involving nearly 9,000 participants were included. The meta-analysis confirms reports from individual trials that compared with placebo, adjuvant therapy significantly reduces patient off-time and levodopa dose, with improved symptom severity scores (e.g., Unified Parkinson's Disease Rating Scale). However, dyskinesia and numerous other side effects are increased with adjuvant therapy. Few randomized comparisons between drugs have been undertaken, but indirect comparisons suggest that dopamine agonist therapy may be more effective than catechol-O-methyl transferase inhibitor and monoamine oxidase type B inhibitor therapy, which have comparable efficacy. No differences between drugs within each class were observed other than the catechol-O-methyl transferase inhibitor tolcapone appearing more efficacious than entacapone. Discussion: This meta-analysis highlights the need for direct head-to-head randomized trials to assess the impact of adjuvant therapy on patient-rated quality of life and health economic outcomes. © 2011 Movement Disorder Society